CN111205224B - Crystal form of roxasistat hydrate, and preparation method and application thereof - Google Patents
Crystal form of roxasistat hydrate, and preparation method and application thereof Download PDFInfo
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- CN111205224B CN111205224B CN202010319444.7A CN202010319444A CN111205224B CN 111205224 B CN111205224 B CN 111205224B CN 202010319444 A CN202010319444 A CN 202010319444A CN 111205224 B CN111205224 B CN 111205224B
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- C—CHEMISTRY; METALLURGY
- 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
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/66—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems and singly-bound oxygen atoms, bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention belongs to the field of chemical synthesis, and discloses a novel roxasistat hydrate form and a crystal form E thereof, wherein the form is about 6.64 in an X-ray diffraction pattern expressed by a 2 theta angle by using Cu-K α radiation°、9.76°、9.95°、11.77°、13.21°、13.89°、15.43°、16.07°、16.48°、16.86°、18.69°、19.18°、19.83°、20.32°、20.87°、22.03°、23.59°、24.03°、25.17°、26.53°、27.44°、28.30°Has diffraction peak; the method of the invention obtains a brand-new roxasistat hydrate and a crystal form E with characteristics thereof, and the crystal form has good chemical stability and drug forming property.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a new crystal form of a roxasistat hydrate, in particular to a new crystal form E of a roxasistat hydrate and a preparation method thereof.
Background
The structural formula of the roxasistat is shown in a formula 1, the roxasistat is developed by Fabricius Adams company, and is firstly marketed in China in 2018, and the product name of the roxasistat is erezepine. The Rosesarta capsule is the first developed small molecule hypoxia inducible factor prolyl hydroxylase inhibitor (HIF-PHI) medicine for treating renal anemia. The physiological role of Hypoxia Inducible Factor (HIF) is to increase not only erythropoietin expression, but also erythropoietin receptor and protein expression which promotes iron absorption and circulation. Rosemastat inhibits the Prolyl Hydroxylase (PH) enzyme by simulating ketoglutarate, one of the substrates of PH, and influences the action of the PH enzyme in maintaining the balance of HIF generation and degradation rates, thereby achieving the aim of correcting anemia.
Formula 1
Currently, patent CN 10353970 reports on the form a, form B (hemihydrate), form C (hexafluoropropan-2-ol solvate), form D (DMSO/water solvate), sodium salt, L-arginine salt, L-lysine salt, ethanolammonium salt, diethanolamine salt, tromethamine salt, amorphous form and potassium salt of roxasistat.
Disclosure of Invention
One aspect of the invention provides a crystalline form E of the hydrate of rosmarintat.
A crystal of a compound of the formula:
it is irradiated by Cu-K α, and has an X-ray diffraction pattern expressed by 2 theta angle of about 6.64°About 9.76°About 9.95°About 11.77°About 13.21°About 13.89, respectively°About 15.43°About 16.07°About 16.48°About 16.86°About 18.69°About 19.18°About 19.83°About 20.32°About 20.87°About 22.03°About 23.59°About 24.03°About 25.17°About 26.53°About 27.44°About 28.30°Has diffraction peaks.
Rosesarta hydrate form E, irradiated by X-ray diffraction using Cu-K α at an angle of 2 theta (theta)°) The X-ray diffraction pattern shown has peaks at the following positions: 6.64 +/-0.2°、9.76±0.2°、9.95±0.2°,11.77±0.2°、13.21±0.2°、13.89±0.2°、15.43±0.2°、16.07±0.2°、16.48±0.2°、16.86±0.2°、18.69±0.2°、19.18±0.2°、19.83±0.2°、20.32±0.2°、20.87±0.2°、22.03±0.2°、23.59±0.2°、24.03±0.2°、25.17±0.2°、26.53±0.2°、27.44±0.2°、28.30±0.2°。
Further, the melting point of the form E of the hydrate of the rasagiline salt is 211-213 ℃.
Further, the roxasistat hydrate form E, which is dried at 105 ℃ to constant weight, has a moisture content of 3.5-3.8% as determined by the karl fischer method.
Further, the roxasistat hydrate form E, which uses Cu-Ka radiation, has a powder X-ray diffraction pattern as shown in figure 1 of the attached drawings of the specification.
The invention also provides a preparation method of the hydrate form E of the roxasistat.
The preparation method of the roxasistat hydrate form E comprises the following steps: stirring and dissolving the roxasistat in a sodium hydroxide aqueous solution, adding acid to adjust the pH value, precipitating crystals at a specific temperature, filtering, washing with water, and drying to obtain the crystals of the roxasistat hydrate.
Furthermore, the mol ratio of the roxasistat to the sodium hydroxide is 1:1-1.5, and the mass solubility of the sodium hydroxide aqueous solution is 0.5-2.0%.
Further, the acid is acetic acid or hydrochloric acid.
Further, the pH after adjustment is 5.0 to 7.0, preferably 6.5.
Further, the temperature at which crystals are precipitated is 10 to 70 ℃, preferably 30 ℃.
Further, the drying mode is that after the air blowing drying is carried out for 2 to 3 hours at the temperature of between 30 and 40 ℃, the temperature is increased to between 60 and 70 ℃ and the air blowing drying is carried out for 8 to 12 hours until the weight is constant.
The invention also provides application of the hydrate form E of the roxasistat.
The form E of the roxasistat hydrate is applied to preparing the medicine for treating anemia caused by chronic kidney diseases. The Rosemastat hydrate form E prepared by the method is high in purity and suitable for raw material drug development.
Compared with the prior art, the invention has the following beneficial effects because the technology is adopted:
the crystalline form E of the roxasistat hydrate disclosed by the invention has good chemical stability, is beneficial to long-term storage, and also has good drug forming property.
Drawings
FIG. 1 is an X-ray diffraction pattern of form E of roxasistat hydrate;
FIG. 2 is a high performance liquid chromatography spectrum of the form E of roxasistat hydrate;
figure 3 is a graph comparing the dissolution of the tablet form E prepared by the method of example 1 with the original triturate of the roxasistat capsule.
Detailed Description
Description of the atlas data:
it is noted that in the X-ray powder diffraction spectrum, the diffraction pattern obtained from a crystalline compound tends to be characteristic for a specific crystal, wherein the relative intensities of the bands may vary due to the dominant orientation effect produced by differences in crystallization conditions, particle size, and other measurement conditions. Thus, the relative intensities of the diffraction peaks are not characteristic of the crystal aimed at. To judge whether or not to coincide with the known crystalline phase, it is more important to note the relative positions of the peaks rather than their relative intensities. In addition, there may be slight errors in the position of the peaks for any given crystal, which are also well known in the crystallography art. For example, the position of the peak may shift due to temperature change when analyzing the sample, sample movement, calibration of the instrument, or the like, and the measurement error of the 2 θ value is sometimes about ± 0.2°. Therefore, this error should be taken into account when determining each crystalline structure. For the same crystal of the same compound, the peak positions of the XPRD spectrum have similarity as a whole, and the relative intensity error may be large. It should also be noted that in the identification of mixtures, the loss of part of the diffraction lines is caused by, among other things, a reduction in the content, in which case it is not necessary to rely on all the bands observed in the high-purity sample, even one band may be characteristic for a given crystal.
PXRD detection conditions are as follows:
the scanning angle range of the powder X-ray diffractometer can reach 0°～80°Collecting powder X-ray diffraction data in 2015 th edition of pharmacopoeia of the people's republic of China 0451X-ray diffraction methodThe correlation of the ranges is stated to be that when using copper Cu target experiments, the range (2 θ) over which diffraction data is collected should generally be at least 3°～ 60°Sometimes it can be collected to 1°～80°. This is due to the instrument being at a scan angle of 1°A large blank diffraction peak is generated, the intensity of the blank diffraction peak exceeds that of the sample diffraction peak, and the analysis of the sample data is influenced, so that the blank diffraction peak is generally not from 0°The recording of data is started. The range of the strong diffraction peak generated by the organic crystal is generally 2°～40°The experimental conditions thus selected were CuK α radiation, tube pressure 40 kV, tube flow 30mA, graphite curved crystal monochromator, scanning speed 2°·min-1Step interval 0.02°Scanning Range 2°～50°。
Example 1: preparation of Rosemastat hydrate form E
Adding 10g of the sample of the roxasistat (form A) into a 250ml single-neck bottle, adding 150ml of water, adding 1.36g of sodium hydroxide, heating to 50 ℃, stirring for dissolving, filtering, dropwise adding 1N hydrochloric acid into the filtrate until the pH value is 6.0, separating out a large amount of solid at 60 ℃, filtering, washing with water, drying by air blowing at 30 ℃ for 2 hours, then drying by air blowing at 60 ℃ for 8 hours, and obtaining 9.6g of light yellow solid powder.
Example 2: preparation of Rosemastat hydrate form E
Adding 10g of the sample of the roxasistat (form A) into a 250ml single-mouth bottle, adding 150ml of water, adding 1.36g of sodium hydroxide, heating to 30 ℃, stirring for dissolving, filtering, dropwise adding acetic acid into the filtrate until the pH value is 6.5, separating out a large amount of solid at 60 ℃, filtering, washing with water, drying by air blowing at 30 ℃ for 2 hours, then increasing to 60 ℃ for air blowing and drying for 8 hours, and obtaining 9.8g of light yellow solid powder.
Example 3: stability survey
The chemical stability of the crystal form E of the crystal form. The results show that the crystal form E has good chemical stability.
TABLE 1 influence factor test and stability test results
Example 4:
the dissolution of the tablet prepared from the form E of the hydrate of rosxastat prepared in example 1 was compared with the dissolution of the original formulation, rosxastat capsule (erethim), as shown in fig. 3.
The tablets prepared by adopting the crystal form have high similarity with the dissolution curve of the original preparation tablets of erethipine.
Example 5:
the Rosetta hydrate form E sample prepared in example 1 was ground and tabletted using a CuK alpha radiation graphite monochromator at a tube pressure of 40 kV, a tube flow of 30mA, a graphite curved crystal monochromator at a scanning speed
2°·min-1Step interval 0.02°Scanning Range 2°～50°. The data results are shown in FIG. 1.
The above-mentioned embodiments are merely preferred embodiments of the present invention, and should not be construed as limiting the present invention, and the scope of the present invention should be defined by the claims, and equivalents including technical features of the claims, i.e., equivalent modifications within the scope of the present invention.
Claims (5)
1. A crystal of a compound of the formula:
it is radiated by Cu-K α and has an X-ray diffraction pattern expressed by 2 theta angle of 6.64 +/-0.2°、9.76±0.2°、9.95±0.2°、11.77±0.2°、13.21±0.2°、13.89±0.2°、15.43±0.2°、16.07±0.2°、16.48±0.2°、16.86±0.2°、18.69±0.2°、19.18±0.2°、19.83±0.2°、20.32±0.2°、20.87±0.2°、22.03±0.2°、23.59±0.2°、24.03±0.2°、25.17±0.2°、26.53±0.2°、27.44±0.2°、28.30±0.2°Has diffraction peak;
the preparation of the crystal form comprises the following steps: stirring the roxasistat in a sodium hydroxide aqueous solution, adding acid to adjust the pH value, separating out crystals, filtering, washing with water, and drying to obtain crystals of the roxasistat hydrate; the mol ratio of the roxasistat to the sodium hydroxide is 1:1-1.5, and the mass solubility of the sodium hydroxide aqueous solution is 0.5-2.0%;
the adjusted pH value is 5.0-7.0; the temperature for separating out the crystal is 10-70 ℃;
the drying mode is drying for 2-3 hours at 30-40 ℃, and then heating to 60-70 ℃ for drying for 8-12 hours.
2. The crystal according to claim 1, characterized in that it uses Cu-ka radiation, having a powder X-ray diffraction pattern as shown in figure 1 of the accompanying drawings.
3. The crystal according to claim 1, which has a moisture content of 3.5 to 3.8% as measured by the Karl Fischer method after being dried at 105 ℃ to a constant weight.
4. The crystal according to claim 1, characterized in that: the acid is acetic acid or hydrochloric acid.
5. Use of a crystal according to any one of claims 1-2 for the preparation of a medicament for the treatment of anemia arising from chronic kidney disease.
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| CN114057643B (en) * | 2020-08-04 | 2023-02-28 | 成都苑东生物制药股份有限公司 | Rosemastat eutectic crystal and preparation method thereof |
| CN113956200A (en) * | 2021-12-16 | 2022-01-21 | 南京威凯尔生物医药科技有限公司 | Crystallization process of roxasistat bulk drug with controlled particle size |
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| CN115093370A (en) * | 2012-07-16 | 2022-09-23 | 菲布罗根有限公司 | Crystalline forms of prolyl hydroxylase inhibitors |
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