CN116283804A - Clozapine eutectic with humidity stability and solubility advantages and preparation method thereof - Google Patents

Clozapine eutectic with humidity stability and solubility advantages and preparation method thereof Download PDF

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CN116283804A
CN116283804A CN202211395374.9A CN202211395374A CN116283804A CN 116283804 A CN116283804 A CN 116283804A CN 202211395374 A CN202211395374 A CN 202211395374A CN 116283804 A CN116283804 A CN 116283804A
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clozapine
eutectic
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acid
ethanol
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张春桃
李春容
王海蓉
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Wuhan University of Science and Engineering WUSE
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Abstract

The invention relates to a clozapine eutectic with humidity stability and solubility advantages and a preparation method thereof, and relates to the technical field of pharmaceutical eutectic, in particular to the clozapine eutectic which is formed by combining clozapine with a eutectic formation. The eutectic crystal forming substance comprises any one of maleic acid, oxalic acid, fumaric acid, succinic acid and citric acid, and the preferable clozapine eutectic has good humidity stability and is beneficial to long-term storage of medicines. In addition, compared with the raw medicine clozapine which is almost insoluble in water, the clozapine eutectic disclosed by the invention has the advantage that the solubility of clozapine is obviously improved by the preferred clozapine eutectic. The clozapine eutectic with the advantages of humidity stability and solubility can better realize the production of clozapine and the effectiveness of clinical application.

Description

Clozapine eutectic with humidity stability and solubility advantages and preparation method thereof
Technical Field
The invention belongs to the technical field of pharmaceutical co-crystals, and particularly relates to a clozapine co-crystal with advantages of humidity stability and solubility and a preparation method thereof.
Background
Clozapine is a well-known third-generation atypical antipsychotic drug which has a good effect on clinically treating negative and positive symptoms of schizophrenia, and is mainly used for treating schizophrenia and manic depression. Clozapine, an excellent antipsychotic with less side effects, can be administered orally and also treated by intramuscular injection. Clozapine is a first drug approved for treating refractory schizophrenia, has a certain curative effect on controlling symptoms such as agitation behavior, action behavior disturbance and the like of patients, and has a good curative effect on patients with symptoms such as hallucinations, delusions, autism, fear, withdrawal and the like.
However, clozapine is almost insoluble in water, and its low solubility and high permeability are classified as BCS (biopharmaceutical classification system) class II drugs, which have low bioavailability, severely restrict the production and use of clozapine formulations, and jeopardize the effectiveness, safety, quality reliability and consistency of clozapine drugs, etc. Therefore, the invention develops the clozapine eutectic, researches related humidity stability and solubility, and develops the clozapine eutectic with humidity stability and higher solubility.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and aims to provide a clozapine eutectic with advantages of humidity stability and solubility and a preparation method thereof.
In order to achieve the above purpose, the technical scheme adopted by the invention comprises the following specific steps:
the invention provides a clozapine eutectic with humidity stability and solubility advantages, which comprises any one of binary eutectic formed by combining clozapine with a eutectic formation, ternary eutectic formed by combining clozapine with a eutectic formation and a solvent; the eutectic formation is any one of maleic acid, oxalic acid, fumaric acid, succinic acid and citric acid; the solvent is any one of methanol, ethanol, acetonitrile and water.
Preferably, the binary eutectic I of clozapine and maleic acid, wherein the mol ratio of clozapine to maleic acid is 1:2; the X-ray powder diffraction pattern of the clozapine and maleic acid eutectic I has the following angle 2θCharacteristic 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..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 °, 30.1.+ -. 0.2 °, 31.3.+ -. 0.2 °, 34.1.+ -. 0.2 °, 34.5.+ -. 0.2 °.
Preferably, ternary eutectic II of clozapine, oxalic acid and acetonitrile is adopted, wherein the molar ratio of clozapine, oxalic acid and acetonitrile is 2:3:1; the X-ray powder diffraction spectrum of the cocrystal II of clozapine, oxalic acid and acetonitrile has the following angle 2θCharacteristic peaks represented: 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 °.
Preferably, ternary eutectic III of clozapine, oxalic acid and ethanol is prepared, wherein the mol ratio of clozapine, oxalic acid and ethanol is 2:3:1; the X-ray powder diffraction pattern of the cocrystal III of clozapine and oxalic acid and ethanol has the following structureAngle 2θCharacteristic 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 °.
Preferably, the ternary eutectic IV of clozapine, oxalic acid and ethanol is prepared, wherein the molar ratio of clozapine to oxalic acid to ethanol is 2:1:1; the X-ray powder diffraction spectrum of the cocrystal IV of clozapine and oxalic acid and ethanol has the following angle 2θCharacteristic 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 °, 31.7.+ -. 0.2 °, 32.0.+ -. 0.2 °, 33.4.+ -. 0.2.+ -. 0.2 °, 34.2.+ -. 0.2 °, 36.5.+ -. 0.37.2 °, 0.0.9.+ -. 0.2 °, 38.+ -. 0.0.2 °, 0.39.2.+ -. 0.2 °.
Preferably, the ternary eutectic V of clozapine, fumaric acid and methanol is characterized in that the mol ratio of clozapine, fumaric acid and methanol is 2:1:1; the X-ray powder diffraction spectrum of the cocrystal V of clozapine, fumaric acid and methanol has the following angle 2θCharacteristic 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 °, 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 °, 28.6.+ -. 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 °, 0.0.0.2.+ -. 0.38.+ -. 0.0.0.2 °, 0.38..0.0.2 °, 0.38.+ -. 0.0.2 °, 0.2 ° and 38 °.
Preferably, the ternary eutectic VI of the clozapine, the fumaric acid and the ethanol is formed, wherein the mol ratio of the clozapine to the fumaric acid to the ethanol is 2:1:1; the X-ray powder diffraction spectrum of the cocrystal VI of clozapine and fumaric acid and ethanol has the following angle 2θCharacteristic 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 °, 19.8.+ -. 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 °.
Preferably, ternary eutectic VII of clozapine, succinic acid and water is adopted, wherein the molar ratio of clozapine to succinic acid to water is 2:1:1; the X-ray powder diffraction spectrum of the cocrystal VII of clozapine, succinic acid and water has the following angle 2θCharacteristic peaks represented: 8.7 + -0.2 DEG, 10.9 + -0.2 DEG, 12.5 + -0.2 DEG, 13.8 + -0.2 DEG, 15.7 + -0.2 DEG, 16.4 + -0.2 DEG, 17.5 + -0.2 DEG, 17.9 + -0.2 DEG, 18.2 + -0.2 DEG, 19.6 + -0.2 DEG, 20.8 + -0.2 DEG, 21.3 + -0.2 DEG, 21.9 + -0.2 DEG, 22.5 + -0.2 DEG, 23.3 + -0.2 DEG, 23.8 + -0.2 DEG, 24.9 + -0.2 DEG, 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 °.
Preferably, the ternary eutectic VIII of clozapine, citric acid and methanol is characterized in that the mol ratio of clozapine, citric acid and methanol is 1:1:1; the X-ray powder diffraction spectrum of the chlorazepine, citric acid and methanol eutectic VIII has the following angle 2θCharacteristic 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 °.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°。
Preferably, a differential scanning calorimeter spectrum of the binary eutectic I of clozapine and maleic acid shows that the melting initial temperature Tonset is 180.76 +/-1.00 ℃ and the peak temperature Teak is 181.97 +/-1.00 ℃;
the differential scanning calorimeter thermogram of the ternary eutectic II of clozapine, oxalic acid and acetonitrile shows that the melting initial temperature Tonset is 226.97 +/-1.00 ℃ and the peak temperature Teak is 228.46 +/-1.00 ℃;
the differential scanning calorimeter thermogram of the ternary eutectic III of clozapine, oxalic acid and ethanol shows that the melting initial temperature Tonset is 227.38 +/-1.00 ℃ and the peak temperature Teak is 228.42 +/-1.00 ℃;
the differential scanning calorimeter spectrogram of the ternary eutectic IV of clozapine, oxalic acid and ethanol shows that the melting initial temperature Tonset is 147.81 +/-1.00 ℃ and the peak temperature Teak is 155.43 +/-1.00 ℃;
the differential scanning calorimeter thermogram of the ternary eutectic V of clozapine, fumaric acid and methanol shows that the melting initial temperature Tonset is 132.25+/-1.00 ℃ and the peak temperature Teak is 142.09 +/-1.00 ℃;
the differential scanning calorimeter spectrogram of the ternary eutectic VI of clozapine, fumaric acid and ethanol shows that the melting initial temperature Tonset is 133.40 +/-1.00 ℃ and the peak temperature Teak is 140.47 +/-1.00 ℃;
the differential scanning calorimetric spectrum of the ternary eutectic VII of clozapine, succinic acid and water shows that the melting initial temperature Tonset is 102.34 +/-1.00 ℃ and the peak temperature Teak is 112.78 +/-1.00 ℃;
the differential scanning calorimetric spectrum of the ternary eutectic VIII of clozapine, citric acid and methanol shows that the melting initial temperature Tonset is 173.21 +/-1.00 ℃ and the peak temperature Teak is 193.02 +/-1.00 ℃.
Preferably, the binary eutectic of clozapine and maleic acidI is triclinic system, and space group is
Figure SMS_1
The unit cell parameters are:
Figure SMS_2
Figure SMS_3
α＝78.820°，β＝77.430°，γ＝65.234°；
the ternary eutectic II of clozapine, oxalic acid and acetonitrile is a triclinic system, and the space group is
Figure SMS_4
The unit cell parameters are:
Figure SMS_5
Figure SMS_6
α＝86.480(19)°，β＝85.261(19)°，γ＝85.287(19)°；
the ternary eutectic III triclinic system of clozapine, oxalic acid and ethanol has a space group of
Figure SMS_7
The unit cell parameters are:
Figure SMS_8
Figure SMS_9
α＝89.592(3)°，β＝84.617(3)°，γ＝85.313(3)°；
the ternary eutectic IV of clozapine, oxalic acid and ethanol is a monoclinic system; the space group is P2 1 And/n, the unit cell parameters are:
Figure SMS_10
Figure SMS_11
α＝90°，β＝94.02°，γ＝90°；
the ternary eutectic V of clozapine, fumaric acid and methanol is monoclinic system, and the space group is P2 1 /c, crystalThe cell parameters are:
Figure SMS_12
α＝90°，β＝100.35(2)°，γ＝90°；
the ternary eutectic VI of clozapine, fumaric acid and ethanol is monoclinic system, and the space group is P2 1 And/n, the unit cell parameters are:
Figure SMS_13
α＝90°，β＝93.831(4)°，γ＝90°；
the ternary eutectic VII of clozapine, succinic acid and water is monoclinic system, and the space group is P2 1 And/c, the unit cell parameters are as follows:
Figure SMS_14
α＝90°，β＝103.033(4)°，γ＝90°；
the ternary eutectic VIII of clozapine, citric acid and methanol is an orthorhombic system, and the space group is P2 1 2 1 2 1 The unit cell parameters are:
Figure SMS_15
α＝90°，β＝90°，γ＝90°。
on the other hand, the invention provides a preparation method of the clozapine eutectic with the advantages of humidity stability and solubility, wherein the method is one of the following methods:
the method comprises the following steps:
the method one comprises the following steps:
(a) Separately weighing the powder of the clozapine and the eutectic formation;
(b) Adding the powder and an auxiliary solvent in the step (a) into a crushing device to fully contact the powder and the auxiliary solvent through mechanical force, and obtaining a clozapine eutectic after all the reactions;
the second method is as follows:
the second method comprises the following steps:
(c) Separately weighing the powder of the clozapine and the eutectic formation;
(d) Dissolving the powder in step (c) in a solvent to form a saturated slurry of clozapine and co-crystal formations;
(e) Filtering the solids of step (d);
(f) And (3) slowly volatilizing the saturated solution obtained in the step (e) until crystals are separated out, thus obtaining the clozapine eutectic.
And a third method:
the method III comprises the following steps:
(g) Separately weighing the powder of the clozapine and the eutectic formation;
(h) Dissolving the powder in step (g) in a solvent to form a saturated slurry of clozapine and eutectic formation powder;
(i) Fully stirring the saturated slurry obtained in the step (h);
(j) Separating the solid in step (i) to obtain the clozapine eutectic.
In a specific embodiment, in steps (a), (c) and (g), the molar ratio of clozapine to co-crystal former is
1:1 to 2:1, preferably 1:2,2:3,2:1,1:1;
in a specific embodiment, in steps (b), (d) and (h), the co-solvent/the organic solvent is selected from methanol, ethanol, acetonitrile, isopropanol, water;
in a specific embodiment, in step (b), the pulverizing device is selected from the group consisting of a ball mill, a pulverizer and a mixer, preferably the pulverizing device is a ball mill, the oscillation frequency of which is 5-60 Hz, preferably 40Hz, and the oscillation time is 10-180 min, preferably 30-180 min;
in a specific embodiment, in step (f), the volatilization is carried out at a temperature of 2 to 25 ℃, preferably at a temperature of 10 ℃;
in a specific embodiment, in step (j), the separating comprises:
(j1) Filtering to obtain clozapine eutectic;
in a specific embodiment, after step (j 1), step (j 2) is further included: evaporating to remove the solvent in the solid separated in the step (j 1), thereby obtaining the clozapine eutectic.
In yet another aspect, the present invention provides a pharmaceutical composition comprising a clozapine co-crystal as an active ingredient and an acceptable carrier; the dosage form of the pharmaceutical composition is selected from the group consisting of: liquid, solid, semisolid formulations.
In a further aspect, the present invention provides a co-crystal of clozapine as described above or a composition as described above for better use in the action of clozapine against both positive and negative symptoms of psychosis.
By adopting the technical scheme, compared with the prior art, the invention has the following beneficial effects:
(1) The invention provides a clozapine eutectic crystal with humidity stability and solubility advantages, which is used for improving the solubility of clozapine medicines. Compared with the clozapine raw material medicine, the clozapine eutectic provided by the invention has the advantages of good solubility and high humidity stability, is favorable for being used as a medicine component, improves the bioavailability, improves the clinical application effect, reduces the loss in the production and storage processes, and has higher medicine development value.
(2) The preparation method of the clozapine eutectic with the advantages of humidity stability and solubility has the advantages of simple process and good repeatability, and is suitable for industrial production.
Detailed Description
The invention is further described in connection with the following detailed description, which is not intended to limit the scope of the invention. Unless otherwise indicated, the raw materials and reagents used in the examples were all commercially available; the reagents, instruments or procedures not described herein are those routinely determinable by one of ordinary skill in the art.
Example 1
The utility model provides a clozapine-maleic acid eutectic crystal with humidity stability and solubility advantage and a preparation method thereof, which comprises the following specific implementation steps:
separately, clozapine powder (0.20 g,6 mmol) and maleic acid powder (0.19 g,12 mmol) were weighed into a 50mL ball milling tank, 90. Mu.L of methanol was added as an auxiliary solvent, the oscillation frequency was 40Hz, and after 180min milling, a red crystalline powder with good fluidity was obtained as a eutectic of clozapine and maleic acid.
Single crystal X-ray diffraction (SCXRD) structure of clozapine-maleic acid co-crystals with parameters as shown in the table below:
Figure SMS_16
example 2
The utility model provides a clozapine-fumaric acid-methanol eutectic crystal with humidity stability and solubility advantage and a preparation method thereof, which comprises the following specific implementation steps:
0.20g (6 mmol) of clozapine and 0.19g (12 mmol) of fumaric acid are weighed respectively into a 10mL glass bottle, 2mL of methanol is added, the mixture is magnetically stirred and suspended for 48 hours, the supernatant is removed by centrifugation, and the obtained precipitate is the clozapine and fumaric acid eutectic powder.
Single crystal X-ray diffraction (SCXRD) structure of clozapine-fumaric acid-methanol co-crystals with parameters as shown in the following table:
Figure SMS_17

Claims (14)

1. the clozapine eutectic with the advantages of humidity stability and solubility is characterized by comprising any one of binary eutectic formed by combining clozapine with a eutectic formation, ternary eutectic formed by combining clozapine with a eutectic formation and a solvent; the eutectic formation is any one of maleic acid, oxalic acid, fumaric acid, succinic acid and citric acid; the solvent is any one of methanol, ethanol, acetonitrile and water.
2. The clozapine co-crystal with humidity stability and solubility advantages according to claim 1, characterized in that it is a binary co-crystal 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 clozapine and maleic acid eutectic I has the following characteristic peaks expressed in terms of angle 2 theta: 11.3+ -0.2 °, 16.9+ -0.2 °, 18.1+ -0.2 °, 20.0+ -0.2 °, 21.9+ -0.2 °, 23.8+ -0.2 °;
preferably, the characteristic peaks expressed in terms of angle 2θ are as follows: 11.3+ -0.2 °, 14.0+ -0.2 °, 16.9+ -0.2 °, 18.1+ -0.2 °, 20.0+ -0.2 °, 20.6+ -0.2 °, 21.9+ -0.2 °, 22.7+ -0.2 °, 23.8+ -0.2 °, 28.2+ -0.2 °;
more preferably, the characteristic peak expressed in terms of angle 2θ is as follows: 5.6+ -0.2 °, 10.7+ -0.2 °, 11.3+ -0.2 °, 12.9+ -0.2 °, 14.0+ -0.2 °, 16.9+ -0.2 °, 18.1+ -0.2 °, 20.0+ -0.2 °, 20.6+ -0.2 °, 21.9+ -0.2 °, 22.7+ -0.2 °, 23.8+ -0.2 °, 28.2+ -0.2 °, 30.1+ -0.2 °, 34.1+ -0.2 °;
most preferably, the said characteristic peaks expressed in terms of angle 2 theta are as follows: 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..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 °, 30.1.+ -. 0.2 °, 31.3.+ -. 0.2 °, 34.1.+ -. 0.2 °, 34.5.+ -. 0.2 °.
3. The clozapine co-crystal with advantages of humidity stability and solubility according to claim 1, characterized in that it is ternary co-crystal II with oxalic acid, acetonitrile, wherein the molar ratio of clozapine, oxalic acid, acetonitrile is 2:3:1; the X-ray powder diffraction spectrum of the cocrystal II of clozapine, oxalic acid and acetonitrile has the following characteristic peaks expressed in terms of angle 2 theta: 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 °.
4. The clozapine co-crystal with advantages of humidity stability and solubility according to claim 1, characterized in that it is ternary co-crystal III with oxalic acid, ethanol, wherein the molar ratio of clozapine, oxalic acid, ethanol is 2:3:1; the X-ray powder diffraction spectrum of the cocrystal III of clozapine, oxalic acid and ethanol has the following characteristic peaks expressed in terms of angle 2 theta: 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 °;
the ternary eutectic IV of clozapine, oxalic acid and ethanol is characterized in that the molar ratio of clozapine to oxalic acid to ethanol is 2:1:1; the X-ray powder diffraction spectrum of the cocrystal IV of clozapine, oxalic acid and ethanol has the following characteristic peaks expressed in terms of angle 2 theta: 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 °, 31.7.+ -. 0.2 °, 32.0.+ -. 0.2 °, 33.4.+ -. 0.2.+ -. 0.2 °, 34.2.+ -. 0.2 °, 36.5.+ -. 0.37.2 °, 0.0.9.+ -. 0.2 °, 38.+ -. 0.0.2 °, 0.39.2.+ -. 0.2 °.
5. The clozapine co-crystal with humidity stability and solubility advantages according to claim 1, characterized in that the ternary co-crystal V of clozapine with fumaric acid, methanol, wherein the molar ratio of clozapine, fumaric acid, methanol is 2:1:1; the X-ray powder diffraction spectrum of the cocrystal V of clozapine, fumaric acid and methanol has the following characteristic peaks expressed in terms of angle 2 theta: 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 °, 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 °, 28.6.+ -. 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 °, 0.0.0.2.+ -. 0.38.+ -. 0.0.0.2 °, 0.38..0.0.2 °, 0.38.+ -. 0.0.2 °, 0.2 ° and 38 °.
6. The clozapine co-crystal with humidity stability and solubility advantages according to claim 1, characterized in that the ternary co-crystal VI of clozapine with fumaric acid, ethanol, wherein the molar ratio of clozapine, fumaric acid, ethanol is 2:1:1; the X-ray powder diffraction spectrum of the cocrystal VI of clozapine, fumaric acid and ethanol has the following characteristic peaks expressed in terms of angle 2 theta: 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 °, 19.8.+ -. 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 °.
7. The clozapine co-crystal with advantages of humidity stability and solubility according to claim 1, characterized in that it is ternary co-crystal VII with succinic acid, water, wherein the molar ratio of clozapine, succinic acid, water is 2:1:1; the X-ray powder diffraction spectrum of the cocrystal VII of clozapine, succinic acid and water has the following characteristic peaks expressed in terms of angle 2 theta: 8.7 + -0.2 DEG, 10.9 + -0.2 DEG, 12.5 + -0.2 DEG, 13.8 + -0.2 DEG, 15.7 + -0.2 DEG, 16.4 + -0.2 DEG, 17.5 + -0.2 DEG, 17.9 + -0.2 DEG, 18.2 + -0.2 DEG, 19.6 + -0.2 DEG, 20.8 + -0.2 DEG, 21.3 + -0.2 DEG, 21.9 + -0.2 DEG, 22.5 + -0.2 DEG, 23.3 + -0.2 DEG, 23.8 + -0.2 DEG, 24.9 + -0.2 DEG, 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 °.
8. The clozapine co-crystal with humidity stability and solubility advantages according to claim 1, characterized in that the ternary co-crystal VIII of clozapine, citric acid, methanol, wherein the molar ratio of clozapine, citric acid, methanol is 1:1:1; the X-ray powder diffraction spectrum of the co-crystal VIII of clozapine, citric acid and methanol has the following characteristic peaks expressed in terms of angle 2 theta: 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 °, 27.3+ -0.2 °, 28.8+ -0.2 °, 29.3+ -0.2 °, 29.2.2:4+ -0.2 °, 0.2.2+ -0.3+ -0.2 °, 35.2:3+ -0.2 °, 35.3+ -0.2 °, 0.2.3+ -0.2 °, 35.3+ -0.2 °, and 35.3+ -0.2 °, 0.3+ -0.2 °, 35.3+ -0.2 °, and 35.3+ -0.2 °.
9. The clozapine co-crystal with humidity stability and solubility advantages according to claim 1, characterized in that the differential scanning calorimeter of clozapine and maleic acid binary co-crystal I shows a melting onset temperature Tonset of 180.76 ±1.00 ℃ and a peak temperature Tpeak of 181.97 ±1.00 ℃;
the differential scanning calorimeter thermogram of the ternary eutectic II of clozapine, oxalic acid and acetonitrile shows that the melting initial temperature Tonset is 226.97 +/-1.00 ℃ and the peak temperature Teak is 228.46 +/-1.00 ℃;
the differential scanning calorimeter thermogram of the ternary eutectic III of clozapine, oxalic acid and ethanol shows that the melting initial temperature Tonset is 227.38 +/-1.00 ℃ and the peak temperature Teak is 228.42 +/-1.00 ℃;
the differential scanning calorimeter spectrogram of the ternary eutectic IV of clozapine, oxalic acid and ethanol shows that the melting initial temperature Tonset is 147.81 +/-1.00 ℃ and the peak temperature Teak is 155.43 +/-1.00 ℃;
the differential scanning calorimeter thermogram of the ternary eutectic V of clozapine, fumaric acid and methanol shows that the melting initial temperature Tonset is 132.25+/-1.00 ℃ and the peak temperature Teak is 142.09 +/-1.00 ℃;
the differential scanning calorimeter spectrogram of the ternary eutectic VI of clozapine, fumaric acid and ethanol shows that the melting initial temperature Tonset is 133.40 +/-1.00 ℃ and the peak temperature Teak is 140.47 +/-1.00 ℃;
the differential scanning calorimetric spectrum of the ternary eutectic VII of clozapine, succinic acid and water shows that the melting initial temperature Tonset is 102.34 +/-1.00 ℃ and the peak temperature Teak is 112.78 +/-1.00 ℃;
the differential scanning calorimetric spectrum of the ternary eutectic VIII of clozapine, citric acid and methanol shows that the melting initial temperature Tonset is 173.21 +/-1.00 ℃ and the peak temperature Teak is 193.02 +/-1.00 ℃.
10. The clozapine co-crystal with humidity stability and solubility advantages according to claim 1, wherein the binary co-crystal I of clozapine and maleic acid is triclinic system, and the space group is
Figure QLYQS_1
The unit cell parameters are:
Figure QLYQS_2
Figure QLYQS_3
α＝78.820°，β＝77.430°，γ＝65.234°；
the ternary eutectic II of clozapine, oxalic acid and acetonitrile is a triclinic system, and the space group is
Figure QLYQS_4
The unit cell parameters are: />
Figure QLYQS_5
Figure QLYQS_6
α＝86.480(19)°，β＝85.261(19)°，γ＝85.287(19)°；
The ternary eutectic III triclinic system of clozapine, oxalic acid and ethanol has a space group of
Figure QLYQS_7
The unit cell parameters are:
Figure QLYQS_8
Figure QLYQS_9
α＝89.592(3)°，β＝84.617(3)°，γ＝85.313(3)°；
the ternary eutectic IV of clozapine, oxalic acid and ethanol is a monoclinic system; the space group is P2 1 And/n, the unit cell parameters are:
Figure QLYQS_10
Figure QLYQS_11
α＝90°，β＝94.02°，γ＝90°；
the ternary eutectic V of clozapine, fumaric acid and methanol is monoclinic system, and the space group is P2 1 And/c, the unit cell parameters are as follows:
Figure QLYQS_12
α＝90°，β＝100.35(2)°，γ＝90°；
the ternary eutectic VI of clozapine, fumaric acid and ethanol is monoclinic system, and the space group is P2 1 And/n, the unit cell parameters are:
Figure QLYQS_13
α＝90°，β＝93.831(4)°，γ＝90°；
the ternary eutectic VII of clozapine, succinic acid and water is monoclinic system, and the space group is P2 1 And/c, the unit cell parameters are as follows:
Figure QLYQS_14
α＝90°，β＝103.033(4)°，γ＝90°；
the ternary eutectic VIII of clozapine, citric acid and methanol is an orthorhombic system, and the space group is P2 1 2 1 2 1 The unit cell parameters are:
Figure QLYQS_15
α＝90°，β＝90°，γ＝90°。
11. a process for the preparation of clozapine co-crystals having advantages of humidity stability and solubility according to any one of claims 1 to 10, said process being one of the following:
the method comprises the following steps:
the method one comprises the following steps:
(a) Separately weighing the powder of the clozapine and the eutectic formation;
(b) Adding the powder in the step (a) and an auxiliary solvent into a crushing device to fully contact the powder by mechanical force, and after all the reactions,
obtaining clozapine eutectic;
the second method is as follows:
the second method comprises the following steps:
(c) Separately weighing the powder of the clozapine and the eutectic formation;
(d) Dissolving the powder in step (c) in a solvent to form a saturated slurry of clozapine and co-crystal formations;
(e) Filtering the solids of step (d);
(f) And (3) slowly volatilizing the saturated solution obtained in the step (e) until crystals are separated out, thus obtaining the clozapine eutectic.
And a third method:
the method III comprises the following steps:
(g) Separately weighing the powder of the clozapine and the eutectic formation;
(h) Dissolving the powder in step (g) in a solvent to form a saturated slurry of clozapine and eutectic formation powder; (i) thoroughly stirring the saturated slurry obtained in the step (h);
(j) Separating the solid in step (i) to obtain the clozapine eutectic.
12. The method of claim 11, wherein,
in steps (a), (c) and (g), the molar ratio of clozapine to co-crystal former is from 1:1 to 2:1, preferably 1:2,2:3,2:1,1:1;
optionally, in steps (b), (d) and (h), the co-solvent/the organic solvent is selected from methanol, ethanol, acetonitrile, isopropanol, water;
optionally, in step (b), the comminution apparatus is selected from the group consisting of a ball mill, a pulverizer and a mixer, preferably the comminution apparatus is a ball mill, the oscillation frequency of which is 5 to 60Hz, preferably 40Hz, the oscillation time is 10 to 180min, preferably 30 to 180min;
optionally, in step (f), volatilizing is carried out at a temperature of from 2 to 25 ℃, preferably at a temperature of 10 ℃;
optionally, in step (j), the separating comprises:
(j1) Filtering to obtain clozapine eutectic;
optionally, after step (j 1), further comprising step (j 2): evaporating to remove the solvent in the solid separated in the step (j 1), thereby obtaining the clozapine eutectic.
13. A pharmaceutical composition comprising a clozapine co-crystal as active ingredient and an acceptable carrier; the dosage form of the pharmaceutical composition is selected from the group consisting of: liquid, solid, semisolid formulations.
14. A clozapine co-crystal according to any one of claims 1 to 10 or a composition according to claim 13 for better use in the action of clozapine against both positive and negative symptoms of psychosis.
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