CN114174264A

CN114174264A - Crystal form XI of varlitinib mesylate and preparation method thereof

Info

Publication number: CN114174264A
Application number: CN202180004022.3A
Authority: CN
Inventors: 谷慧科; 先小超; 丁哲; 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: 2020-04-24
Filing date: 2021-04-22
Publication date: 2022-03-11
Anticipated expiration: 2041-04-22
Also published as: JP7466642B2; KR20230003036A; KR102581450B1; CN114174264B; WO2021213453A1; JP2023510684A

Abstract

An X-ray powder diffraction pattern of a varlitinib mesylate crystal form XI is shown in figure 1. The crystal form XI of the pravastatin mesylate has good solubility, better pharmacokinetic property and good stability, and the preparation method of the crystal form XI of the pravastatin mesylate has mild technological conditions, simple and easily-recycled solvent system, simple and convenient operation and good stability.

Description

Crystal form XI of varlitinib mesylate and preparation method thereof

Technical Field

The application relates to the field of pharmaceutical crystal forms, in particular to a pravastatin mesylate crystal form and a preparation method thereof.

Background

Lunvatinib (Lenvatinib), chemical name: 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide, which has a structural formula shown in the formula (I).

Lovatinib is a drug for thyroid and liver cancer developed by Nippon kawakame K.K. Lovatinib is an oral multi-Receptor Tyrosine Kinase (RTK) inhibitor with a novel binding pattern to its receptor that selectively inhibits the kinase activity of Vascular Endothelial Growth Factor (VEGF) receptors in addition to inhibiting other angiogenesis and oncogenic signaling pathway related RTKs involved in tumor proliferation. FDA approval was obtained on day 02/13 of 2015 for treatment of patients with advanced differentiated thyroid cancer with radioactive iodine refractory local recurrence or metastasis, and then subsequently approved in the european union and japan sequentially, and approved by the chinese drug administration on day 09/05 of 2018 for treatment of unresectable liver cancer patients who have not received systemic treatment.

Patents CN100569753C, CN101337931B, CN101337932B and CN101337933B disclose crystalline form A, B, C, F, I of melphalan mesylate. Wherein, the anhydrous crystal form B can be transformed into the crystal form C or mixed crystal with the crystal form C under different humidity conditions, and the crystal form I can be transformed into the crystal form C or mixed crystal with the crystal form C under different humidity conditions, so the crystal form B and the crystal form I are not stable.

In view of the above, there is still a need in the art to provide a crystal form of varlitinib mesylate and a preparation method thereof, wherein the crystal form has good stability, better product quality, simple and convenient preparation process, and is suitable for industrial production.

Disclosure of Invention

The invention aims to provide a crystal form of pravastatin mesylate, and solves the problems that the crystal form of pravastatin mesylate in the prior art is poor in stability, unstable in product quality, complex in preparation process, incapable of large-scale production and the like.

In order to solve the technical problems, the technical scheme of the invention is as follows:

crystalline form XI of orvatinib mesylate has an X-ray powder diffraction pattern including diffraction peaks at angles (2 θ) of about 5.73 ° ± 0.2 °, 8.03 ° ± 0.2 °, 11.45 ° ± 0.2 °, 12.75 ° ± 0.2 °, 16.15 ° ± 0.2 °, 17.24 ° ± 0.2 °, 18.16 ° ± 0.2 °, 19.69 ° ± 0.2 °, 20.68 ° ± 0.2 °, 22.15 ± 0.2 °, 22.96 ± 0.2 °, 23.76 ± 0.2 °, 24.32 ± 0.2 °, 25.13 ± 0.2 °, 26.32 ± 0.2 °, 27.00 ± 0.2 °, 28.87 ± 0.2 °, 29.51 ± 0.2 °, 34.90 ± 0.2 °.

Preferably, said crystalline form XI exhibits an X-ray powder diffraction pattern substantially as shown in figure 1.

Preferably, said form XI has Differential Scanning Calorimetry (DSC) endothermic peaks at 114.05 + -5 deg.C and 158.56 + -5 deg.C, respectively.

Preferably, said crystalline form XI has a weight loss of about 6.94% by thermogravimetric analysis (TGA) in the range of 30-140 ℃.

Preferably, said crystalline form XI has a moisture content of 6.5%.

Preferably, said crystalline form XI is varenib mesylate dihydrate containing 2 water of crystallization.

The invention also provides a preparation method of the pravastatin mesylate crystal form XI, which comprises the following steps:

(1) stirring and mixing ethyl acetate and purified water at room temperature according to a certain volume ratio;

(2) adding the varlitinib mesylate to the mixed solvent in the step (1);

(3) and (3) after the suspension obtained in the step (2) is uniformly dispersed, adding a certain amount of crystal seed crystal of the crystal form XI, stirring for 4-24h at the temperature of 15-40 ℃, and performing suction filtration and drying to obtain solid powder, thus obtaining the crystal form XI of the methanesulfonic acid lunvatinib.

Preferably, in step (1), the volume ratio of ethyl acetate to purified water is 100 mL: (2-10) mL; further preferably, the volume ratio of ethyl acetate to purified water is 100 mL: (2-5) mL; most preferably 100 mL: 3 mL.

Preferably, in the step (2), the mass-to-volume ratio of the pravastatin mesylate to the ethyl acetate in the mixed solvent of the step (1) is 1 g: (10-30) mL; further preferably, the mass-to-volume ratio of the varlitinib mesylate to the ethyl acetate in the mixed solvent of the step (1) is 1 g: (15-25) mL; most preferably 1 g: 20 mL.

Preferably, in the step (3), the crystal seeds of a certain amount of the crystal form XI are 0-10% of the mass fraction of the fed amount of the varlitinib mesylate; further preferably, the seed crystal of the crystal form XI in a certain amount is 2-6% of the mass fraction of the varlitinib mesylate; most preferably 5%.

Preferably, the reaction temperature is 20-30 ℃; preferably 20 to 25 ℃; most preferably 25 deg.c.

Preferably, the stirring time is 6-12 h; preferably 6-10 h; most preferably 8 h.

Further preferably, the preparation method of the crystalline form XI of the pravastatin mesylate comprises the following steps:

(1) and uniformly mixing ethyl acetate and purified water at room temperature with stirring, wherein the volume ratio of the ethyl acetate to the purified water is 100 mL: 3 mL;

(2) adding the pravastatin mesylate to the mixed solvent in the step (1), wherein the mass-volume ratio of the pravastatin mesylate to the ethyl acetate is 1 g: 20 mL;

(3) and (3) after the suspension in the step (2) is uniformly dispersed, adding crystal seeds of a crystal form XI, wherein the dosage of the crystal seeds is 5% of the mass fraction of the feeding amount of the varlitinib mesylate, stirring for 8 hours at 25 ℃, and performing suction filtration and drying to obtain solid powder, thus obtaining the varlitinib mesylate crystal form XI.

The crystal form XI of the methanesulfonic acid lunvatinib, which is prepared by the invention, has the following advantages:

1. the crystal form XI of the methanesulfonic acid lunvatinib has good solubility, good pharmacokinetic characteristic and good stability, and is suitable for preparing pharmaceutical preparations.

2. The crystal form XI of the methanesulfonic acid lunvatinib can keep stable under the conditions of high temperature, high humidity and illumination.

3. The crystal form XI of the methanesulfonic acid lunvatinib is good in fluidity, good in compressibility, large in bulk density, low in hygroscopicity and uniform in particle size distribution.

4. The crystal form XI of the methanesulfonic acid lunvatinib is high in purity, is not an organic solvate, has no risk of organic solvent residue, and is high in safety.

5. The preparation method of the methanesulfonic acid lunvatinib crystal form XI can avoid using acetic acid, and the obtained product has high purity, low impurity, high yield, mild process condition, simple and easily-recovered solvent system, simple and convenient operation, good stability, can stably prepare kilogram-grade products, and is beneficial to large-scale industrial production.

Drawings

FIG. 1 XRD pattern of crystalline form XI of EXAMPLE 1 Revatinib mesylate

FIG. 2 DSC pattern of crystalline form XI of example 1 Revatinib mesylate

FIG. 3 TGA spectrum of crystalline form XI of EXAMPLE 1 Revatinib mesylate

FIG. 4 DVS map of crystalline form XI of example 1 Revatinib mesylate

Figure 5 example 11 crystalline form XI of varlitinib mesylate XRD contrast patterns under different standing conditions

Detailed Description

The present application will be described in further detail with reference to the following examples, which are only for illustrating the technical solutions of the present application and are not intended to limit the spirit and scope of the present application.

The abbreviations used in this application are explained as follows:

XRD: powder X-ray diffraction

The determination of X-ray powder diffraction (XRD) described in this application is collected by powder diffractometer Liaoning Danhaoyuan DX-2700B, and the specific parameters are as follows:

DSC: differential scanning calorimeter

The Differential Scanning Calorimetry (DSC) described herein employs METTLER TOLEDO model DSC-1 for collection, with a temperature rise rate of 10 deg.C/min, a temperature range of 25-250 deg.C, and a nitrogen purge rate of 60mL/min during testing.

TGA: thermogravimetric analyzer

Thermogravimetric analysis (TGA) described herein is measured using a METTLER TOLEDO model TGA-2 with a temperature rise rate of 10 ℃/min, a temperature range of 30-250 ℃, and a nitrogen purge rate of 20mL/min during the test.

DVS: dynamic steam adsorption analyzer

The dynamic vapor sorption analysis (DVS) described herein was performed using a TA model Q5000SA acquisition with an equilibrium temperature of 25 ℃ and the specific test parameters are shown in the table below.

KF: ka's moisture tester

The moisture described herein was measured using a Metrohm model 870KF Titrino plus karman moisture meter.

GC: gas chromatograph

The solvent residue described in the present application was determined using an agilent model 7890B gas chromatograph, the specific parameters of which are shown in the table below.

Equilibrium temperature	110℃	Temperature of detector	250℃
Quantitative ring
	120℃	Air flow rate	400mL/min
Transmission line
	130℃	Flow rate of hydrogen	30mL/min
Time of equilibrium	30miN	Auxiliary gas flow	25mL/min
GC cycle time	42min	Flow rate of carrier gas (nitrogen)	1.5mL/min
Head space bottle	20mL	Temperature at sample inlet	180℃
Split ratio	1:1	Sample introduction/run time	0.5/34min

HPLC: high performance liquid chromatography

The HPLC spectra were determined using an Agilent model 1260DAD, Agilent, Ach. In the present application, the purity of the varlitinib mesylate HPLC was performed by the following method:

(1) chromatographic column using octadecylsilane chemically bonded silica as filler

(2) A detector: ultraviolet detector (wavelength 252nm and 205nm)

(3) Flow rate: 1mL per minute

(4) Operating time: about 2.7 times the retention time of the Ranvatinib peak, measured from the solvent peak

(5) Test solution: taking 12.5mg of the product, precisely weighing, adding solvent, dissolving and diluting to obtain solution containing 0.5mg per 1mL, and using as test solution

(6) Sample introduction amount: and 10 mu l of the test solution is measured by an automatic integration method, and the purity of the test sample in the Ranatinib is calculated according to the peak area.

Solvent screening experiments

In order to find a new crystal form of the pravastatin mesylate, the inventor screens the new crystal form by suspending a certain amount of pravastatin mesylate in a reaction solvent, stirring for 6-8h at 25 ℃, and carrying out suction filtration and drying.

In screening the reaction solvents, it was surprisingly found that when the reaction solvent was a mixed solvent of ethyl acetate and water, a novel crystalline form XI of varlitinib mesylate was obtained, the results of which are shown in table 1 below.

Table 1 experimental results for the preparation of form XI in different solvent systems

Solvent system	Crystal form
Methanol	Crystal form A
Ethanol	Crystal form A
Acetone (II)	Crystal form A
Acetonitrile	Crystal form A
Ethyl acetate	Crystal form C
Ethanol and water	Crystal form A
Acetone and water	Crystal form A
Ethyl acetate: water 100 mL: 15mL of	Jelly
Ethyl acetate: water 100 mL: 10mL	Crystalline form XI
Ethyl acetate: water 100 mL: 5mL	Crystalline form XI
Ethyl acetate: water 100 mL: 3mL of	Crystalline form XI
Ethyl acetate: water 100 mL: 2mL	Crystalline form XI
Ethyl acetate: water 100 mL: 1mL of	Solvates

As can be seen from table 1 above, when pure organic solvents are used as reaction solvents, such as methanol, ethanol, acetone, etc., the obtained product is form a or form C; when other mixed solvents are used as the reaction solvent, such as a mixed solvent of ethanol and water, the obtained product is the crystal form a; from table 1, it can be seen that when the volume ratio of ethyl acetate to water is 100 mL: (2-10) mL, the best effect and the most stable method can be obtained.

Example 1: preparation of crystalline form XI of varlitinib mesylate

Stirring and mixing 200mL of ethyl acetate and 10mL of purified water at room temperature, then adding 10.0g of methane sulfonic acid ranvatinib into a mixed solvent of the ethyl acetate and the purified water, stirring for 24h at 25 ℃ after the suspension is dispersed uniformly, and performing suction filtration and drying to obtain 9.1g of solid powder. The yield was 91.0% and the purity was 99.73%.

¹The H-NMR data are as follows:

¹H NMR(400MHz,d ₆-DMSO)δ9.00(d,J＝6.5Hz,1H),8.72(s,1H),8.36(d,J＝9.1Hz,1H),8.09(s,1H),7.95(d,J＝24.3Hz,2H),7.68(s,1H),7.66(d,J＝2.8Hz,1H),7.37(dd,J＝9.1,2.8Hz,1H),7.28(d,J＝2.4Hz,1H),6.97(d,J＝6.6Hz,1H),4.10(s,3H),2.58(m,1H),2.40(s,3H),0.64-0.70(m,2H),0.56–0.30(m,2H).

x-ray powder measurements were performed on the obtained crystalline form XI of varlitinib mesylate using Cu-ka radiation, the obtained XRD pattern is shown in fig. 1, and the associated data are shown in table 2:

TABLE 2

Wherein the error of the 2 theta diffraction angle is +/-0.2 deg.

DSC analysis of the obtained crystalline form XI of varlitinib mesylate showed in figure 2, with endothermic peaks at 114.05 ± 5 ℃ and 158.56 ± 5 ℃.

TGA analysis of the crystalline form XI of varlitinib mesylate obtained, as shown in figure 3, lost about 6.94% in weight over the range of 30-140 ℃.

Moisture content of the obtained crystalline form XI of varlitinib mesylate was measured to be 6.5%.

The obtained crystalline form XI of varlitinib mesylate was tested for ethyl acetate solvent residue, which was 0.068%.

Combining TGA weight loss, moisture and solvent residue data, form XI is varlitinib mesylate dihydrate containing 2 water of crystallization (theoretical water content 6.44%).

Example 2: preparation of crystalline form XI of varlitinib mesylate

Stirring and mixing 200mL of ethyl acetate and 4mL of purified water at room temperature, then adding 10.0g of electrovatinib mesylate into a mixed solvent of the ethyl acetate and the purified water, after the suspension is dispersed uniformly, adding 0.3g of crystal form XI seed crystal, stirring for 8h at 25 ℃, and carrying out suction filtration and drying to obtain 9.2g of solid powder. The yield was 92.0% and the purity was 99.77%, with the XRD data substantially in accordance with the data of example 1.

Example 3: preparation of crystalline form XI of varlitinib mesylate

Stirring and mixing 2000mL of ethyl acetate and 60mL of purified water at room temperature, then adding 100.0g of electrovatinib mesylate into a mixed solvent of the ethyl acetate and the purified water, after the suspension is dispersed uniformly, adding 5.0g of crystal form XI seed crystal, stirring for 8h at 25 ℃, and performing suction filtration and drying to obtain 93.0g of solid powder. The yield was 93.0% and the purity was 99.76%, with the XRD data substantially in accordance with the data of example 1.

Example 4: preparation of crystalline form XI of varlitinib mesylate

Stirring and mixing 200mL of ethyl acetate and 20mL of purified water at room temperature, then adding 10.0g of electrovatinib mesylate into a mixed solvent of the ethyl acetate and the purified water, after the suspension is dispersed uniformly, adding 1.0g of crystal form XI seed crystal, stirring for 8h at 20 ℃, and carrying out suction filtration and drying to obtain 9.2g of solid powder. The yield was 92.0% and the purity was 99.75%, with the XRD data substantially in accordance with the data of example 1.

Example 5: preparation of crystalline form XI of varlitinib mesylate

Stirring and mixing 100mL of ethyl acetate and 2mL of purified water at room temperature, then adding 10.0g of electrovatinib mesylate into a mixed solvent of the ethyl acetate and the purified water, after the suspension is dispersed uniformly, adding 0.5g of crystal form XI seed crystal, stirring for 8h at 15 ℃, and carrying out suction filtration and drying to obtain 9.3g of solid powder. The yield was 93.0% and the purity was 99.73%, with the XRD data substantially in accordance with the data of example 1.

Example 6: preparation of crystalline form XI of varlitinib mesylate

Stirring and mixing 100mL of ethyl acetate and 10mL of purified water at room temperature, then adding 10.0g of electrovatinib mesylate into a mixed solvent of the ethyl acetate and the purified water, after the suspension is dispersed uniformly, adding 0.5g of crystal form XI seed crystal, stirring for 8h at 30 ℃, and carrying out suction filtration and drying to obtain 9.1g of solid powder. The yield was 91.0% and the purity was 99.71%, with the XRD data substantially in accordance with the data of example 1.

Example 7: preparation of crystalline form XI of varlitinib mesylate

Stirring and mixing 300mL of ethyl acetate and 6mL of purified water at room temperature, then adding 10.0g of electrovatinib mesylate into a mixed solvent of the ethyl acetate and the purified water, after the suspension is dispersed uniformly, adding 0.2g of crystal form XI seed crystal, stirring for 4h at 40 ℃, and carrying out suction filtration and drying to obtain 9.0g of solid powder. The yield was 90.0% and the purity was 99.69%, with the XRD data substantially in accordance with those of example 1.

Example 8: preparation of crystalline form XI of varlitinib mesylate

Stirring and mixing 300mL of ethyl acetate and 30mL of purified water at room temperature, then adding 10.0g of electrovatinib mesylate into a mixed solvent of the ethyl acetate and the purified water, after the suspension is dispersed uniformly, adding 0.6g of crystal form XI seed crystal, stirring for 8h at 25 ℃, and carrying out suction filtration and drying to obtain 9.1g of solid powder. The yield was 91.0% and the purity was 99.76%, with the XRD data substantially in accordance with the data of example 1.

Example 9: preparation of crystalline form XI of varlitinib mesylate

Stirring and mixing 150mL of ethyl acetate and 3mL of purified water at room temperature, then adding 10.0g of electrovatinib mesylate into a mixed solvent of the ethyl acetate and the purified water, after the suspension is dispersed uniformly, adding 0.5g of crystal form XI seed crystal, stirring for 6h at 25 ℃, and carrying out suction filtration and drying to obtain 9.2g of solid powder. The yield was 92.0% and the purity was 99.72%, with the XRD data substantially in accordance with the data of example 1.

Example 10: preparation of crystalline form XI of varlitinib mesylate

Stirring and mixing 250mL of ethyl acetate and 5mL of purified water at room temperature, then adding 10.0g of electrovatinib mesylate into a mixed solvent of the ethyl acetate and the purified water, after the suspension is dispersed uniformly, adding 0.5g of crystal form XI seed crystal, stirring for 12h at 25 ℃, and carrying out suction filtration and drying to obtain 9.1g of solid powder. The yield was 91.0% and the purity was 99.73%, with the XRD data substantially in accordance with the data of example 1.

Example 11: preparation of crystalline form XI of varlitinib mesylate

5000mL of ethyl acetate and 150mL of purified water are stirred and mixed uniformly at room temperature, then 250.0g of methane sulfonic acid ranvatinib is added into a mixed solvent of the ethyl acetate and the purified water, after the suspension is dispersed uniformly, 12.50g of crystal form XI seed crystal is added, then the mixture is stirred for 8 hours at 25 ℃, and the mixture is filtered and dried to obtain 232.8g of solid powder. The yield was 93.1% and the purity was 99.78%, with the XRD data substantially in accordance with the data of example 1.

Example 12: preparation of crystalline form XI of varlitinib mesylate

30L of ethyl acetate and 750mL of purified water are stirred and mixed uniformly at room temperature, then 1.5kg of methane sulfonic acid lunvatinib is added into a mixed solvent of the ethyl acetate and the purified water, the mixture is kept at 25 ℃ and stirred for 10h, and solid powder 1.4kg is obtained after suction filtration and drying. The yield was 93.3% and the purity was 99.95%, with the XRD data substantially in accordance with the data of example 1.

Test example 1: ranvatinib mesylate form XI hygroscopicity test

The crystalline form XI of ranvatinib mesylate prepared in example 1 was subjected to DVS analysis as shown in fig. 4. As can be seen from FIG. 4, the weight loss is about 0.33% in the range of 0-40% relative humidity, which indicates that the crystal form is relatively stable and will not lose crystal water even if the relative humidity is reduced to 0%; the moisture absorption weight gain of the crystal form is about 0.25% in the relative humidity range of 40-80%, which shows that the moisture absorption of the crystal form is very small, and the moisture absorption weight gain is still very small even if the relative humidity is up to 80%.

Test example 2: ranvatinib mesylate Crystal form XI stability test

The samples of the crystalline form XI of the varlitinib mesylate prepared in example 11 were respectively placed under different storage conditions, the crystalline form and the impurity stability of the samples were investigated, the samples were sampled for 30 days, the purity was detected according to the provided HPLC detection method, the results are shown in table 3, and the XRD spectrogram is shown in fig. 5.

Table 3 stability test data for form XI of ranvatinib mesylate prepared in example 11

Under the above conditions, as can be seen from fig. 5, XRD patterns of the crystalline form XI of varenib mesylate prepared in example 11 are substantially consistent between 0-day and 30-day, and the crystalline form is unchanged.

Under the above conditions, as can be seen from the data in table 3, the purity of the crystalline form XI of varenib mesylate prepared in example 11 does not change significantly under the conditions of high temperature of 60 ℃, high humidity of 92.5%, high humidity of 75% and light.

In conclusion, the crystalline form XI of the varlitinib mesylate prepared in example 11 can be kept stable under the conditions of high temperature, high humidity and illumination, and has better high temperature resistance, high humidity resistance and light resistance.

Test example 3: flowability test of Rivatinib mesylate crystal form XI powder

The powder flowability test was performed on the crystalline form XI of varlitinib mesylate prepared in example 12 and the crystalline form C prepared in patent reference CN100569753C, and the test results are shown in table 4 below.

TABLE 4 powder flowability data for form XI and form C

Crystal form	Bulk Density (g/mL)	Tap density (g/mL)	Compressibility (%)
XI	0.2225	0.3290	32.4
C	0.1940	0.3458	43.9

According to the statement of "flowability of solid material" in volume 1 of encyclopedia of pharmaceutical technology, 2 nd edition, the material is compacted more tightly in a tap density experiment, the flowability is poorer, the compression coefficient can be used for evaluating the flowability of the powder, the compression coefficient (%) (100% (tap density-bulk density)/tap density is higher, the flowability of the powder is poorer, the powder is more unfavorable for uniform mixing of the powder, the filling of a tabletting die or a capsule is further influenced, and finally the quality, the content uniformity, the hardness and the disintegration and dissolution of a preparation product are influenced. From table 4, it can be seen that the compression coefficient of the crystal form C is significantly higher than that of the crystal form XI, thereby indicating that the flowability of the crystal form XI is significantly better than that of the crystal form C, and facilitating the subsequent preparation production process.

Test example 4: pharmacokinetic testing of crystalline form XI rats with varlitinib mesylate

1. Purpose of the experiment

The level of the concentration of ranvatinib in plasma and its pharmacokinetic profile after a single oral administration of form XI of ranvatinib mesylate in rats at the same dose were examined.

2. Materials and methods

2.1, tested medicine: example 12 crystalline form XI of varlitinib mesylate obtained.

2.2 test animals

SD rats 3, male, body weight 220-: SCXK (Xiang) 2019-.

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 veins 15min, 30min, 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h and 24h before and after administration, the mixture is placed in an EDTA-K2 tube for 3000r/min, centrifuged for 10min, and plasma is separated and refrigerated and stored in a refrigerator at minus 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 internal standard acetonitrile precipitant, vortex shaking for 2min, centrifuging at 12000r/min for 10min, mixing supernatant 2 μ L with 200 μ L of pure water: acetonitrile (1:1) was mixed well and analyzed by sample injection at a volume of 3. mu.L.

3. And (3) test results:

after all blood samples are collected, the blood concentration in each blood sample is autonomously analyzed and measured, and parameters of the test substance (time to reach maximum plasma concentration Tmax, maximum plasma concentration Cmax, AUClast) are calculated. Based on the obtained parameters, the average values and standard deviations thereof were calculated, and the specific results are shown in Table 5.

TABLE 5 pharmacokinetic test data for form XI

As can be seen from Table 5, the time taken for form XI of the present invention to reach the maximum plasma concentration was 4.00. + -. 1.73h, the maximum plasma concentration was 2290. + -. 216ng/mL, and AUC_last22852 + -2840 h ng/mL. The crystal form XI is shown to be well absorbed in animal bodies, and the bioavailability of the medicine is improved, so that the treatment effect of the medicine is improved.

Test example 5: dissolution test of crystalline form XI of varlitinib mesylate

The preparation method comprises the steps of preparing the crystal form XI of the varlitinib mesylate prepared in the example 12 into capsules, adding 900ml of medium with the pH value of 4.0, stirring at 37 ℃ (the rotating speed is 75r/min), taking a solution at 10min, 15min, 20min, 30min, 45min, 60min, 90min and 120min by a paddle method, measuring absorbance at the wavelength of 250nm by an ultraviolet-spectrophotometry method, and calculating the dissolution amount of each capsule. The results of the experiment are shown in table 6 below.

TABLE 6 dissolution test data for form XI in pH4.0 media

From the data in the table, the crystal form XI is basically dissolved in a pH4.0 medium (the medium has the best discrimination) within 120min, which shows that the dissolution rate of the crystal form XI is better and the bioavailability is better.

It will be apparent to those skilled in the art that various modifications and variations can be made in the compounds of the present application and the methods of making the same without departing from the spirit or scope of the application, and therefore, the scope of the invention encompasses all modifications and variations that fall within the scope of the claims and their equivalents.

Claims

Crystalline form XI of orvatinib mesylate characterized by an X-ray powder diffraction pattern including peaks at diffraction angles (2 θ) of about 5.73 ° ± 0.2 °, 8.03 ° ± 0.2 °, 11.45 ° ± 0.2 °, 12.75 ° ± 0.2 °, 16.15 ° ± 0.2 °, 17.24 ° ± 0.2 °, 18.16 ° ± 0.2 °, 19.69 ° ± 0.2 °, 20.68 ° ± 0.2 °, 22.15 ± 0.2 °, 22.96 ± 0.2 °, 23.76 ± 0.2 °, 24.32 ± 0.2 °, 25.13 ± 0.2 °, 26.32 ± 0.2 °, 27.00 ± 0.2 °, 28.87 ± 0.2 °, 29.51 ± 0.2 °, 34.90 ± 0.2 °.
Crystalline form XI of ranvatinib mesylate according to claim 1, wherein the crystalline form has an X-ray powder diffraction pattern substantially as shown in figure 1.
Crystalline form XI of ranvatinib mesylate according to claim 1 or 2, wherein the crystalline form has differential scanning calorimetry in which the temperatures of the endothermic peaks are 114.05 ± 5 ℃ and 158.56 ± 5 ℃, respectively.
A process for the preparation of crystalline form XI of varlitinib mesylate according to any one of claims 1 to 3, comprising the steps of:

(1) stirring and mixing ethyl acetate and purified water at room temperature according to a certain volume ratio;

(2) adding the varlitinib mesylate to the mixed solvent in the step (1);

(3) and (3) after the suspension obtained in the step (2) is uniformly dispersed, adding a certain amount of crystal seed crystal of the crystal form XI, stirring for 4-24h at the temperature of 15-40 ℃, and performing suction filtration and drying to obtain solid powder, thus obtaining the crystal form XI of the methanesulfonic acid lunvatinib.
The process for the preparation of crystalline form XI of orvatinib mesylate according to claim 4, wherein in step (1), the volume ratio of ethyl acetate to purified water is 100 mL: (2-10) mL.
The process for the preparation of crystalline form XI of orvatinib mesylate according to claim 4, wherein in step (1), the volume ratio of ethyl acetate to purified water is 100 mL: (2-5) mL.
The process for the preparation of crystalline form XI of orvatinib mesylate according to claim 4, wherein in step (1), the volume ratio of ethyl acetate to purified water is 100 mL: 3 mL.
The process for the preparation of pravastatin form XI mesylate according to claim 4, wherein the mass-to-volume ratio of the pravastatin form mesylate to the ethyl acetate in the mixed solvent of the step (1) in the step (2) is 1 g: (10-30) mL.
The process for the preparation of pravastatin form XI mesylate according to claim 4, wherein the mass-to-volume ratio of the pravastatin form mesylate to the ethyl acetate in the mixed solvent of the step (1) in the step (2) is 1 g: (15-25) mL.
The process for the preparation of pravastatin form XI mesylate according to claim 4, wherein the mass-to-volume ratio of the pravastatin form mesylate to the ethyl acetate in the mixed solvent of the step (1) in the step (2) is 1 g: 20 mL.
The process according to claim 4, wherein in step (3), the amount of crystalline form XI seed crystals is 0-10% by mass of the amount of Rankine charged.
The process according to claim 4, wherein in step (3), the amount of seed crystals of form XI is 2-6% by mass of the feeds of varlitinib mesylate.
The process according to claim 4, wherein in step (3) the crystalline form XI mesylate is seeded with a dose of 5% by mass of crystalline form XI mesylate.
The process for the preparation of crystalline form XI of orvatinib mesylate according to claim 4, wherein the reaction temperature is 20-30 ℃ and the stirring time is 6-12 h.
The process for the preparation of crystalline form XI of orvatinib mesylate according to claim 4, wherein the reaction temperature is from 20 to 25 ℃ and the stirring time is from 6 to 10 hours.
The process for the preparation of crystalline form XI of orvatinib mesylate according to claim 4, wherein the reaction temperature is 25 ℃ and the stirring time is 8 h.
A process for the preparation of crystalline form XI of Ranuncutinib mesylate according to claim 4, comprising the steps of:

(1) and uniformly mixing ethyl acetate and purified water at room temperature with stirring, wherein the volume ratio of the ethyl acetate to the purified water is 100 mL: 3 mL;

(2) adding the pravastatin mesylate to the mixed solvent in the step (1), wherein the mass-volume ratio of the pravastatin mesylate to the ethyl acetate is 1 g: 20 mL;

(3) and (3) after the suspension in the step (2) is uniformly dispersed, adding crystal seeds of a crystal form XI, wherein the dosage of the crystal seeds is 5% of the mass fraction of the feeding amount of the varlitinib mesylate, stirring for 8 hours at 25 ℃, and performing suction filtration and drying to obtain solid powder, thus obtaining the varlitinib mesylate crystal form XI.
The method of claim 4, comprising the steps of:

stirring and mixing 200mL of ethyl acetate and 20mL of purified water at room temperature, then adding 10.0g of methanesulfonic acid lunvatinib into a mixed solvent of the ethyl acetate and the purified water, after the suspension is dispersed uniformly, adding 1.0g of crystal form XI seed crystal, stirring for 8h at 20 ℃, and performing suction filtration and drying to obtain 9.2g of solid powder, wherein the yield is 92.0%, and the purity is 99.75%.
The method of claim 4, comprising the steps of:

stirring and mixing 5000mL of ethyl acetate and 150mL of purified water at room temperature, then adding 250.0g of pravastatin mesylate into a mixed solvent of the ethyl acetate and the purified water, after the suspension is dispersed uniformly, adding 12.5g of crystal form XI seed crystal, stirring for 8h at 25 ℃, and performing suction filtration and drying to obtain solid powder of pravastatin mesylate crystal form XI 232.8g, wherein the yield is 93.1%, and the purity is 99.78%.
The method of claim 4, comprising the steps of:

30L of ethyl acetate and 750mL of purified water are stirred and mixed uniformly at room temperature, then 1.5kg of methane sulfonic acid lunvatinib is added into a mixed solvent of the ethyl acetate and the purified water, the mixture is stirred for 10 hours at 25 ℃, and solid powder 1.4kg is obtained after suction filtration and drying, the yield is 93.3%, and the purity is 99.95%.