WO2019001325A1 - Crystal form xv of lesinurad and preparation method therefor - Google Patents

Abstract

The present invention relates to a new crystal form of lesinurad, a preparation method therefor, a pharmaceutical composition containing the crystal form, and use of the crystal form in the preparation of a uric acid transporter inhibitor and a pharmaceutical preparation for treating hyperuricemia. The new crystal form of lesinurad provided in the present invention has one or more improved properties with respect to those in the prior art, having great value in the optimization and development of this medicament in the future.

Description

Crystal form XV of Resina and preparation method thereof Technical field

The invention relates to the technical field of pharmaceutical crystal forms, in particular to a crystal form of Resinadine and a preparation method and use thereof.

Background technique

2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (Lesinurad), by Developed by AstraZeneca, AstraZeneca is an uric acid excretion oral drug that treats gout patients with hyperuricemia by inhibiting the uric acid transporter URAT1 of the renal proximal convoluted tubule. Resina has been approved by the US FDA on December 22, 2015, and its structural formula is as shown in formula (I) (hereinafter referred to as "compound (I)").

Patent US8003681B2 and CN101817793B disclose S-triazolyl-α-mercaptoacetanilide as an HIV reverse transcriptase inhibitor, but it does not disclose a crystalline form of the compound; US8546436B2 and CN103298796B disclose crystalline polymorphic forms of Resina 1 and Form 2; CN104557748A discloses crystal form α and crystal form β of Resinadine; CN104447590A discloses Form III, Form IV, Form V, Form VI of Resina.

The inventors found through analysis that the crystal form β and the crystal form α disclosed in CN104557748A are the same as the crystal form III and form IV of CN104447590A. In addition, the inventors have also found that CN104447590A crystal form IV is a methylene chloride solvate, and form V is tetrahydrofuran. Solvate, Form VI is a chloroform solvate. Dichloromethane, tetrahydrofuran and chloroform are all two types of solvents, which are highly toxic and are prepared into drugs which seriously endanger human health. The crystal form III disclosed by Resinadine Form 1 and Form 2 and CN 104447590A disclosed in CN103298796B is relatively safe and non-toxic.

The inventors of the present application have unexpectedly discovered the compound (I) crystalline form XV provided by the present invention in terms of stability, melting point, solubility, dissolution, wettability, bioavailability, on the basis of attempts to prepare different crystal forms. Adhesion, compressibility, fluidity, and processing, purification, in vitro dissolution, formulation production, etc. have advantages in at least one aspect, especially high solubility, good stability, uniform distribution, good purification effect, and Sinad's drug development offers new and better choices and is of great importance.

Summary of the invention

The main object of the present invention is to provide a novel crystalline form of the compound (I), a process for its preparation and use.

According to the object of the present invention, the present invention provides a crystal form XV of the compound (I) (hereinafter referred to as "crystal form XV").

Using Cu-Kα radiation, the X-ray powder diffraction of the crystal form XV has a characteristic peak at a diffraction angle 2θ of 6.3 ° ± 0.2 °, 13.0 ° ± 0.2 °, and 23.3 ° ± 0.2 °.

Further, the X-ray powder diffraction of the crystal form XV has a characteristic peak at one, or two, or three points of 2θ of 18.3°±0.2°, 21.0°±0.2°, and 25.0°±0.2°; The X-ray powder diffraction of the crystal form XV has a characteristic peak at a diffraction angle 2θ of 18.3°±0.2°, 21.0°±0.2°, and 25.0°±0.2°.

Further, the X-ray powder diffraction pattern of the crystal form XV is also characterized by 1 or 2, or 3 at 2θ values of 22.9°±0.2°, 27.3°±0.2°, 28.6°±0.2°. Peak; preferably, the X-ray powder diffraction of the Form XV has a characteristic peak at a diffraction angle 2θ of 22.9°±0.2°, 27.3°±0.2°, and 28.6°±0.2°.

Using Cu-Kα radiation, the X-ray powder diffraction of the crystal form XV is 6.3°±0.2°, 13.0°±0.2°, 23.3°±0.2°, 18.3°±0.2°, 21.0°±0.2° at the diffraction angle 2θ. 3, 4, 4, 5, or 6, or 7, or 8, 2, 2, 2, 2, 2, 2, 2 9 characteristic peaks.

Further, the form XV of the present invention is an isopropanol solvate, preferably one isopropanol solvate.

Without limitation, in one embodiment of the invention, the X-ray powder diffraction pattern of Form XV is shown in FIG.

According to the object of the present invention, the present invention also provides a method for preparing the crystalline form XV, comprising: adding a solid of the compound (I) to an isopropanol solvent, then heating at a temperature of 40 ° C to 50 ° C, and filtering. The filtrate was cooled to 35 ° C to 5 ° C, then an anti-solvent was added and crystallization was carried out to obtain a crystal form XV.

Further, the cooling may be two steps of cooling, the first step of cooling is to devitrify; the second step of cooling is to increase the yield.

Further, the temperature at which the first step is lowered is in the range of 35 to 15 ° C; preferably 30 ° C.

Further, the temperature of the second step of cooling is in the range of 20-5 ° C; preferably 5 ° C.

Among them, the temperature of the second step of cooling is lower than the temperature of the first step of cooling.

Further, the anti-solvent is an alkane solvent or water; further, the alkane solvent is n-pentane, n-hexane, n-heptane, n-octane or a mixture thereof; preferably n-heptane.

Further, the crystallization time is 12 to 36 hours; preferably 24 hours.

The crystal form XV provided by the present invention has the following beneficial effects:

(1) Compared with the existing solid, the crystalline form XV of the present invention has higher solubility in an acetate buffer solution containing and not containing sodium chloride, and especially in an acetate buffer containing sodium chloride. In solution, the solubility is 3-4 times higher than the Form III solubility of Form 1 and Form 2 of CN103298796B and CN104447590A.

Solubility is the rate limiting factor of drug bioavailability. Therefore, the significant increase in the solubility of crystal form XV will help to improve the bioavailability of Resinadine drugs, thereby improving the drug-forming properties and efficacy of drugs; At the same time, the dosage of the drug is lowered, thereby reducing the side effects of the drug and improving the safety of the drug.

(2) Compared with the existing solid, the crystalline form XV of the present invention has higher stability in a mixed solution of isopropyl alcohol and water, and its stability is much higher than that of the forms 1 and 2 of the prior art CN103298796B and the crystal of CN104447590A. Type III.

Isopropanol and water are preferred solvents in industrial production because of their low toxicity, no pollution, and low cost. The crystal form is stable in a preferred solvent, and is not easily converted into other compounds and crystal forms, which can ensure its preparation in synthesis and preparation. The use of preferred solvents in the process without special reaction conditions, to achieve green environmental protection based on greatly reducing production costs.

(3) Compared with the existing solids, the crystalline form XV of the present invention has higher solubility in various organic solvents, especially in ethanol, acetonitrile and toluene, and has higher solubility than the forms 1 and 2 of the prior art CN103298796B and CN104447590A. Form III.

The crystalline form of the drug has a higher solubility in an organic solvent, which allows the crystal form to select more organic solvents during the process development process, and at the same time dissolves the same quality of the drug substance with less organic solvent, and has a low volume effect. The reaction vessel using the same solvent can produce more raw materials, significantly reduce the amount of crystallization solvent, reduce cost, and is environmentally friendly, which is beneficial to process optimization and development.

(4) The crystal form XV of the present invention has a uniform particle size distribution. Its uniform particle size helps to simplify the post-treatment process of the formulation process, such as reducing the grinding of the crystal, saving cost, reducing the crystallinity change and the risk of crystal transformation in the grinding, and improving the quality control.

(5) The crystal form XV of the present invention has a good purification effect. The purity of the raw material is significantly improved by the preparation of the raw material from the raw material. In a specific embodiment, the purity of the raw material used in the present invention is 98.51%. After the preparation of the crystalline form XV, the purity is increased to 99.32%, and the purity is improved by 0.81%.

The purity of the drug is of great significance for ensuring the efficacy and safety of the drug and preventing the occurrence of adverse drug reactions. Impurities in drugs are the main factors affecting purity. For example, if the drug contains more than a limited amount of impurities, it may change the physical and chemical constants, the appearance traits will mutate, and affect the stability of the drug. The increase of impurities also makes the drug content significantly lower or The activity is reduced and the side effects are significantly increased. The crystal form with good purification effect can exhibit extremely strong impurity elimination ability in the crystallization process, so that the raw material medicine with higher purity can be obtained by crystallization, and the drug stability with low drug purity is low, and the curative effect is poor. , high toxicity and other shortcomings.

In the preparation method of the crystal form XV of the present invention:

The "stirring" described herein is carried out by a conventional method in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rpm, wherein the magnetic stirring is preferably 300-900 rpm, and the mechanical stirring is preferably 100. -300 rpm.

The "cooling down" is accomplished using conventional methods in the art, such as slow cooling and rapid cooling. Slow cooling is usually carried out at 0.1 ° C / min. Rapid cooling is usually to transfer the sample directly from the environment below room temperature, such as cooling in the refrigerator.

The "drying" can be carried out at room temperature or higher. Dry at room temperature to about 60 ° C, or to 40 ° C, or to 50 ° C. Drying time can be from 2 to 48 hours, or overnight. Drying is carried out in a fume hood, a forced air oven or a vacuum oven.

According to the present invention, the Resinadine and/or its salt as a raw material means a solid (crystalline or amorphous), semi-solid, wax or oil form. Preferably, the compound (I) and/or its salt as a raw material is in the form of a solid powder.

In the present invention, "crystal" or "crystal form" refers to the characterization by the X-ray diffraction pattern shown. Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized, with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is well known to those skilled in the art that the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor. In fact, the relative intensity of the diffraction peaks in the XRPD pattern is related to the preferred orientation of the crystal. The peak intensities shown here are illustrative and not for absolute comparison. In addition, the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ±0.2° is usually allowed. In addition, due to experimental factors such as sample height, the overall offset of the peak angle is caused, and a certain offset is usually allowed. Thus, it will be understood by those skilled in the art that the X-ray diffraction pattern of one crystal form in the present invention is not necessarily identical to the X-ray diffraction pattern in the example referred to herein, and the "XRPD pattern is the same" as used herein does not mean absolutely the same. The same peak position can differ by ± 0.2° and the peak intensity allows for some variability. Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention. One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.

In some embodiments, the crystalline form XV of the present invention is pure, unitary, and substantially free of any other crystalline form. In the present invention, "substantially free" when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.

It should be noted that the numerical values and numerical ranges recited in the present invention are not to be construed as narrowly construed as a numerical value or a numerical range per se. It will be understood by those skilled in the art that they may vary depending on the specific technical environment without departing from the spirit of the invention. On the basis of the principle, there are fluctuations around specific numerical values. In the present invention, such a floating range which can be foreseen by those skilled in the art is often expressed by the term "about".

Furthermore, the present invention provides a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of the crystalline form XV of the present invention, and at least one pharmaceutically acceptable carrier, diluent or excipient.

Further, the use of the crystalline form XV of the present invention for the preparation of a pharmaceutical preparation of a uric acid transporter inhibitor.

Further, the use of the crystalline form XV of the present invention for the preparation of a pharmaceutical preparation for treating hyperuricemia.

DRAWINGS

1 is an XRPD pattern of a Resina obtained crystal form XV obtained in Example 1;

2 is a ¹ H NMR chart of Resina obtained crystal form XV obtained in Example 1;

3 is a DSC chart of the Resina obtained crystal form XV obtained in Example 1;

4 is a TGA diagram of a Resina obtained crystal form XV obtained in Example 1;

5 is an XRPD pattern of a Resina obtained crystal form XV obtained in Example 2;

6 is an XRPD pattern of the Resina obtained crystal form XV obtained in Example 4 (the upper graph is an XRPD pattern of the crystal form XV obtained by stirring at room temperature, and the lower graph is an XRPD pattern of the crystal form XV obtained by stirring at 4 ° C)

7 is an XRPD pattern of the Resina obtained crystal form XV obtained in Example 5.

Figure 8 is a PSD diagram of a crystalline form XV;

Detailed ways

Parameter description of the test instrument involved in the embodiment

The invention is further defined by the following examples which describe in detail the preparation and use of the crystalline forms of the invention. It will be apparent to those skilled in the art that many changes in the materials and methods can be practiced without departing from the scope of the invention.

The abbreviations used in the present invention are explained as follows:

XRPD: X-ray powder diffraction

DSC: Differential Scanning Calorimetry

TGA: Thermogravimetric Analysis

¹ H NMR: liquid nuclear magnetic resonance spectrum

PSD: Particle Size Analysis

The X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer at a conventional temperature, such as 25 °C. The method parameters of the X-ray powder diffraction described in the present invention are as follows:

X-ray reflection parameters: Cu, Kα

1.540598;

1.544426

Kα2/Kα1 intensity ratio: 0.50

Voltage: 45 volts (kV)

Current: 40 milliamps (mA)

Scan range: from 3.0 to 40.0 degrees

The differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q200. The method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:

Scanning rate: 10 ° C / min;

Protective gas: nitrogen.

The thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000. The method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:

Scanning rate: 10 ° C / min;

Protective gas: nitrogen.

The particle size distribution results described in the present invention were collected on a Microtrac S3500 laser particle size analyzer. The Microtrac S3500 is equipped with an SDC (Sample Delivery Controller) injection system. This test uses a wet method and the test dispersion medium is Isopar G. The method parameters of the laser particle size analyzer are as follows:

*: The flow rate is 60% of 60% of 65 ml/sec.

H NMR data ⁽¹ HNMR) collected from a Bruker Avance II DMX 400M HZ NMR spectrometer. A sample of 1-5 mg was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a solution of 2-10 mg/mL.

The high performance liquid chromatography (HPLC) data of Example 3 of the present invention was taken from Agilent 1100, and the detector used was a diode.

Array Detector (DAD). The HPLC method parameters of the test purity described in the present invention are as follows:

1. Column: Waters Xbridge C18, 150×4.6mm, 5μm

2. Mobile phase: A: 0.1% aqueous solution of trifluoroacetic acid

B: 0.1% trifluoroacetic acid acetonitrile solution

The elution gradient is as follows:

Time(min)	%B
0	40
2	40
5	47
5	60
6	80
7	80
7	40
10	40

3. Flow rate: 1.7mL/min

4, injection volume: 5μL

5, detection wavelength: 230nm

6, column temperature: 40 ° C

7, thinner: acetonitrile: water = 1:1

The high performance liquid chromatography (HPLC) data of Example 6 of the present invention was taken from Agilent 1260, and the detector used was a UV detector (VWD). The HPLC method parameters of the test purity described in the present invention are as follows:

1. Column: Waters Xbridge C18, 150×4.6mm, 5μm

2. Mobile phase: A: 0.1% aqueous solution of trifluoroacetic acid

B: 0.1% trifluoroacetic acid acetonitrile solution

The elution gradient is as follows:

Time(min)	%B
0	40
2	40
5	47
5	60
6	80

7	80
7	40
10	40

3. Flow rate: 1.7mL/min

4, injection volume: 5μL

5, detection wavelength: 230nm

6, column temperature: 40 ° C

7, thinner: acetonitrile

The high performance liquid chromatography (HPLC) data of Example 8 of the present invention was taken from Agilent 1260, and the detector used was a diode array detector (DAD). The HPLC method parameters of the test purity described in the present invention are as follows:

1. Column: phenomenex Gemini C18 110A, 250 × 4.6mm, 3μm

2. Mobile phase: A: (10 mM KH ₂ PO4 + 0.1% TEA, pH 2.5): acetonitrile = 19:1

B: acetonitrile

The elution gradient is as follows:

Time(min)	%B
0.0	30
26.0	44
50.0	75
57.0	75
57.5	30
70	30

3. Flow rate: 1.0mL/min

4, injection volume: 5μL

5, detection wavelength: 220nm

6, column temperature: 40 ° C

7, thinner: acetonitrile: water = 8: 2

The particle size distribution results described in the specific embodiments of the present invention were collected on a Microtrac S3500 laser particle size analyzer. The Microtrac S3500 is equipped with an SDC (Sample Delivery Controller) injection system. This test uses a wet method in which the dispersion medium is Isopar G (containing 0.2% lecithin).

The following examples were operated at room temperature unless otherwise stated.

The Resinadine solid used in the following examples can be prepared according to the method described in the literature of CN 101817793 B or commercially available.

Example 1 Preparation Method of Form XV

About 1.0 g of Resinadine solid was added to 20.0 mL of isopropanol solvent, and then placed in an oven at 50 ° C for 2 hours at a rate of 500 rpm, and the solution was filtered to a folder at 40 ° C. In a crystallizer, stir at a rate of 150 rpm for 10 minutes, then cool to a temperature of 1 ° C / minute to 30 ° C, slowly inject 40.0 mL of n-heptane solvent at 30 ° C, solid precipitation, continue The temperature was lowered to 5 ° C at a rate of 0.1 ° C / minute, after about 1 day, filtered, and the resulting solid was dried in a vacuum oven to collect a solid.

Upon examination, the obtained crystalline solid was the crystalline form XV of the present invention, and its X-ray powder diffraction data is shown in Table 1. Its XRPD diagram is shown in Figure 1.

The liquid nuclear magnetic hydrogen spectrum of the crystalline form XV of the present invention is shown in Fig. 2, and the data is as follows: ¹ H NMR (400 MHz, DMSO) δ 8.59 (d, J = 8.4 Hz, 1H), 7.75 (t, J = 7.2 Hz) , 1H), 7.70–7.56 (m, 2H), 7.44 (d, J = 7.7 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 4.36 (d, J = 4.1 Hz, 1H), 4.00 (d, J = 1.6 Hz, 2H), 3.77 (d, J = 3.9 Hz, 1H), 1.15 (dd, J = 8.4, 2.0 Hz, 2H), 1.04 (d, J = 6.1 Hz, 6H), 0.87 (dd, J = 9.0, 5.4 Hz, 2H). There are multiple peaks at 1.04 and 3.77, a total of 7 hydrogen atoms, corresponding to the chemical shift of two isopropanol hydrogens, and thus the crystal form XV of the present invention is an isopropanol solvate.

The DSC of Form XV is shown in Figure 3. An endothermic peak appears near 80 ° C. The endothermic peak is the solvent desolvation near this temperature.

The TGA of Form XV, as shown in Figure 4, has a mass loss gradient of about 6.55% when heated to about 95 °C.

Table 1

Diffraction angle 2θ	d value	strength%
6.33	13.95	51.50
8.99	9.84	12.21
13.02	6.80	100.00
15.10	5.87	18.16
16.19	5.48	15.55
17.47	5.08	19.89
18.31	4.85	40.66
19.07	4.65	17.42
19.93	4.46	16.62
20.99	4.23	47.62
21.94	4.05	15.31
22.88	3.89	31.33
23.23	3.83	56.27
24.35	3.65	25.02
24.97	3.57	35.46
26.38	3.38	28.82
27.29	3.27	26.78
28.61	3.12	24.45
29.45	3.03	23.27
30.49	2.93	33.46
32.30	2.77	4.22

37.22	2.42	7.83
38.26	2.35	6.28

Example 2 Preparation Method of Form XV

About 0.6 g of Resina's solid was weighed into a glass vial, and 10.0 mL of isopropanol solvent was added, and then placed in an oven at 50 ° C for 1 hour at a rate of 500 rpm, and the solution was filtered. In a jacketed crystallizer at 40 ° C, then cooled to 20 ° C at a rate of 0.3 ° C / minute, 20.0 mL of H ₂ O was slowly injected at 20 ° C, and then stirred at a rate of 150 rpm for about 1 day. Filter and sample the sample for crystallography. Upon examination, the obtained solid was the crystalline form XV of the present invention, and its X-ray powder diffraction data is shown in Table 2, and its XRPD pattern is shown in Fig. 5.

Table 2

Diffraction angle 2θ	d value	strength%
6.34	13.94	86.50
9.04	9.78	10.38
12.66	6.99	8.37
13.02	6.80	100.00
15.20	5.83	5.27
16.20	5.47	8.12
17.53	5.06	15.54
18.34	4.84	31.24
19.12	4.64	16.86
19.36	4.58	13.17
20.01	4.44	10.54
21.02	4.23	19.21
22.65	3.93	17.29
22.90	3.88	13.38
23.34	3.81	28.35
23.73	3.75	8.72
25.03	3.56	16.58
26.22	3.40	16.03
27.37	3.26	14.60
28.65	3.12	9.87
29.48	3.03	9.98
30.55	2.93	12.78

Example 3 Form 1 in Form XV and CN103298796B, Form 2 and Form III in CN104447590A Comparison of solubility in acetate buffer

Form III in CN104447590A and 25 mg of Form XV of the present invention and acetate buffer (25 mM, pH 5, 4 mL) (prepared with and without sodium chloride (ion intensity adjusted to = 0.1 M)) In a glass vial, it was sealed and placed on a laboratory rotator in a 25 ° C incubator. After 1 day, the samples were filtered and analyzed by HPLC. The results are shown in Table 3.

table 3

Note: CN103298796B Form 1 and Form 2 data are from CN103298796B patent text

From the above experimental data, it is known that the crystal form XV of the present invention contains and does not contain sodium chloride as compared with the solubility data of Form 1 and Form 2 disclosed in the prior art (CN103298796B pages 21/25 and 23/25). Higher solubility in acetate buffer, especially in acetate buffer containing sodium chloride, solubility is higher than Form 1 and Form 2 of CN103298796B and Form III of CN104447590A in the prior art. More than double.

Example 4 Stability Relationship between Form XV and Form III in CN104447590A

About 10 mg of CN104447590A Form III and the Form XV of the present invention were separately weighed into a glass vial, and then 0.5 mL of a mixed solution of isopropyl alcohol and water (1:1, v:v) was added and labeled as Sample 1. Sample 2 was configured in the same manner as above. Sample 1 and Sample 2 were then placed at room temperature and 4 ° C, respectively, at 500 rpm. After 1 hour, the solid was collected and tested by XRPD. Both solids were crystalline form XV. The XRPD pattern of the crystal form XV obtained in this example is shown in Fig. 6 (the upper graph is an XRPD pattern of the crystal form XV obtained by stirring at room temperature, and the lower graph is an XRPD pattern of the crystal form XV obtained by stirring at 4 ° C). See Table 4.

Table 4

The above results show that the crystalline form XV of the present invention is more stable than the crystalline form III of CN104447590A in a mixed solvent of isopropyl alcohol and water.

Example 5 Stability relationship between Form XV and Form 2 in CN103298796B

About 10 mg of Form 2 of CN103298796B and Form XV of the present invention were weighed into a glass vial, respectively, and then 0.3 mL of a mixed solution of isopropanol and water (1:1, v:v) was added, followed by 500 at 4 °C. The rotation speed of the revolution/minute was stirred, and after 5 hours, the solid was collected, and the solid obtained was subjected to XRPD, and the obtained solid was the crystal form XV of the present invention. The XRPD pattern of the crystal form XV obtained in this example is shown in Fig. 7, and the experimental results are shown in Table 5.

table 5

The above results indicate that the crystalline form XV of the present invention is stable in Form 2 of CN103298796B in a mixed solvent of isopropyl alcohol and water.

Example 6 Form XV and CN103298796B Form 2 and CN104447590A Form III in water and organic Solubility comparison in solvents

Appropriate amount of crystal form XV, CN103298796B form 2 and CN104447590A form III were added to 1.0 ml of different solvents as shown in Table 5 to form a suspension. After 15 minutes, the sample in the saturated solution was determined by high performance liquid chromatography (HPLC). The content and experimental results are shown in Table 6.

Table 6 Comparison of Solubility of Crystal Forms in Different Solvents

From the comparison results, it can be seen that in water, ethanol, acetonitrile, and toluene, the solubility of the crystalline form XV of the present invention is higher than that of CN103298796B Form 2 and CN104447590A Form III.

Example 7 Particle Size Distribution of Form XV

Take 10-30mg of Form XV, then add 10mL Isopar G (containing 0.2% lecithin), mix the sample to be tested and then add it to the SDC sample system to make the sample amount map reach the appropriate position, start the experiment, and carry out the experiment. The diameter distribution was measured to obtain an average particle diameter calculated by volume, a particle diameter corresponding to 10% of the particle size distribution (volume distribution), and a particle diameter corresponding to 50% of the particle size distribution (volume distribution). The particle size distribution (volume distribution) accounts for 90% of the corresponding particle size and crystal size distribution map. The specific results are shown in Table 7, and the PSD diagram is shown in Figure 8.

Table 7 Particle size data of Form XV

Crystal form	MV (μm)	SD	D10 (μm)	D50 (μm)	D90 (μm)
Crystal form XV	16.9	9.5	4.5	11.4	32.3

MV: average particle size by volume;

SD: indicates standard deviation

D10: indicates a particle diameter corresponding to 10% of the particle size distribution (volume distribution);

D50: indicates the particle size corresponding to the particle size distribution (volume distribution), which is 50%, which is also called the median diameter;

D90: indicates a particle diameter corresponding to 90% of the particle size distribution (volume distribution).

As a result of the above test, the crystal form XV of the present invention has an average particle diameter of about 16.9 μm and has a normal distribution, and has good uniformity and a narrow particle size distribution.

Example 8 The crystal form XV purification effect of the present invention

Weigh 49.2mg of free acid raw material, add 1.0mL of isopropanol solvent, and the obtained suspension is stirred at room temperature for about 24h, then centrifuged and dried in vacuum for about 24h to obtain crystal form XV. The purity of the sample before and after preparation is shown in the table. 8.

Table 8

Initial purity	Prepared crystal form XV purity	Purity change
98.51%	99.32%	+0.81%

It can be seen from the above test results that the crystal form of the present invention has a strong purification effect. By preparing the crystal form XV, the purity of the raw material is increased from 98.51% to 99.32%, and the purity is increased by 0.81%.

The above embodiments are merely illustrative of the technical concept and the features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the present invention and to implement the present invention, and the scope of the present invention is not limited thereto. Equivalent variations or modifications made in accordance with the spirit of the invention are intended to be included within the scope of the invention.

Claims (12)

1. A crystal form XV of Resinadine characterized in that its X-ray powder diffraction pattern (CuKα radiation) has characteristic peaks at 2θ values of 6.3°±0.2°, 13.0°±0.2°, and 23.3°±0.2°. .
2. The crystal form XV according to claim 1, wherein the X-ray powder diffraction pattern has one or more of 2θ values of 18.3°±0.2°, 21.0°±0.2°, and 25.0°±0.2°. Characteristic peaks.
3. The crystal form XV according to claim 1, wherein the X-ray powder diffraction pattern has one or more of 2θ values of 22.9°±0.2°, 27.3°±0.2°, and 28.6°±0.2°. Characteristic peaks.
4. The crystalline form XV according to claim 1, wherein the crystalline form XV is an isopropanol solvate.
5. The invention relates to a method for preparing a crystal form XV of Resina, characterized in that the method comprises the steps of: adding a solid of Resina to an isopropanol solvent, heating at a temperature of 40 ° C to 50 ° C, and filtering. The filtrate was cooled to 35 ° C to 5 ° C, then an anti-solvent was added and crystallization was carried out to obtain a crystal form XV.
6. The preparation method according to claim 5, wherein the temperature reduction is performed in two steps, the temperature range of the first step of cooling is 35-15 ° C, and the temperature range of the second step of cooling is 20-5 ° C, the The second step of lowering the temperature is lower than the temperature of the first step of cooling;
7. The preparation method according to claim 6, wherein the temperature at which the first step is lowered is 30 ° C, and the temperature at which the second step is lowered is 5 ° C.
8. The process according to claim 5, wherein the anti-solvent is an alkane solvent or water.
9. The process according to claim 8, wherein the alkane solvent is n-pentane, n-hexane, n-heptane, n-octane or a mixture thereof.
10. A pharmaceutical composition comprising a therapeutically effective amount of Form XV of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
11. Use of the crystalline form XV of claim 1 for the preparation of a pharmaceutical formulation of a urate transporter inhibitor.
12. Use of Form XV as claimed in Claim 1 for the preparation of a pharmaceutical preparation for the treatment of hyperuricemia.

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