Process for preparing aripiprazole form ii
By using isopropanol as a solvent, the preparation process of aripiprazole crystal form II is simplified, solving the problems of cumbersome preparation methods and solvent toxicity in existing technologies, and realizing safe and convenient industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- ZHUHAI LIVZON MICROSPHERE TECH CO LTD
- Filing Date
- 2026-02-11
- Publication Date
- 2026-06-16
AI Technical Summary
Existing methods for preparing aripiprazole crystal form II are cumbersome and unsuitable for industrial production. Furthermore, the use of acetonitrile as a solvent poses toxicity issues, making it difficult to obtain a single crystal form II.
Using isopropanol as a solvent, aripiprazole crystal form II was obtained by heating a mixture of aripiprazole and isopropanol, followed by cooling and crystallization. This simplified the operation process and improved safety.
A simple, efficient, and green method for preparing aripiprazole crystal form II has been developed, which is suitable for industrial production and uses the safe and environmentally friendly solvent isopropanol. The operation is simple, controllable, and time-saving.
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Figure CN122213014A_ABST
Abstract
Description
Technical Field
[0001] This application relates to the field of drug crystal form technology, and in particular to a method for preparing aripiprazole crystal form II. Background Technology
[0002] Aripiprazole is an antipsychotic drug primarily used to treat schizophrenia, bipolar disorder (manic and depressive episodes), and as adjunctive therapy for major depressive disorder. The structural formula of aripiprazole is as follows:
[0003]
[0004] The literature “Braun DE, et al. Conformational polymorphism in aripiprazole: preparation, stability and structure of five modifications. [J]. Elsevier, 2009(6). DOI:10.1002 / jps.21574.” describes aripiprazole crystal form II as a crystal that easily mixes with other crystal forms to precipitate. Therefore, a single crystal form II plays a crucial role in the qualitative analysis of mixed crystal forms. The preparation method of aripiprazole crystal form II described in the literature is as follows: 40g of aripiprazole crystal form III is dissolved in 1000mL of acetonitrile at 80℃. After about 10 minutes, the solution is cooled to about 70℃ and stored for 30 minutes to allow crystallization. The temperature is then slowly increased to 75℃ and stored at this temperature for 1 hour to allow crystal growth. After about 4 hours, the solution is cooled to 10℃, the precipitate is collected by filtration, and the crystals are air-dried to obtain 37.28g, with a yield of 93.2%.
[0005] However, the crystallization process described above is cumbersome and unsuitable for industrial production. Furthermore, the aforementioned literature also reports that aripiprazole crystal form II can be crystallized using n-butanol, but extensive practical experience has shown that crystallization with n-butanol only yields mixed crystals and does not produce crystal form II. Although acetonitrile can be used to prepare a reference standard for crystal form II according to the literature method, acetonitrile, as a Class II solvent, has a certain degree of toxicity, which does not meet the requirements of green production principles in industry. Summary of the Invention
[0006] Based on this, one or more embodiments of this application provide a method for preparing aripiprazole crystal form II, which can stably obtain aripiprazole crystal form II using a simple operating method.
[0007] The method for preparing aripiprazole crystal form II provided in this application includes the following steps:
[0008] Aripiprazole and isopropanol were mixed to prepare the first mixture;
[0009] The first mixture was heated to obtain an aripiprazole isopropanol solution.
[0010] The aripiprazole isopropanol solution was subjected to a cooling crystallization treatment to obtain aripiprazole crystal form II.
[0011] In some embodiments, the mass-to-volume ratio of aripiprazole to isopropanol is <0.167 g / mL.
[0012] Furthermore, the mass-to-volume ratio of aripiprazole to isopropanol is ≤0.125 g / mL.
[0013] Furthermore, the mass-to-volume ratio of aripiprazole to isopropanol is 0.04 g / mL to 0.125 g / mL.
[0014] Furthermore, the mass-to-volume ratio of aripiprazole to isopropanol is 0.05 g / mL to 0.1 g / mL.
[0015] In some embodiments, the step of heating the first mixture includes:
[0016] The first mixture is heated at a first temperature;
[0017] Preferably, the first temperature is ≥80℃;
[0018] Preferably, the heating time is 30 min to 120 min.
[0019] Furthermore, the first temperature is 80℃-125℃;
[0020] Preferably, the heating time is 30-60 minutes.
[0021] In some embodiments, the step of cooling and crystallizing the aripiprazole isopropanol solution includes:
[0022] After cooling the aripiprazole isopropanol solution to a second temperature, it is kept at the second temperature.
[0023] Preferably, the second temperature is 25℃-75℃.
[0024] In some embodiments, the aripiprazole isopropanol solution is cooled to crystallize, then filtered, and the precipitate is collected.
[0025] The precipitate was dried to obtain aripiprazole crystal form II.
[0026] Furthermore, drying methods include vacuum drying.
[0027] This application provides a simple, efficient, green, and industrially applicable method for preparing aripiprazole crystal form II. Traditional methods use acetonitrile as a solvent, while this application uses isopropanol as the solvent. Isopropanol is a Class III solvent, making it safer and more environmentally friendly. Compared to the traditional cooling-heating-holding-cooling crystallization process, the crystallization process in this application is simpler. After heating isopropanol, cooling and crystallization are sufficient to obtain a single aripiprazole crystal form II. The operation is simple and controllable, time-saving, and suitable for industrial production. Attached Figure Description
[0028] To more clearly illustrate the technical solutions in the specific embodiments of this application or the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this application. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.
[0029] Figure 1 The image shows the XRD pattern of crystal form II of Example 1 of this application (using Cu-Kα radiation, with the horizontal axis representing angle 2θ (°) and the vertical axis representing intensity).
[0030] Figure 2 The DSC spectrum of crystal form II of Example 1 of this application is shown (the horizontal axis is temperature (°C) and the vertical axis is heat flow rate (W / g)).
[0031] Figure 3 The image shows the XRD pattern of the comparative example 1 sample of this application (using Cu-Kα radiation, with the horizontal axis representing angle 2θ (°) and the vertical axis representing intensity).
[0032] Figure 4 The image shows the DSC spectrum of the Comparative Example 1 sample of this application (the horizontal axis represents temperature (°C), and the vertical axis represents heat flow rate (W / g)).
[0033] Figure 5 The image shows the XRD pattern of the comparative example 2 sample of this application (using Cu-Kα radiation, with the horizontal axis representing angle 2θ (°) and the vertical axis representing intensity).
[0034] Figure 6 The DSC spectrum of Comparative Example 2 sample of this application is shown (the horizontal axis is temperature (°C) and the vertical axis is heat flow rate (W / g)).
[0035] Figure 7 The image shows the XRD pattern of the comparative example 3 sample of this application (using Cu-Kα radiation, with the horizontal axis representing angle 2θ (°) and the vertical axis representing intensity).
[0036] Figure 8The image shows the DSC spectrum of the comparative example 3 sample of this application (the horizontal axis is temperature (°C) and the vertical axis is heat flow rate (W / g)). Detailed Implementation
[0037] The present application is further described below with reference to embodiments and examples. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the application. Furthermore, it should be understood that after reading the teachings of this application, those skilled in the art can make various alterations or modifications to this application, and these equivalent forms also fall within the protection scope of the appended claims.
[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.
[0039] In this article, terms such as "first," "second," "third," and "fourth" serve only as non-exhaustive enumerations and should be understood as not constituting a closed limitation on the quantity.
[0040] In this article, the technical features described in an open-ended manner include both closed technical solutions composed of the listed features and open technical solutions that include the listed features.
[0041] In this document, numerical ranges are referred to as continuous unless otherwise specified, and include the minimum and maximum values of the range, as well as every value between the minimum and maximum values. Furthermore, when a range refers to an integer, it includes every integer between the minimum and maximum values of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are incorporated.
[0042] In this article, "Class III solvents" refers to the third category of solvents classified by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) in its guidance principle "Q3C: Impurities: Residual Solvents" based on the degree of potential harm to human health. These solvents are considered to be low-toxicity solvents with a low risk of harm to human health.
[0043] In this paper, according to the literature "Brittain H G. Aripiprazole: polymorphs and solvatomorphs. [J]. profiles of drug substances, excipients, and relatedmethodology, 2012, 37: 1-29. DOI:10.1016 / B978-0-12-397220-0.00001-5.", the XRD pattern of aripiprazole crystal form II showed diffraction peaks at 7.51°±0.2°, 7.93°±0.2°, 13.38°±0.2°, 13.67°±0.2°, 14.48°±0.2°, 15.36°±0.2°, 17.53°±0.2°, 18.47°±0.2°, 22.37°±0.2°, and 23.99°±0.2°.
[0044] The abbreviations used in this article are explained as follows: XRD refers to X-ray powder diffraction; DSC refers to differential scanning calorimetry.
[0045] Methods for determining crystal form using X-ray powder diffraction (XRPD) are known in the art. XRPD can detect changes in crystal form, crystallinity, and crystal structure, and is a commonly used method for identifying crystal forms. The peak positions in XRPD spectra mainly depend on the structure of the crystal form. The measurement of 2θ in XRPD spectra may vary slightly between different instruments; therefore, the value of 2θ should not be considered absolute. According to the 2025 edition of the Chinese Pharmacopoeia, the diffraction peak positions can have an error of ±0.2°.
[0046] In this article, the mass-to-volume ratio is the ratio of the weight of a substance to the volume of a solution. The unit g / mL means that the substance is measured in grams and the solution is measured in mL.
[0047] In this article, room temperature generally refers to 4℃-30℃, preferably 20℃-30℃.
[0048] Unless otherwise specified, the temperature parameters in this document can be either constant temperature processing or processing within a certain temperature range. The constant temperature processing allows for temperature fluctuations within the precision range controlled by the instrument.
[0049] One or more embodiments of this application provide a method for preparing aripiprazole crystal form II, comprising the following steps:
[0050] Aripiprazole and isopropanol were mixed to prepare the first mixture;
[0051] The first mixture was heated to obtain an aripiprazole isopropanol solution.
[0052] Aripiprazole isopropanol solution was cooled to crystallize, thus obtaining aripiprazole crystal form II.
[0053] In some embodiments, the mass-to-volume ratio of aripiprazole to isopropanol is <0.167 g / mL.
[0054] Preferably, the mass-to-volume ratio of aripiprazole to isopropanol is ≤0.125 g / mL.
[0055] In a further preferred embodiment, the mass-to-volume ratio of aripiprazole to isopropanol is 0.04 g / mL to 0.125 g / mL, for example, it can be 0.04 g / mL, 0.05 g / mL, 0.06 g / mL, 0.07 g / mL, 0.08 g / mL, 0.09 g / mL, 0.1 g / mL, 0.11 g / mL, 0.12 g / mL, 0.125 g / mL, etc.
[0056] In a further preferred embodiment, the mass-to-volume ratio of aripiprazole to isopropanol is 0.05 g / mL to 0.1 g / mL, for example, it can be 0.05 g / mL, 0.06 g / mL, 0.07 g / mL, 0.08 g / mL, 0.09 g / mL, 0.1 g / mL, etc.
[0057] In some embodiments, the first mixture of aripiprazole and isopropanol is heated at a first temperature ≥80°C.
[0058] Preferably, the first temperature is 80℃-125℃, for example, it can be 80℃, 85℃, 90℃, 95℃, 100℃, 105℃, 110℃, 115℃, 120℃, 125℃, etc.
[0059] In some embodiments, the heating time of the first mixture at the first temperature is 30 min to 120 min, for example, 30 min, 60 min, 80 min, 100 min, 120 min, etc.
[0060] Preferably, the heating time is 30-60 minutes, for example, 30 minutes, 40 minutes, 50 minutes, 60 minutes, etc.
[0061] In some embodiments, the step of cooling and crystallizing the aripiprazole isopropanol solution includes:
[0062] After cooling the aripiprazole isopropanol solution to the second temperature, it is kept at the second temperature.
[0063] In some embodiments, the second temperature is 25°C-75°C, for example, it can be 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, etc.
[0064] In the step of cooling the aripiprazole isopropanol solution, stirring or natural cooling can be used. There are no particular restrictions on the cooling rate, as long as the second temperature (crystallization temperature) is reached.
[0065] After cooling the aripiprazole isopropanol solution to a second temperature, it is kept at the second temperature for a period of time without particular limitation. In some embodiments, the holding time is 30 min to 160 min, for example, 30 min, 60 min, 120 min, 160 min, etc.
[0066] In some embodiments, the aripiprazole isopropanol solution is cooled to crystallize, then filtered and the precipitate is collected.
[0067] The precipitate was dried to obtain aripiprazole crystal form II.
[0068] In some embodiments, the method of drying the precipitate includes vacuum drying.
[0069] The drying temperature can be 25℃-60℃, for example, 25℃, 30℃, 35℃, 40℃, 45℃, 50℃, 55℃, 60℃, etc.; the drying time can be 8h-24h, and further can be 12h-20h, for example, 12h, 15h, 18h, 20h, etc.
[0070] The following are some specific examples.
[0071] For experimental parameters not specified in the following specific embodiments, please refer to the guidelines given in this application document first, or refer to experimental manuals or other experimental methods known in the art, or refer to the experimental conditions recommended by the manufacturer.
[0072] The raw materials and reagents involved in the following specific embodiments can be obtained commercially or prepared by those skilled in the art using known methods.
[0073] I. Preparation of aripiprazole crystal form II
[0074] Example 1
[0075] This embodiment provides a method for preparing aripiprazole crystal form II of this application, including the following steps:
[0076] Weigh 10 g of aripiprazole polymorph into a 250 mL pear-shaped reaction flask, add 100 mL of isopropanol, add a stir bar, and connect a condenser. Heat at 85 °C for 1 h, then turn off the heating, maintain stirring, and allow the solution to cool to 75 °C in an oil bath (cooling time approximately 30 min). Maintain at 75 °C for 30 min, filter while hot to collect the precipitate, and dry under vacuum at 25 °C for 15 h.
[0077] The XRD pattern of aripiprazole crystal form II prepared in this embodiment is as follows: Figure 1 As shown.
[0078] The DSC spectrum of aripiprazole crystal form II prepared in this embodiment is as follows: Figure 2 As shown.
[0079] Example 2
[0080] This embodiment provides a method for preparing aripiprazole crystal form II of this application, including the following steps:
[0081] Weigh 5.023 g of aripiprazole crystal form III into a 250 mL eggplant-shaped reaction flask, add 100 mL of isopropanol, add a stir bar, and connect a condenser. Heat at 90 °C for 30 min, then turn off the heating and slowly stir to cool the solution to room temperature (cooling time is about 4 h). Keep at room temperature for 30 min, filter to collect the precipitate, and dry at 60 °C for 12 h.
[0082] Example 3
[0083] This embodiment provides a method for preparing aripiprazole crystal form II of this application, including the following steps:
[0084] Weigh 5.023 g of aripiprazole crystal form III into a 100 mL eggplant-shaped reaction flask, add 50 mL of isopropanol, add a stir bar, and connect a condenser. Heat at 100 °C for 30 min, then turn off the heating and stop stirring. Cool the solution to room temperature (cooling time is about 4 h), keep it at room temperature for 30 min, filter and collect the precipitate, and dry at 60 °C for 12 h.
[0085] Example 4
[0086] This embodiment provides a method for preparing aripiprazole crystal form II of this application, including the following steps:
[0087] Weigh 30.016 g of aripiprazole polymorph into a 1000 mL eggplant-shaped reaction flask, add 450 mL of isopropanol, add a stir bar, and connect a condenser. Heat at 85 °C for 1 h, then turn off the heating and continue stirring while cooling the solution to room temperature (cooling time approximately 4 h). Keep at room temperature for 30 min, filter to collect the precipitate, and dry under vacuum at 25 °C for 15 h.
[0088] Example 5
[0089] This comparative example provides another method for preparing aripiprazole crystal form II, comprising the following steps:
[0090] Weigh 8.165 g of aripiprazole crystal form III into a 250 mL pear-shaped reaction flask, add 80 mL of isopropanol, add a stir bar, and connect a condenser. Heat at 120 °C for 30 min, then turn off the heating and stop stirring. Cool the solution to room temperature (cooling time approximately 4 h), maintain at room temperature for 30 min, filter to collect the precipitate, and dry under vacuum at 25 °C for 15 h.
[0091] Example 6
[0092] This embodiment provides a method for preparing aripiprazole crystal form II of this application, including the following steps:
[0093] Weigh 8.124 g of aripiprazole crystal form III into a 250 mL eggplant-shaped reaction flask, add 80 mL of isopropanol, add a stir bar, and connect a condenser. Heat at 90 °C for 30 min, then turn off the heating and maintain stirring while cooling the solution to 55 °C (cooling time approximately 2 h). Maintain at 55 °C for 30 min, filter and collect the precipitate, and dry the resulting product under vacuum at 25 °C for 15 h.
[0094] Example 7
[0095] This embodiment provides a method for preparing aripiprazole crystal form II of this application, including the following steps:
[0096] Weigh 8.027 g of aripiprazole crystal form III into a 250 mL eggplant-shaped reaction flask, add 80 mL of isopropanol, add a stir bar, and connect a condenser. Heat at 90 °C for 30 min, then turn off the heating and slowly cool the solution to 40 °C (cooling time approximately 2 h) while maintaining stirring. Maintain the temperature at 40 °C for 30 min, filter and collect the precipitate, and dry the resulting product under vacuum at 25 °C for 15 h.
[0097] Example 8
[0098] This embodiment provides a method for preparing aripiprazole crystal form II of this application, including the following steps:
[0099] Weigh 8.102 g of aripiprazole crystal form III into a 250 mL eggplant-shaped reaction flask, add 80 mL of isopropanol, add an olive-shaped stir bar, and connect a condenser. Heat at 90 °C for 30 min, then turn off the heating and slowly cool the solution to 25 °C (cooling time approximately 4 h) while maintaining stirring. Maintain the temperature at 25 °C for 30 min, filter and collect the precipitate, and dry the resulting product under vacuum at 25 °C for 15 h.
[0100] Example 9
[0101] This embodiment provides a method for preparing aripiprazole crystal form II of this application, including the following steps:
[0102] Weigh 8.016 g of aripiprazole crystal form III into a 250 mL pear-shaped reaction flask, add 120 mL of isopropanol, add a stir bar, and connect a condenser. Heat at 90 °C for 30 min, then turn off the heating and slowly cool the solution to 75 °C (cooling time approximately 30 min) while maintaining stirring. Maintain the temperature at 75 °C for 30 min, filter while hot to collect the precipitate, and dry the resulting product under vacuum at 25 °C for 15 h.
[0103] Comparative Example 1
[0104] Weigh 8.006 g of aripiprazole crystal form III into a 250 mL eggplant-shaped reaction flask, add 48 mL of isopropanol, add a stir bar, and connect a condenser. Heat at 90 °C for 30 min, then turn off the heating and slowly cool the solution to 75 °C (cooling time approximately 30 min) while maintaining stirring. Maintain the temperature at 75 °C for 30 min, filter while hot to collect the precipitate, and dry the resulting product under vacuum at 25 °C for 15 h.
[0105] The XRD pattern of the aripiprazole mixed crystals prepared in this embodiment is as follows: Figure 3 As shown. Analysis revealed it to be a mixed crystal of crystal form IV.
[0106] The DSC spectrum of the aripiprazole mixed crystals prepared in this embodiment is as follows: Figure 4 As shown.
[0107] Comparative Example 2
[0108] Weigh 10g of aripiprazole crystal material into a 250mL eggplant-shaped reaction flask, add 100mL of n-butanol, add a stir bar, and connect a condenser. Heat at 85℃ for 1 hour, then turn off the heating and slowly cool the solution to 75℃ (cooling time is about 30 minutes) while maintaining stirring. Maintain the temperature at 75℃ for 30 minutes. If no precipitate forms, continue cooling to room temperature, filter while hot to collect the precipitate, and dry under vacuum at 25℃ for 15 hours.
[0109] The XRD pattern of the aripiprazole mixed crystals prepared in this embodiment is as follows: Figure 5 As shown. Analysis indicates it is crystal form III.
[0110] The DSC spectrum of the aripiprazole mixed crystals prepared in this embodiment is as follows: Figure 6 As shown.
[0111] Comparative Example 3
[0112] 4.136 g of aripiprazole crystals were dissolved in 100 ml of n-butanol and heated to 80 °C. The n-butanol solution was allowed to stand for about 10 min, then cooled to about 70 °C and allowed to stand for about 30 min at this temperature to precipitate seed crystals. The temperature of the solution was then slowly increased to 75 °C and maintained at this temperature for 1 h to allow crystal growth. The solution was then cooled to 25 °C, and the precipitated crystals were filtered off. The resulting crystals were dried under vacuum.
[0113] The XRD pattern of the aripiprazole mixed crystals prepared in this embodiment is as follows: Figure 7 As shown. Analysis revealed it to be a mixed crystal of crystal form III and crystal form IV.
[0114] The DSC spectrum of the aripiprazole mixed crystals prepared in this embodiment is as follows: Figure 8 As shown.
[0115] II. Product Crystal Form Identification
[0116] X-ray powder diffraction patterns were acquired using an Empyrean X-ray powder diffractometer at room temperature (approximately 25°C). The X-ray powder diffraction parameters were as follows: X-ray reflection parameters: Cu, Kα; Kα1 1.54060; Kα2 1.54443; Kα2 / Kα1 intensity ratio: 0.50; voltage: 45 kV; current: 40 mA; scanning range: from 3 to 60 degrees.
[0117] Differential scanning calorimetry (DSC) images were acquired on a TA DSC25. The DSC parameters were as follows: scan rate: 10 °C / min; protective gas: nitrogen.
[0118] Table 1 shows the comparison of XRD data between aripiprazole crystal form II prepared in Examples 1-9 and aripiprazole crystal form II in the literature "Brittain H G. Aripiprazole: polymorphs and solvatomorphs. [J]. Profiles of drug substances, excipients, and related methodology, 2012, 37: 1-29. DOI:10.1016 / B978-0-12-397220-0.00001-5." According to the 2025 edition of the Chinese Pharmacopoeia, the 2θ diffraction peak position error range needs to be ±0.2. o Inside.
[0119] Table 1. Comparison of XRD measurement data from Examples 1-9 with XRD data recorded in the literature.
[0120]
[0121] The DSC result of the aripiprazole crystal form prepared in Example 1 was 144℃, which is consistent with multiple literature reports.
[0122] II. Product Crystal Form Detection Results and Yield Statistics
[0123] The crystal form detection results and yields of the products in each embodiment and comparative example are shown in Table 2.
[0124] Table 2 Comparison of XRD measurement data from Examples 1-9 with XRD data recorded in the literature
[0125]
[0126] The technical features of the above-described embodiments and examples can be combined in any suitable manner. For the sake of brevity, not all possible combinations of the technical features in the above-described embodiments and examples are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.
[0127] The embodiments described above merely illustrate several implementation methods of this application and should not be construed as limiting the scope of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Furthermore, it should be understood that after reading the above teachings, those skilled in the art can make various alterations or modifications to this application, and the equivalent forms obtained also fall within the protection scope of this application. It should also be understood that technical solutions obtained by those skilled in the art based on the technical solutions provided in this application through logical analysis, reasoning, or limited experimentation are all within the protection scope of the appended claims. Therefore, the protection scope of this patent application should be determined by the appended claims, and the specification can be used to interpret the content of the claims.
Claims
1. A method for preparing aripiprazole crystal form II, characterized in that, Includes the following steps: Aripiprazole and isopropanol were mixed to prepare the first mixture; The first mixture was heated to obtain an aripiprazole isopropanol solution. The aripiprazole isopropanol solution was subjected to a cooling crystallization treatment to obtain aripiprazole crystal form II.
2. The method for preparing aripiprazole crystal form II according to claim 1, characterized in that, The mass-to-volume ratio of aripiprazole to isopropanol is <0.167 g / mL.
3. The method for preparing aripiprazole crystal form II according to claim 2, characterized in that, The mass-to-volume ratio of aripiprazole to isopropanol is ≤0.125 g / mL.
4. The method for preparing aripiprazole crystal form II according to claim 3, characterized in that, The mass-to-volume ratio of aripiprazole to isopropanol is 0.04 g / mL to 0.125 g / mL.
5. The method for preparing aripiprazole crystal form II according to claim 4, characterized in that, The mass-to-volume ratio of aripiprazole to isopropanol is 0.05 g / mL to 0.1 g / mL.
6. The method for preparing aripiprazole crystal form II according to any one of claims 1-5, characterized in that, The step of heating the first mixture includes: The first mixture is heated at a first temperature; Preferably, the first temperature is ≥80℃; Preferably, the heating time is 30 min to 120 min.
7. The method for preparing aripiprazole crystal form II according to claim 6, characterized in that, The first temperature is 80℃-125℃; Preferably, the heating time is 30-60 minutes.
8. The method for preparing aripiprazole crystal form II according to any one of claims 1-5 and 7, characterized in that, The steps of cooling and crystallizing the aripiprazole isopropanol solution include: After cooling the aripiprazole isopropanol solution to a second temperature, it is kept at the second temperature. Preferably, the second temperature is 25℃-75℃.
9. The method for preparing aripiprazole crystal form II according to any one of claims 1-5 and 7, characterized in that, After cooling the aripiprazole isopropanol solution to induce crystallization, the solution was filtered and the precipitate was collected. The precipitate was dried to obtain aripiprazole crystal form II.
10. The method for preparing aripiprazole crystal form II according to claim 9, characterized in that, Drying methods include vacuum drying.