Method for simultaneously regulating aripiprazole new crystal form and crystal habit and new crystal form thereof

Abstract

The application discloses a method for simultaneously regulating a new crystal form and crystal habit of aripiprazole; in the technical scheme, proteins are added in the crystallization process of aripiprazole to prepare aripiprazole with different crystal habits, and new crystal forms APZ-H1 and APZ-H2 of aripiprazole are found; the application creatively applies the protein, which is harmless to human bodies, to regulate the crystal habit of drugs, so as to replace other toxic and harmful crystal habit additives and guarantee the safety of the drugs; the method has the characteristics of simplicity, high efficiency and no pollution, is harmless to human bodies, is more green and environmental protection, and is easy to realize green industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, and in particular relates to a method for regulating the crystallization of aripiprazole using proteins. Background Technology

[0002] Crystallization is a key separation and purification technology in the pharmaceutical industry, with over 90% of active pharmaceutical ingredients (APIs) purified through crystallization. Crystallization not only improves drug purity but also enhances solubility, flowability, and stability. For example, poorly soluble drugs can have their water solubility improved by preparing cocrystals or salts, or by reducing particle size or adding solubilizers. Crystal morphology (crystal habit / crystal habit) significantly impacts the physical and chemical properties of drugs and formulation processes. The diversity of crystal habits (e.g., needle-like, layered, rod-like) is caused by differences in molecular arrangement, affecting product flowability and particle size distribution, and consequently, energy consumption and costs in downstream processes.

[0003] In the pharmaceutical industry, crystal habit has a significant impact on the dissolution rate and stability of drugs. Different crystal habits can lead to changes in the pharmacodynamic and pharmacokinetic properties of drugs, thereby affecting their efficacy and safety. For example, in pharmaceutical manufacturing, CaCO3 with an asymmetric needle-like crystal habit tends to agglomerate into cake-like shapes after standing, while cylindrical crystals are less prone to this phenomenon. Differences in crystal habit affect the processing of formulations. For instance, drugs with a fine needle-like crystal habit have poor flowability and are very prone to clogging and aggregation in the formulation process, resulting in situations such as failure to feed the drug. Differences in crystal habit affect tableting performance; for example, the symmetry of crystal habit is an important condition for direct compression tableting. Differences in crystal habit affect dissolution rate and dissolution performance. For example, the absorption curves of the antitumor drug sorafenib mesylate with different morphologies under the same crystal form and sieve particle size show significant differences in pure water, gastric juice simulated at pH 1.2, and in mice. Therefore, precise control of crystal behavior is crucial in the pharmaceutical industry. By controlling the crystal behavior of drugs, drug performance can be optimized and subsequent drug production can be facilitated.

[0004] Crystal habit is regulated by a variety of parameters, including growth rate, intermolecular forces, solvent selection, supersaturation, temperature, stirring intensity, and additives. Regulating crystal habit involves reducing the growth rate of crystal faces, which promotes stable growth of low-energy crystal faces, while increasing supersaturation tends to induce needle-like crystal formation. Additives play a role by altering the interaction between the solute and the crystal lattice, thus affecting crystal form development. Temperature control is also essential; rapid cooling tends to produce lamellar crystals, while slow cooling favors the formation of denser crystal structures. Increased stirring rate usually leads to smaller crystal size and more uniform distribution. Other factors influencing crystal habit include smaller crystal size and better distribution at high stirring rates; delayed nucleation and formation of symmetrical crystals when solute-solvent interactions are strong; and the use of ultrasound to prepare narrow-sized, spherical crystals. Among these numerous influencing factors, the use of macromolecular additives plays a crucial role in regulating crystal habit.

[0005] Additives are mainly classified into small molecule additives and macromolecule additives. Compared with small molecule additives, macromolecule additives have the advantage of large molecular weight and molecular structure, possessing abundant interaction sites and the ability to stably adsorb onto crystal surfaces. Literature reports that macromolecule additives can significantly affect crystal nucleation and growth processes at ppm-level concentrations. The stagnation region of crystal growth is closely related to the geometric roughness of the crystal facets. Two-dimensional structures on crystal facets often form cavities or pocket-like features. These structures tend to capture solvent molecules, thereby occupying potential solute adsorption sites and inhibiting crystal growth. When macromolecule additives interact with these crystal facets, their steric hindrance effectively slows down the solvation of the crystal facets, thus finely controlling the crystal growth rate. Based on this, this paper selects proteins as a macromolecule additive as the research object, with human serum albumin as a representative example.

[0006] Aripiprazole (APZ), chemically named 7-{4-[4-(2,3-dichlorophenyl)-l-piperazinylbutoxy}-3,4-dihydro-2(1H)-quinolinone, has the chemical formula C1. 23 H 27Cl2N3O2, primarily used as an antipsychotic drug, is employed to treat various types of schizophrenia. International clinical trials have shown that aripiprazole is significantly effective for both positive and negative symptoms of schizophrenia, and can also improve accompanying affective symptoms and reduce the relapse rate. The chemical structure of APZ is shown in the figure below. According to known reports, APZ has 9 amorphous forms, 4 solvate forms, and 4 hydrate forms, each corresponding to different crystal habits. For example, patent US7910589 discloses APZ-related crystal forms A, B, C, D, E, G, and the amorphous form invented by Otsuka Pharmaceutical Co., Ltd. of Japan. Patent US7504504 discloses APZ-related crystal forms I, II, VI, VIII, and X invented by Teva Co., Ltd. of India.

[0007]

[0008] PCT patent application WO03 / 026659 discloses six anhydrous aripiprazole crystal forms: B, C, D, E, F, and G. Crystal form B, due to its low hygroscopicity, is widely used in pharmaceutical formulations. There are many methods for preparing crystal form B; for example, CN101948426 discloses another method for preparing crystal form B, specifically involving dissolving APZ in a mixed solvent (butanone and acetone system), cooling to crystallize, and then filtering and drying. Chinese patent publication CN114644588 discloses a method for preparing aripiprazole crystal form B using a tubular continuous crystallization method. Chinese Patent Publication No. CN105924393 discloses a crystal form M of APZ with X-ray powder diffraction patterns of 2θ values ​​of 12.54, 12.70, 15.06, 17.44, 18.14, 18.76, 19.44, 20.52, 22.54, 24.84, and 35.79. A large amount of organic solvent was used in the preparation of crystal form M. For example, Chinese Patent Publication No. CN108602774 discloses a crystalline form N of APZ (aripiperazole hydrate), with X-ray powder diffraction patterns having 2θ values ​​of 12.6±0.1°, 15.1±0.1°, 17.4±0.1°, 18.2±0.1°, 18.7±0.1°, 22.5±0.1°, 23.2±0.1°, 24.8±0.1°, and 27.5±0.1°. Chinese Patent Publication No. CN106674103 discloses a method for preparing a new crystalline form α, with X-ray powder diffraction patterns having 2θ values ​​of 17.4, 18.1, 19.6, 23.2, 24.4, and 27.8. The preparation of crystalline form α requires conditions at -5°C.

[0009] However, most of the above methods are somewhat arbitrary, relying solely on traditional solvent and temperature adjustments. These methods utilize large amounts of organic solvents in the preparation process, and the reactions often require low temperatures or specific temperature controls. This not only impacts drug safety but also hinders environmental sustainability and the health of drug manufacturers. Summary of the Invention

[0010] The purpose of this invention is to provide a method for obtaining two new crystal forms, APZ-H1 and APZ-H2, by adding proteins to the APZ crystallization system, and to discover different crystal habits of the same crystal form of APZ in three solvent systems.

[0011] The second objective of this invention is to provide two new crystal forms.

[0012] Therefore, the first technical solution provided by this invention is as follows:

[0013] A method for simultaneously controlling the new crystal form and crystal habit of aripiprazole involves adding human serum albumin to the aripiprazole solvent crystallization system, resulting in two new crystal forms; and simultaneously controlling the different crystal habits of the same crystal form of aripiprazole.

[0014] The ratio of human serum albumin to aripiprazole is 1:1 to 1:10.

[0015] Furthermore, in the above-mentioned method for simultaneously regulating the new crystal form and crystal habit of aripiprazole, the solvent is one of acetonitrile, isopropanol, acetone, and methanol.

[0016] The second technical solution provided by the present invention is a new crystal form of aripiprazole obtained by the regulation method described in the first technical solution, wherein the new crystal forms of aripiprazole are APZ-H1 and APZ-H2.

[0017] Furthermore, the X-ray powder diffraction patterns of the aforementioned new aripiprazole crystal form, APZ-H1, have 2θ values ​​of 5.74°, 7.52°, 11.47°, 17.28°, 18.71°, 19.79°, 22.01°, 23.01°, 24.32°, and 26.84°.

[0018] Furthermore, the X-ray powder diffraction patterns of the aforementioned new aripiprazole crystal form, APZ-H2, have 2θ values ​​of 7.48°, 11.49°, 12.37°, 13.23°, 15.05°, 17.53°, 18.65°, 19.45°, 20.47°, 22.01°, 22.58°, 24.29°, 24.83°, and 31.17°.

[0019] Compared with the prior art, the technical solution provided by the present invention has the following technical advantages:

[0020] 1. The technical solution provided by this invention uses protein as a regulator added to the APZ solvent crystallization system to regulate the crystal habit of aripiprazole drug, resulting in the same crystal form but different crystal habits. At the same time, two new crystal forms of aripiprazole were also discovered in this process.

[0021] 2. The technical solution provided by this invention uses proteins, which are essential substances for the human body. When added to medicines, these proteins are not only non-toxic and harmless but also meet the body's requirements. At the same time, it avoids the use of large amounts of toxic and harmful organic solvents, which not only regulates the crystallinity of the medicine but also aligns with the green and environmentally friendly production philosophy that the country has long advocated.

[0022] 3. The technical solution provided by this invention obtains aripiprazole crystals with different concentrations of human serum protein. Experiments show that as the protein concentration increases, the aripiprazole crystals exhibit a more curved characteristic.

[0023] 4. The technical solution provided by this invention is based on the interaction between human serum protein and aripiprazole to achieve efficient regulation of crystal habit, which provides certain guidance for the production of subsequent drug formulations. Attached Figure Description

[0024] Figure 1 These are the X-ray powder diffraction patterns of the new crystal forms APZ-H1 and APZ-H2 obtained in Example 1;

[0025] Figure 2 These are microscopic images of the new crystalline form APZ-H1 prepared in Example 1;

[0026] Figure 3 These are microscopic images of the new crystalline form APZ-H2 prepared in Example 2;

[0027] Figure 4 These are the DSC diagrams of the new aripiprazole crystal forms APZ-H1 and APZ-H2;

[0028] Figure 5 The X-ray powder diffraction pattern of Comparative Example 1 without the addition of protein solvent crystals is shown below.

[0029] Figure 6 This is a microscopic observation of the crystallization of Comparative Example 1 without the addition of protein solvent;

[0030] Figure 7 These are microscopic images of APZ under different serum protein concentrations in different individuals.

[0031] Among them: (A) 4.5 mg human serum protein buffer solution, (B) 6.0 mg human serum protein buffer solution, (C) 9.0 mg human serum protein buffer solution, (D) 18.0 mg human serum protein buffer solution, (E) 45.0 mg human serum protein buffer solution; Detailed Implementation

[0032] The following section describes a new method for regulating the crystal habit and crystal form of aripiprazole, in conjunction with specific implementation methods and the content of the invention. However, it is not limited to these methods, and all related methods are protected.

[0033] Example 1

[0034] 1) Dissolve 10 mg of human serum albumin in 15 mL of deionized water to obtain an HSA aqueous solution;

[0035] 2) Take 90 mg of aripiprazole in an Erlenmeyer flask, add 15 mL of methanol, and heat and stir at 60 °C until APZ is completely dissolved.

[0036] 3) Slowly add the aripiprazole solution prepared in step 2) to the HSA aqueous solution prepared in step 1).

[0037] 4) After sealing and puncturing the conical flask, cool it to room temperature for crystallization.

[0038] A portion of the crystals was observed under an inverted microscope. Simultaneously, the remaining crystals were separated from the solution by filtration and dried at 50℃. The sample was then sent for XRD analysis to obtain the corresponding crystal habit observation pattern and the sample's XRD pattern. The X-ray powder diffraction pattern of crystalline treglitin was recorded under the following conditions: room temperature 25℃, relative humidity <60%; X'PertPRO polycrystalline X-ray diffractometer (PANalytical, Netherlands); CuKα radiation. The photodiode voltage was 40kV, the tube current was 40mA, the 2θ scanning range was 4–50°, the step size was 0.01313°, the counting time was 30ms / step, and the detection results were as follows: Figure 1 As shown, the 2θ values ​​of the new crystalline form of aripiprazole, APZ-H1, are 5.74°, 7.52°, 11.47°, 17.28°, 18.71°, 19.79°, 22.01°, 23.01°, 24.32°, and 26.84°. Microscopic images of the new crystalline form APZ-H1 are shown below. Figure 2 As shown, the differences compared to existing crystal forms confirm that it is a new crystal form.

[0039] Differential scanning calorimetry (DSC) analysis was performed on the novel aripiprazole crystal form APZ-H1 prepared in Example 1 of this invention. The DSC results were recorded under the following conditions: DSC800 differential scanning calorimeter (PerkinElmer, USA), N2 protection, gas flow rate of 20 mL / min, detection temperature range of 0℃~160℃, and heating rate of 10℃ / min. The detection results are as follows: Figure 4 As shown, the differential scanning calorimetry curve of the new crystal form APZ-H1 provided in Example 1 is significantly different from that of the aripiprazole technical. The results indicate that the new crystal form APZ-H1 of aripiprazole has an endothermic peak at 139.6℃, which is significantly different from that of the technical.

[0040] Example 2

[0041] 1) Take 18 mg of human serum albumin and add 10 mL of PBS buffer solution (pH = 7.41X) to dissolve it, and obtain HSA buffer solution.

[0042] 2) Take 120 mg of aripiprazole (APZ) into an Erlenmeyer flask, add 20 mL of methanol, and heat and stir at 60 °C until APZ is completely dissolved.

[0043] 3) Slowly add the APZ solution prepared in step 2) to the HSA buffer solution prepared in step 1).

[0044] 4) After sealing and puncturing the conical flask, cool it to room temperature for crystallization.

[0045] A portion of the crystals was observed under an inverted microscope. Simultaneously, the remaining crystals were separated from the solution using filtration and dried at 50°C. The sample was then sent for XRD analysis, yielding the corresponding crystal habit observation pattern and the sample's XRD pattern. The X-ray powder diffraction pattern of crystalline treglitazone was recorded under the following conditions: room temperature 25°C, relative humidity <60%; X'PertPRO polycrystalline X-ray diffractometer (PANalytical, Netherlands); CuKα radiation. The photodiode voltage was 40kV, the tube current was 40mA, the 2θ scanning range was 4–50°, the step size was 0.01313°, the counting time was 30ms / step, and the detection results were as follows: Figure 1 The 2θ values ​​of the new crystalline form APZ-H2 are 7.48°, 11.49°, 12.37°, 13.23°, 15.05°, 17.53°, 18.65°, 19.45°, 20.47°, 22.01°, 22.58°, 24.29°, 24.83°, and 31.17°. Microscopic images of the new crystalline form APZ-H2 are shown below. Figure 3 As shown, the differences compared to existing crystal forms confirm that it is a new crystal form.

[0046] Differential scanning calorimetry (DSC) analysis was performed on the novel aripiprazole crystal form APZ-H2 prepared in Example 2 of this invention. The DSC results were recorded under the following conditions: DSC800 differential scanning calorimeter (PerkinElmer, USA), N2 protection, gas flow rate of 20 mL / min, detection temperature range of 0℃~160℃, and heating rate of 10℃ / min. The detection results are as follows: Figure 4 As shown, the differential scanning calorimetry curve of the new crystal form APZ-H2 provided in Example 2 is significantly different from that of the aripiprazole technical. The results indicate that the new crystal form APZ-H2 of aripiprazole has an endothermic peak at 139.1℃, which is significantly different from that of the technical.

[0047] Comparative Example 1

[0048] 90 mg of aripiprazole was placed in an Erlenmeyer flask, and 15 mL of methanol was added. The mixture was heated and stirred at 60 °C until APZ was completely dissolved. Then, it was slowly added dropwise to 15 mL of deionized water. The Erlenmeyer flask was sealed and perforated, and then cooled to room temperature for crystallization. A portion of the crystals was observed under an inverted microscope. Simultaneously, the remaining crystals were separated from the solution by filtration and dried at 50 °C. The sample was then sent for XPRD analysis. The final results are as follows: Figure 5 As shown, it can be observed that no new crystal forms were found in the aripiprazole solvent crystallization system without added protein, and the crystal habit was observed as follows. Figure 6 As shown, the crystal habit without the addition of proteome is straight, which is significantly different from the crystal habit with the addition of proteome.

[0049] Comparative Example 2

[0050] 90 mg of aripiprazole was placed in an Erlenmeyer flask, 15 mL of methanol was added, and the mixture was heated and stirred at 60 °C until APZ was completely dissolved. Then, it was slowly added dropwise to 15 mL of PBS buffer. The Erlenmeyer flask was sealed and perforated, and then cooled to room temperature for crystallization. A portion of the crystals was observed under an inverted microscope. At the same time, the remaining crystals were separated from the solution by filtration and dried at 50 °C. The samples were then sent for XRD analysis to obtain the corresponding crystallographic images and the XRD of the samples. The results showed that the aripiprazole solvent crystallization system without added protein had the same results as Comparative Example 1, with no new crystal form.

[0051] Example 3

[0052] 1) Take 15 mg of human serum albumin and dissolve it in 15 mL of deionized water to obtain an HSA aqueous solution.

[0053] 2) Take 120 mg of aripiprazole in an Erlenmeyer flask, add 20 mL of methanol, and heat and stir at 60 °C until APZ is completely dissolved.

[0054] 3) Slowly add the HSA aqueous solution prepared in step 1) to the solution prepared in step 2).

[0055] 4) After sealing and puncturing the conical flask, cool it to room temperature for crystallization. Take a portion of the crystals and observe them in an inverted microscope. At the same time, use filtration to separate the remaining crystals from the solution and dry them at 50°C. Then send the sample to be tested for XRD to obtain the new crystal form APZ-H1.

[0056] Example 4

[0057] 1) Take 30 mg of human serum albumin and dissolve it in 15 mL of PBS buffer solution to obtain HSA buffer solution.

[0058] 2) Take 120 mg of aripiprazole in an Erlenmeyer flask, add 25 mL of methanol, and heat and stir at 60 °C until APZ is completely dissolved.

[0059] 3) Slowly add the HSA buffer solution prepared in step 1) to the solution prepared in step 2).

[0060] 4) After sealing and puncturing the conical flask, cool it to room temperature for crystallization. Take a portion of the crystals and observe them under an inverted microscope. At the same time, use filtration to separate the remaining crystals from the solution and dry them at 50°C. Then send the sample to measure XPRD to obtain the new crystal form APZ-H2.

[0061] Comparative Example 3

[0062] 90 mg of aripiprazole was placed in an Erlenmeyer flask, and 15 mL of methanol was added. The mixture was heated and stirred at 60 °C until APZ was completely dissolved. Then, 15 mL of deionized water was slowly added dropwise to the aripiprazole solution. The Erlenmeyer flask was sealed and perforated, and then cooled to room temperature for crystallization. A portion of the crystals was observed under an inverted microscope. The remaining crystals were separated from the solution by filtration and dried at 50 °C. The sample was then sent for XRD analysis to obtain the corresponding crystal habit observation pattern and the sample's XRD. The results showed that the aripiprazole solvent crystallization system without added protein had the same results as Comparative Example 1, with no new crystal form.

[0063] Comparative Example 4

[0064] 90 mg of aripiprazole was placed in an Erlenmeyer flask, and 15 mL of methanol was added. The mixture was heated and stirred at 60 °C until APZ was completely dissolved. Then, 15 mL of PBS buffer was slowly added dropwise to the aripiprazole solution. The Erlenmeyer flask was sealed and perforated, and then cooled to room temperature for crystallization. A portion of the crystals was observed under an inverted microscope. The remaining crystals were separated from the solution by filtration and dried at 50 °C. The samples were then sent for XRD analysis to obtain the corresponding crystal habit observation diagram and the sample XRD. The results showed that the aripiprazole solvent crystallization system without added protein had the same results as Comparative Example 1, with no new crystal form.

[0065] Example 5

[0066] 1) Dissolve 8 mg of human serum albumin in 15 mL of deionized water to obtain an HSA aqueous solution;

[0067] 2) Take 90 mg of aripiprazole in an Erlenmeyer flask, add 15 mL of acetonitrile, and heat and stir at 60 °C until APZ is completely dissolved.

[0068] 3) Slowly add the APZ solution prepared in step 2) to the HSA aqueous solution prepared in step 1).

[0069] 4) After sealing and puncturing the conical flask, cool it to room temperature for crystallization. Take a portion of the crystals and observe them in an inverted microscope. At the same time, use filtration to separate the remaining crystals from the solution and dry them at 50°C. Then send the sample to measure XPRD to obtain the observation diagram of the corresponding crystal habit and the XRD of the sample, thus obtaining the new crystal form APZ-H1.

[0070] Example 6

[0071] 1) Take 45 mg of human serum albumin and dissolve it in 15 mL of PBS buffer solution to obtain HSA buffer solution.

[0072] 2) Take 90 mg of aripiprazole in an Erlenmeyer flask, add 15 mL of acetonitrile, and heat and stir at 60 °C until APZ is completely dissolved.

[0073] 3) Slowly add the APZ solution prepared in step 2) to the HSA buffer solution prepared in step 1).

[0074] 4) After sealing and puncturing the conical flask, cool it to room temperature for crystallization. Take a portion of the crystals and observe them under an inverted microscope. At the same time, use filtration to separate the remaining crystals from the solution and dry them at 50°C. Then send the sample to measure XPRD to obtain the new crystal form APZ-H2.

[0075] Comparative Example 5

[0076] 90 mg of aripiprazole was placed in an Erlenmeyer flask, and 15 mL of acetonitrile was added. The mixture was heated and stirred at 60 °C until APZ was completely dissolved. Then, it was slowly added dropwise to 15 mL of deionized water. The Erlenmeyer flask was sealed and perforated, and then cooled to room temperature for crystallization. A portion of the crystals was observed under an inverted microscope. The remaining crystals were separated from the solution by filtration and dried at 50 °C. The sample was then sent for XRD analysis to obtain the corresponding crystal habit observation diagram and the sample's XRD. The results showed that the aripiprazole solvent crystallization system without added protein had the same results as Comparative Example 1, with no new crystal form.

[0077] Comparative Example 6

[0078] 90 mg of aripiprazole was placed in an Erlenmeyer flask, and 15 mL of acetonitrile was added. The mixture was heated and stirred at 60 °C until APZ was completely dissolved. Then, it was slowly added dropwise to 15 mL of PBS buffer solution. The Erlenmeyer flask was sealed and perforated, and then cooled to room temperature for crystallization. A portion of the crystals was observed under an inverted microscope. At the same time, the remaining crystals were separated from the solution by filtration and dried at 50 °C. The sample was then sent for XRD analysis to obtain the corresponding crystal habit observation diagram and the sample XRD. The results showed that the aripiprazole solvent crystallization system without added protein had the same results as Comparative Example 1, with no new crystal form.

[0079] Example 7

[0080] 1) Dissolve 30 mg of human serum albumin in 15 mL of deionized water to obtain an HSA aqueous solution;

[0081] 2) Take 90 mg of aripiprazole in an Erlenmeyer flask, add 15 mL of acetonitrile, and heat and stir at 60 °C until APZ is completely dissolved.

[0082] 3) Slowly add the HSA aqueous solution prepared in step 1) to the aripiprazole solution prepared in step 2).

[0083] 4) After sealing and puncturing the conical flask, cool it to room temperature for crystallization. Take a portion of the crystals and observe them under an inverted microscope. At the same time, use filtration to separate the remaining crystals from the solution and dry them at 50°C. Then send the sample to measure XPRD to obtain the new crystal form APZ-H2.

[0084] Example 8

[0085] 1) Take 40 mg of human serum albumin and dissolve it in 10 mL of PBS buffer solution to obtain HSA buffer solution.

[0086] 2) Take 90 mg of aripiprazole in an Erlenmeyer flask, add 15 mL of acetonitrile, and heat and stir at 60 °C until APZ is completely dissolved.

[0087] 3) Slowly add the HSA buffer solution prepared in step 1) to the aripiprazole solution prepared in step 2).

[0088] 4) After sealing and puncturing the conical flask, cool it to room temperature for crystallization. Take a portion of the crystals and observe them under an inverted microscope. At the same time, use filtration to separate the remaining crystals from the solution and dry them at 50°C. Then send the sample to measure XPRD to obtain the new crystal form APZ-H2.

[0089] Comparative Example 7

[0090] 90 mg of aripiprazole was placed in an Erlenmeyer flask, and 15 mL of acetonitrile was added. The mixture was heated and stirred at 60 °C until APZ was completely dissolved. Then, 15 mL of deionized water was slowly added dropwise to the aripiprazole solution. The Erlenmeyer flask was sealed and perforated, then cooled to room temperature for crystallization. A portion of the crystals was observed under an inverted microscope. Simultaneously, the remaining crystals were separated from the solution by filtration and dried at 50 °C. The sample was then sent for XRD analysis to obtain the corresponding crystal habit observation pattern and the sample's XRD. The results showed that the aripiprazole solvent crystallization system without added protein had the same results as Comparative Example 1, with no new crystal form.

[0091] Comparative Example 8

[0092] 90 mg of aripiprazole was placed in an Erlenmeyer flask, and 15 mL of acetonitrile was added. The mixture was heated and stirred at 60 °C until APZ was completely dissolved. Then, 15 mL of PBS buffer solution was slowly added dropwise to the aripiprazole solution. The Erlenmeyer flask was sealed and perforated, and then cooled to room temperature for crystallization. A portion of the crystals was observed under an inverted microscope. The remaining crystals were separated from the solution by filtration and dried at 50 °C. The samples were then sent for XRD analysis to obtain the corresponding crystal habit observation diagram and the XRD of the samples. The results showed that the aripiprazole solvent crystallization system without added protein had the same results as Comparative Example 1, with no new crystal form.

[0093] Example 9

[0094] 1) Dissolve 20 mg of human serum albumin in 8 mL of deionized water to obtain an HSA aqueous solution;

[0095] 2) Take 90 mg of aripiprazole in an Erlenmeyer flask, add 15 mL of acetone, and heat and stir at 60 °C until APZ is completely dissolved.

[0096] 3) Slowly add the APZ solution prepared in step 2) to the HSA aqueous solution prepared in step 1).

[0097] 4) After sealing and puncturing the conical flask, cool it to room temperature for crystallization. Take a portion of the crystals and observe them under an inverted microscope. At the same time, use filtration to separate the remaining crystals from the solution and dry them at 50°C. Then send the sample to measure XPRD to obtain the new crystal form APZ-H2.

[0098] Example 10

[0099] 1) Take 28 mg of human serum albumin, add 15 mL of PBS buffer solution to dissolve it, and obtain HSA buffer solution;

[0100] 2) Take 90 mg of aripiprazole in an Erlenmeyer flask, add 15 mL of acetone, and heat and stir at 60 °C until APZ is completely dissolved.

[0101] 3) Slowly add the APZ solution prepared in step 2) to the HSA buffer solution prepared in step 1).

[0102] 4) After sealing and puncturing the conical flask, cool it to room temperature for crystallization. Take a portion of the crystals and observe them under an inverted microscope. At the same time, use filtration to separate the remaining crystals from the solution and dry them at 50°C. Then send the sample to measure XPRD to obtain the new crystal form APZ-H2.

[0103] Comparative Example 9

[0104] 90 mg of aripiprazole was placed in an Erlenmeyer flask, and 15 mL of acetone was added. The mixture was heated and stirred at 60 °C until APZ was completely dissolved. Then, it was slowly added dropwise to 15 mL of deionized water. The Erlenmeyer flask was sealed and perforated, and then cooled to room temperature for crystallization. A portion of the crystals was observed under an inverted microscope. The remaining crystals were separated from the solution by filtration and dried at 50 °C. The sample was then sent for XRD analysis to obtain the corresponding crystal habit observation diagram and the sample's XRD. The results showed that the aripiprazole solvent crystallization system without added protein had the same results as Comparative Example 1, with no new crystal form.

[0105] Comparative Example 10

[0106] 90 mg of aripiprazole was placed in an Erlenmeyer flask, and 15 mL of acetone was added. The mixture was heated and stirred at 60 °C until APZ was completely dissolved. Then, it was slowly added dropwise to 15 mL of PBS buffer solution. The Erlenmeyer flask was sealed and perforated, and then cooled to room temperature for crystallization. A portion of the crystals was observed under an inverted microscope. The remaining crystals were separated from the solution by filtration and dried at 50 °C. The sample was then sent for XRD analysis to obtain the corresponding crystal habit observation pattern and the sample's XRD. The results showed that the aripiprazole solvent crystallization system without added protein had the same results as Comparative Example 1, with no new crystal form.

[0107] Example 11

[0108] 1) Dissolve 38 mg of human serum albumin in 15 mL of deionized water to obtain an HSA aqueous solution;

[0109] 2) Take 90 mg of aripiprazole in an Erlenmeyer flask, add 15 mL of acetone, and heat and stir at 60 °C until APZ is completely dissolved.

[0110] 3) Slowly add the HSA aqueous solution prepared in step 1) to the aripiprazole solution prepared in step 2).

[0111] 4) After sealing and puncturing the conical flask, cool it to room temperature for crystallization. Take a portion of the crystals and observe them under an inverted microscope. At the same time, use filtration to separate the remaining crystals from the solution and dry them at 50°C. Then send the sample to measure XPRD to obtain the new crystal form APZ-H2.

[0112] Example 12

[0113] 1) Dissolve 18 mg of human serum albumin in 30 mL of PBS buffer to obtain HSA buffer solution;

[0114] 2) Take 90 mg of aripiprazole in an Erlenmeyer flask, add 15 mL of acetone, and heat and stir at 60 °C until APZ is completely dissolved.

[0115] 3) Slowly add the HSA buffer solution prepared in step 1) to the aripiprazole solution prepared in step 2).

[0116] 4) After sealing and puncturing the conical flask, cool it to room temperature for crystallization. Take a portion of the crystals and observe them under an inverted microscope. At the same time, use filtration to separate the remaining crystals from the solution and dry them at 50°C. Then send the sample to measure XPRD to obtain the new crystal form APZ-H1.

[0117] Comparative Example 11

[0118] 90 mg of aripiprazole was placed in an Erlenmeyer flask, and 15 mL of acetone was added. The mixture was heated and stirred at 60 °C until APZ was completely dissolved. Then, 15 mL of deionized water was slowly added dropwise to the aripiprazole solution. The Erlenmeyer flask was sealed and perforated, and then cooled to room temperature for crystallization. A portion of the crystals was observed under an inverted microscope. The remaining crystals were separated from the solution by filtration and dried at 50 °C. The sample was then sent for XRD analysis to obtain the corresponding crystal habit observation diagram and the sample's XRD. The results showed that the aripiprazole solvent crystallization system without added protein had the same results as Comparative Example 1, with no new crystal form.

[0119] Comparative Example 12

[0120] 90 mg of aripiprazole was placed in an Erlenmeyer flask, and 15 mL of acetone was added. The mixture was heated and stirred at 60 °C until APZ was completely dissolved. Then, 15 mL of PBS buffer solution was slowly added dropwise to the aripiprazole solution. The Erlenmeyer flask was sealed and perforated, and then cooled to room temperature for crystallization. A portion of the crystals was observed under an inverted microscope. The remaining crystals were separated from the solution by filtration and dried at 50 °C. The sample was then sent for XRD analysis to obtain the corresponding crystal habit observation pattern and the sample's XRD. The results showed that the aripiprazole solvent crystallization system without added protein had the same results as Comparative Example 1, with no new crystal form.

[0121] Example 13

[0122] 1) Take one portion each of 4.5mg, 6mg, 9mg, 18mg, and 45mg of human serum albumin, and dissolve them in 15mL of buffer solution respectively (to obtain five groups of HSA buffer solutions);

[0123] 2) Then take 5 portions of 90mg aripiprazole into an Erlenmeyer flask, add 15mL of methanol, and heat and stir at 60℃ until APZ is completely dissolved.

[0124] 3) Then, the APZ methanol solution was slowly added dropwise to the five sets of HSA buffer solutions above, with corresponding concentrations of 5% HSA PBS solution, 6.7% HSA PBS solution, 10% HSA PBS solution, 20% HSA PBS solution, and 50% HSA PBS solution, respectively.

[0125] 4) Take a portion of the crystal and observe it under an inverted microscope to obtain an observation image of the corresponding crystal habit, such as... Figure 7 As shown, it can be observed that the curvature of aripiprazole crystals gradually increases with increasing protein concentration.

[0126] Example 14

[0127] 1) Take one portion each of 4.5mg, 6mg, 9mg, 18mg, and 45mg of human serum albumin, and dissolve them in 15mL of deionized water respectively (to obtain five groups of HSA aqueous solutions);

[0128] 2) Then take 5 portions of 90mg aripiprazole into an Erlenmeyer flask, add 15mL of methanol, and heat and stir at 60℃ until APZ is completely dissolved.

[0129] 3) Then, the APZ methanol solution is slowly added dropwise to the five HSA aqueous solutions above, with corresponding concentrations of 5% HSA ultrapure aqueous solution, 6.7% HSA ultrapure aqueous solution, 10% HSA ultrapure aqueous solution, 20% HSA ultrapure aqueous solution, and 50% HSA ultrapure aqueous solution.

[0130] 4) After sealing and perforating the conical flasks, cool them to room temperature for crystallization. Take a portion of the crystals and observe them under an inverted microscope to obtain an observation diagram of the corresponding crystal habit, as shown below. Figure 7 As shown, it can be observed that the curvature of aripiprazole crystals gradually increases with increasing protein concentration.

[0131] Example 15

[0132] 1) Take one portion each of 4.5mg, 6mg, 9mg, 18mg, and 45mg of human serum albumin, and dissolve them in 15mL of deionized water respectively (to obtain five groups of HSA aqueous solutions);

[0133] 2) Then take 5 portions of 90mg aripiprazole into an Erlenmeyer flask, add 15mL of methanol, and heat and stir at 60℃ until APZ is completely dissolved.

[0134] 3) Then slowly add the above five groups of HSA aqueous solutions to the APZ methanol solution, with corresponding concentrations of 5% HSA ultrapure aqueous solution, 6.7% HSA ultrapure aqueous solution, 10% HSA ultrapure aqueous solution, 20% HSA ultrapure aqueous solution, and 50% HSA ultrapure aqueous solution.

[0135] 4) After sealing and perforating the conical flasks, cool them to room temperature for crystallization. Take a portion of the crystals and observe them under an inverted microscope to obtain an observation diagram of the corresponding crystal habit, as shown below. Figure 7 As shown, it can be observed that the curvature of aripiprazole crystals gradually increases with increasing protein concentration.

[0136] To demonstrate the efficacy of the two novel aripiprazole crystal forms, APZ-H1 and APZ-H2, provided in this application, the solubility of the original aripiprazole crystal form and the two novel aripiprazole crystal forms, APZ-H1 and APZ-H2, in hydrochloric acid solution at pH 1.2 was measured below.

[0137] The specific procedure is as follows: After the original crystal form of aripiprazole and the two new crystal forms APZ-H1 and APZ-H2 have reached dissolution equilibrium, samples are taken and filtered through a 0.22 μm filter membrane. An appropriate amount of filtrate is taken and the absorbance value is measured at a wavelength of 249 nm using ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2020 edition). The absorbance is then substituted into the standard curve to obtain the solubility of the original crystal form of aripiprazole and the two new crystal forms APZ-H1 and APZ-H2, as shown in Table 2.

[0138] Table 2 Solubility Table

[0139]

[0140] The results in Table 2 show that in hydrochloric acid solution at pH 1.2, the solubility of the new aripiprazole crystal form APZ-H2 was significantly higher than that of the original crystal form, while the solubility of the new aripiprazole crystal form APZ-H1 was similar to that of the original crystal form.

[0141] The above description is only a specific embodiment of the present invention and not all embodiments. Any equivalent modifications made by other people skilled in the art based on the present invention specification are covered by the claims of the present invention and are also protected by the present invention.

Claims

1. A method for simultaneously modulating aripiprazole new crystal form and crystal habit, characterized in that, The human serum albumin is dissolved in solvent A, and then added into the solvent crystallization system of aripiprazole to obtain a new crystal form and different crystal habits of the same crystal form. The ratio of the amount of human serum albumin to aripiprazole is 1:1-1:

10. The solvent A is one of deionized water and PBS buffer solution. The aripiprazole new crystal form is APZ-H1 and APZ-H2. The X-ray powder diffraction spectrum of the new crystal form APZ-H1 has 2θ values of 5.74°±0.2°, 7.52°±0.2°, 11.47°±0.2°, 17.28°±0.2°, 18.71°±0.2°, 19.79°±0.2°, 22.01°±0.2°, 23.01°±0.2°, 24.32°±0.2° and 26.84°±0.2°. The X-ray powder diffraction spectrum of the new crystal form APZ-H2 has 2θ values of 7.48°±0.2°, 11.49°±0.2°, 12.37°±0.2°, 13.23°±0.2°, 15.05°±0.2°, 17.53°±0.2°, 18.65°±0.2°, 19.45°±0.2°, 20.47°±0.2°, 22.01°±0.2°, 22.58°±0.2°, 24.29°±0.2°, 24.83°±0.2° and 31.17°±0.2°.

2. The method for simultaneously regulating the aripiprazole new crystal form and crystal habit according to claim 1, characterized in that, The solvent is one of acetonitrile, isopropyl alcohol, acetone and methanol.

Images