Crystal form of benzothiazole derivative, and preparation method therefor and use thereof

Abstract

The present disclosure relates to the field of drug crystal forms, and in particular to a crystal form of a benzothiazole derivative, and a preparation method therefor and a use thereof. The crystal form of a benzothiazole derivative has better solubility, stability and flowability, and good bioavailability. The preparation method for the crystal form is simple, has good reproducibility, achieves high yield, is easy to operate and environmentally friendly, requires a small amount of solvent which facilitates recycling, effectively reduces reagent costs, and is easy to realize large-scale mass production. The crystal form can be advantageously used for promoting the excretion of uric acid, particularly in the treatment of diseases associated with abnormal uric acid metabolism.

Description

Benzothiazole derivative crystal forms, preparation methods and uses Technical Field

[0001] This disclosure relates to the field of pharmaceutical crystal forms, specifically to a benzothiazole derivative crystal form, its preparation method, and its uses. Background Technology

[0002] Dotenorazole (trade name Urexa) is a selective URAT1 inhibitor developed by Fuji Pharmaceutical Co., Ltd. for the treatment of gout and hyperuricemia. Dotenorazole inhibits urate transporter 1 (URAT1), a protein involved in urate reabsorption in the kidneys, thereby reducing serum uric acid levels. As a selective URAT1 inhibitor, dotenorazole effectively inhibits URAT1 in the proximal tubules of the kidneys without affecting the function of uric acid excretion factors ABCG2 and OAT1 / 3. Compared to non-selective URAT1 inhibitors, dotenorazole is more efficient at lowering serum uric acid. The structure of dotenorazole is shown in formula (I) below:

[0003] Existing technology CN110914246B discloses 10 crystal forms of dotenoroxetine, namely crystal form I, crystal form II, hydrate, sodium salt, and 6 solvates. However, in the pharmaceutical field, different crystal forms of drugs may have different physicochemical properties (such as solubility) and may affect the properties of the finished drug. Therefore, the study of drug crystal forms has important practical value. Summary of the Invention

[0004] To address the aforementioned problems in existing technologies, this application provides a crystalline form of dotenoradine, its preparation method, and its uses. The crystalline form of dotenoradine exhibits good solubility, stability, flowability, and bioavailability. The preparation method is simple, reproducible, has a high yield, is easy to operate, environmentally friendly, uses a small amount of solvent which facilitates recycling, effectively reduces reagent costs, and is easily scaled up for mass production. The crystalline form of dotenoradine can be advantageously used to promote uricosuric excretion, particularly in the treatment of diseases with abnormal uric acid metabolism.

[0005] The first aspect of this application provides a crystal form of dotenoroxetine, whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 8.4±0.2°, 14.6±0.2°, 17.0±0.2°, 18.2±0.2°, and 25.5±0.2°.

[0006] In some embodiments of this application, the X-ray powder diffraction pattern of the crystal form has characteristic peaks at 2θ angles of 8.4380±0.2°, 14.5899±0.2°, 16.9858±0.2°, 18.2284±0.2°, and 25.4950±0.2°.

[0007] In some embodiments of this application, the X-ray powder diffraction pattern of the crystal form has characteristic peaks at 6 or 7 locations selected from 2θ angles of 8.4±0.2°, 11.5±0.2°, 14.6±0.2°, 17.0±0.2°, 18.2±0.2°, 20.5±0.2°, and 25.5±0.2°.

[0008] In some embodiments of this application, the X-ray powder diffraction pattern of the crystal form has characteristic peaks at 2θ angles of 8.4±0.2°, 11.5±0.2°, 14.6±0.2°, 17.0±0.2°, 18.2±0.2°, and 25.5±0.2°.

[0009] In some embodiments of this application, the X-ray powder diffraction pattern of the crystal form has characteristic peaks at 2θ angles of 8.4±0.2°, 11.5±0.2°, 14.6±0.2°, 17.0±0.2°, 18.2±0.2°, 20.5±0.2°, and 25.5±0.2°.

[0010] In some embodiments of this application, the X-ray powder diffraction pattern of the crystal form has characteristic peaks at 2θ angles of 8.4380±0.2°, 11.5438±0.2°, 14.5899±0.2°, 16.9858±0.2°, 18.2284±0.2°, 20.4726±0.2°, and 25.4950±0.2°.

[0011] In some embodiments of this application, the X-ray powder diffraction pattern of the crystal form has characteristic peaks at 2θ angles of 8.4±0.2°, 11.5±0.2°, 14.6±0.2°, 15.8±0.2°, 17.0±0.2°, 18.2±0.2°, 20.5±0.2°, and 25.5±0.2°.

[0012] In some embodiments of this application, the X-ray powder diffraction pattern of the crystal form has characteristic peaks at 2θ angles of 8.4±0.2°, 11.5±0.2°, 14.6±0.2°, 15.8±0.2°, 17.0±0.2°, 18.2±0.2°, 20.5±0.2°, 22.5±0.2°, 22.9±0.2°, 24.1±0.2°, 25.5±0.2°, 27.5±0.2°, and 27.9±0.2°.

[0013] In some embodiments of this application, the X-ray powder diffraction pattern of the crystal form has characteristic peaks at 2θ angles of 8.4380±0.2°, 11.5438±0.2°, 14.5899±0.2°, 15.8298±0.2°, 16.9858±0.2°, 18.2284±0.2°, 20.4726±0.2°, 22.4643±0.2°, 22.9474±0.2°, 24.0517±0.2°, 25.4950±0.2°, 27.5196±0.2°, and 27.91516±0.2°.

[0014] In some embodiments of this application, the X-ray powder diffraction patterns of the crystal form are at 2θ angles of 8.4±0.2°, 11.5±0.2°, 13.4±0.2°, 14.6±0.2°, 15.8±0.2°, 17.0±0.2°, 18.2±0.2°, 19.1±0.2°, 19.7±0.2°, 20.5±0.2°, 21.0±0.2°, 22.5±0.2°, and 2 Characteristic peaks are present at 2.9±0.2°, 23.6±0.2°, 24.1±0.2°, 25.5±0.2°, 27.5±0.2°, 27.9±0.2°, 28.2±0.2°, 28.7±0.2°, 29.1±0.2°, 30.2±0.2°, 30.6±0.2°, 31.5±0.2°, 31.8±0.2°, 32.0±0.2°, and 34.4±0.2°. Those skilled in the art will understand that, as determined by X-ray powder diffraction (XRD), a crystal form exhibiting at least three of the characteristic peaks described in this application substantially falls within the scope of protection of this application.

[0015] In some embodiments of this application, the X-ray powder diffraction patterns of the crystal form are at 2θ angles of 8.4380±0.2°, 11.5438±0.2°, 13.4435±0.2°, 14.5899±0.2°, 15.8298±0.2°, 16.9858±0.2°, 18.2284±0.2°, 19.0744±0.2°, 19.6605±0.2°, 20.4726±0.2°, 21.0294±0.2°, 22.4643±0.2°, and 22.947°. Characteristic peaks are found at 4±0.2°, 23.6228±0.2°, 24.0517±0.2°, 25.4950±0.2°, 27.5196±0.2°, 27.91516±0.2°, 28.2189±0.2°, 28.6897±0.2°, 29.1074±0.2°, 30.1951±0.2°, 30.5697±0.2°, 31.5183±0.2°, 31.8077±0.2°, 32.0383±0.2°, and 34.3674±0.2°.

[0016] In some specific embodiments of this application, the characteristic peaks of the X-ray powder diffraction pattern of the crystal form are shown in Table 2. In some specific embodiments of this application, the relative intensities of the characteristic peaks of the X-ray powder diffraction pattern of the crystal form are shown in Table 2.

[0017] In some specific embodiments of this application, the X-ray powder diffraction pattern of the crystal form is basically as shown in Figure 1.

[0018] In some embodiments of this application, the DSC spectrum of the crystal form has endothermic peaks at 191.21±5℃ and 212.44±5℃.

[0019] In some specific embodiments of this application, the DSC spectrum of the crystal form is basically as shown in Figure 2.

[0020] In some specific embodiments of this application, the TGA spectrum of the crystal form is basically as shown in Figure 3.

[0021] The second aspect of this application provides a method for preparing the polytenolol crystal form described in the first aspect, comprising:

[0022] (1) Dissolve dotenolol in solvent A to obtain solution I;

[0023] (2) The seed crystals of the crystal form are suspended in solvent B to obtain suspension I;

[0024] (3) Mix the solution I and the suspension I, and crystallize to obtain the crystal form.

[0025] In some embodiments of this application, the mass-to-volume ratio of dotenoroxetine to solvent A is from 1:5 g / mL to 1:20 g / mL, for example, 1:5 g / mL, 1:10 g / mL, 1:15 g / mL, 1:20 g / mL, or a range consisting of any two of the aforementioned values; preferably 1:10 g / mL.

[0026] In some embodiments of this application, the mass-to-volume ratio of dotenoroxetine to solvent B is 1:20 to 100 g / mL, for example, 1:20 g / mL, 1:30 g / mL, 1:40 g / mL, 1:50 g / mL, 1:60 g / mL, 1:70 g / mL, 1:80 g / mL, 1:90 g / mL, 1:100 g / mL, or a range consisting of any two of the aforementioned values; preferably 1:50 g / mL.

[0027] In some embodiments of this application, the amount of seed crystals of the crystal form is 1 wt% to 10 wt% of the amount of dotenoroxetine, for example, 1 wt%, 4 wt%, 5 wt%, 6 wt%, 8 wt%, 10 wt%, or a range consisting of any two of the aforementioned values; preferably 5 wt%.

[0028] In some embodiments of this application, solvent A is 2-methyltetrahydrofuran and / or DMSO, preferably 2-methyltetrahydrofuran.

[0029] In some embodiments of this application, solvent B is an alkane solvent, preferably n-heptane and / or cyclohexane, more preferably n-heptane.

[0030] In some embodiments of this application, step (3) specifically includes: adding the solution I dropwise into the suspension I, crystallizing, and obtaining the crystal form.

[0031] In some embodiments of this application, the crystallization is carried out by stirring for 1 to 4 hours, for example, 1 hour, 2 hours, 3 hours, 4 hours, or a range consisting of any two of the aforementioned values; preferably, crystallization is carried out for 2 hours.

[0032] In some embodiments of this application, the dropping temperature is 0°C to 25°C, for example: 0°C, 5°C, 8°C, 10°C, 15°C, 20°C, or a range consisting of any two of the aforementioned values; preferably 10°C.

[0033] In some embodiments of this application, in step (3), the crystallization is performed by stirring, and the stirring time is preferably 1 to 4 hours, for example: 1 hour, 2 hours, 3 hours, 4 hours, or a range consisting of any two of the aforementioned values; more preferably, 2 hours. In some embodiments of this application, after crystallization, the crystal form is obtained by filtration and drying. In some embodiments of this application, the drying is vacuum drying, for example, vacuum drying at 30°C to 80°C, 40°C to 60°C, or 50°C.

[0034] In some embodiments of this application, the method further includes the step of preparing seed crystals of the crystal form. In some embodiments of this application, the step of preparing seed crystals of the crystal form may include the crystal form preparation method provided in the third aspect of this application.

[0035] A third aspect of this application provides another method for preparing the polytenorheic crystalline form described in the first aspect, comprising:

[0036] (a) Dotenolol was suspended in solvent C to obtain suspension II;

[0037] (b) The suspension II is filtered, and the resulting solid is suspended in solvent D to obtain suspension III. The suspension is then filtered and dried to obtain the crystal form.

[0038] In some embodiments of this application, the mass-to-volume ratio of dotenoramide to solvent C in step (a) is from 1:10 g / mL to 1:20 g / mL, for example, 1:10 g / mL, 1:15 g / mL, 1:20 g / mL, or a range consisting of any two of the aforementioned values; preferably 1:20 g / mL.

[0039] In some embodiments of this application, the mass-to-volume ratio of dotenoroxetine in step (a) to solvent D in step (b) is from 1:10 g / mL to 1:20 g / mL, for example, 1:10 g / mL, 1:15 g / mL, 1:20 g / mL, or a range consisting of any two of the foregoing values; preferably 1:20 g / mL.

[0040] In some embodiments of this application, the solvent C is isopropanol.

[0041] In some embodiments of this application, the solvent D is n-heptane.

[0042] In some embodiments of this application, in step (a), the suspension temperature is 10–25°C.

[0043] In some embodiments of this application, the suspension temperature in step (b) is 10–25°C.

[0044] In some embodiments of this application, in step (a), the suspension time is 12h-48h, for example: 12h, 24h, 48h, or a range consisting of any two of the aforementioned values; preferably 24h.

[0045] In some embodiments of this application, in step (b), the suspension time is 12h-48h, for example: 12h, 24h, 48h, or a range consisting of any two of the aforementioned values; preferably 24h.

[0046] The crystal form of dotenoroxetine prepared according to the third aspect of this application can be used as a seed crystal for the crystal form in step (2) of the second aspect.

[0047] The fourth aspect of this application provides the use of the dotenorazole crystal form described herein in the preparation of uricosuric drugs.

[0048] In some embodiments, the drug is used to treat disorders of uric acid metabolism. In this document, uric acid metabolism disorder refers to a metabolic abnormality where excessive uric acid production or reduced excretion in the body leads to elevated blood uric acid levels exceeding the normal range, which can cause gout, kidney stones, or chronic kidney disease.

[0049] In some embodiments, this application provides the dotenorazole crystal form described herein for promoting uricosuric excretion. In some embodiments, this application provides the dotenorazole crystal form described herein for treating disorders of uric acid metabolism.

[0050] In some embodiments, this application provides the use of the dotenorazole crystal form described herein for promoting uricosuric excretion. In some embodiments, this application provides the use of the dotenorazole crystal form described herein for treating diseases of uric acid metabolism disorders.

[0051] In some embodiments, this application provides a method for promoting uricosuric excretion, comprising administering a therapeutically effective amount of the dotenorazole crystal form described herein to a subject in need. In some embodiments, this application provides a method for treating a disorder of uric acid metabolism, comprising administering a therapeutically effective amount of the dotenorazole crystal form described herein to a subject in need.

[0052] In some embodiments, the uric acid metabolism disorder is hyperuricemia, gout, gout with hyperuricemia, or a complication thereof.

[0053] The therapeutically effective dose described herein can be determined by those skilled in the art based on the subject's age, sex, weight, disease severity, and general health condition. The dotenorazole crystal form of this application can be administered to the subject via conventional routes, including oral, subcutaneous, transdermal, intraperitoneal, and intramuscular administration.

[0054] The beneficial effects of this application are:

[0055] The dotenorazole crystal form of this application and / or the dotenorazole crystal form prepared by the preparation method of this application have good physicochemical properties, especially good stability, solubility and bioavailability. They exhibit excellent pharmacokinetic properties in animals and are expected to have good drug-like properties.

[0056] The method for preparing the polytenoxate crystal form of this application is simple, reproducible, has a high yield, is easy to operate, is environmentally friendly, requires a small amount of solvent and is easy to recycle, can effectively reduce reagent costs, and is easy to scale up for production. Attached Figure Description

[0057] Figure 1 shows the XRD pattern of dotenoroxetine crystal form A.

[0058] Figure 2 shows the DSC diagram of dotenoroxetine crystal form A.

[0059] Figure 3 shows the TGA diagram of dotenoroxetine crystal form A.

[0060] Figure 4 shows a comparison of the crystal forms of dotenoroxetine crystal form A over a 3-month long-term and accelerated stability study.

[0061] Figure 5 shows a comparison of the crystal forms of dotenoroxetine crystal form A after 30 days of stability study under the influence of high temperature, high humidity and light.

[0062] Figure 6 shows the average drug concentration-time curves for dotenorazole crystal form A and crystal form II.

[0063] Figure 7 shows a comparison of the crystal forms of dotenoroxetine crystal form A over 6 months of long-term and accelerated stability studies. Detailed Implementation

[0064] To make this disclosure easier to understand, the contents of this disclosure will be described in detail below with reference to embodiments. These embodiments are for illustrative purposes only and are not limited to the scope of application of this disclosure, nor do they limit the scope of protection of this disclosure.

[0065] The terms used in this disclosure are explained as follows:

[0066] XRD: X-ray powder diffraction

[0067] The X-ray powder diffraction (XRD) measurements described in this disclosure were performed using a Malvern-Panaco Empyrean X-ray powder diffractometer, with specific parameters as shown in the table below:

[0068] Table 1

[0069] In this article, "the X-ray powder diffraction pattern is basically the same as that in Figure 1" means that the X-ray powder diffraction pattern is basically the same as that in Figure 1. The term "basically the same" in X-ray powder diffraction pattern means that the representative peak positions and intensity variations are taken into account.

[0070] DSC: Differential Scanning Calorimetry

[0071] The differential scanning calorimetry (DSC) measurement described in this disclosure was performed using a METTLER TOLEDO DSC-1, with a heating rate of 10 °C / min and a temperature range of 25-250 °C. The nitrogen purging rate during the test was 60 mL / min.

[0072] In this article, "the DSC spectrum is basically the same as that in Figure 2" means that the DSC spectrum is basically the same as that in Figure 2. The term "basically the same" in DSC spectrum means that the representative characteristic peak positions will be taken into account.

[0073] TGA: Thermogravimetric Analysis

[0074] The thermogravimetric analysis (TGA) described in this disclosure was performed using a METTLER TOLEDO TGA-2 thermometer with a heating rate of 10 °C / min and a temperature range of 30-300 °C. The nitrogen purging rate during the test was 20 mL / min.

[0075] The error of TGA can be within approximately ±0.5% of mass. In this article, "the TGA spectrum is basically as shown in Figure 3" means that the TGA spectrum is basically the same as Figure 3. The term "basically the same" for the TGA spectrum means that this error variation is taken into account.

[0076] The term "room temperature" as used in this disclosure refers to a temperature of 10–25°C.

[0077] In this article, unless otherwise stated, percentages are mass percentages.

[0078] In this article, DMSO refers to dimethyl sulfoxide (DMSO).

[0079] In this article, when describing the 2θ values ​​of each characteristic peak in the XRD pattern, two different ways of writing the value are given, one for retaining tenths and the other for retaining ten-thousandths, just to clearly show the original reading and the value obtained after rounding the original reading. However, the protection range of the two ways of writing is actually the same. For example, the original reading of the 2θ value "8.4380°" is written as "8.4" after rounding.

[0080] The terms “comprise,” “containing,” and “comprising” and their equivalents (e.g., contain, contains, containing, include, includes, and including) shall be understood as “including but not limited to,” meaning that in addition to the listed elements, components, and steps, other unspecified elements, components, and steps may also be covered.

[0081] In this document, unless the context clearly indicates otherwise, singular terms encompass plural referents, and vice versa.

[0082] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0083] The term "subject" includes mammals and non-mammals, such as humans, non-human primates, sheep, dogs, cats, horses, cattle, chickens, rodents, fish, emus, etc. For example, the subject is a human. Unless otherwise stated, the terms "patient" or "subject" are used interchangeably.

[0084] Unless otherwise stated, the parameter values, reaction conditions, etc. of this disclosure are considered to be modified by the term “about”. The term “about” means that the object it modifies has an experimental error acceptable in the art, and when used in conjunction with a numerical value, it means any value within ±1%, such as ±0.5% or ±0.1% of the specified value.

[0085] Example

[0086] The following examples are for illustrative purposes, but the scope of this disclosure is not limited thereto. Unless otherwise stated, reagents, materials, or instruments used in the following examples, unless otherwise specified, are all commercially available products.

[0087] Example 1: Preparation of seed crystals of dotenoroxetine crystal form A

[0088] Weigh 0.1 g of dotenorazole and suspend it in 2 mL of isopropanol at room temperature for 24 h. Filter the solid and suspend it in 2 mL of n-heptane at room temperature for 24 h. Filter the solid and dry it under vacuum at 50 °C overnight to obtain 0.09 g of seed crystals of crystal form A.

[0089] Example 2: Preparation of Dotenorazine Crystal Form A

[0090] Weigh 1.0 g of dotenoramide and dissolve it in 10 mL of 2-methyltetrahydrofuran by stirring to obtain a solution of dotenoramide and 2-methyltetrahydrofuran; weigh 0.05 g of seed crystal A (the seed crystal obtained in Example 1) and suspend it in 50 mL of n-heptane to obtain a suspension; add the solution of dotenoramide and 2-methyltetrahydrofuran dropwise to the suspension at 10 °C, stir for 2 h to crystallize, filter, and vacuum dry overnight at 50 °C to obtain 0.93 g of dotenoramide crystal A.

[0091] XRD, DSC and TGA analyses were performed on the obtained dotenoroxetine crystal form A. The XRD pattern of dotenoroxetine crystal form A is shown in Figure 1, the characteristic peak values ​​are shown in Table 2, the DSC pattern is shown in Figure 2, and the TGA pattern is shown in Figure 3.

[0092] Table 2. Characteristic peak data of XRD patterns of dotinore crystal form A

[0093] Example 3: Preparation of Dotenorazine Crystal Form A Seed Crystal

[0094] Weigh 100 mg of dotenoradine and suspend it in 2 mL of isopropanol at room temperature for 24 h. After filtration, the solid was suspended in 2 mL of n-heptane at room temperature for 24 h. After filtration, the solid was dried under vacuum at 50 °C overnight to obtain crystal form A. The XRD pattern was consistent with Figure 1.

[0095] Example 4: Preparation of Dotenorazine Crystal Form A Seed Crystal

[0096] Weigh 100 mg of dotenoradine and suspend it in 1 mL of isopropanol at room temperature for 12 h. Filter the solid and suspend it in 1 mL of n-heptane at room temperature for 48 h. Filter the solid and dry it under vacuum at 50 °C overnight to obtain crystal form A. The XRD pattern is consistent with Figure 1.

[0097] Example 5: Preparation of Dotenorazine Crystal Form A

[0098] Weigh 1.0 g of dotenoradine and dissolve it in 5 mL of DMSO with stirring to obtain a solution of dotenoradine and DMSO; weigh 0.05 g of seed crystal A (prepared according to Example 1) and suspend it in 20 mL of cyclohexane to obtain a suspension; add the solution of dotenoradine and DMSO dropwise to the suspension at 0 °C, stir for 2 h to crystallize, filter, and vacuum dry overnight at 50 °C to obtain 0.87 g of dotenoradine crystal A, the XRD pattern of which is consistent with Figure 1.

[0099] Example 6: Preparation of Dotenorazine Crystal Form A

[0100] Weigh 1.0 g of dotenoramide and dissolve it in 20 mL of 2-methyltetrahydrofuran by stirring to obtain a solution of dotenoramide and 2-methyltetrahydrofuran; weigh 0.05 g of seed crystal A (prepared according to Example 1) and suspend it in 100 mL of n-heptane to obtain a suspension; at 25 °C, add the solution of dotenoramide and 2-methyltetrahydrofuran dropwise to the suspension, stir for 2 h to crystallize, filter, and vacuum dry overnight at 50 °C to obtain 0.94 g of dotenoramide crystal A, the XRD pattern of which is consistent with Figure 1.

[0101] Example 7: Preparation of Dotenorazine Crystal Form A

[0102] 10.0 g of dotenoramide was weighed and dissolved in 100 mL of 2-methyltetrahydrofuran by stirring to obtain a solution of dotenoramide and 2-methyltetrahydrofuran; 0.5 g of seed crystals of crystal form A (prepared according to Example 1) was weighed and suspended in 500 mL of n-heptane to obtain a suspension; the solution of dotenoramide and 2-methyltetrahydrofuran was added dropwise to the suspension at 10 °C, and the mixture was stirred for 2 h to crystallize. After filtration, the crystals were dried under vacuum at 50 °C overnight to obtain 9.1 g of dotenoramide crystal form A. The XRD pattern was consistent with that in Figure 1.

[0103] Experimental Example 1: Stability Study of Dotenoroxetine Crystal Form A

[0104] To investigate the storage stability of the dotenoroxetine crystal form A prepared in Example 2 of this disclosure, the sample was placed under long-term and accelerated stability conditions of 25°C / RH60% (60% relative humidity) and 40°C / RH75% for 3 months and 6 months, respectively, and under high temperature and high humidity conditions of 60°C and RH92.5% and light exposure conditions of 4500 lx ± 500 lx for 30 days. Its crystal form stability and chemical stability (purity) were investigated, and the results are shown in Table 3 below.

[0105] Table 3. Stability test of dotinoride crystal form A

[0106] The stability test results are shown in Figure 4 (comparison of crystal forms after long-term and accelerated stability studies for 3 months), Figure 7 (comparison of crystal forms after long-term and accelerated stability studies for 6 months), and Figure 5 (comparison of crystal forms after 30 days of stability studies under the influence of high temperature, high humidity, and light). The stability test results indicate that dotenoroxetine crystal form A exhibits good crystal form stability and chemical stability (purity) under the tested conditions.

[0107] Experimental Example 2: Solubility Investigation of Dotenoroxetine Crystal Form A and CN110914246B Crystal Form II in Different Media

[0108] Currently, it is reported that less than 40% of drug candidates ultimately succeed in reaching the market. This is attributed to the inherent physicochemical defects of the drug candidates themselves, especially solubility defects, which are the primary factor preventing most drug candidates from becoming druggable. Therefore, it is necessary to develop pharmaceutical crystal forms with solubility advantages through creative research to improve the druggability of candidate drugs.

[0109] The solubility of dotenoroxetine crystal form A prepared in Example 2 of this disclosure and crystal form II as a control were tested in different media at different temperatures, and the difference in solubility between the two under the same conditions was compared. The results are shown in Table 4 below:

[0110] Table 4. Solubility data of dotenoroxetine crystal form A and crystal form II in different solvents at different temperatures.

[0111] Experimental results show that dotenoroxetine crystal form A has higher solubility than crystal form II under various test conditions (in different media and at different temperatures). Therefore, dotenoroxetine crystal form A of this disclosure combines good crystal form / chemical stability with good solubility.

[0112] Experimental Example 3: Pharmacokinetic Study of Dotenorazole Crystal Form A and CN110914246B Crystal Form II

[0113] Animal experiments were conducted using dotenorazole crystal forms A and II prepared in Example 2. The test drug was accurately weighed, mixed with 0.5% methylcellulose solution, and a 0.5 mg / mL suspension was prepared for oral administration. Rats (n=2) were given a single oral dose of 1 mg / kg of the test drug. Whole blood was collected before administration and at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. Plasma was obtained after centrifugation. The drug concentration in rat plasma samples was quantitatively detected using LC-MS / MS. Pharmacokinetic parameters were calculated using the non-compartmental model method with WinNonlin software. Figure 6 shows the mean drug concentration-time curve in rat plasma after a single oral administration. The main pharmacokinetic parameters are shown in Table 5 below.

[0114] Table 5. Pharmacokinetic parameters of dotenorazole crystal form A and CN110914246B crystal form II

[0115] The experimental results showed that the Tmax, AUC and Cmax of dotenorazole crystal form A rats were superior to those of crystal form II. It was not only absorbed faster and had a rapid onset of action in the animals, but also showed higher peak concentration and higher in vivo exposure. Therefore, this crystal form has significantly better pharmacokinetic properties.

[0116] Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. For purposes of description and disclosure, all patents, patent applications, and other publications are expressly incorporated herein by reference. These publications are provided solely because their publications predate the filing date of this application. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of these documents. Furthermore, in any country, any reference to these publications herein does not constitute an endorsement that such publications are part of the general knowledge in the art.

[0117] Those skilled in the art will recognize that the scope of this application is not limited to the various specific implementations and embodiments described above, but rather that various modifications, substitutions, or recombinations can be made without departing from the spirit of this application, all of which fall within the protection scope of this application.

Claims

1. A polytenorheic crystalline form, wherein, The X-ray powder diffraction pattern of the crystal form has characteristic peaks at 2θ angles of 8.4±0.2°, 14.6±0.2°, 17.0±0.2°, 18.2±0.2° and 25.5±0.2°.

2. The polytenorheic crystalline form according to claim 1, wherein, The X-ray powder diffraction pattern of the crystal form has characteristic peaks at 6 or 7 locations among the following 2θ angles: 8.4±0.2°, 11.5±0.2°, 14.6±0.2°, 17.0±0.2°, 18.2±0.2°, 20.5±0.2°, and 25.5±0.2°.

3. The polytenorheic form according to claim 1 or 2, wherein, The X-ray powder diffraction pattern of the crystal form has characteristic peaks at 2θ angles of 8.4±0.2°, 11.5±0.2°, 14.6±0.2°, 15.8±0.2°, 17.0±0.2°, 18.2±0.2°, 20.5±0.2°, 22.5±0.2°, 22.9±0.2°, 24.1±0.2°, 25.5±0.2°, 27.5±0.2°, and 27.9±0.2°.

4. The polytenoric form according to any one of claims 1-3, wherein, Its X-ray powder diffraction patterns at 2θ angles of 8.4±0.2°, 11.5±0.2°, 13.4±0.2°, 14.6±0.2°, 15.8±0.2°, 17.0±0.2°, 18.2±0.2°, 19.1±0.2°, 19.7±0.2°, 20.5±0.2°, 21.0±0.2°, 22.5±0.2°, and 22.9±0.2° were respectively. Characteristic peaks are observed at 23.6±0.2°, 24.1±0.2°, 25.5±0.2°, 27.5±0.2°, 27.9±0.2°, 28.2±0.2°, 28.7±0.2°, 29.1±0.2°, 30.2±0.2°, 30.6±0.2°, 31.5±0.2°, 31.8±0.2°, 32.0±0.2°, and 34.4±0.2°. Preferably, the X-ray powder diffraction pattern of the crystal form is basically as shown in Figure 1.

5. The polytenoric form according to any one of claims 1-4, wherein, The DSC spectrum of the crystal form shows endothermic peaks at 191.21±5℃ and 212.44±5℃. Preferably, the DSC spectrum of the crystal form is basically as shown in Figure 2.

6. The polytenoric form according to any one of claims 1-5, wherein, The TGA spectrum of the crystal form is basically shown in Figure 3.

7. A method for preparing the polytenolol crystal form according to any one of claims 1-6, comprising: (1) Dissolve dotenolol in solvent A to obtain solution I; (2) The seed crystals of the crystal form are suspended in solvent B to obtain suspension I; (3) Mix the solution I and the suspension I, crystallize, and obtain the crystal form.

8. The preparation method according to claim 7, wherein, In step (1), the mass-to-volume ratio of dotenoramide to solvent A is 1:5 g / mL to 1:20 g / mL; preferably 1:10 g / mL; and / or In step (2), the mass-to-volume ratio of dotenorazole to solvent B is 1:20 g / mL to 1:100 g / mL; preferably 1:50 g / mL; and / or The amount of seed crystals used is 1 wt% to 10 wt% of the amount of dotenoroxetine added; preferably 5 wt%.

9. The preparation method according to claim 7 or 8, wherein, The solvent A is 2-methyltetrahydrofuran and / or DMSO, preferably 2-methyltetrahydrofuran; and / or Solvent B is an alkane solvent, preferably n-heptane and / or cyclohexane, more preferably n-heptane.

10. The preparation method according to any one of claims 7-9, wherein, Step (3) specifically includes: adding solution I dropwise to suspension I, crystallizing to obtain the crystal form; preferably, the dropping temperature is 0℃~25℃, more preferably 10℃; and / or In step (3), the crystallization is stirred crystallization, and the stirred crystallization time is preferably 1 to 4 hours, more preferably 2 hours; and / or In step (3), after crystallization, the crystal form is obtained by filtration and drying.

11. A method for preparing the polytenolol crystal form according to any one of claims 1-6, comprising: (a) Dotenolol was suspended in solvent C to obtain suspension II; (b) The suspension II is filtered, and the resulting solid is suspended in solvent D to obtain suspension III. The suspension is then filtered and dried to obtain the crystal form.

12. The preparation method according to claim 11, characterized in that, In step (a), the mass-to-volume ratio of dotenoroxetine to solvent C is 1:10 g / mL to 1:20 g / mL; preferably 1:20 g / mL, and / or The mass-to-volume ratio of dotenoramide in step (a) to solvent D in step (b) is 1:10 g / mL to 1:20 g / mL; preferably 1:20 g / mL.

13. The preparation method according to claim 11 or 12, wherein, The solvent C is isopropanol; and / or The solvent D is n-heptane.

14. The preparation method according to any one of claims 11-13, wherein, In step (a), the suspension temperature is 10–25°C; and / or In step (b), the suspension temperature is 10–25°C; and / or In step (a), the suspension time is 12h-48h, preferably 24h; and / or In step (b), the suspension time is 12h-48h, preferably 24h.

15. A dotenorazole crystal form according to any one of claims 1-6 for promoting uric acid excretion, preferably for treating diseases of abnormal uric acid metabolism, wherein the abnormal uric acid metabolism is hyperuricemia, gout, gout with hyperuricemia, or a complication thereof.

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