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

Abstract

The invention discloses a method for simultaneously regulating and controlling a new crystal form and a crystal habit of aripiprazole. According to the technical scheme, in the aripiprazole crystallization process, protein is added for induction to prepare aripiprazole with different crystal habits, and meanwhile new crystal forms APZ-H1 and APZ-H2 of aripiprazole are found; according to the invention, protein which is a substance having no toxic effect on a human body is creatively applied to adjust the crystal habit of the medicine to replace other toxic and harmful crystal habit additives, so that the safety of the medicine is guaranteed; the method has the characteristics of simplicity, convenience, high efficiency, no pollution and the like, is non-toxic and harmless to a human body, is more environment-friendly, and is easy to realize green industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug preparation, and in particular relates to a method for regulating the crystal habit of aripiprazole drugs by using proteins. Background Art

[0002] Crystallization is a key separation and purification technology in the pharmaceutical industry, and more than 90% of active pharmaceutical ingredients (API) are purified by crystallization. Crystallization not only improves drug purity, but also improves solubility, fluidity and stability. For example, poorly soluble drugs can be made more water soluble by preparing co-crystals or salts, or by reducing particle size, adding solubilizers, and other methods. Among them, the crystal morphology (crystal habit / crystal habit) has a significant effect on the physical and chemical properties and formulation process of the drug, and the diversity of crystal habits (such as needle-shaped, layered, and rod-shaped) is caused by differences in molecular arrangement, which will affect product fluidity and particle size distribution, and thus affect the energy consumption and cost of downstream processes.

[0003] In the pharmaceutical industry, crystal habit has an important influence on the dissolution rate and stability of drugs. Different crystal habits may cause changes in the pharmacodynamics and pharmacokinetic properties of drugs, thereby affecting the efficacy and safety of drugs. For example, in the pharmaceutical production process, the use of CaCO 3 Asymmetric needle-shaped particles with a crystal habit tend to form cakes after standing, while cylindrical particles are less likely to do so. Differences in crystal habits affect the preparation process. For example, drugs with fine needle-shaped crystal habits have poor fluidity and are very likely to become blocked and agglomerated during the preparation process, resulting in the inability to feed materials. Differences in crystal habits affect tableting performance. For example, the symmetry of crystal habits is an important condition for the direct compression process of tablets. Differences in crystal habits affect dissolution rate and dissolution performance. For example, the anti-tumor drug sorafenib mesylate has obvious differences in absorption curves of sorafenib mesylate with different morphologies in pure water, pH=1.2 gastric fluid simulation fluid, and mice under the same crystal form and sieved particle size. Therefore, precise control of crystal habits is crucial in the pharmaceutical industry. By regulating the crystal habits of drugs, the performance of drugs 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 state, temperature conditions, stirring intensity, and the role of additives. Regulating crystal habit involves reducing the growth rate of crystal faces, which can promote the stable growth of low-energy crystal faces, while increasing supersaturation tends to induce the formation of needle-shaped crystals. The role of additives is that they can change the interaction between solute and crystal lattice, thereby affecting the development of crystal form. Temperature control is also indispensable. Rapid cooling tends to produce thin flaky crystals, while slow cooling is conducive to the formation of a denser crystal structure. Increasing the stirring rate usually leads to a decrease in crystal size and a more uniform distribution. Factors affecting crystal habit also include small crystal size and excellent distribution at high stirring rates; when the solute-solvent interaction is strong, nucleation is delayed to form symmetrical crystals; ultrasound helps to prepare spherical crystals with narrow particle size distribution. Among these many influencing factors, the use of macromolecular additives plays a vital role in regulating crystal habit.

[0005] Additives are mainly divided into small molecule additives and macromolecular additives. Compared with small molecule additives, the advantages of macromolecular additives are that they have large molecular weight and molecular structure, rich action sites, and can be stably adsorbed on the crystal surface. According to literature reports, macromolecular additives can have a significant impact on the crystal nucleation and growth process at ppm concentrations. The stagnation area of ​​crystal growth is closely related to the geometric roughness of the crystal surface. The two-dimensional structure on the crystal surface often forms cavity or pocket-like features. These structures tend to capture solvent molecules, thereby occupying potential solute adsorption positions and inhibiting crystal growth. When macromolecular additives interact with these crystal surfaces, their steric hindrance effect effectively slows down the solvation of the crystal surface, thereby finely regulating the growth rate of the crystal. Based on this, this article selected protein as a macromolecular additive as the research object, represented by human serum albumin.

[0006] Aripiprazole (APZ), chemical name 7-{4-[4-(2,3-dichlorophenyl)-l-piperazinylbutyloxy}-3,4-dihydro-2(1H)-quinolinone, chemical formula C 23 H 27 Cl 2 N 3 O 2, mainly used as an antipsychotic drug for the treatment of various types of schizophrenia. Foreign clinical trials have shown that aripiprazole has significant therapeutic effects on both positive and negative symptoms of schizophrenia, and can also improve associated emotional symptoms and reduce the relapse rate of schizophrenia. The chemical structure of APZ is shown in the figure below. According to known reports, APZ has 9 anhydrous crystal forms, 4 solvates, and 4 hydrate crystal forms, and different crystal forms correspond to different crystal habits. For example, patent US7910589 announced APZ-related crystal forms A, B, C, D, E, G and amorphous invented by Otsuka Pharmaceutical Company of Japan. Patent US7504504 announced APZ-related crystal forms Ⅰ, Ⅱ, Ⅵ, Ⅷ, Ⅹ, etc. invented by Teva Company of India.

[0007]

[0008] PCT patent application WO03 / 026659 discloses six anhydrous aripiprazole crystal forms B, C, D, E, F and G. Among them, crystal form B is widely used in pharmaceutical preparations due to its low hygroscopicity. There are many methods for preparing crystal form B. For example, CN101948426 discloses another method for preparing crystal form B, in which APZ is dissolved in a mixed solvent (butanone and acetone system), cooled and crystallized, and then filtered and dried. In Chinese patent publication number CN114644588, it is disclosed that aripiprazole crystal form B is prepared by a tubular continuous crystallization method. A crystal form M of APZ is disclosed in Chinese patent publication No. CN105924393, and the 2θ values ​​of the X-ray powder diffraction spectrum are 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 is used in the preparation process of the crystal form M. For example, Chinese Patent Publication No. CN108602774 discloses a crystal form N of APZ (aripiprazole hydrate), and the 2θ values ​​of the X-ray powder diffraction spectrum are 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 crystal form α, and the 2θ values ​​of the X-ray powder diffraction spectrum are 17.4, 18.1, 19.6, 23.2, 24.4, and 27.8. The preparation of the crystal form α requires a temperature of -5°C.

[0009] However, most of the above methods are blind. Existing methods only rely on traditional solvent adjustment, temperature adjustment, etc., and a large amount of organic solvents are used in the preparation process. Most of the reaction processes have low temperatures or certain temperature requirements. This not only affects the safety of drugs, but is also not conducive to the green development of the environment and the health of drug producers. Summary of the invention

[0010] The purpose of the present invention is to provide a method for obtaining APZ-H by adding protein to the APZ crystallization system. 1 、APZ-H 2 Two new crystal forms were obtained, and different crystal habits of the same crystal form of APZ in three solvent systems were discovered.

[0011] The second object of the present invention is to provide two new crystal forms

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

[0013] A method for simultaneously regulating aripiprazole new crystal forms and crystal habits is to add human serum albumin to the aripiprazole solvent crystallization system to obtain two new crystal forms; and simultaneously regulate different crystal habits of the same crystal form of aripiprazole;

[0014] Wherein: the dosage 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 control method described in the first technical solution, wherein the new crystal form of aripiprazole is APZ-H 1 and APZ-H 2 .

[0017] Furthermore, the above-mentioned new crystal form of aripiprazole, the new crystal form APZ-H 1 The 2θ values ​​of the X-ray powder diffraction pattern are 5.74°, 7.52°, 11.47°, 17.28°, 18.71°, 19.79°, 22.01°, 23.01°, 24.32°, and 26.84°.

[0018] Furthermore, the above-mentioned new crystal form of aripiprazole, the new crystal form APZ-H 2The 2θ values ​​of the X-ray powder diffraction pattern 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°.

[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 the present invention uses protein as a regulator added to the APZ solvent crystallization system to regulate the crystal habits of the aripiprazole drug, and obtains the same crystal form but different crystal habits. At the same time, two new crystal forms of aripiprazole are also discovered in this process.

[0021] 2. The protein used in the technical solution provided by the present invention is a substance necessary for the human body. When added to the medicine, it is not only non-toxic and harmless, but also meets the needs of the human body. At the same time, it avoids the use of a large amount of toxic and harmful organic solvents, which can not only adjust the crystal habit of the medicine, but also conforms to the green and environmentally friendly production concept that the country has always advocated.

[0022] 3. The technical solution provided by the present invention obtains the effect of human serum protein of different concentrations on the crystal habit of aripiprazole. The experiment found that with the increase of protein concentration, the crystal habit of aripiprazole showed an increasingly curved characteristic.

[0023] 4. The technical solution provided by the present invention is based on the interaction between human serum albumin and aripiprazole, which realizes efficient regulation of crystal habit and provides certain guidance for the production of subsequent pharmaceutical preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is the new crystal form APZ-H obtained in Example 1 1 and APZ-H 2 X-ray powder diffraction pattern of

[0025] Figure 2 The new crystal form APZ-H was prepared in Example 1 1 Microscope observation diagram;

[0026] Figure 3 The new crystal form APZ-H was prepared in Example 2 2 Microscope observation diagram;

[0027] Figure 4 It is a new crystal form of aripiprazole APZ-H 1 and APZ-H 2 DSC diagram of

[0028] Figure 5This is the X-ray powder diffraction spectrum of the crystallization of Comparative Example 1 without adding protein solvent;

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

[0030] Figure 7 This is a microscopic observation of APZ under different human serum protein concentrations;

[0031] Wherein: (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 DESCRIPTION

[0032] Next, a new method for regulating the crystal habit and crystal form of aripiprazole is described in combination with the specific implementation method and the content of the invention, but it is not limited to these methods, and all related methods are protected.

[0033] Example 1

[0034] 1) Take 10 mg of human serum albumin and add 15 mL of deionized water to dissolve it to obtain an HSA aqueous solution;

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

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

[0037] 4) Seal the conical flask and pierce a hole, then cool to room temperature to allow crystallization.

[0038] Part of the crystals were observed under an inverted microscope, and the remaining crystals were separated from the solution by filtration and dried at 50°C. The samples were then sent for XRD measurement to obtain the corresponding crystal habit observation diagram and the XRD of the sample. The X-ray powder diffraction pattern of crystalline trelagliptin was recorded under the following conditions: room temperature 25°C, relative humidity <60%; X'PertPRO polycrystalline X-ray diffractometer (PANalytical, the Netherlands), CuKα radiation The light tube voltage is 40 kV, the tube current is 40 mA, the 2θ scanning range is 4 to 50°, the step length is 0.01313°, and the counting time is 30 ms / step. The test results are as follows Figure 1 As shown, the new crystal form of aripiprazole APZ-H 1The 2θ values ​​are 5.74°, 7.52°, 11.47°, 17.28°, 18.71°, 19.79°, 22.01°, 23.01°, 24.32°, and 26.84°. 1 Microscope observation of Figure 2 As shown, compared with the existing crystal form, there are differences confirming that it is a new crystal form.

[0039] The new crystal form of aripiprazole APZ-H prepared in Example 1 of the present invention 1 The differential scanning calorimetry analysis was performed and the differential scanning calorimetry results of the new aripiprazole crystal form were recorded under the following conditions: DSC800 differential scanning calorimeter (PerkinElmer, USA), N 2 Protection, air flow rate is 20mL / min, detection temperature range is 0℃~160℃, heating rate is 10℃ / min. The test results are as follows Figure 4 As shown, it can be seen that the new crystal form APZ-H provided in Example 1 1 The differential scanning calorimetry curve of aripiprazole was significantly different from that of the original drug. The results showed that the new aripiprazole crystal form APZ-H 1 It has an endothermic peak at 139.6℃, which is quite different from the original drug.

[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 to obtain HSA buffer solution.

[0042] 2) Take 120 mg of aripiprazole (APZ) in a conical 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) dropwise to the HSA buffer solution prepared in step 1).

[0044] 4) Seal the conical flask and pierce a hole, then cool to room temperature to allow crystallization.

[0045] A portion of the crystals were observed under an inverted microscope, and the remaining crystals were separated from the solution by filtration and dried at 50°C. The samples were then sent for XRD measurement to obtain the corresponding crystal habit observation diagram and the sample's XRD. At the same time, the X-ray powder diffraction pattern of crystalline Trelagliptin was recorded under the following conditions: room temperature 25°C, relative humidity <60%; X'PertPRO polycrystalline X-ray diffractometer (PANalytical, the Netherlands), CuKα radiation The light tube voltage is 40 kV, the tube current is 40 mA, the 2θ scanning range is 4 to 50°, the step length is 0.01313°, and the counting time is 30 ms / step. The test results are as follows Figure 1 The new crystal form APZ-H 2 The 2θ values ​​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°. 2 Microscope observation of Figure 3 As shown, compared with the existing crystal form, there are differences confirming that it is a new crystal form.

[0046] The new crystal form of aripiprazole APZ-H prepared in Example 2 of the present invention 2 The differential scanning calorimetry analysis was performed and the differential scanning calorimetry results of the new aripiprazole crystal form were recorded under the following conditions: DSC800 differential scanning calorimeter (PerkinElmer, USA), N 2 Protection, air flow rate is 20mL / min, detection temperature range is 0℃~160℃, heating rate is 10℃ / min. The test results are as follows Figure 4 As shown, it can be seen that the new crystal form APZ-H provided in Example 2 2 The differential scanning calorimetry curve of aripiprazole was significantly different from that of the original drug. The results showed that the new aripiprazole crystal form APZ-H 2 It has an endothermic peak at 139.1℃, which is quite different from the original drug.

[0047] Comparative Example 1

[0048] Take 90 mg of aripiprazole in a conical flask, add 15 mL of methanol, heat and stir at 60 ° C until APZ is completely dissolved, then slowly add it dropwise to 15 mL of deionized water, seal the conical flask and pierce it, cool it to room temperature for crystallization, take a part of the crystals and observe them under an inverted microscope, and separate the remaining crystals from the solution by filtering and dry them at a drying temperature of 50 ° C, and then send the sample for XPRD measurement. The final result is as follows: Figure 5 As shown in the figure, it can be found that there is no new crystal form in the aripiprazole solvent crystallization system without adding protein. The crystal habit observation is as follows Figure 6 As shown, the crystal habit of the group without protein addition is straight, which is very different from the crystal habit of the group with protein addition.

[0049] Comparative Example 2

[0050] 90 mg of aripiprazole was placed in a conical flask, 15 mL of methanol was added, and the mixture was heated and stirred at 60° C. until APZ was completely dissolved. The mixture was then slowly added dropwise to 15 mL of PBS buffer. The conical flask was sealed and pierced, and then cooled to room temperature for crystallization. A portion of the crystals was observed under an inverted microscope, and the remaining crystals were separated from the solution by filtration and dried at a drying temperature of 50° C. The sample was then sent for XRD measurement to obtain an observation diagram of the corresponding crystal habit and the XRD of the sample. The results showed that the aripiprazole solvent crystallization system without the addition of protein had no new crystal form, as was the case with Comparative Example 1.

[0051] Example 3

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

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

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

[0055] 4) After sealing and piercing the conical flask, cool it to room temperature for crystallization, take a portion of the crystals and observe them under an inverted microscope, and separate the remaining crystals from the solution by filtering and drying at a drying temperature of 50°C. Then send the sample for XRD measurement to obtain a new crystal form APZ-H 1 .

[0056] Example 4

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

[0058] 2) Take 120 mg of aripiprazole in a conical 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) dropwise to the solution prepared in step 2).

[0060] 4) After sealing and piercing the conical flask, cool it to room temperature for crystallization, take a portion of the crystals and observe them under an inverted microscope, and separate the remaining crystals from the solution by filtering and drying at a drying temperature of 50°C, and then send the sample for XPRD measurement to obtain a new crystal form APZ-H 2 .

[0061] Comparative Example 3

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

[0063] Comparative Example 4

[0064] 90 mg of aripiprazole was placed in a conical flask, 15 mL of methanol was added, and 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 conical flask was sealed and pierced, and then cooled to room temperature for crystallization. A portion of the crystals was observed under an inverted microscope, and the remaining crystals were separated from the solution by filtration and dried at 50°C. The sample was then sent for XPRD measurement to obtain the corresponding crystal habit observation diagram and the sample's XRD. The results showed that the aripiprazole solvent crystallization system without the addition of protein had no new crystal form, as was the case with the comparative example 1.

[0065] Example 5

[0066] 1) Take 8 mg of human serum albumin and add 15 mL of deionized water to dissolve it to obtain an HSA aqueous solution;

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

[0068] 3) The APZ solution prepared in step 2) is slowly added dropwise to the HSA aqueous solution prepared in step 1).

[0069] 4) After sealing and piercing the conical flask, cool it to room temperature for crystallization, take a portion of the crystals and observe them under an inverted microscope, and separate the remaining crystals from the solution by filtering and drying them at a drying temperature of 50°C. Then send the sample for XPRD measurement to obtain the corresponding crystal habit observation diagram and the sample's XRD, and obtain the new crystal form APZ-H 1 .

[0070] Example 6

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

[0072] 2) Take 90 mg of aripiprazole in a conical 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) dropwise to the HSA buffer solution prepared in step 1).

[0074] 4) After sealing and piercing the conical flask, cool it to room temperature for crystallization, take a portion of the crystals and observe them under an inverted microscope, and separate the remaining crystals from the solution by filtering and drying at a drying temperature of 50°C, and then send the sample for XPRD measurement to obtain a new crystal form APZ-H 2 .

[0075] Comparative Example 5

[0076] 90 mg of aripiprazole was placed in a conical flask, 15 mL of acetonitrile was added, and the mixture was heated and stirred at 60°C until APZ was completely dissolved, and then slowly added dropwise to 15 mL of deionized water solution. After the conical flask was sealed and pierced, it was cooled to room temperature for crystallization, and 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 a drying temperature of 50°C. The sample was then sent for XPRD measurement to obtain the corresponding crystal habit observation diagram and the sample's XRD. The results showed that the aripiprazole solvent crystallization system without the addition of protein had no new crystal form, as was the case with the comparative example 1.

[0077] Comparative Example 6

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

[0079] Example 7

[0080] 1) Take 30 mg of human serum albumin and add 15 mL of deionized water to dissolve it to obtain an HSA aqueous solution;

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

[0082] 3) slowly adding the HSA aqueous solution prepared in step 1) dropwise to the aripiprazole solution prepared in step 2).

[0083] 4) After sealing and piercing the conical flask, cool it to room temperature for crystallization, take a portion of the crystals and observe them under an inverted microscope, and separate the remaining crystals from the solution by filtering and drying at a drying temperature of 50°C, and then send the sample for XPRD measurement to obtain a new crystal form APZ-H 2 .

[0084] Example 8

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

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

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

[0088] 4) After sealing and piercing the conical flask, cool it to room temperature for crystallization, take a portion of the crystals and observe them under an inverted microscope, and separate the remaining crystals from the solution by filtering and drying at a drying temperature of 50°C, and then send the sample for XPRD measurement to obtain a new crystal form APZ-H 2 .

[0089] Comparative Example 7

[0090] Take 90 mg of aripiprazole in a conical flask, add 15 mL of acetonitrile, heat and stir at 60 ° C until APZ is completely dissolved. Then slowly add 15 mL of deionized water solution to the aripiprazole solution. After sealing and piercing the conical flask, cool it to room temperature for crystallization, take a portion of the crystals and observe them under an inverted microscope, and separate the remaining crystals from the solution by filtering and dry them at a drying temperature of 50 ° C. Then send the sample for XPRD measurement to obtain the observation diagram of the corresponding crystal habit and the XRD of the sample. The results show that the aripiprazole solvent crystallization system without adding protein has no new crystal form as in Comparative Example 1.

[0091] Comparative Example 8

[0092] 90 mg of aripiprazole was placed in a conical flask, 15 mL of acetonitrile was added, and 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 conical flask was sealed and pierced, and then cooled to room temperature for crystallization. A portion of the crystals was observed under an inverted microscope, and the remaining crystals were separated from the solution by filtration and dried at a drying temperature of 50°C. The sample was then sent for XPRD measurement to obtain the corresponding crystal habit observation diagram and the sample's XRD. The results showed that the aripiprazole solvent crystallization system without the addition of protein had no new crystal form, as was the case with the comparative example 1.

[0093] Example 9

[0094] 1) Take 20 mg of human serum albumin and add 8 mL of deionized water to dissolve it to obtain an HSA aqueous solution;

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

[0096] 3) The APZ solution prepared in step 2) is slowly added dropwise to the HSA aqueous solution prepared in step 1).

[0097] 4) After sealing and piercing the conical flask, cool it to room temperature for crystallization, take a portion of the crystals and observe them under an inverted microscope, and separate the remaining crystals from the solution by filtering and drying at a drying temperature of 50°C, and then send the sample for XPRD measurement to obtain a new crystal form APZ-H 2 .

[0098] Example 10

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

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

[0101] 3) The APZ solution prepared in step 2) is slowly added dropwise to the HSA buffer solution prepared in step 1).

[0102] 4) After sealing and piercing the conical flask, cool it to room temperature for crystallization, take a portion of the crystals and observe them under an inverted microscope, and separate the remaining crystals from the solution by filtering and drying at a drying temperature of 50°C, and then send the sample for XPRD measurement to obtain a new crystal form APZ-H 2 .

[0103] Comparative Example 9

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

[0105] Comparative Example 10

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

[0107] Embodiment 11

[0108] 1) Take 38 mg of human serum albumin and add 15 mL of deionized water to dissolve it to obtain an HSA aqueous solution;

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

[0110] 3) slowly adding the HSA aqueous solution prepared in step 1) dropwise to the aripiprazole solution prepared in step 2).

[0111] 4) After sealing and piercing the conical flask, cool it to room temperature for crystallization, take a portion of the crystals and observe them under an inverted microscope, and separate the remaining crystals from the solution by filtering and drying at a drying temperature of 50°C, and then send the sample for XPRD measurement to obtain a new crystal form APZ-H 2 .

[0112] Example 12

[0113] 1) Take 18 mg of human serum albumin and add 30 mL of PBS buffer solution to dissolve it to obtain HSA buffer solution;

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

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

[0116] 4) After sealing and piercing the conical flask, cool it to room temperature for crystallization, take a portion of the crystals and observe them under an inverted microscope, and separate the remaining crystals from the solution by filtering and drying at a drying temperature of 50°C, and then send the sample for XPRD measurement to obtain a new crystal form APZ-H 1 .

[0117] Comparative Example 11

[0118] 90 mg of aripiprazole was placed in a conical flask, 15 mL of acetone was added, and 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 conical flask was sealed and pierced, and then cooled to room temperature for crystallization. A portion of the crystals was observed under an inverted microscope, and the remaining crystals were separated from the solution by filtration and dried at 50°C. The sample was then sent for XPRD measurement to obtain the corresponding crystal habit observation diagram and the sample's XRD. The results showed that the aripiprazole solvent crystallization system without the addition of protein had no new crystal form, as was the case with the comparative example 1.

[0119] Comparative Example 12

[0120] 90 mg of aripiprazole was placed in a conical flask, 15 mL of acetone was added, and 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 conical flask was sealed and pierced, and then cooled to room temperature for crystallization. A portion of the crystals was observed under an inverted microscope, and the remaining crystals were separated from the solution by filtration and dried at 50°C. The sample was then sent for XPRD measurement to obtain the corresponding crystal habit observation diagram and the sample's XRD. The results showed that the aripiprazole solvent crystallization system without the addition of protein had no new crystal form, as was the case with the comparative example 1.

[0121] Embodiment 13

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

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

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

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

[0126] Embodiment 14

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

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

[0129] 3) Then the APZ methanol solution was slowly added dropwise to the above five groups of HSA aqueous solutions, wherein the corresponding concentrations were 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) Seal and pierce the conical flasks, cool them to room temperature and allow them to crystallize. Take a portion of the crystals and observe them under an inverted microscope to obtain the corresponding crystal habit observation diagram, as shown in the figure below. Figure 7 As shown, it can be found that with the continuous increase of protein concentration, the curvature of the aripiprazole crystal habit gradually increases.

[0131] Embodiment 15

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

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

[0134] 3) Then the above five groups of HSA aqueous solutions were slowly dripped into the APZ methanol solution, wherein the corresponding concentrations were 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) Seal and pierce the conical flasks, cool them to room temperature and allow them to crystallize. Take a portion of the crystals and observe them under an inverted microscope to obtain the corresponding crystal habit observation diagram, as shown in the figure below. Figure 7 As shown, it can be found that with the continuous increase of protein concentration, the curvature of the aripiprazole crystal habit gradually increases.

[0136] In order to prove that the two new aripiprazole crystal forms APZ-H provided in this application 1 and APZ-H 2 The following is the effect of the original aripiprazole crystal form and the two new aripiprazole crystal forms APZ-H 1 and APZ-H 2 Solubility in hydrochloric acid solution at pH = 1.2.

[0137] The specific operation is: take the original crystal form of aripiprazole and two new crystal forms of aripiprazole APZ-H 1 and APZ-H 2 After reaching the dissolution equilibrium, a sample was taken and filtered with a 0.22um filter membrane. An appropriate amount of the filtrate was taken and the absorbance value was measured at a wavelength of 249nm according to the UV-visible spectrophotometry (Chinese Pharmacopoeia 2020 edition). The absorbance value was substituted into the standard curve to obtain the original aripiprazole crystal form and two new aripiprazole crystal forms APZ-H 1 and APZ-H 2 The solubility of

[0138] Table 2 Solubility table

[0139]

[0140] The results in Table 2 show that in a hydrochloric acid solution with a pH of 1.2, aripiprazole new crystal form APZ-H 2 The solubility of the new aripiprazole crystal form APZ-H is significantly higher than that of the original crystal form. 1 The solubility is similar to that of the original crystalline form.

[0141] The above description is only a specific implementation mode of the present invention, not all implementation modes. Any equivalent transformations made by other technicians in the field based on the description of the present invention are all covered by the claims of the present invention and are also the contents protected by the present invention.

Claims

1. A method for simultaneously regulating aripiprazole new crystal form and crystal habit, characterized in that: Human serum albumin is dissolved in solvent A and then added into the aripiprazole solvent crystallization system to obtain a new crystal form and different crystal habits under the same crystal form; Wherein: the dosage ratio of human serum albumin to aripiprazole is 1:1 to 1:

10.

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

3. The method for simultaneously regulating the new crystal form and crystal habit of aripiprazole according to claim 1, characterized in that: The solvent A is one of deionized water and PBS buffer solution.

4. A new crystal form of aripiprazole obtained by the control method according to claim 1 or 2, characterized in that: The new aripiprazole crystal forms are APZ-H1 and APZ-H2.

5. The new crystal form of aripiprazole according to claim 3, characterized in that: The 2θ values ​​of the X-ray powder diffraction pattern of the new crystal form APZ-H1 are 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°.

6. The new crystal form of aripiprazole according to claim 3, characterized in that: The 2θ values ​​of the X-ray powder diffraction pattern of the new crystal form APZ-H2 are 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°.

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