Clozapine cocrystal with moisture stability and solubility advantages and preparation method thereof
By combining with different acid eutectics, binary or ternary eutectics of clozapine are formed, which solves the problems of low solubility and high permeability of clozapine, and significantly improves its bioavailability and humidity stability.
Patent Information
- Application Number
- CN202211395374.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2022-11-09
- Publication Date
- 2025-05-13
- Estimated Expiration
- 2042-11-09
AI Technical Summary
The low solubility and high permeability of clozapine lead to its low bioavailability, severely limiting the production and use of its pharmaceutical preparations.
By combining with eutectics such as maleic acid, oxalic acid, fumaric acid, succinic acid, citric acid, etc., binary or ternary eutectics are formed, thereby improving the solubility and humidity stability of clozapine.
It significantly improves the solubility and humidity stability of clozapine, enhances its bioavailability, improves clinical application effects, and reduces losses during production and storage.
Smart Images
Figure SMS_16 
Figure SMS_17
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of drug co-crystals, and particularly relates to a clozapine co-crystal having advantages in humidity stability and solubility and a preparation method thereof. Background Art
[0002] Clozapine is a well-known third-generation atypical antipsychotic drug that has a good effect on the clinical treatment of negative and positive symptoms of schizophrenia. It is mainly used to treat schizophrenia and manic depression. As an excellent antipsychotic drug with fewer side effects, clozapine can be taken orally and can also be treated by intramuscular injection. Clozapine is the first drug approved for the treatment of refractory schizophrenia. It has a certain effect in controlling the patient's excited and restless behavior, movement and behavior disorders and other symptoms. At the same time, it also has a good therapeutic effect on patients with hallucinations, delusions, loneliness, fear, withdrawal and other symptoms.
[0003] However, clozapine is almost insoluble in water, and its low solubility and high permeability make it classified as a BCS (Biopharmaceutical Classification System) Class II drug, and its bioavailability is low, which seriously restricts the production and use of clozapine preparations, and endangers the effectiveness, safety, quality reliability and consistency of clozapine drugs. Therefore, the present invention develops clozapine cocrystals, studies the relevant humidity stability and solubility, and develops clozapine cocrystals with humidity stability and higher solubility. Summary of the invention
[0004] The present invention aims to overcome the defects of the prior art and aims to provide a clozapine cocrystal having advantages in humidity stability and solubility and a preparation method thereof.
[0005] To achieve the above purpose, the specific steps of the technical solution adopted by the present invention are:
[0006] The present invention provides a clozapine cocrystal with advantages of humidity stability and solubility, including any one of a binary cocrystal formed by combining clozapine with a cocrystal former and a ternary cocrystal formed by combining clozapine with a cocrystal former and a solvent; the cocrystal former is any one of maleic acid, oxalic acid, fumaric acid, succinic acid and citric acid; and the solvent is any one of methanol, ethanol, acetonitrile and water.
[0007] Preferably, the binary cocrystal I of clozapine and maleic acid, wherein the molar ratio of clozapine to maleic acid is 1:2; the X-ray powder diffraction pattern of the cocrystal I of clozapine and maleic acid has the following iCharacteristic peaks represented: 5.6±0.2°, 9.6±0.2°, 10.7±0.2°, 11.3±0.2°, 12.9±0.2°, 14.0±0.2°, 14.4±0.2°, 15.7±0.2°, 16.9±0.2°, 18.1±0.2°, 19.4±0.2°, 20.0±0.2°, 20.6±0.2°, 21.9±0.2°, 22.7±0.2°, 23.8±0.2°, 24.8±0.2°, 26.1±0.2°, 26.8±0.2°, 27.4±0.2°, 28.2±0.2°, 29.0±0.2°, 30.1±0.2°, 31.3±0.2°, 34.1±0.2°, 34.5±0.2°.
[0008] Preferably, the ternary eutectic II of clozapine, oxalic acid and acetonitrile, wherein the molar ratio of clozapine, oxalic acid and acetonitrile is 2:3:1; the X-ray powder diffraction pattern of the eutectic II of clozapine, oxalic acid and acetonitrile has the following i Characteristic peaks indicated: 7.5±0.2°, 9.9±0.2°, 11.1±0.2°, 12.1±0.2°, 13.±0.2°, 14.9±0.2°, 16.4±0.2°, 16.8±0.2°, 17.8±0.2°, 18.2±0.2°, 18.6±0.2°, 19.8±0.2°, 20.6±0.2°, 21.6±0.2°, 22.3±0.2°, 22.8±0.2°, 23.4±0.2 °, 24.3±0.2°, 24.7±0.2°, 25.3±0.2°, 26.1±0.2°, 26.5±0.2°, 27.0±0.2°, 28.0±0.2°, 28.6±0.2°, 30.1±0.2°, 30.7±0.2°, 31.3±0.2°, 32.1±0.2°, 33.6±0.2°, 34.3±0.2°, 35.0±0.2°, 35.4±0.2°, 36.7±0.2°.
[0009] Preferably, the ternary eutectic III of clozapine, oxalic acid and ethanol, wherein the molar ratio of clozapine, oxalic acid and ethanol is 2:3:1; the X-ray powder diffraction pattern of the eutectic III of clozapine, oxalic acid and ethanol has the following iCharacteristic peaks represented: 7.8±0.2°, 9.7±0.2°, 10.8±0.2°, 12.9±0.2°, 13.6±0.2°, 14.5±0.2°, 15.0±0.2°, 15.4±0.2°, 17.1±0.2°, 17.5±0.2°, 18.6±0.2°, 19.4±0.2°, 20.0±0.2°, 20.6±0.2°, 21.6±0.2°, 22.6±0.2°, 23.8±0.2°, 24.4±0. 2°, 25.5±0.2°, 25.7±0.2°, 26.4±0.2°, 27.3±0.2°, 27.7±0.2°, 28.2±0.2°, 29.2±0.2°, 30.1±0.2°, 30.9±0.2°, 31.6±0.2°, 32.6±0.2°, 33.4±0.2°, 34.0±0.2°, 34.7±0.2°, 35.1±0.2°, 35.9±0.2°, 38.5±0.2°, 40.2±0.2°.
[0010] Preferably, the ternary eutectic IV of clozapine, oxalic acid and ethanol, wherein the molar ratio of clozapine, oxalic acid and ethanol is 2:1:1; the X-ray powder diffraction pattern of the eutectic IV of clozapine, oxalic acid and ethanol has the following i Characteristic peaks represented: 8.6±0.2°, 11.7±0.2°, 12.5±0.2°, 13.6±0.2°, 14.6±0.2°, 15.8±0.2°, 17.3±0.2°, 18.6±0.2°, 19.8±0.2°, 21.3±0.2°, 22.2±0.2°, 23.2±0.2°, 24.0±0.2°, 24.4±0.2°, 24.7±0.2°, 25.4±0. 2°, 26.2±0.2°, 27.1±0.2°, 28.0±0.2°, 29.2±0.2°, 29.7±0.2°, 30.4±0.2°, 31.7±0.2°, 32.0±0.2°, 33.4±0.2°, 33.7±0.2°, 34.2±0.2°, 36.5±0.2°, 37.6±0.2°, 38.9±0.2°, 39.7±0.2°, 40.0±0.2°.
[0011] Preferably, the ternary eutectic V of clozapine, fumaric acid and methanol, wherein the molar ratio of clozapine, fumaric acid and methanol is 2:1:1; the X-ray powder diffraction pattern of the eutectic V of clozapine, fumaric acid and methanol has the following iCharacteristic peaks represented: 8.4±0.2°, 11.1±0.2°, 12.2±0.2°, 12.7±0.2°, 13.8±0.2°, 15.5±0.2°, 16.5±0.2°, 17.2±0.2°, 18.1±0.2°, 19.5±0.2°, 19.9±0.2°, 20.9±0.2°, 21.9±0.2°, 22.5±0.2°, 23.3±0.2°, 24.2±0.2°, 24.8±0. 2°, 25.2±0.2°, 25.7±0.2°, 26.8±0.2°, 27.2±0.2°, 28.1±0.2°, 28.6±0.2°, 29.3±0.2°, 30.4±0.2°, 30.7±0.2°, 32.6±0.2°, 33.4±0.2°, 35.4±0.2°, 36.0±0.2°, 37.0±0.2°, 38.2±0.2°, 38.8±0.2°, 40.1±0.2°.
[0012] Preferably, the ternary eutectic VI of clozapine, fumaric acid and ethanol, wherein the molar ratio of clozapine, fumaric acid and ethanol is 2:1:1; the X-ray powder diffraction pattern of the eutectic VI of clozapine, fumaric acid and ethanol has the following i Characteristic peaks represented: 8.2±0.2°, 9.7±0.2°, 10.6±0.2°, 11.2±0.2°, 11.8±0.2°, 13.0±0.2°, 13.2±0.2°, 14.2±0.2°, 14.8±0.2°, 15.4±0.2°, 16.1±0.2°, 16.6±0.2°, 17.5±0.2°, 18.5±0.2°, 19.0±0.2°, 19.5±0.2°, 19.8±0.2°, 21.2±0.2°, 21.5±0.2°, 22 .5±0.2°, 22.7±0.2°, 24.0±0.2°, 24.9±0.2°, 25.6±0.2°, 26.1±0.2°, 26.9±0.2°, 27.3±0.2°, 27.5±0.2°, 28.4±0.2°, 29.6±0.2°, 30.1±0.2°, 30.4±0.2°, 31.3±0.2°, 32.7±0.2°, 34.8±0.2°, 35.5±0.2°, 36.0±0.2°, 36.8±0.2°, 37.3±0.2°.
[0013] Preferably, the ternary eutectic VII of clozapine, succinic acid and water, wherein the molar ratio of clozapine, succinic acid and water is 2:1:1; the X-ray powder diffraction pattern of the eutectic VII of clozapine, succinic acid and water has the following iCharacteristic peaks represented: 8.7±0.2°, 10.9±0.2°, 12.5±0.2°, 13.8±0.2°, 15.7±0.2°, 16.4±0.2°, 17.5±0.2°, 17.9±0.2°, 18.2±0.2°, 19.6±0.2°, 20.8±0.2°, 21.3±0.2°, 21.9±0.2°, 22.5±0.2°, 23.3±0.2°, 23.8±0.2°, 24.9±0. 2°, 25.3±0.2°, 26.6±0.2°, 26.9±0.2°, 28.2±0.2°, 28.7±0.2°, 29.7±0.2°, 30.4±0.2°, 31.0±0.2°, 32.0±0.2°, 32.4±0.2°, 33.4±0.2°, 35.6±0.2°, 36.8±0.2°, 37.5±0.2°, 38.6±0.2°, 39.1±0.2°, 40.2±0.2°.
[0014] Preferably, the ternary eutectic VIII of clozapine, citric acid and methanol, wherein the molar ratio of clozapine, citric acid and methanol is 1:1:1; the X-ray powder diffraction pattern of the eutectic VIII of clozapine, citric acid and methanol has the following i Characteristic peaks represented: 6.1±0.2°, 9.3±0.2°, 10.8±0.2°, 11.9±0.2°, 12.5±0.2°, 12.8±0.2°, 13.8±0.2°, 15.3±0.2°, 17.5±0.2°, 18.2±0.2°, 19.0±0.2°, 19.6±0.2°, 20.2±0.2°, 20.6±0.2°, 20.9±0.2°, 21.5±0.2°, 21.9±0.2°, 23.0±0.2°, 23.3±0.2°, 24 .7±0.2°, 25.1±0.2°, 25.8±0.2°, 26.8±0.2°, 27.1±0.2°, 27.3±0.2°, 27.9±0.2°, 28.8±0.2°, 29.3±0.2°, 29.8±0.2°, 30.4±0.2°, 31.1±0.2°, 32.9±0.2°, 33.3±0.2°, 33.9±0.2°, 35.2±0.2°, 35.6±0.2°, 38.2±0.2°, 38.6±0.2°, 40.3±0.2°.
[0015] Preferably, the differential scanning calorimetry spectrum of the clozapine and maleic acid binary cocrystal I shows that the melting onset temperature Tonset is 180.76±1.00°C and the peak temperature Tpeak is 181.97±1.00°C;
[0016] The differential scanning calorimetry spectrum of the ternary eutectic II of clozapine, oxalic acid and acetonitrile showed that the melting onset temperature Tonset was 226.97±1.00°C and the peak temperature Tpeak was 228.46±1.00°C;
[0017] The differential scanning calorimetry spectrum of the ternary eutectic III of clozapine, oxalic acid and ethanol showed that the melting onset temperature Tonset was 227.38±1.00°C and the peak temperature Tpeak was 228.42±1.00°C;
[0018] The differential scanning calorimetry spectrum of the ternary eutectic IV of clozapine, oxalic acid and ethanol showed that the melting onset temperature Tonset was 147.81±1.00°C and the peak temperature Tpeak was 155.43±1.00°C;
[0019] The differential scanning calorimetry spectrum of the ternary eutectic V of clozapine, fumaric acid and methanol showed that the melting onset temperature Tonset was 132.25±1.00°C and the peak temperature Tpeak was 142.09±1.00°C;
[0020] The differential scanning calorimetry spectrum of the ternary eutectic VI of clozapine, fumaric acid and ethanol showed that the melting onset temperature Tonset was 133.40±1.00°C and the peak temperature Tpeak was 140.47±1.00°C;
[0021] The differential scanning calorimetry spectrum of the ternary eutectic VII of clozapine, succinic acid and water showed that the melting onset temperature Tonset was 102.34±1.00°C and the peak temperature Tpeak was 112.78±1.00°C;
[0022] The differential scanning calorimetry spectrum of the ternary eutectic VIII of clozapine, citric acid and methanol showed that the melting onset temperature Tonset was 173.21±1.00°C and the peak temperature Tpeak was 193.02±1.00°C.
[0023] Preferably, the clozapine and maleic acid binary eutectic I is a triclinic system with a space group of The unit cell parameters are: α=78.820°, β=77.430°, γ=65.234°;
[0024] The ternary eutectic II of clozapine, oxalic acid and acetonitrile is a triclinic system with a space group of The unit cell parameters are: α=86.480(19)°, β=85.261(19)°, γ=85.287(19)°;
[0025] The ternary eutectic of clozapine, oxalic acid and ethanol is a triclinic system with a space group of The unit cell parameters are: α=89.592(3)°, β=84.617(3)°, γ=85.313(3)°;
[0026] The ternary eutectic IV of clozapine, oxalic acid and ethanol is a monoclinic system; the space group is P2 1 / n, the unit cell parameters are: α=90°, β=94.02°, γ=90°;
[0027] The ternary eutectic V of clozapine, fumaric acid and methanol is a monoclinic system with a space group of P2 1 / c, the unit cell parameters are:
[0028] α=90°, β=100.35(2)°, γ=90°;
[0029] The ternary eutectic VI of clozapine, fumaric acid and ethanol is a monoclinic system with a space group of P2 1 / n, the unit cell parameters are:
[0030] α=90°, β=93.831(4)°, γ=90°;
[0031] The ternary eutectic VII of clozapine, succinic acid and water is a monoclinic system with a space group of P2 1 / c, the unit cell parameters are:
[0032] α=90°, β=103.033(4)°, γ=90°;
[0033] The ternary eutectic VIII of clozapine, citric acid and methanol is an orthorhombic system with a space group of P2 1 2 1 2 1 , the unit cell parameters are: α=90°, β=90°, γ=90°.
[0034] On the other hand, the present invention provides a method for preparing the above-mentioned clozapine cocrystal having advantages in humidity stability and solubility, which method is one of the following methods:
[0035] Method 1:
[0036] Method 1 includes the following steps:
[0037] (a) weighing the powders of clozapine and the co-crystal former respectively;
[0038] (b) adding the powder and auxiliary solvent in step (a) into a pulverizing device and allowing them to fully contact with each other through mechanical force, and obtaining clozapine cocrystal after all reactions;
[0039] Method 2:
[0040] Method 2 includes the following steps:
[0041] (c) weighing the powders of clozapine and the co-crystal former respectively;
[0042] (d) dissolving the powder from step (c) in a solvent to form a saturated slurry of clozapine and the co-crystal former;
[0043] (e) filtering out the solid in step (d);
[0044] (f) slowly volatilizing the saturated solution obtained in step (e) until crystals are precipitated, thereby obtaining clozapine cocrystals.
[0045] Method 3:
[0046] Method 3 includes the following steps:
[0047] (g) weighing the powders of clozapine and the co-crystal former respectively;
[0048] (h) dissolving the powder from step (g) in a solvent to form a saturated slurry of clozapine and co-crystal former powders;
[0049] (i) fully stirring the saturated slurry obtained in step (h);
[0050] (j) isolating the solid in step (i) to obtain clozapine cocrystal.
[0051] In a specific embodiment, in steps (a), (c) and (g), the molar ratio of clozapine to the cocrystal former is
[0052] 1:1-2:1, preferably 1:2, 2:3, 2:1, 1:1;
[0053] In a specific embodiment, in steps (b), (d) and (h), the auxiliary solvent / the organic solvent is selected from methanol, ethanol, acetonitrile, isopropanol, water;
[0054] In a specific embodiment, in step (b), the pulverizing device is selected from a ball mill, a pulverizer and a mixer. Preferably, the pulverizing device is a ball mill, and its oscillation frequency is 5 to 60 Hz, preferably 40 Hz, and the oscillation time is 10 to 180 min, preferably 30 to 180 min;
[0055] In a specific embodiment, in step (f), volatilization is carried out at a temperature of 2 to 25° C., preferably at a temperature of 10° C.;
[0056] In a specific embodiment, in step (j), the separation comprises:
[0057] (j1) obtaining clozapine cocrystal by filtering;
[0058] In a specific embodiment, after step (j1), the method further comprises step (j2): evaporating and removing the solvent in the solid separated in step (j1), thereby obtaining clozapine cocrystal.
[0059] In yet another aspect, the present invention provides a pharmaceutical composition, comprising clozapine cocrystal as an active ingredient and an acceptable carrier; the dosage form of the pharmaceutical composition is selected from the following group: liquid preparation, solid preparation, semisolid preparation.
[0060] In another aspect, the present invention provides the above-mentioned clozapine cocrystal or the above-mentioned composition for better exerting the effect of clozapine on the positive and negative symptoms of psychosis.
[0061] Due to the adoption of the above technical solution, the present invention has the following beneficial effects compared with the prior art:
[0062] (1) The present invention provides a clozapine cocrystal having advantages in humidity stability and solubility, which is used to improve the solubility of clozapine drugs. Compared with clozapine bulk drugs, the clozapine cocrystal provided by the present invention has good solubility and high humidity stability, is conducive to being used as a drug component, improves its bioavailability, improves clinical application effects, reduces losses during production and storage, and has high drug development value.
[0063] (2) The method for preparing the clozapine cocrystal with advantages of humidity stability and solubility of the present invention has a simple process, good repeatability, and is suitable for industrial production. DETAILED DESCRIPTION
[0064] The present invention is further described below in conjunction with specific embodiments, which does not limit the scope of protection thereof. Unless otherwise specified, the raw materials and reagents used in the examples are all commercially available products; the reagents, instruments or operating steps not described herein are all contents that can be routinely determined by ordinary technicians in the field.
[0065] Example 1
[0066] A clozapine-maleic acid cocrystal having advantages in humidity stability and solubility and a preparation method thereof, wherein the specific implementation steps are as follows:
[0067] Clozapine powder (0.20 g, 6 mmol) and maleic acid powder (0.19 g, 12 mmol) were weighed separately and added into a 50 mL ball mill, 90 μL of methanol was added as an auxiliary solvent, the oscillation frequency was 40 Hz, and after grinding for 180 min, a red crystalline powder with good fluidity was obtained, which was the cocrystal of clozapine and maleic acid.
[0068] The single crystal X-ray diffraction (SCXRD) structure of clozapine-maleic acid cocrystal has the following parameters:
[0069]
[0070] Example 2
[0071] A clozapine-fumaric acid-methanol cocrystal having advantages in humidity stability and solubility and a preparation method thereof, wherein the specific implementation steps are as follows:
[0072] Weigh 0.20 g (6 mmol) of clozapine and 0.19 g (12 mmol) of fumaric acid respectively into a 10 mL glass bottle, add 2 mL of methanol, stir magnetically, suspend for 48 h, and remove the supernatant by centrifugation. The resulting precipitate is the clozapine and fumaric acid cocrystal powder.
[0073] The single crystal X-ray diffraction (SCXRD) structure of clozapine-fumaric acid-methanol cocrystal has the following parameters:
[0074]
Claims
1. A clozapine cocrystal having advantages in humidity stability and solubility, characterized in that: Binary cocrystal I formed by the combination of clozapine and maleic acid; The clozapine and maleic acid binary eutectic I, wherein the molar ratio of clozapine to maleic acid is 1:2; The clozapine and maleic acid binary eutectic I is a triclinic system with a space group of The unit cell parameters are: α=78.820°, β=77.430°, γ=65.234°.
2. The clozapine cocrystal having moisture stability and solubility advantages according to claim 1, characterized in that: The X-ray powder diffraction pattern of the clozapine and maleic acid cocrystal I has the following characteristic peaks represented by angles 2θ: 11.3±0.2°, 16.9±0.2°, 18.1±0.2°, 20.0±0.2°, 21.9±0.2°, and 23.8±0.2°.
3. The clozapine cocrystal having moisture stability and solubility advantages according to claim 1, characterized in that: The differential scanning calorimetry spectrum of the clozapine and maleic acid binary eutectic I showed that the melting onset temperature Tonset was 180.76±1.00°C and the peak temperature Tpeak was 181.97±1.00°C.
4. A method for preparing a clozapine cocrystal having moisture stability and solubility advantages as claimed in any one of claims 1 to 3, the method comprising the following steps: (a) weighing the powders of clozapine and the co-crystal former respectively; (b) adding the powder and auxiliary solvent in step (a) into a pulverizing device and allowing them to fully contact with each other through mechanical force, and obtaining clozapine cocrystal after all reactions.
5. The method according to claim 4, wherein: In step (a), the molar ratio of clozapine to the cocrystal former is 1:2; In step (b), the auxiliary solvent is selected from methanol, ethanol, acetonitrile, isopropanol, and water; In step (b), the pulverizing equipment is selected from a ball mill, a pulverizer and a mixer, and its oscillation frequency is 5 to 60 Hz and the oscillation time is 10 to 180 min.