CN114276294A - Novel crystal form of roxasistat salt and preparation method and application thereof - Google Patents
Novel crystal form of roxasistat salt and preparation method and application thereof Download PDFInfo
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- CN114276294A CN114276294A CN202111519715.4A CN202111519715A CN114276294A CN 114276294 A CN114276294 A CN 114276294A CN 202111519715 A CN202111519715 A CN 202111519715A CN 114276294 A CN114276294 A CN 114276294A
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Abstract
The invention discloses a novel crystal form of a salt of roxasistat, a preparation method and application thereof. The crystal form provided by the invention has excellent stability, shows good physical and chemical stability under long-term, accelerated, low-humidity or high-humidity conditions, and remarkably improved stability is beneficial to improving the bioavailability of medicaments taking the roxasistat and the salt thereof as main active ingredients, thereby improving the clinical curative effect. Meanwhile, the new crystal form of the roxasistat salt has excellent solubility, so that the patent drug property and the drug effect of the medicine are improved. In addition, the preparation method of the crystal form is simple and is suitable for industrial mass production.
Description
Technical Field
The invention relates to the technical field of drug crystals, in particular to a new crystal form of a roxasistat salt, a preparation method and application thereof.
Background
Rosesarta (also known as "Roxadustat" or "Rosesartat") is known under the chemical name N- (4-hydroxy-1-methyl-phenoxyisoquinoline-3-carbonyl) glycine and is an orally available potent reversible hypoxia inducible factor prolyl hydroxylase inhibitor (HIF-PHI). In 12 months in 2018, the roxasistat is approved to be marketed by NMPA in China at first and is used for treating anemia of chronic renal disease dialysis patients. In 8 months of 2019, indications for anemia treatment in non-dialysis dependent chronic kidney disease patients were approved by NMPA.
Disclosure of Invention
In order to solve at least part of the technical problems in the prior art, the invention provides a specific crystalline form of a salt of rosxastat, which has excellent properties more suitable for the preparation of pharmaceutical preparations. For example, higher stability, commercial availability and higher bioavailability. Specifically, the present invention includes the following.
In a first aspect of the invention, there is provided a salt of rosxastat-histidine.
Preferably, the structural formula of the roxasistat-histidine salt is shown as the following formula (I):
preferably, the salt of rasagiline-histidine is in a crystalline state having at least three characteristic diffraction peaks selected from 9.93 ± 0.2 °, 11.23 ± 0.2 °, 15.37 ± 0.2 °, 18.89 ± 0.2 ° and 19.85 ± 0.2 ° in an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 Θ.
The crystalline form of rosisastat-histidine salt according to the first aspect of the invention preferably further has at least one characteristic diffraction peak selected from 9.12 ± 0.2 °, 13.12 ± 0.2 °, 19.01 ± 0.2 °, 22.49 ± 0.2 ° and 24.27 ± 0.2 ° in an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 Θ.
The crystalline form of rosisastat-histidine salt according to the first aspect of the invention preferably further has, in an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 Θ, at least one characteristic diffraction peak selected from 20.99 ± 0.2 °, 26.93 ± 0.2 °, 29.25 ± 0.2 °, 24.77 ± 0.2 ° and 17.86 ± 0.2 °.
Preferably, the crystalline form according to the first aspect of the present invention has X-ray powder diffraction data as shown in table 1.
Preferably, the crystalline form according to the first aspect of the invention has an X-ray powder diffraction pattern substantially as shown in figure 1.
Preferably, the TGA characterisation of the crystalline form according to the first aspect of the invention shows 2.5 water.
The crystalline form of rosisastat-histidine salt according to the first aspect of the invention, preferably said crystalline form having a fourier infrared spectrum as shown in figure 2.
In a second aspect of the invention, there is provided a salt of rosmarin-piperazine having the formula (II)
The crystalline form of the salt of roxasistat-piperazine has at least three characteristic diffraction peaks selected from the group consisting of 3.82 ± 0.2 °, 7.54 ± 0.2 °, 12.14 ± 0.2 °, 14.75 ± 0.2 ° and 19.09 ± 0.2 ° in an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 θ.
The crystalline form of the salt of rosuvastatin-piperazine according to the second aspect of the present invention preferably further has at least one characteristic diffraction peak selected from 10.26 ± 0.2 °, 11.26 ± 0.2 °, 14.99 ± 0.2 °, 19.45 ± 0.2 ° and 22.25 ± 0.2 ° in an X-ray powder diffraction pattern expressed in diffraction angle 2 θ.
The crystalline form of the salt of rosuvastatin-piperazine according to the second aspect of the present invention preferably further has at least one characteristic diffraction peak selected from the group consisting of 20.51 ± 0.2 °, 21.82 ± 0.2 °, 26.99 ± 0.2 °, 30.12 ± 0.2 ° and 38.76 ± 0.2 ° in an X-ray powder diffraction pattern expressed in diffraction angle 2 θ.
Preferably, the X-ray powder diffraction data of the crystalline form according to the second aspect of the invention is as shown in table 4.
Preferably, the crystalline form of the second aspect of the invention has an X-ray powder diffraction pattern substantially as shown in figure 3.
Preferably, the TGA characterisation of the crystalline form according to the second aspect of the invention shows no water.
The crystalline form of the salt of rosuvastatin-piperazine according to the second aspect of the present invention, preferably, the crystalline form has an infrared spectrum as shown in fig. 4.
In a third aspect of the present invention, there is provided a process for the preparation of the crystalline form of the salt of rosmarin-histidine as described in the first aspect, comprising the steps of:
(1) mixing the roxasistat and the histidine, adding a mixed solvent formed by an organic solvent and water, and stirring to obtain a white suspension;
(2) and (4) centrifugally drying the white suspension to obtain the crystalline form of the rosmarintat-histidine salt.
According to the preparation method of the crystalline form of the rosxastat-histidine salt, the weight ratio of the rosxastat and the histidine is preferably 1-5:1, more preferably 1-3:1, and even more preferably 1-2: 1.
According to the preparation method of the crystalline form of the salt of rosxastat-histidine, the organic solvent is preferably at least one selected from methanol, ethanol and acetonitrile.
According to the preparation method of the crystalline form of the rosisastat-histidine salt, the volume ratio of the organic solvent to the water is preferably 1:1-3, more preferably 1:1-2, and even more preferably 1: 1-1.5.
According to the preparation method of the crystalline form of the rosisastat-histidine salt, the concentration of the rosisastat in the mixed solvent is preferably 5-25mg/mL, more preferably 6-20mg/mL, and even more preferably 8-15 mg/mL.
According to the preparation method of the crystalline form of the crystalline salt of rosisastat-histidine, provided by the invention, in the step (1), stirring is preferably carried out at room temperature.
According to the preparation method of the crystalline form of the salt of rosmarinic acid, provided by the invention, in the step (2), the drying temperature is preferably 20-50 ℃, more preferably 30-45 ℃, and even more preferably 35-45 ℃.
In a fourth aspect of the present invention, there is provided a process for preparing crystalline forms of the salt of rospasolamine piperazine as defined in the second aspect, which comprises the steps of:
a. mixing the roxasistat and the piperazine, adding an alcohol solvent, and stirring to obtain a suspension;
b. and centrifuging and drying the suspension to obtain the crystal form of the salt of the roxasistat piperazine.
According to the preparation method of the crystalline form of the salt of the roxasistat-piperazine, preferably, the alcohol solvent is C1-C3An alkyl alcohol.
According to the preparation method of the crystalline form of the salt of roxasistat-piperazine, the alcohol solvent is preferably methanol.
According to the preparation method of the crystalline form of the salt of roxasistat-piperazine, the weight ratio of roxasistat to piperazine is preferably 1-7:1, more preferably 2-6:1, and even more preferably 2-5: 1.
According to the preparation method of the crystalline form of the salt of roxarstat-piperazine, the concentration of the roxarstat in the alcohol solvent is preferably 8-35mg/mL, more preferably 9-32mg/mL, and even more preferably 10-30 mg/mL.
According to the preparation method of the crystalline form of the salt of roxasistat-piperazine, step a is preferably carried out at room temperature by stirring.
According to the preparation method of the crystalline form of the rosuvastatin-piperazine salt, in the step b, the drying temperature is preferably 20 to 50 ℃, more preferably 30 to 45 ℃, and still more preferably 35 to 45 ℃.
In a fifth aspect of the present invention, there is provided a pharmaceutical composition comprising the crystalline form of the salt of rosxata-histidinate according to the first aspect, or the crystalline form of the salt of rosxata-piperazine according to the second aspect, or the crystalline form obtained according to the preparation process of the third aspect, or the crystalline form obtained according to the preparation process of the fourth aspect, or any combination of these crystalline forms, and at least one pharmaceutically acceptable carrier.
The pharmaceutically acceptable carrier in the present invention includes a diluent or excipient or other additives, examples of which include, but are not limited to, for example, wetting agents, disintegrants, lubricants, binders, surfactants, and the like. Examples of other additives include, but are not limited to, for example, shellac, gum arabic, talc, titanium oxide, sugars (e.g., sucrose), gelatin, water, polysaccharides such as lactose or glucose, paraffin (e.g., petroleum fractions), vegetable oils (e.g., peanut or sesame oil), and pharmaceutically acceptable organic solvents such as alcohols (e.g., ethanol or glycerol), natural mineral powders (e.g., kaolin, clay, talc, and chalk), synthetic mineral powders (e.g., highly dispersed silicic acid and silicates), emulsifiers (e.g., lignin, sulfite solutions, methylcellulose, starch, and polyvinylpyrrolidone), magnesium stearate, stearic acid, sodium lauryl sulfate, and the like.
The pharmaceutical composition of the present invention may be prepared in various dosage forms including, but not limited to, for example, pharmaceutical preparations suitable for oral administration, such as solid oral preparations including tablets, coatings, capsules, granules, powders, pills, powders, and the like, or liquid oral preparations including solutions, syrups, suspensions, emulsions, and the like; pharmaceutical preparations suitable for parenteral administration, for example in the form of intravenous drip preparations, intramuscular or subcutaneous injection preparations, suppositories for rectal administration, inhalant preparations for intranasal administration, or else transdermal patches for topical administration. In the production of the preparation, additional auxiliary materials can be further included, and the addition of the auxiliary materials is preferably not caused to change the crystal form.
In a sixth aspect of the present invention, there is provided a use of the crystalline form of rosmarinic acid salt according to the first aspect, or the crystalline form of rosmarinic acid salt according to the second aspect, or the crystalline form obtained by the preparation method according to the third aspect, or the crystalline form obtained by the preparation method according to the fourth aspect, or the pharmaceutical composition according to the fifth aspect, for the manufacture of a medicament for the prevention or treatment of a disease, including chronic kidney disease, or anemia, ischemia, hypoxia, or myelodysplastic syndrome MDS anemia, caused by chronic kidney disease.
In a seventh aspect of the present invention, there is provided a method for the prevention or treatment of a disease comprising the step of administering to a subject in need thereof the crystalline form of rosxastat-histidinate according to the first aspect, or the crystalline form of rosxastat-piperazine salt according to the second aspect, or the crystalline form obtained by the process of preparation according to the third aspect, or the crystalline form obtained by the process of preparation according to the fourth aspect, or any combination of these crystalline forms, or the pharmaceutical composition according to the fifth aspect, wherein said disease comprises chronic kidney disease, or anemia resulting from chronic kidney disease, ischemia, hypoxia, or myelodysplastic syndrome MDS anemia. Preferably, the pharmaceutical composition comprises a prophylactically and/or therapeutically effective amount of the crystalline form.
In the present invention, a "therapeutically effective amount" means an amount of the crystalline form of the present invention sufficient to significantly improve the symptoms or symptoms of chronic kidney disease or renal anemia without causing serious side effects. Generally, the pharmaceutical composition contains l to 2000mg of the crystalline form/dosage of the present invention, more preferably, 10 to 200mg of the crystalline form/dosage of the present invention. Preferably, the formulation is a capsule or tablet. For a person with a body weight of 60kg, the daily dose administered is generally 1-2000mg, preferably 20-500 mg. Of course, the particular dosage regimen will take into account factors such as the route of administration, the health of the patient, and the like, which are within the skill of the skilled practitioner.
In an eighth aspect of the present invention, there is provided a crystalline form of the salt of rosmarinic acid according to the first aspect, or a crystalline form of the salt of rosmarinic acid according to the second aspect, or a crystalline form obtained by the preparation method according to the third aspect, or a crystalline form obtained by the preparation method according to the fourth aspect, or any combination of these crystalline forms, or a pharmaceutical composition according to the fifth aspect, for use in combination with a further medicament, preferably a further medicament associated with chronic kidney disease, or anemia, ischemia, hypoxia, or MDS anemia caused by chronic kidney disease.
Drawings
FIG. 1 is an XRPD pattern of the Rosemastat histidine hydrate Form I prepared according to example 1.
FIG. 2 is an FT-IR spectrum of the Rosemastat histidine hydrate Form I prepared according to example 1.
Figure 3 is an XRPD pattern of the rosuvastatin-piperazine anhydrate prepared according to example 4.
Fig. 4 is an FT-IR spectrum of the anhydrous rosisastat-piperazine prepared according to example 4.
Detailed Description
Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but as a more detailed description of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. Further, for numerical ranges in this disclosure, it is understood that the upper and lower limits of the range, and each intervening value therebetween, is specifically disclosed. Every smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in a stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only the preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference herein for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control. Unless otherwise indicated, "%" is percent by weight.
In the process of the present invention, the crystalline form of the present invention is generally prepared using rosxastat as the starting material, which is available as a commercially available product or prepared by the method mentioned in CN 107382859A. Unless otherwise specified, the starting material used herein is the free Form a of the rasagile salt prepared by known methods.
The term "subject" as used herein includes mammals. The mammal can be, for example, any mammal, e.g., a human, primate, bird, mouse, rat, poultry, dog, cat, cow, horse, goat, camel, sheep, or pig. Preferably, the mammal is a human.
As used herein, the term "room temperature" generally means 10-30 deg.C, preferably 20. + -. 5 deg.C.
In the present invention, the term "crystalline form" refers to a certain lattice configuration of a crystalline substance. It is known in the art that crystalline forms are involved in stability, dissolution and mechanicalness in pharmaceutical formulations. Different crystalline forms of the same substance typically have different crystal lattices (e.g., unit cells) with different physical properties characteristic thereof. The different crystalline forms can be characterized by methods known in the art. For example, identification can be by solid state characterization methods, such as by X-ray powder diffraction (XRPD). Other methods of characterization include Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), Dynamic Vapor Sorption (DVS), solid state NMR, and the like. The crystal form can be characterized by any of the above methods, or by a combination of two or more methods.
Other experimental methods are known in the art, except for the specific description of the present invention, and reference may be made to, for example, "pharmacopoeia of the people's republic of china" or the like. The parameters for detection are set as follows:
the specific conditions for XRPD (X-ray powder diffraction) measurements were: bruker D8, Cu-Kalpha radiation, detection range of 3-40 degrees 2 theta, step size of 0.02 degrees 2 theta, scanning speed of 0.2s.step-1, current voltage of 40mA and 40 KV.
The test conditions of the Fourier infrared spectrum are as follows: bruker tenor 27, ATR method, acquisition range 600 cm-1-4000cm-1, resolution 4 cm-1.
The HPLC standard curve determination procedure is as follows: adding 2ml of deionized water to a 20ml sample bottle, adding an excess amount of a sample of the salt of the roxasistat until the sample is not completely dissolved, stirring at room temperature for 24 hours, sampling and filtering to obtain a saturated solution of the sample, and analyzing the concentration of the sample in the solution by HPLC.
The various reagents used in the examples are commercially available unless otherwise specified. The examples were run at room temperature unless otherwise indicated.
Example 1
About 35.52mg of the free Form A of roxasistat and 31.43mg of histidine were taken, 3mL of acetone: water 1:1 for 3 days at room temperature to give a white suspension.
And centrifuging and filtering the obtained suspension, and drying the obtained solid at 40 ℃ for 12 hours in vacuum to obtain the roxasistat-histidine hydrate.
The sample of example 1 was taken for characterization as follows.
1. XRPD pattern analysis
FIG. 1 is an XRPD pattern of the Rosemastat-histidine hydrate Form I, and Table 1 shows X-ray powder diffraction data of the Rosemastat-histidine hydrate Form I.
Table 1: x-ray powder diffraction data of roxasistat-histidine hydrate Form I
2. HPLC analysis
The prepared samples were analyzed by HPLC as shown in table 2, with the molar ratio of rosxastat to histidine in the rosxastat-histidine determined by HPLC being about 1:1, and the composition of rosxastat-histidine salt calculated in combination with the amount of water content determined by TGA was rosxastat: histidine: water 1:1: 2.5.
TABLE 2 Rosemastat-histidine hydrate Form I composition (HPLC test results)
3. FT-IR analysis
The Fourier infrared spectrum results are shown in FIG. 2.
Example 2
About 35.11mg of the free roxasistat crystal Form a, and 31.64mg of histidine were taken, 3mL of methanol: water 1:1 for 3 days at room temperature to give a white suspension.
And centrifuging and filtering the obtained suspension, and drying the obtained solid at 40 ℃ for 12 hours in vacuum to obtain the roxasistat-histidine hydrate.
Example 3
About 35.51mg of the free Form a of rosmarinat and 30.81mg of histidine were taken and 3mL of acetonitrile: water 1:1 for 3 days at room temperature to give a white suspension.
And centrifuging and filtering the obtained suspension, and drying the obtained solid at 40 ℃ for 12 hours in vacuum to obtain the roxasistat-histidine hydrate.
Example 4
35.67mg of free roxasistat crystal Form A and 9.56mg of piperazine were added into 3mL of methanol solvent and stirred at room temperature for 1 day to obtain white suspension 1.
The resulting suspension was centrifuged and the resulting solid was dried under vacuum at 40 ℃ for 12 hours to give the anhydrous salt of roxasistat-piperazine.
The sample of example 4 was taken for characterization as follows.
1. XRPD pattern analysis
Fig. 3 is an XRPD pattern of the rosuvastatin-piperazine anhydrate, and table 3 shows X-ray powder diffraction data of the rosuvastatin-piperazine anhydrate.
TABLE 3X-ray powder diffraction data for Rosesarta-piperazine anhydrate
| 2θ±0.2° | Relative strength% |
| 3.82 | 100 |
| 7.54 | 37.3 |
| 10.263 | 9.1 |
| 11.261 | 7.4 |
| 12.144 | 96.6 |
| 14.747 | 46.5 |
| 14.987 | 15.3 |
| 19.086 | 43.8 |
| 19.447 | 21.9 |
| 20.506 | 6 |
| 21.824 | 7.4 |
| 22.249 | 9.7 |
| 23.811 | 3.7 |
| 26.988 | 4.8 |
| 28.991 | 3.7 |
| 30.117 | 6.5 |
| 36.727 | 3.1 |
| 38.761 | 9.6 |
2、1H-NMR spectrum
Process for preparing anhydrous salt of roxasistat-piperazine1H-NMR quantitative results show that the molar ratio of the roxasistat to the piperazine is 2:1,1the H-NMR measurement results were: 1H NMR (400MHz, DMSO-d6) δ 8.93(t, J ═ 5.5Hz,1H),8.32(d, J ═ 9.0Hz,1H),7.64(d, J ═ 2.4Hz,1H), 7.58-7.44 (m,3H), 7.38-7.24 (m,1H), 7.23-7.13 (m,2H),3.87(d, J ═ 5.4Hz,2H),2.91(s,4H), 2.72(s, 3H).
3. IR analysis
The infrared spectrum results are shown in FIG. 4.
Example 5
176.42mg of free-state roxasistat crystal Form A and 43.67mg of piperazine are taken, 6mL of methanol solvent is added, and stirring is carried out at room temperature for 4h to obtain white suspension 1; the resulting suspension was centrifuged and filtered, and the resulting solid was dried under vacuum at 40 ℃ for 12 hours to give Rosesarta-piperazine anhydrate.
While the invention has been described with reference to exemplary embodiments, it is to be understood that the invention is not limited to the disclosed exemplary embodiments. Many modifications and variations may be made to the exemplary embodiments of the present description without departing from the scope or spirit of the present invention. The scope of the claims is to be accorded the broadest interpretation so as to encompass all modifications and equivalent structures and functions.
Claims (10)
1. A salt of rosmarinic acid.
Preferably, the structural formula of the roxasistat-histidine salt is shown as the following formula (I):
preferably, the salt of rasagiline-histidine is in a crystalline state characterized by having at least one characteristic diffraction peak selected from 9.93 ± 0.2 °, 11.23 ± 0.2 °, 15.37 ± 0.2 °, 18.89 ± 0.2 ° and 19.85 ± 0.2 ° in an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 Θ.
2. The crystalline form of rosuvastatin-histidine salt according to claim 1, characterized by further having at least one characteristic diffraction peak selected from the group consisting of 9.12 ± 0.2 °, 13.12 ± 0.2 °, 19.01 ± 0.2 °, 22.49 ± 0.2 ° and 24.27 ± 0.2 ° in an X-ray powder diffraction pattern expressed in diffraction angle 2 Θ;
preferably, it further has at least one characteristic diffraction peak selected from the group consisting of 20.99 ± 0.2 °, 26.93 ± 0.2 °, 29.25 ± 0.2 °, 24.77 ± 0.2 ° and 17.86 ± 0.2 ° in an X-ray powder diffraction pattern expressed by diffraction angle 2 θ;
preferably, in the Fourier infrared spectrum, at a wavelength selected from 1624.61 + -2 cm-1、1521.19±2cm-1、1241.23±2cm-1And 1161.89 + -2 cm-1Has a characteristic peak at least one of;
preferably, in the Fourier infrared spectrum, further in the spectrum selected from 3461.95 + -2 cm-1、3236.53±2cm-1、2658.14±2cm-1、2365.69±2cm-1、2080.80±2cm-1、2015.76±2cm-1、1420.51±2cm-1、1098.30±2cm-1Has a characteristic peak at least one of;
preferably, the crystalline Form is Form I in crystalline Form, which has a dehydration temperature of 112.9 ± 2 ℃.
3. The process for the preparation of crystalline form of rosmarin-his histidine salt according to any of claims 1 or 2, characterized in that it comprises the following steps:
(1) mixing the roxasistat and the histidine, adding a mixed solvent formed by an organic solvent and water, and stirring to obtain a white suspension;
(2) centrifuging and drying the white suspension to obtain a crystalline form of the rosisasetamide-histidine salt;
preferably, the weight ratio of the roxasistat and the histidine is 1-5: 1;
preferably, the organic solvent is selected from at least one of methanol, ethanol and acetonitrile;
preferably, the volume ratio of the organic solvent to the water is 1: 1-3;
preferably, the concentration of the roxasistat in the mixed solvent is 5-25 mg/mL;
preferably, in step (1), the stirring is performed at room temperature;
preferably, in step (2), the drying temperature is 20 to 50 ℃.
4. A salt of rosmarin-piperazine with structural formula (II)
Preferably, the salt of roxasistat-piperazine is in a crystalline state characterized in that the crystalline form has at least three characteristic diffraction peaks selected from 3.82 ± 0.2 °, 7.54 ± 0.2 °, 12.14 ± 0.2 °, 14.75 ± 0.2 ° and 19.09 ± 0.2 ° in an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 θ.
5. Crystalline form of the salt of rosuvastatin-piperazine according to claim 4, further having at least one characteristic diffraction peak selected from the group consisting of 10.26 ± 0.2 °, 11.26 ± 0.2 °, 14.99 ± 0.2 °, 19.45 ± 0.2 ° and 22.25 ± 0.2 ° in an X-ray powder diffraction pattern expressed in diffraction angle 2 θ;
preferably, it further has at least one characteristic diffraction peak selected from the group consisting of 20.51 ± 0.2 °, 21.82 ± 0.2 °, 26.99 ± 0.2 °, 30.12 ± 0.2 ° and 38.76 ± 0.2 ° in an X-ray powder diffraction pattern expressed by diffraction angle 2 θ;
preferably, in the Fourier infrared spectrum, at a wavelength selected from 3405.56 + -2 cm-1、1506.56±2cm-1、1487.78±2cm-1、1401.98±2cm-1、3015.17±2cm-1、2918.74±2cm-1、1624.58±2cm-1、1577.25±2cm-1、1309.60±2cm-1、1283.63±2cm-1、1227.89±2cm-1、1166.99±2cm-1Has a characteristic peak at least one of them;
preferably, the crystalline Form is the roxasistat-piperazine anhydrate Form I having a decomposition temperature of 175 ± 2 ℃.
6. The process for the preparation of crystalline forms of the salt of rospastat-piperazine according to any one of claims 4 or 5, characterized in that it comprises the following steps:
a. mixing the roxasistat and the piperazine, adding an alcohol solvent, and stirring to obtain a suspension;
b. centrifuging and drying the suspension to obtain a crystalline form of the salt of the roxasistat piperazine;
preferably, the alcoholic solvent is a C1-C3 alkyl alcohol;
preferably, the alcoholic solvent is methanol;
preferably, the weight ratio of the roxasistat and the piperazine is 1-7: 1;
preferably, the concentration of the roxarstat in the alcohol solvent is 8-35 mg/mL;
preferably, in step a, the stirring is carried out at room temperature;
preferably, in step b, the drying temperature is 20-50 ℃.
7. A pharmaceutical composition comprising the crystalline form of the salt of rosxastat-histidine according to any one of claims 1 or 2 or the crystalline form of the salt of rosxastat-piperazine according to any one of claims 4 or 5, and at least one pharmaceutically acceptable carrier.
8. Use of the crystalline form of rosxastat-histidine salt selected from claim 1 or 2 or the crystalline form of rosxastat-piperazine salt selected from claim 4 or 5 or the pharmaceutical composition selected from claim 7 for the preparation of a medicament for the prevention or treatment of a disease, wherein the disease comprises chronic kidney disease, or anemia arising from chronic kidney disease, ischemia, hypoxia, or myelodysplastic syndrome MDS anemia.
9. A method for the prevention or treatment of a disease, characterized in that it comprises the step of administering to a subject in need thereof a crystalline form of rosisastat-histidinate according to claim 1 or 2, or a crystalline form of rosisastat-piperazine salt according to claim 4 or 5, or a pharmaceutical composition according to claim 7;
preferably, the disease comprises chronic kidney disease, or anemia, ischemia, hypoxia, or myelodysplastic syndrome MDS anemia caused by chronic kidney disease;
preferably, the method further comprises the step of administering to the subject in need thereof an additional pharmaceutically active ingredient.
10. The crystalline form of rosxastat-histidine salt according to any one of claims 1 or 2 and/or the crystalline form of rosxastat-piperazine salt according to any one of claims 4 or 5 for use in combination with a further medicament, wherein the further medicament is associated with chronic kidney disease, or anemia, ischemia, hypoxia caused by chronic kidney disease, or myelodysplastic syndrome MDS anemia.
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