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CN-121974871-A - Novel crystal form of kalirazine and preparation method thereof

CN121974871ACN 121974871 ACN121974871 ACN 121974871ACN-121974871-A

Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a novel crystal form of calicheazine, in particular to a crystal form of a calicheazine-fumaric acid-methanol-acetonitrile solvate, and a preparation method and application thereof. The novel crystal form of the calicheazine-fumaric acid provided by the invention has basic units of one molecule of the calicheazine, 1 molecule of the fumaric acid, one molecule of the methanol and one molecule of the acetonitrile, and is greatly improved in the aspects of stability, solubility and the like, and the preparation method is simple to operate, good in reproducibility and suitable for industrial production.

Inventors

  • ZHAI LIHAI
  • ZHENG JIAFANG
  • ZHANG MINGMING
  • LU LAIJU

Assignees

  • 山东新时代药业有限公司

Dates

Publication Date
20260505
Application Date
20260228

Claims (10)

  1. 1. The novel crystal form of the kallizin is characterized in that the molar ratio of the kallizin, fumaric acid, methanol and acetonitrile in the crystal unit structure is 1:1:1:1.
  2. 2. The novel crystalline form of calicheazine according to claim 1, characterized by the characteristic diffraction peaks at 5.7±0.2°, 7.9±0.2°, 12.3±0.2°, 16.6±0.2°, 20.3±0.2°, 24.7±0.2° by X-ray powder diffraction expressed by an angle of 2 θ ° using Cu-K α radiation.
  3. 3. The novel crystalline form of calicheazine according to claim 1, characterized by the fact that the X-ray powder diffraction, expressed as an angle of 2 θ , has a diffraction peak at 5.7±0.2°、7.9±0.2°、12.3±0.2°、12.8±0.2°、16.6±0.2°、16.8±0.2°、17.5±0.2°、18.4±0.2°、19.2±0.2°、19.9±0.2°、20.3±0.2°、20. 8±0.2°、21.1±0.2°、22.0±0.2°、22.7±0.2°、24.7±0.2°、25.7±0.2°、34.1±0.2°、35.5±0.2°、37.8±0.2°、40.5±0.2°、45.0±0.2° using Cu-K α radiation.
  4. 4. The novel crystalline form of calicheazine according to claim 1, wherein said crystalline form has an X-ray powder diffraction pattern as shown in figure 1.
  5. 5. The novel crystalline form of calicheazine of claim 1, wherein the crystalline form has a molecular formula of C 28 H 42 Cl 2 N 5 O 6 , a crystallographic parameter of triclinic crystal system, a space group of P-1, a unit cell parameter of a= 11.8275 (2) a, b= 11.9066 (2) a, c= 12.6811 (3) a, α= 101.272 (2) °, β= 104.565 (2) °, γ= 97.367 (2) °, and a unit cell volume of v= 1665.23 (6) a, 3 .
  6. 6. A preparation method of a novel crystal form of the kallizin as claimed in any one of claims 1 to 5 is characterized by comprising the following steps of dissolving the crystal form of the kallizin and the crystal form of the fumaric acid in a mixed solvent, heating and stirring, filtering, cooling, standing, volatilizing, crystallizing, filtering and drying to obtain the crystal form of the solvate of the kallizin and the fumaric acid.
  7. 7. The preparation method of claim 6, wherein the solvent is selected from one of methanol, acetonitrile, acetone, tetrahydrofuran, toluene, ethanol and ethyl acetate, and the volume ratio is 4.0-5.5:1.5-2.5:1.
  8. 8. The preparation method of claim 6, wherein the mass-to-volume ratio of the kali lazine to the organic solvent is 1:0.07-0.15.
  9. 9. The method according to claim 6, wherein the molar ratio of the kali lazine to the fumaric acid is 1:1.1-1.7.
  10. 10. The method according to claim 6, wherein the heating temperature is 65 to 80 ℃.

Description

Novel crystal form of kalirazine and preparation method thereof Technical Field The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a novel crystal form of kallizin, in particular to a crystal form of kallizin fumaric acid, and a preparation method and application thereof. Background Carilazine (Cariprazine, RGH 188) is an atypical antipsychotic developed by the United states forest laboratory (ForestLab) and is a partial agonist of the dopamine D2, D3 receptors. The drug was approved by the FDA in the united states for marketing, trade name Vraylar, 9 months 2015, for the treatment of adult schizophrenia and bipolar disorder. The structural formula of the calicheazine is as follows: the prior market is the kalirazine hydrochloride capsule, and the product is an oral preparation, and needs to be administered daily to maintain the blood concentration of the product, but the frequent administration is needed, so that the medication compliance of patients is poor. Chinese patent CN101679315A discloses various salts of calicheazine including monohydrochloride, dihydrochloride, monohydrobromide, maleate and mesylate salts. Chinese patent CN105218484a discloses a calicheazine tartrate salt and provides a solubility of the calicheazine tartrate salt, the calicheazine hydrochloride salt, the calicheazine maleate salt, the calicheazine besylate salt and the calicheazine phosphate salt, all greater than 3mg/mL. Patent WO2020056929a discloses a new crystalline form of the hydrochloride salt of calicheazine, among which mention is made. The salt quickly dissociates to the free base in pH 6.5 buffer. The solid-state form of the API of the prior commercially available kallizine medicine is hydrochloride, the free alkali form of the kallizine has lower solubility, and the free alkali can be used for developing pharmaceutical preparations such as long-acting injection and the like by utilizing the characteristic that the free alkali has relatively lower solubility. The invention provides a kali lazine-fumaric acid-methanol-acetonitrile solvate, which has the advantages of simplicity, high yield and convenience and is suitable for industrial production. Disclosure of Invention The invention aims at overcoming the defects of the prior art and provides a calicheazine-fumaric acid-methanol-acetonitrile solvate and a preparation method thereof, so as to solve the problems of the prior art. The present invention aims to provide a novel crystalline form of calicheazine with low hygroscopicity, namely a calicheazine-fumaric acid-methanol-acetonitrile solvate. In addition, the invention provides a method for preparing the kali-frazine-fumaric acid-methanol-acetonitrile solvate, which is simple, convenient and suitable for industrial production. The specific technical content of the invention is as follows: In one aspect, the present invention provides a solvate of calicheazine-fumaric acid-methanol-acetonitrile, characterized in that Cu-ka radiation is used, and an X-ray diffraction pattern expressed as 2 θ has characteristic peaks at least at 7.9±0.2 °, 12.3±0.2 °, 16.6±0.2 °, 20.3±0.2 °, 24.7±0.2°. Preferably, the crystal form of the calicheazine-fumaric acid uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has at least a characteristic peak at 5.7±0.2°、7.9±0.2°、12.3±0.2°、12.8±0.2°、16.6±0.2°、16.8±0.2°、17.5±0.2°、18.4±0.2°、19.2±0.2°、19.9±0.2°、20.3±0.2°、20. 8±0.2°、21.1±0.2°、22.0±0.2°、22.7±0.2°、24.7±0.2°、25.7±0.2°、34.1±0.2°、35.5±0.2°、37.8±0.2°、40.5±0.2°、45.0±0.2°. Preferably, the calicheazine-fumaric acid eutectic crystal uses Cu-K alpha radiation, and the characteristic peak accords with an X-ray powder diffraction pattern shown in figure 1. Preferably, the crystal form of the calicheazine-fumaric acid has a molecular formula of C 28H42Cl2N5O6, a crystal system of triclinic, a space group of P-1, unit cell parameters of a= 11.8275 (2) A, b= 11.9066 (2) A, c= 12.6811 (3) A, a= 101.272 (2) DEG, beta= 104.565 (2) DEG, gamma= 97.367 (2) DEG, and a unit cell volume V= 1665.23 (6) A 3. In another aspect, the present invention provides a method of preparing a crystalline form of calicheazine-fumaric acid comprising the steps of: And dissolving the crystal forms of the calicheazine and the fumaric acid in a mixed solvent, heating, stirring, filtering, cooling, standing, volatilizing, crystallizing, filtering and drying to obtain the crystal forms of the calicheazine-fumaric acid. Preferably, the solvent is selected from one of methanol, acetonitrile, acetone, tetrahydrofuran, toluene, ethanol and ethyl acetate. Particularly preferred are mixed solvents of methanol, acetonitrile and acetone in a volume ratio of 4.0-5.5:1.5-2.5:1, preferably 5:2:1. Preferably, the mass-volume ratio of the kali-prazine to the organic solvent is 1:0.07-0.15, and preferably 1.0:0.09. Preferably, the molar ratio of the kali lazine to the fumaric acid is 1:1.1-1.7, preferably 1:1.4.