CN115724796A

CN115724796A - New crystal form of roxasistat and preparation method thereof

Info

Publication number: CN115724796A
Application number: CN202110987741.3A
Authority: CN
Inventors: 曾雪遥; 谷慧科; 黄翠; 陈洪; 王颖
Original assignee: Sichuan Qingmu Pharmaceutical Co ltd; Chengdu Easton Biopharmaceuticals Co Ltd
Current assignee: Sichuan Qingmu Pharmaceutical Co ltd; Chengdu Easton Biopharmaceuticals Co Ltd
Priority date: 2021-08-26
Filing date: 2021-08-26
Publication date: 2023-03-03

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a novel crystal form of roxasistat and a preparation method thereof. The new crystal form of the roxasistat has the advantages of remarkably improved water solubility, high bioavailability, high stability, good pharmacy property and the like. The preparation method of the new crystal form takes water as a solvent, has good repeatability, low cost and environmental protection, and is suitable for industrial production.

Description

New crystal form of roxasistat and preparation method thereof

Technical Field

The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a novel crystal form of roxasistat and a preparation method thereof.

Background

Rosemastat is an oral Hypoxia Inducible Factor HIF (Hypoxia inductively Factor) prolyl hydroxylase inhibitor and is clinically used for treating anemia. HIF plays an important role in the homeostasis of oxygen in many organisms and is also a key regulator of hypoxia response. Genes regulated by the transcriptional activity of HIF play a pivotal role in angiogenesis, erythropoiesis, energy metabolism, inflammation, vasomotor function, apoptosis, and cell proliferation. The chemical name of the Rosemastat is N- [ (4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline) carbonyl ] glycine, which is sold in China at a rate of 17 days in 2018 by the Minn company's agency, and the product name of the Rosemastat is Eleutron. The structural formula is as follows:

erythropoietin (EPO), also known as erythropoiesis stimulating factor, is an endogenous glycoprotein hormone in humans that stimulates erythropoiesis. Hypoxia stimulates the production of Erythropoietin (EPO), a naturally occurring hormone produced by HIF α, which increases in levels with hypoxia, and induces HIF α production in animals suffering from anemia or hypoxia. Anemia of renal disease (i.e., renal anemia) refers to anemia arising from the relative or absolute deficiency of Erythropoietin (EPO) caused by various types of kidney diseases, as well as anemia arising from the interference of the production and metabolism of red blood cells by some toxic substances in the plasma of uremic patients. Renal anemia can accelerate the progression of Chronic Kidney Disease (CKD), increase hospitalization rate and mortality rate, significantly affect the quality of life of CKD patients, and is an independent risk factor for CKD patients with concurrent cardiovascular disease.

The compounds may exist in one or more crystalline forms. The crystal forms may also exhibit different stabilities, solubilities, dissolution rates, and bioavailabilities. The solubility of a drug is one of the many factors that affect drug absorption, and a drug needs to have a suitable solubility in an aqueous medium to exhibit a preferable bioavailability and therapeutic effect. The most stable crystal form of a drug product is generally selected during drug product development based on its minimal likelihood of conversion to another crystal form and its higher chemical stability. In order to ensure the quality, safety and efficacy of pharmaceutical products, it is important to select a crystal morphology that is stable, reproducibly manufactured and has favorable physicochemical properties.

At present, patents CN201380037479.X and CN201280036322.0 provide crystalline forms A, B, C, D, I, II, III, IV, V, VI and VII of roxasistat, wherein the crystalline forms C and D are solvates of hexafluoropropan-2-ol and DMSO-water respectively, and are difficult to apply to preparations due to the problems of excessive solvent toxicity or solvent residues and the like, and the crystalline forms of the two are unstable and are easy to convert into the crystalline form A. The preparation process of the crystal forms II, III, IV, V and VI is more than 48 hours, the crystal form I is subjected to volatilization crystallization, the time consumption is long, the efficiency is low, the crystal form VII is obtained by heating the crystal form V at 180 ℃, more impurities are easily generated at high temperature, and the actual substance basis of the crystal form VII can be isomers of the roxarsone according to the provided synthetic route; the crystal form B has poor stability, and can be crystallized after being placed at room temperature; form a is the most stable, but it is almost insoluble in water.

Patent CN111511371A discloses a hydrate crystal form δ, but it is easy to be transformed into crystal form a at high temperature, and formic acid is easy to form solvate γ with roxasistat, and there is also a problem that the dissolution residue is difficult to control.

Therefore, in order to ensure the quality, safety and efficacy of the pharmaceutical product, a crystalline form of roxasistat with low residual toxicity, good stability, good solubility and high bioavailability still needs to be developed, so that more choices are provided for preparation and clinic.

Disclosure of Invention

In order to solve the problems, the invention provides a new crystal form Y-1 of the roxasistat, and simultaneously discloses a preparation method of the new crystal form Y-1 of the roxasistat.

In a first aspect, the invention provides a new crystalline form Y-1 of roxasistat, wherein the X-ray powder diffraction pattern of the new crystalline form Y-1 of roxasistat is shown in the specification of diffraction angle 2 theta: characteristic peaks are arranged at 3.12 +/-0.2 degrees, 6.24 +/-0.2 degrees, 12.64 +/-0.2 degrees, 16.96 +/-0.2 degrees, 24.70 +/-0.2 degrees, 25.46 +/-0.2 degrees and 26.70 +/-0.2 degrees.

Preferably, the X-ray powder diffraction pattern of the crystalline form Y-1 is characterized by a diffraction angle of 2 θ: characteristic peaks are arranged at the positions of 3.12 +/-0.2 degrees, 6.24 +/-0.2 degrees, 12.64 +/-0.2 degrees, 13.46 +/-0.2 degrees, 16.96 +/-0.2 degrees, 20.80 +/-0.2 degrees, 24.70 +/-0.2 degrees, 25.46 +/-0.2 degrees, 26.12 +/-0.2 degrees, 26.70 +/-0.2 degrees and 29.18 +/-0.2 degrees.

More preferably, the crystalline form Y-1 has an X-ray powder diffraction pattern at diffraction angles 2 θ: characteristic peaks are arranged at 3.12 +/-0.2 degrees, 6.24 +/-0.2 degrees, 10.94 +/-0.2 degrees, 11.36 +/-0.2 degrees, 11.92 +/-0.2 degrees, 12.64 +/-0.2 degrees, 13.46 +/-0.2 degrees, 15.50 +/-0.2 degrees, 16.48 +/-0.2 degrees, 16.96 +/-0.2 degrees, 17.84 +/-0.2 degrees, 18.80 +/-0.2 degrees, 20.18 +/-0.2 degrees, 20.80 +/-0.2 degrees, 21.86 +/-0.2 degrees, 23.20 +/-0.2 degrees, 24.70 +/-0.2 degrees, 25.46 +/-0.2 degrees, 26.12 +/-0.2 degrees, 26.70 +/-0.2 degrees, 27.28 +/-0.2 degrees, 29.18 +/-0.2 degrees, 29.92 +/-0.2 degrees, 30.24 +/-0.2 degrees, 30.52 +/-0.2 degrees.

The X-ray powder diffraction pattern of the crystal form Y-1 is basically shown in figure 1.

The DSC pattern of the crystal form Y-1 is basically shown in figure 2, and the crystal form Y-1 has an endothermic peak at 153 +/-3 ℃. The TGA spectrum of the crystal form Y-1 is basically shown in figure 3, and the weight loss of the crystal form Y-1 is about 6.91 percent in the range of 30-160 ℃.

The crystal form Y-1 is 1.5 aqueous hemisodium hydrate of the roxasistat.

In one embodiment, single crystal data for form Y-1 is provided.

In a second aspect, the invention also provides a preparation method of the new crystal form Y-1 of the roxasistat.

The preparation method of the new crystal form Y-1 of the roxasistat comprises the following steps:

under certain conditions, dissolving the roxasistat in a single solvent of phosphate buffer aqueous solution with the pH value of 6.0-6.9 or a binary solvent consisting of the roxasistat and tetrahydrofuran, completely dissolving to obtain a roxasistat dissolved solution, filtering, crystallizing, and collecting obtained solid to obtain the new crystal form Y-1.

Preferably, the pH value of the phosphate buffer aqueous solution is 6.6-6.8.

Preferably, the phosphate buffer aqueous solution is prepared from disodium hydrogen phosphate/sodium dihydrogen phosphate.

Preferably, the concentration of the solution of the roxarsone is 0.6 mg/ml-1.5 mg/ml.

More preferably, the concentration of the solution of the roxarsone is 0.7 mg/ml-1.2 mg/ml.

Preferably, the crystallization method is selected from stirring crystallization or crystallization by adding Y-1 crystal form seed crystal.

More preferably, the crystallization method is crystallization by adding Y-1 crystal seed crystal.

Preferably, the crystallization temperature is 5 to 35 ℃.

Preferably, the crystallization time is 2h to 72h.

More preferably, the crystallization time is 4 to 24 hours.

Preferably, the preparation method of the new crystal form Y-1 of the roxasistat comprises the following steps: dissolving the roxasistat in phosphate buffer aqueous solution with the pH value of 6.0-6.9 under the condition of temperature rise, filtering after complete dissolution, stirring for crystallization at room temperature or under the condition of temperature reduction or adding Y-1 crystal form crystal seeds for crystallization for 2-72 h, collecting obtained solid, and drying to obtain the new crystal form Y-1.

The inventor researches and discovers that the solubility of the crystal form A of the roxasistat with poor water solubility is abnormally increased in a phosphate buffer solution with a medium pH6.8, and a new crystal form is screened out by taking the medium as a good solvent; the solubility of the roxasistat in water can be obviously improved through acid-base salt formation, but the same effect cannot be achieved through acid-base salt formation reaction under the condition of the same pH end point, and the obtained product is basically in a crystal form A.

The beneficial technical effects of the invention are as follows:

compared with the crystal form A in the prior art, the novel crystal form Y-1 of the rosxastat provided by the invention has the advantages that the water solubility of the crystal form Y-1 is obviously improved, the pharmacokinetic characteristic is excellent, and the bioavailability is high, so that the novel crystal form Y-1 of the rosxastat has the characteristic of good drug forming property and also has the potential of preparing various dosage forms of drugs.

The preparation method of the new crystal form Y-1 of the roxasistat, provided by the invention, takes water as a main solvent, and is simple in preparation process, good in repeatability, high in stability, high in yield, low in cost, environment-friendly and suitable for industrial production.

Drawings

FIG. 1 shows the XRD pattern of the new crystalline form Y-1 of Rosemaxostat

FIG. 2 shows the DSC pattern of new crystalline form Y-1 of Rosemastat

FIG. 3 shows a TGA profile of new crystalline form Y-1 of Rosemastat

FIG. 4 shows a microscope topography picture of the new crystalline form Y-1 of Rosemastat

FIG. 5 shows a molecular structure diagram of new crystalline form Y-1 of Rosemastat

FIG. 6 shows the mean drug concentration-time curve of the new crystalline form Y-1 of Rosemastat

Detailed Description

Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention.

The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.

The terms used in this application are explained as follows:

the term XRD refers to X-ray powder diffraction. In the invention, the related powder X-ray diffraction test instrument is as follows: powder diffractometer DANDONHUAN DX-2700B; and (3) testing conditions: ray of Cu K instrument, 40kV,40mA,

3-40°。

the term DSC refers to a differential scanning calorimeter. In the invention, the differential scanning calorimeter is as follows: mettler-toledo DSC1; and (3) testing conditions: 25-250 ℃ at 10 ℃/min; n is a radical of hydrogen ₂ (50mL/min)。

The term TGA refers to a thermogravimetric analyzer. In the invention, the related thermogravimetric analyzer is as follows: mettler-tolliduo TGA2; and (3) testing conditions: 30-250 ℃ and 10 ℃/min; n is a radical of ₂ (50mL/min)。

The term LC/MS/MS biological sample analysis refers to the biological sample analysis by using a liquid chromatography-mass spectrometry technology, and the technology has higher sensitivity and selectivity and wide applicability to the analysis of mixtures and can carry out rapid and reliable quantitative or qualitative analysis on trace compounds in complex biological matrixes.

In the invention, the liquid chromatograph-mass spectrometer (mass spectrum) comprises: AB Sciex Triple Quad 4500.

In the present invention, the polarizing microscope is: shanghai Chuikang optical XP-550C polarizing microscope.

The high performance liquid chromatograph of the invention is: agilent 1260 Infinity.

In the invention, the related single crystal X-ray diffractometer is as follows: physics xtlab PRO.

In the context of the present invention, the diffraction angle 2 θ (also called 2theta or diffraction peak) values in the X-ray powder diffraction pattern are all in degrees (. Degree.).

The term "diffraction peak" when referring to a map and/or data in a map refers to a feature that one skilled in the art would not ascribe to background noise.

The X-ray powder diffraction peaks of the crystals, the measurements of the 2theta or diffraction peaks of the X-ray powder diffraction pattern of which have experimental errors, may differ slightly between one machine and another and between one sample and another, may have values of +/-0.2 units, and therefore the values of the 2theta or diffraction peaks cannot be considered absolute.

The Differential Scanning Calorimetry (DSC) curve of the crystal has experimental errors, the position and peak value of the endothermic peak may slightly differ between one machine and another machine and between one sample and another sample, and the value of the experimental error or difference may be 5 ℃ or less, 4 ℃ or less, 3 ℃ or less, 2 ℃ or less, or 1 ℃ or less, so the value of the peak position or peak value of the endothermic peak of the DSC cannot be regarded as absolute.

The thermogravimetric analysis curve (TGA) of the crystal has experimental errors, the endothermic curve or the weight loss rate may slightly differ between one machine and another and between one sample and another, the numerical value of the experimental error or difference may be less than or equal to 0.004% or 0.003% or 0.002% or 0.001%, and thus the thermogravimetric analysis curve or the weight loss rate thereof cannot be regarded as absolute.

EXAMPLE 1 preparation of crystalline form Y-1

Weighing 1.0g of roxasistat, adding 0.83L of disodium hydrogen phosphate/sodium dihydrogen phosphate buffer water solution (the concentration of the roxasistat is 1.2 mg/ml) with the pH value of 6.6, heating to 70 ℃, stirring, dissolving, filtering, cooling to 5 ℃, stirring, crystallizing for 72h, collecting obtained solid, washing filter cakes with purified water, and drying to obtain crystal form Y-1.71g, light yellow crystalline solid, wherein the yield is 64.17%, and the purity is 99.94%. The XRD patterns are substantially as shown in table 1 and figure 1.

TABLE 1 diffraction angle, interplanar spacing and relative intensity for crystalline form Y-1 of Rosesarta

EXAMPLE 2 preparation of crystalline form Y-1

Weighing 1.0g of roxasistat, adding 1.43L of disodium hydrogen phosphate/sodium dihydrogen phosphate buffer water solution (the concentration of the roxasistat is 0.7 mg/ml) with the pH value of 6.8, heating to 70 ℃, stirring for dissolving, filtering, cooling to 15 ℃, adding crystal form Y-1 seed crystal, stirring for crystallization for 2 hours, collecting obtained solid, washing filter cakes with purified water, and drying to obtain crystal form Y-10.78g of light yellow crystalline solid, wherein the yield is 70.50% and the purity is 99.94%. The XRD pattern substantially corresponds to that of fig. 1. The DSC pattern is basically shown in figure 2, and the TGA pattern is basically shown in figure 3.

EXAMPLE 3 preparation of crystalline form Y-1

Weighing 1.0g of roxasistat, adding 1.67L of disodium hydrogen phosphate/sodium dihydrogen phosphate buffer water solution (the concentration of the roxasistat is 0.6 mg/ml) with the pH value of 6.0, heating to 70 ℃, stirring for dissolving, filtering, cooling to 5 ℃, adding crystal form Y-1 seed crystal, stirring for crystallization for 24 hours, collecting obtained solid, washing filter cakes with purified water, and drying to obtain crystal form Y-1.68g of light yellow crystalline solid with the yield of 61.46 percent and the purity of 99.93 percent. The XRD pattern substantially corresponds to that of fig. 1. The micrograph of the sample is substantially as shown in FIG. 4 and is a rhombohedral plate crystal.

EXAMPLE 4 preparation of crystalline form Y-1

Weighing 1.0g of roxasistat, adding 0.67L of disodium hydrogen phosphate/sodium dihydrogen phosphate buffer water solution (the concentration of the roxasistat is 1.5 mg/ml) with the pH value of 6.9, heating to 80 ℃, stirring, dissolving, filtering, cooling to 35 ℃, adding crystal form Y-1 seed crystal, stirring, crystallizing for 4 hours, collecting obtained solid, washing filter cakes with purified water, and drying to obtain crystal form Y-10.82g of light yellow crystalline solid with the yield of 74.11% and the purity of 99.95%. The XRD pattern substantially corresponds to that of fig. 1.

EXAMPLE 5 preparation of crystalline form Y-1

Weighing 1.0g of roxasistat, adding 0.71L of disodium hydrogen phosphate/sodium dihydrogen phosphate buffer water solution (the concentration of the roxasistat is 1.41 mg/ml) with the pH value of 6.8, heating to 70 ℃, stirring, dissolving, filtering, cooling to 25 ℃, adding crystal form Y-1 seed crystal, stirring, crystallizing for 24 hours, collecting obtained solid, washing filter cakes with purified water, and drying to obtain crystal form Y-1.83g of light yellow crystalline solid with the yield of 75.02% and the purity of 99.95%. The XRD pattern substantially corresponds to that of fig. 1.

EXAMPLE 6 preparation of crystalline form Y-1

Weighing 1.0g of roxasistat, adding 0.57L of disodium hydrogen phosphate/sodium dihydrogen phosphate buffer water solution with the pH value of 6.8 and 0.10L of tetrahydrofuran (the concentration of the roxasistat is 1.5 mg/ml), heating to 70 ℃, stirring, dissolving, filtering, cooling to 25 ℃, adding crystal form Y-1 crystal seeds, stirring, crystallizing for 24 hours, collecting obtained solid, washing filter cakes with purified water, and drying to obtain crystal form Y-1.79g of light yellow crystalline solid with the yield of 71.40% and the purity of 99.92%. The XRD pattern substantially corresponds to that of fig. 1.

EXAMPLE 7 Single Crystal growth and Single Crystal diffraction of form Y-1

Weighing 50mg of roxasistat, adding 5.0ml of disodium hydrogen phosphate/sodium dihydrogen phosphate buffer water solution, heating to dissolve, filtering, volatilizing at the high temperature of 40 ℃ until the mixture is dried to obtain a single crystal sample with large particle size and regular shape, performing single crystal diffraction analysis on the single crystal sample, wherein the obtained single crystal data are shown in Table 2, and the structure diagram of the single crystal analytic molecule is shown in figure 5.

TABLE 2 Rosemastat crystal form Y-1 single crystal data sheet

Comparative example 1 preparation of a novel crystalline form using purified water as solvent

Weighing 1.0g of roxasistat, adding 1.43L of purified water with the pH value of 6.8, heating to 70 ℃, stirring, wherein a large amount of solid is difficult to dissolve, performing suction filtration, and drying a filter cake to obtain about 0.989g of crystal form A of the roxasistat, wherein the roxasistat is found to be almost insoluble. The filtrate is cooled to 5 ℃, and no solid is separated out. The crystal form Y-1 seed crystal is added, and the obvious crystallization phenomenon is avoided.

Comparative example 2 preparation of a novel crystalline form by acid-base neutralization

Weighing 1.0g of roxasistat, adding 15.0ml of water, adding 0.136g of sodium hydroxide, heating to 30 ℃, stirring to dissolve, filtering, dropwise adding 1N hydrochloric acid into the filtrate until the pH value is 6.8, precipitating a large amount of solid, filtering, washing with water, drying, and determining the obtained solid to be a crystal form A through XRD.

Test example 1 solubility test of crystalline form Y-1 of Rosesartat

In order to examine the solubility difference between the crystalline form Y-1 of the crystalline rosisase prepared in example 1 of the present invention and the pharmaceutical crystalline form A purchased from Shanghai Yingrui biomedical science and technology Co., ltd, the present invention examines the equilibrium solubility (saturated solution) of the crystalline form Y-1 prepared in example 1 and the pharmaceutical crystalline form A measured by external standard method under the conditions of pure water, pH4.5 and pH6.8 medium at 25 ℃/37 ℃ respectively, and the results are shown in the following Table 3:

TABLE 3 solubility test

Solubility test results show that compared with the medicinal crystal form A, the new crystal form Y-1 has obvious advantages in equilibrium solubility in three media, namely pure water, pH4.5 and pH6.8 under two temperature conditions, and the solubility is obviously improved.

Experimental example 2 stability investigation experiment of crystalline form Y-1 of Rosemastat

To examine the stability obtained by the preparation of example 1 of the present invention, the obtained samples were subjected to the influence factor test under high humidity and illumination, and the long-term stability test was laid out at 25. + -.2 ℃ -60. + -.5% RH and the accelerated stability test at 40. + -. 2 ℃ -75. + -.5% RH, with the results shown in the following Table 4:

TABLE 4 stability test

The stability test result shows that the crystal form Y-1 has good crystal form stability under the investigated conditions, and basically no obvious impurity increase occurs within 1 month under each condition.

Test example 3 in vivo pharmacokinetic test in rats

1. Purpose of the test

The concentration level of the rosxastat in the plasma and the pharmacokinetic characteristics thereof after a single oral administration of the rosxastat crystal form a and the crystal form Y-1 in rats under the same administration dose are examined.

2. Materials and methods

2.1 test drugs

Crystalline form a of roxasistat, provided by bio-pharmaceutical technology ltd, won rui, shanghai, as a white-like solid, lot No. 20200705, purity: 99.97 percent;

the crystalline form Y-1 of the roxasistat, provided by the research department on the crystalline forms of Chengdouyuan Dong biopharmaceutical GmbH, is a light yellow solid with purity: 99.94 percent;

2.2 test animals

SD rats 6, female, weighing 220-240g, purchased from slacquard laboratory animals ltd, hannan, by cheneservier, inc, license number: SCXK (Xiang) 2019-0004.

2.3 test methods

After the tested medicine is prepared into 1.25mg/kg uniform suspension by corn oil, the uniform suspension is immediately orally administered to rats according to the volume of 4mL/kg, 0.1mL of blood is taken from jugular vein before and after administration for 15min, 30min, 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h and 24h, the blood is placed in an EDTA-K2 tube for 3000r/min, centrifugation is carried out for 10min, and blood plasma is separated and is frozen and stored in a refrigerator at the temperature of-80 ℃.

2.4, LC/MS/MS biological sample analysis:

mixing 50 μ L of plasma with 5 μ L of working solution or blank diluent, adding 150 μ L of acetonitrile precipitant containing internal standard, vortex vibrating for 2min, centrifuging for 10min at 12000r/min, mixing supernatant 2 μ L with 200 μ L of pure water: after mixing acetonitrile (1.

2.5, test results:

respectively carrying out animal experiments on the roxasistat crystal form A and the roxasistat crystal form Y-1, namely testing the average concentration (ng.mL) of API in blood plasma at different times after single oral administration to female rats ^-1 ) The mean drug concentration-time curves in plasma of female rats after a single oral administration are plotted in fig. 6, with the main pharmacokinetic parameters as follows:

parameter(s)	Crystal form A	Crystal form Y-1
			T _1/2 (h)	4.06±2.25	4.24±1.82
T _max (h)	0.67±0.29	2.17±1.61
			C _max (ng·mL ^-1 )	79.43±8.26	74.47±9.45
AUC _last (h·ng·mL ^-1 )	576.2±64.03	825.13±211.11
			Cl_F_obs(mL/hr/kg)	16.98±1.93	12.44±3.82
MRT(h)	5.24±0.96	5.93±0.85

The experimental result shows the AUC of the crystal form Y-1 _last Is obviously larger than AUC of the crystal form A _last And other pharmacokinetic parameters are similar to those of the medicinal crystal form A, so that the bioavailability of the crystal form Y-1 obtained by the invention is higher than that of the crystal form A, and the crystal form A has more advantages.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. Crystalline form Y-1 of roxasistat, characterized in that the X-ray powder diffraction pattern of crystalline form Y-1 is at diffraction angle 2 θ: characteristic peaks are arranged at 3.12 +/-0.2 degrees, 6.24 +/-0.2 degrees, 12.64 +/-0.2 degrees, 16.96 +/-0.2 degrees, 24.70 +/-0.2 degrees, 25.46 +/-0.2 degrees and 26.70 +/-0.2 degrees.

2. Crystalline form Y-1 of rosuvastatin according to claim 1, wherein the crystalline form Y-1 has an X-ray powder diffraction pattern at diffraction angles 2 Θ: characteristic peaks are arranged at the positions of 3.12 +/-0.2 degrees, 6.24 +/-0.2 degrees, 12.64 +/-0.2 degrees, 13.46 +/-0.2 degrees, 16.96 +/-0.2 degrees, 20.80 +/-0.2 degrees, 24.70 +/-0.2 degrees, 25.46 +/-0.2 degrees, 26.12 +/-0.2 degrees, 26.70 +/-0.2 degrees and 29.18 +/-0.2 degrees.

3. Crystalline form Y-1 of rosuvastatin according to claim 2, wherein the crystalline form Y-1 has an X-ray powder diffraction pattern at diffraction angles 2 Θ: characteristic peaks are arranged at 3.12 +/-0.2 degrees, 6.24 +/-0.2 degrees, 10.94 +/-0.2 degrees, 11.36 +/-0.2 degrees, 11.92 +/-0.2 degrees, 12.64 +/-0.2 degrees, 13.46 +/-0.2 degrees, 15.50 +/-0.2 degrees, 16.48 +/-0.2 degrees, 16.96 +/-0.2 degrees, 17.84 +/-0.2 degrees, 18.80 +/-0.2 degrees, 20.18 +/-0.2 degrees, 20.80 +/-0.2 degrees, 21.86 +/-0.2 degrees, 23.20 +/-0.2 degrees, 24.70 +/-0.2 degrees, 25.46 +/-0.2 degrees, 26.12 +/-0.2 degrees, 26.70 +/-0.2 degrees, 27.28 +/-0.2 degrees, 29.18 +/-0.2 degrees, 29.92 +/-0.2 degrees, 30.24 +/-0.2 degrees, 30.52 +/-0.2 degrees.

4. Crystalline form Y-1 of rosmarinic acid of claim 3, wherein crystalline form Y-1 has an X-ray powder diffraction pattern substantially as shown in figure 1.

5. Crystalline form Y-1 of rosxastat according to claim 3, wherein the crystalline form Y-1 is 1.5 hemihydrates of rosxastat.

6. Crystalline form Y-1 of rosuvastatin according to claim 3, wherein the crystalline form Y-1 exhibits an endothermic peak at 153 ± 3 ℃ in differential scanning calorimetry, preferably the crystalline form Y-1 differential scanning calorimetry is as shown in figure 2.

7. Crystalline form Y-1 of rosmarinic acid of claim 3, wherein the crystalline form Y-1 has a thermogravimetric analysis profile with a weight loss of about 6.91% at 30-160 ℃, preferably the crystalline form Y-1 thermogravimetric analysis profile is shown in figure 3.

8. A process for the preparation of crystalline form Y-1 of roxasistat according to claim 1, wherein the process comprises: under certain conditions, dissolving the roxasistat in a single solvent of phosphate buffer aqueous solution with the pH value of 6.0-6.9 or a binary solvent consisting of tetrahydrofuran, completely dissolving to obtain a roxasistat dissolved solution, filtering, crystallizing, and collecting the obtained solid to obtain the crystal form Y-1.

9. The method according to claim 8, wherein the aqueous phosphate buffered solution has a pH of 6.6 to 6.8; the concentration of the solution of the roxasistat is 0.6 mg/ml-1.5 mg/ml; the preferred concentration is 0.7mg/ml to 1.2mg/ml.

10. The method of claim 8, wherein the aqueous phosphate buffer solution is selected from the group consisting of sodium phosphate dibasic/sodium phosphate monobasic; the crystallization method is selected from stirring crystallization or adding Y-1 crystal form seed crystal for crystallization, preferably adding Y-1 crystal form seed crystal for crystallization; the crystallization temperature is 5-35 ℃; the crystallization time is 2-72 h; preferably 4 to 24 hours.