Aripiprazole-2, 3-dihydroxybenzoic acid-hydrate crystal form and preparation method thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to an aripiprazole-2, 3-dihydroxy benzoic acid-hydrate crystal form and a preparation method thereof. According to the crystal form, a basic unit is composed of tetramolecular aripiprazole, tetramolecular 2, 3-dihydroxybenzoic acid and bimolecular water. The aripiprazole crystal form provided by the invention has excellent solubility and good storage stability, and is helpful for improving the dissolution rate and bioavailability of drugs. In addition, the preparation method of the crystal form is simple in process, convenient to operate, easy to control and suitable for large-scale industrial production, and has a good application prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemistry, and particularly relates to aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form and a preparation method thereof. BACKGROUND

[0002] Aripiprazole, the chemical name of which is 7-{4-[4-(2,3-dichlorophenyl)-l-piperazinyl]butoxy}-3,4-dihydro-2(lH)-quinolinone, the English name of which is Aripiprazole, and the structural formula of which is as follows: .

[0003] Aripiprazole is a quinolinone derivative, belongs to the third generation of atypical antipsychotic drugs, and treats schizophrenia through dopamine D2 receptor partial agonism and 5-hydroxytryptamine receptor regulation mechanism. Schizophrenia is a serious and complex mental illness, and its clinical symptoms are often manifested as hallucinations, delusions, thought disorder and social function regression. The disease often occurs in people aged 16-25 years, and the global prevalence rate is about 1%, which is significantly higher than that of nervous system diseases such as Alzheimer's disease, and early treatment can significantly improve the prognosis.

[0004] The clinical efficacy of aripiprazole has been confirmed, but its application is limited by extremely low solubility, and the most soluble form in water at 25°C is only 0.045 mg / L. At present, there are immediate-release tablets, oral disintegrating tablets, oral solutions, injections and sustained-release tablets and other dosage forms, and the requirements for dissolution kinetics of different administration methods are significantly different. Therefore, accurately regulating the solubility and dissolution rate of aripiprazole to match the specific administration route is a key technical challenge to improve its clinical drug effect.

[0005] CN02801754.4 discloses aripiprazole hydrate A and six anhydrous aripiprazole crystal forms B, C, D, E, F and G and a preparation method thereof, wherein the crystal form B is a preferred crystal form, has low hygroscopicity, is suitable for pharmaceutical preparations, but has low solubility, is not conducive to improving the bioavailability, and the preparation method is complicated, time-consuming and energy-consuming, and is not conducive to large-scale industrial production of products. CN201610529009.0 discloses aripiprazole M crystal form, which improves the solubility to some extent.

[0006] To improve the physicochemical properties of aripiprazole bulk drug, its salt or co-crystal crystal form can be prepared. The salt has high solubility, which is beneficial to rapid release, but its thermal stability is insufficient, it is easy to transform in humid or high temperature environment, and the mechanical strength is low when tabletting, resulting in batch-to-batch quality fluctuation; the co-crystal is favored due to low melting point, convenient processing and relatively good solubility, but the crystal lattice is loose, lacking thermal-mechanical stability, and is easy to separate or phase change when temperature and humidity change, affecting long-term stability. Therefore, it is urgent to develop a new crystal form to improve the solubility and stability of aripiprazole, and to provide more suitable bulk drug and product for formulation development and clinical use. SUMMARY

[0007] In view of the defects of the prior art, the present application provides aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form, which is composed of four molecules of aripiprazole, four molecules of 2,3-dihydroxybenzoic acid and two molecules of water as a basic unit. The aripiprazole crystal form provided by the present application has excellent solubility and good storage stability, which helps to improve the dissolution and bioavailability of the drug. In addition, the preparation method of the crystal form is simple, easy to operate and control, suitable for large-scale industrial production, and has good application prospect.

[0008] The specific technical content of the present application is as follows:

[0009] In one aspect, the present application provides aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form, which is composed of four molecules of aripiprazole, four molecules of 2,3-dihydroxybenzoic acid and two molecules of water as a basic unit, and the X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation has characteristic peaks at least at 10.1±0.2°, 12.9±0.2°, 13.4±0.2°, 19.0±0.2°, 19.5±0.2°, 27.4±0.2°, 41.7±0.2°.

[0010] Preferably, the aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form has characteristic peaks at least at 10.1±0.2°, 12.9±0.2°, 13.4±0.2°, 19.0±0.2°, 19.5±0.2°, 21.9±0.2°, 23.5±0.2°, 27.4±0.2°, 31.9±0.2°, 41.7±0.2° in the X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

[0011] Preferably, the aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form has characteristic peaks in the X-ray powder diffraction spectrum expressed in 2θ using Cu-Kα radiation, as shown in Figure 1

[0012] ​Preferably, the aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form has a molecular formula of C 120 H 136 Cl8N 12 O 26 , and crystallographic parameters are: monoclinic crystal system, space group P21 / c, cell parameters are: a = 58.9789(7) Å, b = 9.52870(10) Å, c = 21.3870(3) Å, α = 90°, β = 94.9710(10) °, γ = 90°, cell volume V = 11974.1(3) Å 3 .

[0013] In another aspect, the present application provides a method for preparing aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form, comprising the following steps: adding aripiprazole monohydrate and 2,3-dihydroxybenzoic acid into a mixed solvent, heating and stirring, filtering while hot, standing and volatilizing to crystallize by cooling, filtering and drying to obtain aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form.

[0014] Preferably, in the method, the mixed solvent is selected from the group consisting of ethanol and ethyl acetate, acetonitrile and diethyl ether; the mixed solvent is further preferably a mixture of ethanol and diethyl ether, with a volume ratio of 1:4.

[0015] Preferably, in the method, the mass / volume ratio of aripiprazole monohydrate to the mixed solvent is 15-20:1; the mass / volume ratio is further preferably 18:1, wherein the mass is in mg and the volume is in mL.

[0016] Preferably, in the method, the molar ratio of aripiprazole monohydrate to 2,3-dihydroxybenzoic acid is 1.0:1.1-2.0; the molar ratio is further preferably 1.0:1.5.

[0017] Preferably, in the method, the heating temperature is 55-65°C.

[0018] Preferably, in the method, the temperature for crystallization by cooling is 0-10°C.

[0019] Preferably, in the method, the crystallization time is 48-72h.

[0020] Preferably, in the method, the drying temperature is 55-70°C, and the drying time is 24-36h.

[0021] The raw material aripiprazole monohydrate used in the preparation method can be prepared according to any method in the prior art, such as CN 1817882B, CN114957115A, or purchased from commercially available products.

[0022] Finally, the present application provides a pharmaceutical composition comprising the aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form of the present application and other pharmaceutically acceptable components.

[0023] Preferably, the other pharmaceutically acceptable components can be co-usable pharmaceutically active ingredients and / or pharmaceutically acceptable auxiliary ingredients.

[0024] Confirmation of crystal structure

[0025] The X-ray crystal data of the aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form of the present application were collected on a Japanese Rigaku XtaLAB Synergy model instrument at a temperature of 293(2) K, using Cu-Ka radiation, with data collected in ω scan mode and L p correction. The structure was solved by direct methods, and all non-hydrogen atoms were located by difference Fourier methods, with hydrogen atoms on all carbons and nitrogens being placed in calculated positions. The structure was refined by full-matrix least-squares methods.

[0026] The crystallographic data of the aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form of the present application prepared in the present application (as shown in Table 1) are as follows: monoclinic crystal system, space group P21 / c, cell parameters: a = 58.9789(7) Å, b = 9.52870(10) Å, c = 21.3870(3) Å, α = 90°, β = 94.9710(10)°, γ = 90°, cell volume V = 11974.1(3) Å 3 .

[0027] Table 1 Main crystallographic data of aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form

[0028] The ORTEP diagram of the aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form of the present application shows that the crystal form contains four molecules of aripiprazole, four molecules of 2,3-dihydroxybenzoic acid and two molecules of water, as shown in the accompanying Figure 2 hydrogen bond diagram of the aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form of the present application, as shown in the accompanying Figure 3 According to the above crystallographic data, the characteristic peaks in the X-ray powder diffraction pattern (Cu-Ka) of the corresponding aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form are shown in the accompanying Figure 1 and Table 2.

[0029] Table 2 PXRD peaks of aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form

[0030] The TGA / DSC test results of the aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form prepared by the method of the present invention are as follows: Figure 4 As shown, the DSC test results show two endothermic peaks, corresponding to a water loss endothermic temperature of 166.39℃ and a melting point peak of 226.50℃, respectively. According to the TGA test results, there is a weight loss step. Calculations indicate that the aripiprazole crystal form is a dihydrate.

[0031] In the specific embodiments of the present invention, the aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form samples prepared in Examples 1 to 5 all have the same crystallographic parameters and X-ray powder diffraction patterns as described above.

[0032] Compared with the prior art, the technical effects achieved by the present invention are as follows:

[0033] The aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form provided by this invention possesses the dual structural advantages of salt ion pairs and water of crystallization, significantly enhancing the solubility of aripiprazole. Furthermore, it outperforms simple salts, simple hydrates, or cocrystals in terms of thermal stability, process controllability, formulation compatibility, and quality consistency, exhibiting strong pharmaceutical value. The resulting crystal form is not easily hygroscopic and is not prone to crystal transformation. Simultaneously, the crystallization process of this invention is easy to control and exhibits good reproducibility. Attached Figure Description

[0034] Figure 1 PXRD pattern of aripiprazole-2,3-dihydroxybenzoic acid hydrate crystal form.

[0035] Figure 2 ORTEP diagram of the crystal form of aripiprazole-2,3-dihydroxybenzoic acid-hydrate.

[0036] Figure 3 Hydrogen bond diagram of the aripiprazole-2,3-dihydroxybenzoic acid hydrate crystal form.

[0037] Figure 4 TGA / DSC spectra of aripiprazole-2,3-dihydroxybenzoic acid hydrate crystal form. Detailed Implementation

[0038] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection claimed by the present invention.

[0039] Example 1

[0040] Aripiprazole monohydrate 506.2 mg and 2,3-dihydroxybenzoic acid 249.7 mg were added to a mixed solvent of 5.6 mL of ethanol and 22.4 mL of diethyl ether, heated and stirred in a 60 °C water bath until completely dissolved, filtered while hot, and left to stand at 5 °C for 60 h to volatilize and crystallize, filtered, and dried in a vacuum at 60 °C for 28 h to obtain aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form, yield: 95.3%, purity: 99.94%.

[0041] Example 2

[0042] Aripiprazole monohydrate 527.4 mg and 2,3-dihydroxybenzoic acid 191.7 mg were added to a mixed solvent of 5.2 mL of ethanol and 20.8 mL of ethyl acetate, heated and stirred in a 55 °C water bath until completely dissolved, filtered while hot, left to stand at 10 °C for 48 h to volatilize and crystallize, filtered, and dried in a vacuum at 55 °C for 24 h to obtain aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form, yield: 94.6%, purity: 99.92%.

[0043] Example 3

[0044] Aripiprazole monohydrate 506.2 mg and 2,3-dihydroxybenzoic acid 332.9 mg were added to a mixed solvent of 6.8 mL of ethanol and 27.2 mL of diethyl ether, heated and stirred in a 65 °C water bath until completely dissolved, filtered while hot, left to stand at 0 °C for 72 h to volatilize and crystallize, filtered, and dried in a vacuum at 55 °C for 36 h to obtain aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form, yield: 95.1%, purity: 99.94%.

[0045] Example 4

[0046] Aripiprazole monohydrate 506.2 mg and 2,3-dihydroxybenzoic acid 665.8 mg were dissolved in a mixed solvent of 6.5 mL of ethanol and 26 mL of diethyl ether, heated and stirred in a 60 °C water bath until completely dissolved, filtered while hot, left to stand at 5 °C for 60 h to volatilize and crystallize, filtered, and dried in a vacuum at 60 °C for 28 h to obtain aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form, yield: 76.4%, purity: 99.91%.

[0047] Example 5

[0048] Aripiprazole monohydrate 506.2 mg and 2,3-dihydroxybenzoic acid 249.7 mg were added to a mixed solvent of 12.6 mL of ethanol and 50.4 mL of diethyl ether, heated and stirred in a 60 °C water bath until completely dissolved, filtered while hot, left to stand at 5 °C for 60 h to volatilize and crystallize, filtered, and dried in a vacuum at 60 °C for 28 h to obtain aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form, yield: 87.5%, purity: 99.93%.

[0049] Comparative Example 1

[0050] 50.0 mg of aripiprazole monohydrate and 16.5 mg of 2,5-dihydroxybenzoic acid were added to 18.0 mL of acetonitrile-water mixed solvent, heated and dissolved, filtered, and left to stand at room temperature to crystallize, to obtain aripiprazole-2,5-dihydroxybenzoic acid hemihydrate crystal form, with a yield of 89.3% and a purity of 99.93%.

[0051] Comparative Example 2

[0052] 50.0 mg of aripiprazole monohydrate and 13.0 mg of benzoic acid were added to 18.0 mL of acetonitrile-water mixed solvent, heated and dissolved, filtered, and left to stand at room temperature to crystallize, to obtain aripiprazole-benzoic acid monohydrate crystal form, with a yield of 91.8% and a purity of 99.94%.

[0053] Verification Example

[0054] The aripiprazole-3,5-dihydroxybenzoic acid-hydrate crystal form prepared in Example 1 of the present application and the crystal forms obtained in the comparative examples were subjected to solubility, stability, hygroscopicity, and crystal form transition tests.

[0055] 1. Solubility

[0056] 10 mL of water and pH 6.8 phosphate buffer medium were respectively measured in a vial, and an excess amount of the sample to be tested was added. The vial was sealed and placed in a 37℃ constant temperature water bath with stirring at 100 rpm for 24 h. Filtration was performed, and the absorbance was measured at a wavelength of 254 nm. The solubility (converted into aripiprazole) was calculated by testing the absorbance of the standard control sample, and the results are shown in Table 3.

[0057] Table 3. Solubility test results

[0058] As shown in Table 3, the solubility of the aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form of the present application is superior to that of other crystal forms, and is expected to improve the bioavailability of the API.

[0059] 2. Stability

[0060] The aripiprazole-2,3-dihydroxybenzoic acid-hydrate prepared in the present application and the crystal forms obtained in the comparative examples were respectively sealed with aluminum foil bags and placed in an accelerated test condition of 40℃ / 75% RH, and the stability of each crystal form was measured, with the results shown in Table 4.

[0061] Table 4. Measurement results of crystal form stability

[0062] As shown in Table 4, the stability of the crystal form obtained in the application is better than that of the crystal form obtained in the comparative examples after being placed under accelerated conditions for 6 months. The content of related substances of the crystal form obtained in the comparative examples increases significantly after being placed under accelerated conditions.

[0063] 3. Hygroscopicity and crystal form transformation test

[0064] The aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form obtained in the application and the crystal forms obtained in the comparative examples were placed in a closed environment at 60°C and 100% relative humidity, and the water content (%) in the samples was determined after 10 days, and the water content increase was calculated; at the same time, the crystal form transformation was observed by detecting the change in melting point. The results show that the water content of the aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form obtained in Example 1 increased by 0.05%, the melting point and crystal form did not change, and the crystal form was not easy to absorb moisture; the water content of the crystal form obtained in Comparative Example 1 increased by 2.36%, the melting point and crystal form did not change; the water content of the crystal form obtained in Comparative Example 2 increased by 1.48%, the melting point increased by 11.5°C, and the crystal form was transformed.

Claims

1. A crystalline form of aripiprazole-2,3-dihydroxybenzoic acid-hydrate characterized by, The crystal form consists of a basic unit of four molecules of aripiprazole, four molecules of 2,3-dihydroxybenzoic acid and two molecules of water, and has characteristic peaks at least at 10.1±0.2°, 12.9±0.2°, 13.4±0.2°, 19.0±0.2°, 19.5±0.2°, 27.4±0.2°, 41.7±0.2° in an X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

2. The crystal form as described in claim 1, characterized in that, The crystal form has characteristic peaks at least at 10.1±0.2°, 12.9±0.2°, 13.4±0.2°, 19.0±0.2°, 19.5±0.2°, 21.9±0.2°, 23.5±0.2°, 27.4±0.2°, 31.9±0.2°, 41.7±0.2° in an X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

3. The crystal form as described in claim 1, characterized in that, The crystal form has characteristic peaks in accordance with the X-ray powder diffraction spectrum as shown in Figure 1 using Cu-Kα radiation.

4. The crystal form as described in claim 1, characterized in that, The molecular formula of the crystal form is C 120 H 136 Cl8N 12 O 26 The crystallographic parameters are: monoclinic crystal system, space group P21 / c, cell parameters: a = 58.9789(7) Å, b = 9.52870(10) Å, c = 21.3870(3) Å, α = 90°, β = 94.9710(10) °, γ = 90°, cell volume V = 11974.1(3) Å 3 .

5. A process for preparing the crystalline form of claim 1, comprising, The method comprises the following steps: adding aripiprazole monohydrate and 2,3-dihydroxybenzoic acid into a mixed solvent, heating and stirring, filtering while hot, standing and evaporating to crystallize by cooling, filtering and drying to obtain aripiprazole-2,3-dihydroxybenzoic acid-hydrate crystal form.

6. The production method according to claim 5, wherein In the method, the mixed solvent is selected from the group consisting of a mixed solvent of ethanol and ethyl acetate, acetonitrile and diethyl ether.

7. The production method according to claim 5, wherein In the method, the mass-volume ratio of aripiprazole monohydrate to the mixed solvent is 15-20:1, wherein the mass is in mg and the volume is in mL.

8. The production method according to claim 7, wherein In the method, the mass-volume ratio of aripiprazole monohydrate to the mixed solvent is further preferably 18:1, wherein the mass is in mg and the volume is in mL.

9. The production method according to claim 5, wherein In the method, the molar ratio of aripiprazole monohydrate to 2,3-dihydroxybenzoic acid is 1.0:1.1-2.

0.

10. The production method according to claim 9, wherein In the method, the molar ratio of aripiprazole monohydrate to 2,3-dihydroxybenzoic acid is 1.0:1.5.

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