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CN112500344B - Crystalline form of roxasistat and preparation method thereof - Google Patents

Crystalline form of roxasistat and preparation method thereof Download PDF

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CN112500344B
CN112500344B CN202011298865.2A CN202011298865A CN112500344B CN 112500344 B CN112500344 B CN 112500344B CN 202011298865 A CN202011298865 A CN 202011298865A CN 112500344 B CN112500344 B CN 112500344B
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crystalline form
rosxastat
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roxasistat
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CN112500344A (en
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连小刚
李响
周炳城
魏娜
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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Abstract

The invention discloses a crystal form of roxasistat, a preparation method thereof, a pharmaceutical composition thereof and application of the crystal form in treatment of diseases such as chronic renal anemia and the like. The structure of the rasagiline is as follows:
Figure DDA0002786234720000011

Description

Crystalline form of roxasistat and preparation method thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a crystal form of roxasistat, and a preparation method and application thereof.
Background
Rasagilat, named Roxadustat english, chinese: trade name:
Figure BDA0002786234700000012
the chemical name is [ (4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl) -amino ]]-acetic acid, of formula (1):
Figure BDA0002786234700000011
the rosxastat is the first global oral hypoxia inducible factor prolyl hydroxylase inhibitor developed by FibroGen company and Aslicon, the medicine is firstly clinically researched in China in the world and is first listed in China in 2018 and 12 months, and is used for treating anemia of Chronic Kidney Disease (CKD) dialysis patients, including hemodialysis and peritoneal dialysis patients, and a second clinical indication research, namely non-dialyzed chronic renal (NDD-CKD) anemia, is carried out in China in 2019 and 8 months. The medicine has four characteristics: firstly, the curative effect is not influenced by inflammation, a plurality of inflammatory reactions exist in the body in the chronic kidney disease period, especially the uremia period, and the rosxastat is still effective under the inflammatory condition; secondly, the intravenous supplement of iron is not needed; thirdly, the oral dosage form is not affected by diet, so that the treatment compliance is greatly improved; fourth, the safety is good, and no serious drug-related adverse events have been found so far.
There are many crystalline forms of roxasistat. Patent CN109369524A discloses four crystal forms of rasagile, namely Form A, Form B, Form C and Form D, wherein Form A is a pure crystal Form, Form B is a hydrate crystal Form and can be spontaneously converted into Form A, Form C is a solvate containing hexafluoropropan-2-ol, and Form D is a solvate containing DMSO and water; WO2013013069 discloses seven crystal forms of roxasistat, namely Form I, Form II, Form III, Form IV, Form V, Form VI and Form VII, wherein most of the crystal forms are solvates and are not suitable for being developed as drug crystal forms; patent CN109369525A discloses 12 crystal forms of rasagiline, which ARE crystal form ARE, ARE-B, ARE-C, ARE-D, ARE-E, ARE-F, ARE-G, ARE-H, ARE-I, ARE-J, ARE-K and ARE-L, which ARE solvate crystal forms and metastable crystal forms, have poor stability, cannot be developed as drug crystal forms and cannot be industrially produced. Therefore, among the many crystal forms of the roxasistat, the crystal form A is the most thermodynamically stable crystal form and is suitable for being developed as a medicine crystal form, but the crystal form A has the big defect that the crystal form A is poor in solubility and almost insoluble in water, so that the solubility in a human body is low, the absorption is influenced, and the medicine effect is difficult to exert.
Disclosure of Invention
Aiming at the defect of poor solubility of the crystal form A, the invention aims to provide a new crystal form of the roxasistat suitable for drug development and a preparation method thereof.
The crystalline form of the roxasistat prepared by the invention has the advantages of simple preparation method, good reproducibility, high crystalline form purity and good crystalline form stability, particularly the solubility of the crystalline form is far greater than that of the crystalline form A, so that the great obstruction of the compound in the aspect of drug development is overcome, and the crystalline form is very suitable for pharmaceutical development.
In one aspect, the invention provides crystalline form D of rosmarinic acid, wherein the crystalline form D has an X-ray powder diffraction pattern with a diffraction peak at 5.0 ± 0.2 ° 2 Θ; or a diffraction peak at 11.3 ± 0.2 °; or a diffraction peak at 20.1 ± 0.2 °; or a diffraction peak at 22.7 ± 0.2 °; or a diffraction peak at 14.8 ± 0.2 °; or a diffraction peak at 18.4 ± 0.2 °; or a diffraction peak at 27.4 ± 0.2 °; or a diffraction peak at 32.0 ± 0.2 °; preferably, any 2 to 5, or 3 to 6, or 3 to 8, and more preferably any 4, 6, or 8 of the diffraction peaks are included.
In a preferred embodiment of the invention, the form D has an X-ray powder diffraction pattern having diffraction peaks, preferably two of them, more preferably three of them, at one or more positions in 2 Θ of 5.0 ± 0.2 °, 11.3 ± 0.2 ° or 20.1 ± 0.2 °; optionally, further comprising at least one of 14.8 ± 0.2 °, 18.4 ± 0.2 °, 22.7 ± 0.2 °, 27.4 ± 0.2 ° or 32.0 ± 0.2 °, preferably 2, 3, 4 or 5 thereof; for example, the form D has an X-ray powder diffraction pattern with diffraction peaks at the following positions 2 θ:
5.0±0.2°、11.3±0.2°；
5.0±0.2°、11.3±0.2°、20.1±0.2°；
5.0±0.2°、11.3±0.2°、14.8±0.2°；
5.0±0.2°、11.3±0.2°、14.8±0.2°、20.1±0.2°；
5.0±0.2°、11.3±0.2°、18.4±0.2°、20.1±0.2°；
5.0±0.2°、11.3±0.2°、20.1±0.2°、22.7±0.2°；
5.0±0.2°、11.3±0.2°、20.1±0.2°、27.4±0.2°；
5.0±0.2°、11.3±0.2°、20.1±0.2°、32.0±0.2°；
5.0±0.2°、11.3±0.2°、14.8±0.2°、18.4±0.2°、20.1±0.2°；
5.0±0.2°、11.3±0.2°、14.8±0.2°、20.1±0.2°、22.7±0.2°；
5.0±0.2°、11.3±0.2°、14.8±0.2°、20.1±0.2°、27.4±0.2°；
5.0±0.2°、11.3±0.2°、14.8±0.2°、20.1±0.2°、32.0±0.2°；
5.0±0.2°、11.3±0.2°、18.4±0.2°、20.1±0.2°、22.7±0.2°；
5.0±0.2°、11.3±0.2°、18.4±0.2°、20.1±0.2°、27.4±0.2°；
5.0±0.2°、11.3±0.2°、18.4±0.2°、20.1±0.2°、32.0±0.2°；
5.0±0.2°、11.3±0.2°、20.1±0.2°、22.7±0.2°、27.4±0.2°；
5.0±0.2°、11.3±0.2°、20.1±0.2°、22.7±0.2°、32.0±0.2°；
5.0±0.2°、11.3±0.2°、20.1±0.2°、27.4±0.2°、32.0±0.2°；
5.0±0.2°、11.3±0.2°、14.8±0.2°、18.4±0.2°、20.1±0.2°、22.7±0.2°；
5.0±0.2°、11.3±0.2°、14.8±0.2°、18.4±0.2°、20.1±0.2°、27.4±0.2°；
5.0±0.2°、11.3±0.2°、14.8±0.2°、18.4±0.2°、20.1±0.2°、32.0±0.2°；
5.0±0.2°、11.3±0.2°、14.8±0.2°、18.4±0.2°、20.1±0.2°、22.7±0.2°、27.4±0.2°；
5.0±0.2°、11.3±0.2°、14.8±0.2°、18.4±0.2°、20.1±0.2°、22.7±0.2°、32.0±0.2°；
5.0±0.2°、11.3±0.2°、14.8±0.2°、18.4±0.2°、20.1±0.2°、22.7±0.2°、27.4±0.2°、32.0±0.2°。
preferably, the form D optionally further comprises one or more diffraction peaks at 12.5 ± 0.2 °, 17.4 ± 0.2 °, 20.9 ± 0.2 °, 23.4 ± 0.2 °, 31.0 ± 0.2 °, 33.8 ± 0.2 ° or 37.0 ± 0.2 ° 2 Θ; preferably at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, 7 thereof; for example
12.5±0.2°、17.4±0.2°；
12.5±0.2°、20.9±0.2°；
12.5±0.2°、23.4±0.2°；
12.5±0.2°、31.0±0.2°；
12.5±0.2°、33.8±0.2°；
12.5±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°；
12.5±0.2°、17.4±0.2°、23.4±0.2°；
12.5±0.2°、17.4±0.2°、31.0±0.2°；
12.5±0.2°、17.4±0.2°、33.8±0.2°；
12.5±0.2°、17.4±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、23.4±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、31.0±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、33.8±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、23.4±0.2°、31.0±0.2°；
12.5±0.2°、17.4±0.2°、23.4±0.2°、33.8±0.2°；
12.5±0.2°、17.4±0.2°、23.4±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、31.0±0.2°、33.8±0.2°；
12.5±0.2°、17.4±0.2°、31.0±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、33.8±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、23.4±0.2°、31.0±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、23.4±0.2°、33.8±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、23.4±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、31.0±0.2°、33.8±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、31.0±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、33.8±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、23.4±0.2°、31.0±0.2°、33.8±0.2°；
12.5±0.2°、17.4±0.2°、23.4±0.2°、31.0±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、23.4±0.2°、33.8±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、31.0±0.2°、33.8±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、23.4±0.2°、31.0±0.2°、33.8±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、23.4±0.2°、31.0±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、23.4±0.2°、33.8±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、31.0±0.2°、33.8±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、23.4±0.2°、31.0±0.2°、33.8±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、23.4±0.2°、31.0±0.2°、33.8±0.2°、37.0±0.2°。
Still more preferably, the X-ray powder diffraction pattern is substantially as shown in figure 1, or the TGA pattern is substantially as shown in figure 2.
In a further preferred embodiment of the invention, form D is a pure form, the crystal lattice being free of organic solvents.
The invention provides a crystalline form E of roxasistat, wherein an X-ray powder diffraction pattern of the crystalline form E has a diffraction peak at a 2 theta of 3.2 +/-0.2 degrees; or a diffraction peak at 6.3 ± 0.2 °; or a diffraction peak at 9.4 ± 0.2 °; or a diffraction peak at 12.6 ± 0.2 °; or a diffraction peak at 2 theta + -0.2 DEG; or a diffraction peak at 9.8 ± 0.2; or a diffraction peak at 11.7 ± 0.2; or a diffraction peak at 15.8 + -0.2; or a characteristic peak at 22.2 ± 0.2; preferably, any 2 to 5, or 3 to 6, or 3 to 8, and more preferably any 4, 6, or 8, of the diffraction peaks are included.
In a preferred embodiment of the invention, the form E has an X-ray powder diffraction pattern having diffraction peaks, preferably two of them, more preferably three of them, at one or more of 3.2 ± 0.2 °, 6.3 ± 0.2 ° or 9.4 ± 0.2 ° 2 Θ; optionally, further comprising at least one of 9.8 ± 0.2 °, 11.7 ± 0.2 °, 12.6 ± 0.2 °, 15.8 ± 0.2 ° or 22.2 ± 0.2 °, preferably 2, 3, 4 or 5 thereof; for example, the form E has an X-ray powder diffraction pattern with diffraction peaks at the following positions 2 θ:
3.2±0.2°、6.3±0.2°；
3.2±0.2°、9.4±0.2°；
6.3±0.2°、9.4±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°；
3.2±0.2°、6.3±0.2°、9.8±0.2°；
3.2±0.2°、6.3±0.2°、11.7±0.2；
3.2±0.2°、6.3±0.2°、12.6±0.2°；
3.2±0.2°、6.3±0.2°、15.8±0.2°；
3.2±0.2°、6.3±0.2°、22.2±0.2°；
3.2±0.2°、9.4±0.2°、9.8±0.2；
3.2±0.2°、9.4±0.2°、11.7±0.2；
3.2±0.2°、9.4±0.2°、12.6±0.2°；
3.2±0.2°、9.4±0.2°、15.8±0.2°；
3.2±0.2°、9.4±0.2°、22.2±0.2°；
6.3±0.2°、9.4±0.2°、9.8±0.2°；
6.3±0.2°、9.4±0.2°、11.7±0.2°；
6.3±0.2°、9.4±0.2°、12.6±0.2°；
6.3±0.2°、9.4±0.2°、15.8±0.2°；
6.3±0.2°、9.4±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、9.8±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、11.7±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、12.6±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、15.8±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、9.8±0.2°、11.7±0.2°；
3.2±0.2°、6.3±0.2°、9.8±0.2°、12.6±0.2°；
3.2±0.2°、6.3±0.2°、9.8±0.2°、15.8±0.2°；
3.2±0.2°、6.3±0.2°、9.8±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、11.7±0.2°、12.6±0.2°；
3.2±0.2°、6.3±0.2°、11.7±0.2°、15.8±0.2°；
3.2±0.2°、6.3±0.2°、11.7±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、12.6±0.2°、15.8±0.2°；
3.2±0.2°、6.3±0.2°、12.6±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、15.8±0.2°、22.2±0.2°；
3.2±0.2°、9.4±0.2°、9.8±0.2°、11.7±0.2°；
3.2±0.2°、9.4±0.2°、9.8±0.2°、12.6±0.2°；
3.2±0.2°、9.4±0.2°、9.8±0.2°、15.8±0.2°；
3.2±0.2°、9.4±0.2°、9.8±0.2°、22.2±0.2°；
3.2±0.2°、9.4±0.2°、11.7±0.2、12.6±0.2°；
3.2±0.2°、9.4±0.2°、11.7±0.2°、15.8±0.2°；
3.2±0.2°、9.4±0.2°、11.7±0.2°、22.2±0.2°；
3.2±0.2°、9.4±0.2°、12.6±0.2°、15.8±0.2°；
3.2±0.2°、9.4±0.2°、12.6±0.2°、22.2±0.2°；
3.2±0.2°、9.4±0.2°、15.8±0.2°、22.2±0.2°；
6.3±0.2°、9.4±0.2°、9.8±0.2°、11.7±0.2°；
6.3±0.2°、9.4±0.2°、9.8±0.2°、12.6±0.2°；
6.3±0.2°、9.4±0.2°、9.8±0.2、15.8±0.2°；
6.3±0.2°、9.4±0.2°、9.8±0.2°、22.2±0.2°；
6.3±0.2°、9.4±0.2°、11.7±0.2°、12.6±0.2°；
6.3±0.2°、9.4±0.2°、11.7±0.2°、15.8±0.2°；
6.3±0.2°、9.4±0.2°、11.7±0.2°、22.2±0.2°；
6.3±0.2°、9.4±0.2°、12.6±0.2°、15.8±0.2°；
6.3±0.2°、9.4±0.2°、12.6±0.2°、22.2±0.2°；
6.3±0.2°、9.4±0.2°、15.8±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、9.8±0.2°、11.7±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、9.8±0.2°、12.6±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、9.8±0.2°、15.8±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、9.8±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、11.7±0.2°、12.6±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、11.7±0.2°、15.8±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、11.7±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、12.6±0.2°、15.8±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、12.6±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、15.8±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、9.8±0.2°、11.7±0.2°、12.6±0.2°；
3.2±0.2°、6.3±0.2°、9.8±0.2°、11.7±0.2°、15.8±0.2°；
3.2±0.2°、6.3±0.2°、9.8±0.2°、11.7±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、9.8±0.2°、12.6±0.2°、15.8±0.2°；
3.2±0.2°、6.3±0.2°、9.8±0.2°、12.6±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、9.8±0.2°、15.8±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、11.7±0.2°、12.6±0.2°、15.8±0.2°；
3.2±0.2°、6.3±0.2°、11.7±0.2°、12.6±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、11.7±0.2°、15.8±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、12.6±0.2°、15.8±0.2°、22.2±0.2°；
3.2±0.2°、9.4±0.2°、9.8±0.2°、11.7±0.2°、12.6±0.2°；
3.2±0.2°、9.4±0.2°、9.8±0.2°、11.7±0.2°、15.8±0.2°；
3.2±0.2°、9.4±0.2°、9.8±0.2°、11.7±0.2°、22.2±0.2°；
3.2±0.2°、9.4±0.2°、9.8±0.2°、12.6±0.2°、15.8±0.2°；
3.2±0.2°、9.4±0.2°、9.8±0.2°、12.6±0.2°、22.2±0.2°；
3.2±0.2°、9.4±0.2°、9.8±0.2°、15.8±0.2°、22.2±0.2°；
3.2±0.2°、9.4±0.2°、11.7±0.2、12.6±0.2°、15.8±0.2°；
3.2±0.2°、9.4±0.2°、11.7±0.2、12.6±0.2°、22.2±0.2°；
3.2±0.2°、9.4±0.2°、11.7±0.2°、15.8±0.2°、22.2±0.2°；
3.2±0.2°、9.4±0.2°、12.6±0.2°、15.8±0.2°、22.2±0.2°；
6.3±0.2°、9.4±0.2°、9.8±0.2°、11.7±0.2°、12.6±0.2°；
6.3±0.2°、9.4±0.2°、9.8±0.2°、11.7±0.2°、15.8±0.2°；
6.3±0.2°、9.4±0.2°、9.8±0.2°、11.7±0.2°、22.2±0.2°；
6.3±0.2°、9.4±0.2°、9.8±0.2°、12.6±0.2°、15.8±0.2°；
6.3±0.2°、9.4±0.2°、9.8±0.2°、12.6±0.2°、22.2±0.2°；
6.3±0.2°、9.4±0.2°、9.8±0.2、15.8±0.2°、22.2±0.2°；
6.3±0.2°、9.4±0.2°、11.7±0.2°、12.6±0.2°、15.8±0.2°；
6.3±0.2°、9.4±0.2°、11.7±0.2°、12.6±0.2°、22.2±0.2°；
6.3±0.2°、9.4±0.2°、11.7±0.2°、15.8±0.2°、22.2±0.2°；
6.3±0.2°、9.4±0.2°、12.6±0.2°、15.8±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、9.8±0.2°、11.7±0.2°、12.6±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、9.8±0.2°、11.7±0.2°、15.8±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、9.8±0.2°、11.7±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、9.8±0.2°、12.6±0.2°、15.8±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、9.8±0.2°、12.6±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、9.8±0.2°、15.8±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、11.7±0.2°、12.6±0.2°、15.8±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、11.7±0.2°、12.6±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、11.7±0.2°、15.8±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、12.6±0.2°、15.8±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、9.8±0.2°、11.7±0.2°、12.6±0.2°、15.8±0.2°；
3.2±0.2°、6.3±0.2°、9.8±0.2°、11.7±0.2°、12.6±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、9.8±0.2°、11.7±0.2°、15.8±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、9.8±0.2°、12.6±0.2°、15.8±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、11.7±0.2°、12.6±0.2°、15.8±0.2°、22.2±0.2°；
3.2±0.2°、9.4±0.2°、9.8±0.2°、11.7±0.2°、12.6±0.2°、15.8±0.2°；
3.2±0.2°、9.4±0.2°、9.8±0.2°、11.7±0.2°、12.6±0.2°、22.2±0.2°；
3.2±0.2°、9.4±0.2°、9.8±0.2°、11.7±0.2°、15.8±0.2°、22.2±0.2°；
3.2±0.2°、9.4±0.2°、9.8±0.2°、12.6±0.2°、15.8±0.2°、22.2±0.2°；
3.2±0.2°、9.4±0.2°、11.7±0.2、12.6±0.2°、15.8±0.2°、22.2±0.2°；
6.3±0.2°、9.4±0.2°、9.8±0.2°、11.7±0.2°、12.6±0.2°、15.8±0.2°；
6.3±0.2°、9.4±0.2°、9.8±0.2°、11.7±0.2°、12.6±0.2°、22.2±0.2°；
6.3±0.2°、9.4±0.2°、9.8±0.2°、11.7±0.2°、15.8±0.2°、22.2±0.2°；
6.3±0.2°、9.4±0.2°、9.8±0.2°、12.6±0.2°、15.8±0.2°、22.2±0.2°；
6.3±0.2°、9.4±0.2°、11.7±0.2°、12.6±0.2°、15.8±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、9.8±0.2°、11.7±0.2°、12.6±0.2°、15.8±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、9.8±0.2°、11.7±0.2°、12.6±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、9.8±0.2°、11.7±0.2°、15.8±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、9.8±0.2°、12.6±0.2°、15.8±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、11.7±0.2°、12.6±0.2°、15.8±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、9.8±0.2°、11.7±0.2°、12.6±0.2°、15.8±0.2°、22.2±0.2°；
3.2±0.2°、9.4±0.2°、9.8±0.2°、11.7±0.2°、12.6±0.2°、15.8±0.2°、22.2±0.2°；
6.3±0.2°、9.4±0.2°、9.8±0.2°、11.7±0.2°、12.6±0.2°、15.8±0.2°、22.2±0.2°；
3.2±0.2°、6.3±0.2°、9.4±0.2°、9.8±0.2°、11.7±0.2°、12.6±0.2°、15.8±0.2°、22.2±0.2°。
still more preferably, the X-ray powder diffraction pattern is substantially as shown in figure 3.
On the other hand, the invention provides a preparation method of the crystalline form of the roxasistat, which comprises the following steps:
1) adding any form of the roxasistat into a mixed solvent of a first solvent consisting of water and one or more organic solvents, heating and forming a solution or slurry;
2) cooling the solution in step 1);
3) optionally, adding a second type of organic solvent consisting of one or a mixture of more than one solvent to step 2);
4) optionally, adding seed crystals to the solution in step 3);
5) and continuously stirring to obtain the crystal form.
In a preferred embodiment of the present invention, the organic solvent in step 1) is selected from one or more of ketone, alcohol, ether, acid or nitrile solvents; preferably one or more of acetone, 2-butanone, acetonitrile, tetrahydrofuran, 1, 4-dioxane, methanol, ethanol, isopropanol, formic acid, acetic acid, or propionic acid; more preferably one or more of acetone, methanol, ethanol, formic acid or acetic acid.
In a further preferred embodiment of the present invention, the content of the water in the mixed solvent in the step 1) is in the range of 1% to 90%, preferably 10% to 50%, more preferably 10% to 30%.
In a further preferred embodiment of the present invention, the second type of organic solvent in step 3) is selected from one or more of ketone, alcohol, nitrile or ether solvents; preferably one or more of acetone, 2-butanone, methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, 1, 4-dioxane or methyl ether; more preferably methanol, ethanol or isopropanol.
In a further preferred embodiment of the invention, the amount of seed crystals in step 4) is 0.1% to 10%, preferably 0.5% to 5%, most preferably 1% to 3% of the charge.
In a further preferred embodiment of the present invention, the stirring time described in step 5) is 0.5 to 7 days, preferably 0.5 to 4 days.
The invention provides a preparation method of crystal seeds of a crystalline form D of mosesatat, which comprises the steps of mixing 1g of a mosesatat sample with 10ml of a solvent mixed according to the volume ratio of acetone to water of 3:1, heating to 55 ℃ under the condition of magnetic stirring until the sample is completely dissolved, rapidly cooling to 5 ℃ at the speed of 20 ℃/h, carrying out heat preservation stirring for 6h, filtering to obtain a crystalline form, and heating and dehydrating in the solvent to obtain the crystal seeds of the crystalline form D. Solvents used include, but are not limited to, heptane, octane, toluene, xylene, anisole, and the like.
In another aspect, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable carrier, diluent or excipient of crystalline form of rosxastat. The pharmaceutically acceptable carrier refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. Wherein compatibility herein means that the components of the composition are capable of intermixing with and between the active ingredients of the present invention without significantly diminishing the efficacy of the active ingredient; pharmaceutically acceptable carriers include cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate and the like, solid lubricants such as stearic acid, magnesium stearate and the like, vegetable oils such as soybean oil, castor oil, peanut oil, olive oil and the like, polyols such as propylene glycol, glycerin, mannitol, sorbitol and the like, emulsifiers such as tween series, wetting agents such as sodium dodecylsulfate, gelatin, talc, colorants, flavors, stabilizers and the like.
In another aspect, the invention relates to the use of crystalline form of rosxastat or a pharmaceutically acceptable composition thereof for the treatment of anemia in chronic renal disease (CKD) dialysis patients and non-dialyzed chronic renal (NDD-CKD) anemia.
Drawings
Figure 1 is an X-ray diffraction pattern of crystalline form D of rosuvastatin from example 2.
Figure 2 is a TGA profile of crystalline form D of rosixastat in example 2.
Figure 3 is an X-ray diffraction pattern of crystalline form E of rosuvastatin of example 7.
Figure 4 is an X-ray diffraction pattern of crystalline form a of rosuvastatin of patent CN 109369524A.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1: preparation of form D
Mixing 1g of the roxasistat sample with 10mL of a mixed solvent of acetone/water, namely 3:1, heating to 55 ℃, dissolving the sample completely, slowly cooling to 50 ℃, adding 20mL of ethanol, adding 20mg of seed crystal, keeping the temperature, stirring for 6h, filtering, and drying the sample at 50 ℃ in vacuum for 24h to obtain 0.91g of crystal form D with the purity of 99.66%.
Example 2: preparation of form D
Mixing 1g of the roxasistat sample with 10mL of a mixed solvent of acetone/water 4:1, heating to 65 ℃, dissolving the sample completely, slowly cooling to 50 ℃, adding 30mL of ethanol, adding 10mg of seed crystal, stirring for 6h under heat preservation, filtering, and vacuum-drying the sample at 50 ℃ for 24h to obtain 0.95g of crystal form D with the purity of 99.68%. The X-ray diffraction pattern is shown in figure 1. The TGA profile is shown in FIG. 2.
Example 3: preparation of form D
Mixing 1g of a sample of the roxasistat with 10mL of a mixed solvent of acetone/water, namely 3:1, heating to 55 ℃, dissolving the sample completely, slowly cooling to 35 ℃, adding 30mg of seed crystal, keeping the temperature, stirring for 6 hours, slowly cooling to 2 ℃, and filtering to obtain 0.93g of crystal form D with the purity of 99.65%.
Example 4: preparation of form D
Mixing 1g of the sample of the roxasistat with 10mL of mixed solvent of acetone/water (3: 1), heating to 55 ℃, dissolving the sample completely, slowly cooling to 30 ℃, adding 30mg of seed crystal, stirring for 24 hours while keeping the temperature, slowly cooling to 2 ℃, and filtering to obtain 0.94g of a crystal form D sample with the purity of 99.67%.
Example 5: preparation of form D
Mixing 0.5g of the sample of the roxasistat with 10mL of a mixed solvent of acetone/water, namely 3:1, adding 30mg of seed crystal, keeping the temperature, stirring for 96h, and filtering to obtain 0.43g of the crystal form D with the purity of 99.64%.
Example 6: preparation of form D
Mixing 1g of the sample of the roxasistat with 10mL of mixed solvent of ethanol/water (4: 1), adding seed crystals (50 mg), keeping the temperature, stirring for 7 days, and filtering to obtain 0.92g of crystal form D with the purity of 99.63%.
Example 7: preparation of form E
1g of roxasistat and 40ml of ethanol (25 percent of water content) are heated to 65 ℃ to completely dissolve the solid, the temperature is reduced to 25 ℃ under the condition of stirring, the mixture is kept and stirred for 12 hours, and 0.83g of crystal form E with the purity of 99.51 percent is obtained by filtering. The X-ray diffraction pattern is shown in FIG. 3.
Example 8: preparation of form E
1g of the roxasistat and 50ml of acetic acid (containing 20 percent of water) are heated to 70 ℃ to completely dissolve the solid, the temperature is reduced to 20 ℃ under the condition of stirring, the mixture is kept and stirred for 16 hours, and 0.85g of crystal form E is obtained by filtering, wherein the purity is 99.48 percent.
Experimental example 1: solubility comparison
The solubility of the crystal form A in patent CN109369524A and the solubility of the crystal form D in example 2 in water (25 ℃) are compared, and the result shows that the solubility of the crystal form D in example 2 is 10 times of that of the crystal form A in patent CN 109369524A. Wherein, the X-ray diffraction pattern of the crystal form A of the roxasistat in the patent CN109369524A is shown in figure 4.
Crystal form Solubility in water
Crystal form A 3.5mg/ml
Crystal form D 36mg/ml
Experimental example 2: stability test
(1) Influence factor test content and results
The form D provided in example 2 is stable in physical and chemical properties when left to stand for 30 days under high humidity (RH 92.5%), light and high temperature (40 ℃).
Figure BDA0002786234700000161
Figure BDA0002786234700000171
The experimental results show that the sample of crystalline form D of roxasistat is stable for at least 30 days under the conditions of high temperature (40 ℃), high humidity (RH 75%) and illumination (5000 lux).
(2) Accelerated test Contents and results
Figure BDA0002786234700000172
The experimental result shows that the crystalline form D of the roxasistat can stably exist for at least 6 months under the conditions of the temperature of 25 ℃ and the humidity of RH 60%.
Therefore, the stability of the crystalline form D of the roxasistat can meet the medicinal requirement.
Experimental example 3: fluidity test
The new crystal form D prepared in the embodiments 1-6 of the invention is examined for fluidity, and the result shows that the new crystal form D of the invention has good fluidity.
Example 1 Example 2 Example 3 Example 4 Example 5 Example 6
Angle of repose 34° 34° 35° 34° 36° 37°
Experimental example 4: absolute bioavailability assay
The absolute bioavailability of the crystalline form D prepared in examples 1-6 of the present invention, as measured by intravenous injection and oral administration in rats, is as high as 80% or more, preferably 85% or more, and more preferably 90% or more. Experiments show that the crystal form D prepared by the invention has higher bioavailability.

Claims (13)

1. Crystalline form D of roxasistat, characterized in that the X-ray powder diffraction pattern of crystalline form D of roxasistat has diffraction peaks at 5.0 + -0.2 °, 11.3 + -0.2 °, 14.8 + -0.2 °, 18.4 + -0.2 °, 20.1 + -0.2 °, 22.7 + -0.2 °, 27.4 + -0.2 °, 32.0 + -0.2 ° of 2 θ.
2. Crystalline form D of rosxastat according to claim 1 characterized in that the X-ray powder diffraction pattern of crystalline form D of rosxastat optionally further comprises diffraction peaks at one or more of 12.5 ± 0.2 °, 17.4 ± 0.2 °, 20.9 ± 0.2 °, 23.4 ± 0.2 °, 31.0 ± 0.2 °, 33.8 ± 0.2 ° or 37.0 ± 0.2 ° 2 Θ.
3. Crystalline rosixaglitazone form D according to claim 2 characterized in that it further comprises an X-ray powder diffraction pattern optionally comprising a diffraction peak at any 2 to 3, or at 4 to 5, or at 6 to 7 of the 2 Θ at 12.5 ± 0.2 °, 17.4 ± 0.2 °, 20.9 ± 0.2 °, 23.4 ± 0.2 °, 31.0 ± 0.2 °, 33.8 ± 0.2 ° or 37.0 ± 0.2 °.
4. Crystalline form D of rosxastat according to claim 2 characterized in that the X-ray powder diffraction pattern of crystalline form D of rosxastat optionally further comprises diffraction peaks at any 2, 3, 4, 5, 6, 7 of 12.5 ± 0.2 °, 17.4 ± 0.2 °, 20.9 ± 0.2 °, 23.4 ± 0.2 °, 31.0 ± 0.2 °, 33.8 ± 0.2 ° or 37.0 ± 0.2 ° 2 Θ.
5. Crystalline form D of rosxastat according to claim 2, characterized in that the X-ray powder diffraction pattern of crystalline form D of rosxastat optionally further comprises a crystal modification site
12.5±0.2°、17.4±0.2°；
12.5±0.2°、20.9±0.2°；
12.5±0.2°、23.4±0.2°；
12.5±0.2°、31.0±0.2°；
12.5±0.2°、33.8±0.2°；
12.5±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°；
12.5±0.2°、17.4±0.2°、23.4±0.2°；
12.5±0.2°、17.4±0.2°、31.0±0.2°；
12.5±0.2°、17.4±0.2°、33.8±0.2°；
12.5±0.2°、17.4±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、23.4±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、31.0±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、33.8±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、23.4±0.2°、31.0±0.2°；
12.5±0.2°、17.4±0.2°、23.4±0.2°、33.8±0.2°；
12.5±0.2°、17.4±0.2°、23.4±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、31.0±0.2°、33.8±0.2°；
12.5±0.2°、17.4±0.2°、31.0±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、33.8±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、23.4±0.2°、31.0±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、23.4±0.2°、33.8±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、23.4±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、31.0±0.2°、33.8±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、31.0±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、33.8±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、23.4±0.2°、31.0±0.2°、33.8±0.2°；
12.5±0.2°、17.4±0.2°、23.4±0.2°、31.0±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、23.4±0.2°、33.8±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、31.0±0.2°、33.8±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、23.4±0.2°、31.0±0.2°、33.8±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、23.4±0.2°、31.0±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、23.4±0.2°、33.8±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、20.9±0.2°、31.0±0.2°、33.8±0.2°、37.0±0.2°；
12.5±0.2°、17.4±0.2°、23.4±0.2°、31.0±0.2°、33.8±0.2°、37.0±0.2°；
Diffraction peaks are arranged at 12.5 +/-0.2 degrees, 17.4 +/-0.2 degrees, 20.9 +/-0.2 degrees, 23.4 +/-0.2 degrees, 31.0 +/-0.2 degrees, 33.8 +/-0.2 degrees and 37.0 +/-0.2 degrees.
6. Crystalline form D of rosxastat according to claim 1, characterized in that the crystalline form D of rosxastat has an X-ray powder diffraction pattern substantially as shown in figure 1 or a TGA pattern substantially as shown in figure 2.
7. A process for the preparation of crystalline Rosemastat form D according to any one of claims 1-6, comprising the steps of:
1) adding any form of the roxasistat into a mixed solvent of a first solvent consisting of water and one or more than one organic solvent, heating and forming a solution or slurry;
2) cooling the solution in step 1);
3) optionally, adding a second type of organic solvent consisting of one or a mixture of more than one solvent to step 2);
4) optionally, adding seed crystals to the solution in step 3);
5) continuously stirring to obtain a crystal form;
wherein, the organic solvent in the step 1) is selected from acetone or ethanol;
the second organic solvent in the step 3) is ethanol.
8. The process for the preparation of crystalline form D of rosxata according to claim 7, wherein the amount of seed crystals used in step 4) is 0.1-10% of the batch size.
9. The process for the preparation of crystalline form D of rosxata according to claim 7, wherein the amount of seed crystals used in step 4) is 0.5-5% of the batch size.
10. The process for the preparation of crystalline form D of rosmarinic acid according to claim 7, wherein the seed crystal of step 4) is used in an amount of 1% to 3% of the charge.
11. A pharmaceutical composition comprising a therapeutically effective amount of crystalline form D of rosxastat according to any one of claims 1-6 and one or more pharmaceutically acceptable carriers, diluents or excipients.
12. Pharmaceutical composition according to claim 11, characterized in that it is a tablet or a capsule.
13. Use of crystalline form D of roxasirox according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 11 for the preparation of a medicament for treating anemia in chronic renal dialysis patients and non-dialyzed chronic renal anemia.
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