Crystalline form of 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole and process for its preparation

Abstract

This invention belongs to the field of pharmaceutical technology, specifically relating to the crystal form of 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (compound of formula I) and its preparation method. The X-ray powder diffraction pattern of crystal form F of compound I shows diffraction peaks at 2θ values ​​of 12.0°, 14.0°, 16.5°, 20.3°, 21.7°, 23.9°, 24.5°, 28.0°, 28.8°, and 30.1°, with an error range of ±0.2° for the 2θ values. Compared with existing type II and type I crystals and hydrates of compound I, crystal form F of compound I exhibits lower hygroscopicity, higher solubility, and better flowability, thus possessing value for pharmaceutical industrial applications.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to the crystal form of 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole and its preparation method. Background Technology

[0002] Currently, the industry has discovered 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole, which, compared with existing uric acid excretion promoters, exhibits a higher concentration in unaltered urine and a significant uric acid excretion-promoting effect. However, patent WO2011 / 040449 does not describe the specific crystalline form or salts of 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole, nor does it disclose the problems and related precautions in the industrial production of this compound.

[0003] Patent CN110914246B reports various crystal forms of 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole, including type I, type II crystals and hydrates, several solvates, sodium salts, and other crystal / salt forms. However, the patent does not describe the hygroscopicity, stability, and solubility of these crystal forms. It is well known that for the same drug, different crystal forms may have different bioavailability, and their stability, solubility, hygroscopicity, powder properties, and mechanical properties may also differ. These physicochemical properties can also have a certain impact on the application of the drug.

[0004] Therefore, providing a crystal form of 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole with good crystal stability, low hygroscopicity, high solubility, good mechanical stability and powder properties has important practical application value. Summary of the Invention

[0005] Technical issues

[0006] The present invention aims to provide a crystal form of 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole with good crystal form stability, low hygroscopicity, high solubility, good mechanical stability and powder properties.

[0007] Technical solution

[0008] The first aspect of this application provides a crystal form F of 1,3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole, having the structure shown in Formula I.

[0009] Its X-ray powder diffraction pattern shows diffraction peaks at 2θ values ​​of 12.0°, 14.0°, 16.5°, 20.3°, 21.7°, 23.9°, 24.5°, 28.0°, 28.8° and 30.1°, with an error range of ±0.2° for the 2θ values.

[0010] In some embodiments, the X-ray powder diffraction (XRPD) pattern of crystal form F of the above-mentioned 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole is as follows: Figure 1 As shown.

[0011] In some embodiments, the differential scanning calorimetry (DSC) curve of crystal form F of the above-mentioned 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole is as follows: Figure 2 As shown.

[0012] In some embodiments, the thermogravimetric (TGA) analysis of the crystal form F of 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole showed a total weight loss of less than 0.5% during heating to 150±2°C.

[0013] In some embodiments, the thermogravimetric analysis (TGA) curve of the crystal form F of the above-mentioned 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole is as follows: Figure 3 As shown.

[0014] The second aspect of this application provides a method for preparing crystal form F of 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole as described in any one of the above claims, characterized by comprising the following steps: (a) adding a solid of the compound of formula I to tetrahydrofuran; (b) heating to 40-45°C and stirring to dissolve, then adding n-heptane and stirring to crystallize, then cooling to 25-30°C and stirring; (c) post-treatment to obtain crystal form F of the compound of formula I.

[0015] In some embodiments, the solid form of the Formula I compound is a type I crystal of the Formula I compound, a type II crystal of the Formula I compound, or a hydrate of the Formula I compound.

[0016] A third aspect of this application provides a pharmaceutical composition comprising crystal form F of the above-mentioned 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole and a pharmaceutically permissible carrier.

[0017] Technical effect

[0018] This invention provides the crystal form of 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (compound of formula I) and its preparation method. Studies have revealed that compound I has multiple crystal forms, including but not limited to anhydrous crystal form F, methanol solvate crystal form E, and tetrahydrofuran solvate crystal form G. Comparison of multiple indicators such as stability, solubility, hygroscopicity, and flowability shows that, compared with existing type II and type I crystals and hydrates of compound I, crystal form F of compound I exhibits lower hygroscopicity, higher solubility, and better flowability, thus possessing value for pharmaceutical industrial applications. Attached Figure Description

[0019] Figure 1 XRPD spectrum of compound F of formula I;

[0020] Figure 2 DSC diagram of crystal form F of compound I;

[0021] Figure 3 TGA image of crystal form F of compound I;

[0022] Figure 4 XRPD spectrum of methanol solvate E of compound I;

[0023] Figure 5 TGA image of crystal form E of methanol solvate of compound I;

[0024] Figure 6 XRPD spectrum of tetrahydrofuran solvate G of Formula I;

[0025] Figure 7 TGA image of the tetrahydrofuran solvate G of compound I;

[0026] Figure 8 XRPD spectrum of type II crystallization of compound I;

[0027] Figure 9 XRPD spectrum of type I crystals of compound I;

[0028] Figure 10 XRPD spectrum of the hydrate of compound I. Detailed Implementation

[0029] To facilitate the explanation of the technical solution of this application, the following is a general explanation and definition of the terms and expressions used in this application.

[0030] The terms used in this invention are explained as follows:

[0031] The term XRPD refers to X-ray powder diffraction. In this invention, the powder X-ray diffraction testing instrument involved is a Bruker D2 Phaser. 2nd Powder diffractometer; Test conditions: CuKα radiation, 30kV, 10mA, 3-40°.

[0032] The term DSC refers to Differential Scanning Calorimeter. In this invention, the differential scanning calorimeter involved is the American TADSC25; test conditions: 20-300℃, 10℃ / min; N2 (60mL / min).

[0033] The term TGA refers to thermogravimetric analyzer. In this invention, the thermogravimetric analyzer involved is the American TATGA55; the test conditions are: room temperature - 300℃, 10℃ / min; N2 (50mL / min).

[0034] The terms “comprising,” “including,” or any other variations thereof are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitation, an element defined by the phrase “comprising one…” does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0035] The measurement of the 2θ or diffraction peaks in the X-ray powder diffraction pattern of the crystal is subject to experimental error. The measurement of the 2θ or diffraction peaks in the X-ray powder diffraction pattern may vary slightly between one machine and another, and between one sample and another. The experimental error or difference may be ±0.2 units. Therefore, the value of the 2θ or diffraction peaks cannot be considered absolute.

[0036] The differential scanning calorimetry (DSC) curve of the crystal has experimental errors. The position and peak value of the endothermic peak may vary slightly between one machine and another, and between one sample and another. The experimental error or difference may be less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than or equal to 1°C. Therefore, the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute.

[0037] The thermogravimetric analysis (TGA) curves of the crystals are subject to experimental error. The endothermic curves or weight loss rates may vary slightly between different machines and between different samples. The experimental error or difference may be less than or equal to 0.4%, 0.3%, 0.2%, or 0.1%. Therefore, the thermogravimetric analysis curves or their weight loss rates cannot be considered absolute.

[0038] In the comparative experiments provided in this application, unless otherwise specified, all experimental conditions and materials are kept consistent to ensure comparability.

[0039] Unless otherwise specified, all reagents and instruments used in the embodiments of this invention can be purchased from the market.

[0040] The following provides further details regarding the crystal form of 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole and its preparation method provided in this application.

[0041] Example 1: Preparation of crystal form F of compound I

[0042] 10 g of type II crystals of compound I (prepared according to Example 2 of patent CN110914246B) was added to a 250-mL double-glass jacketed reactor. 40 mL of tetrahydrofuran was added, and the mixture was heated to 40°C and stirred until dissolved. 200 mL of n-heptane was added, and crystals were precipitated by stirring at 40°C. The mixture was cooled to room temperature (25–30°C) and stirred for 0.5 hours. The wet product was dried under reduced pressure at 40±5°C for 8 hours. 9.6 g of the product was collected and characterized by XRPD. Figure 1 The result shows that the substance is crystal form F of compound I, with a purity of 99.96%; the scanning calorimetry (DSC) chromatogram is shown below. Figure 2 Thermogravimetric analysis (TGA) chart is shown below. Figure 3 .

[0043] Table 1 below shows the characteristic XRPD diffraction peaks of the isolated crystal form F of compound I.

[0044] Table 1. XRPD parameters of crystal form F of compound I.

[0045]

[0046]

[0047] Example 2: Preparation of crystal form F of compound I

[0048] 10 g of type I crystals of compound I (prepared according to Example 1 of patent CN110914246B) was added to a 250-mL double-glass jacketed reactor. 40 mL of tetrahydrofuran was added, and the mixture was heated to 40°C and stirred until dissolved. 200 mL of n-heptane was added, and crystals were precipitated by stirring at 40°C. The mixture was cooled to room temperature (25–30°C) and stirred for 0.5 hours. The wet product was dried under reduced pressure at 40±5°C for 8 hours. 9.5 g of the product was collected. XRPD characterization showed that the substance was crystal form F of compound I, with a purity of 99.96%.

[0049] Example 3: Preparation of crystal form F of compound I

[0050] 10 g of the hydrate of compound I (prepared according to Example 3 of patent CN110914246B) was added to a 250-mL double-glass jacketed reactor. 40 mL of tetrahydrofuran was added, and the mixture was heated to 40°C and stirred until dissolved. 200 mL of n-heptane was added, and crystallization was precipitated at 40°C. The mixture was cooled to room temperature (25–30°C) and stirred for 0.5 hours. The wet product was dried under reduced pressure at 40±5°C for 8 hours. 9.0 g of the product was collected. XRPD characterization showed that the substance was crystal form F of compound I, with a purity of 99.98%.

[0051] Example 4: Preparation of crystal form F of compound I

[0052] 100g of type II crystals of compound I (prepared according to Example 2 of patent CN110914246B) was added to a 3-L double-glass jacketed reactor. 400mL of tetrahydrofuran was added, and the mixture was heated to 40°C and stirred until dissolved. 2000mL of n-heptane was added, and crystallization was precipitated at 40°C. The mixture was cooled to room temperature (25–30°C) and stirred for 0.5 hours. The wet product was dried under reduced pressure at 40±5°C for 8 hours. 96.8g of the product was collected. XRPD characterization showed that the substance was crystal form F of compound I, with a purity of 99.96%.

[0053] Example 5: Preparation of crystal form E of compound I

[0054] 10 g of type II crystals of compound I (prepared according to Example 2 of patent CN110914246B) was added to a 250-mL double-glass jacketed reactor, followed by 30 mL of methanol. The mixture was heated to 60°C and stirred until dissolved. The temperature was then lowered to 5°C and stirred for 2 hours. The wet product was dried under reduced pressure at 35±5°C for 3 hours. 6.8 g of the product was collected and characterized by XRPD. Figure 4 The result shows that the substance is crystal form E of compound I, with a purity of 99.99%; the thermogravimetric (TGA) chart is shown below. Figure 5 .

[0055] Table 2 below shows the characteristic XRPD diffraction peaks of the isolated crystal form E of compound I.

[0056] Table 2 shows the XRPD parameters of crystal form E of compound I.

[0057]

[0058]

[0059] Example 6: Preparation of crystal form G of compound I

[0060] 10 g of type II crystalline solid of compound I (prepared according to Example 2 of patent CN110914246B) was added to a 250-mL double-glass jacketed reactor. 30 mL of tetrahydrofuran was added, and the mixture was heated to 50°C and stirred until dissolved. 60 mL of n-heptane was added at 50°C, and crystallization was observed. The mixture was then cooled to 5°C and stirred for 1 hour. The wet product was dried under reduced pressure at 35±5°C for 3 hours. 10.4 g of the product was collected and characterized by XRPD. Figure 6 The result shows that the substance is crystal form G of compound I, with a purity of 99.94%; the thermogravimetric (TGA) plot is shown below. Figure 7 .

[0061] Table 3 below shows the characteristic XRPD diffraction peaks of the isolated crystal form G of compound I.

[0062] Table 3. XRPD parameters of crystal form G of compound I.

[0063]

[0064] Preparation of type II crystals of compound I in Comparative Example 1 (refer to Example 2 of patent CN110914246B)

[0065] Add 45g of the amorphous solid of compound I to a 1-L double-glass jacketed reactor, along with 135mL of ethyl acetate and 855mL of isopropanol. Heat to reflux and stir until dissolved. Cool to 25℃ and stir for 3 hours. Filter to collect the precipitated crystals, wash with 60mL of isopropanol, and dry the wet product under reduced pressure at 100±5℃ for 16 hours. Collect 40.5g of the product, and characterize by XRPD. Figure 8 The results indicate that the substance is a type II crystal of compound I, with a purity of 99.40%.

[0066] Preparation of type I crystals of compound I in Comparative Example 2 (refer to Example 1 of patent CN110914246B)

[0067] 30 g of the amorphous solid of compound I was added to a 1-L double-glass jacketed reactor, followed by 120 mL of tetrahydrofuran. The mixture was heated to dissolve and then cooled to room temperature. 30 mg of seed crystals were added to 600 mL of isopropanol, and the mixture was cooled to -25°C and stirred. The tetrahydrofuran solution of compound I was then added dropwise over 15 minutes. The crystals precipitated at 0°C were filtered out, washed with 60 mL of isopropanol, and dried under reduced pressure at 80°C overnight. 26.8 g of the product was collected and characterized by XRPD. Figure 9 The results show that the substance is a type I crystal of compound I, with a purity of 99.11%.

[0068] Preparation of hydrates of compound I in Comparative Example 3 (refer to Example 3 of patent CN110914246B)

[0069] 25 g of the amorphous solid of compound I was added to a 500-mL double-glass jacketed reactor. A suspension was prepared by adding 50 mL of ethanol / 250 mL of water. 110 mL of a 10% sodium carbonate aqueous solution was then added to dissolve the mixture. The mixture was cooled to approximately 15°C, and the pH was adjusted to 2 by adding 1M hydrochloric acid. The mixture was filtered and dried under reduced pressure at 50°C overnight. 18.8 g of the material was collected and characterized by XRPD. Figure 10 The results indicate that the substance is a hydrate of compound I, with a purity of 99.23%.

[0070] Test Example 1: Physicochemical stability of the crystal forms F, II, and I of Compound I and its hydrate.

[0071] Samples of the F, II, and I crystals and hydrates of compound I were placed at 60℃, 92.5% RH, under light, and at 45℃ / 75% RH, respectively. XRPD was used to determine the crystal form before and after placement, and the results are shown in Table 4. The results indicate that the F, II, and I crystals exhibit good physicochemical stability under light, 60℃, 92.5% RH, and 45℃ / 75% RH conditions; the hydrate shows a tendency to dehydrate and transform into an amorphous form at 60℃.

[0072] Table 4. Physicochemical stability studies of crystal forms F, II, and I of compound I and its hydrates.

[0073]

[0074]

[0075] Experimental Example 2: Investigation of the crystal forms F, II, and I of Compound I and the dynamic solubility of its hydrate.

[0076] Samples of crystals and hydrates of the present invention (types F, II, and I) were prepared into suspensions in water and stirred at 37°C for 24 hours. The suspensions were then filtered to obtain saturated solutions. Crystal form changes were monitored by X-ray powder diffraction. Additionally, the actual concentration of the sample in the saturated solution was determined by high-performance liquid chromatography (HPLC) (the filtrate was diluted as needed). The crystal form of the solid before and after the experiment was characterized by XRPD to check for phase transitions. The experimental results are shown in Table 5.

[0077] Table 5 Solubility of Formula I compound crystals F and II

[0078] Example Crystal form Solubility (mg / mL) Does the crystal form change? Example 1 Crystal form F 1.1 no Comparative Example 1 Type II crystallization 1.0 Slightly hygroscopic Comparative Example 2 Type I crystallization 0.1 Yes, it transforms into type II crystals. Comparative Example 3 hydrates 0.05 no

[0079] The results showed that the crystal form F of compound I was more soluble in water than the crystals and hydrates of type II and type I. Crystal form F, type II crystals and hydrates were stable, while type I crystals were unstable.

[0080] Experimental Example 3: Hygroscopicity of crystal form F, type II and type I crystals and hydrates of compound I.

[0081] Dynamic moisture adsorption tests were conducted on samples of crystals and hydrates of the present invention, including crystal form F, type II, and type I (25°C, 80% RH). The results are shown in Table 6. The test results show that crystal form F has no or almost no hygroscopicity, while type II crystal has slight hygroscopicity.

[0082] Table 6. Hygroscopicity of Formula I compound crystal forms F and II

[0083]

[0084]

[0085] Experimental Example 4: Crystal form F, type II and type I crystals and fluidity of the hydrate of compound I.

[0086] The powder properties of the active pharmaceutical ingredient (API) affect its flowability. Hauss-Nabi tests were performed on the crystal forms F, II, and I of Compound I, as well as its hydrate, to compare their flowability. The flowability evaluation results are shown in Table 7. The adsorption rates of the two crystal forms differed significantly. Crystal form F had better flowability than both II and I crystals and its hydrate; type II crystals had better flowability than type I crystals and its hydrate; and type I crystals had better flowability than its hydrate.

[0087] Methods for testing loose density and tapped density:

[0088] This experiment used a vibratory compactor and determined the density using the fixed volume method. The specific procedure was as follows: the weighed powder was placed into a 50-mL graduated cylinder, which was then fixed to a support. The cylinder was set to vibrate at 55±5 times per minute for 6–8 minutes. The volume change of the powder in the graduated cylinder was measured. The ratio of the powder mass to the volume of the material before compaction (50mL) is the loose density of the powder, and the ratio of the powder mass to the volume of the material after compaction is the tapped density of the powder.

[0089] Table 7. Fluidity parameters for crystallization of crystal types F and II

[0090]

[0091] Note: Material Hausner ratio = tapped density / loose density; Material compressibility = (tapped density - loose density) / tapped density.

[0092] The descriptions of Hausnerby and liquidity are shown in Table 8:

[0093] Table 8. Relationship between Hausner Ratio and Liquidity

[0094] Hausner ratio Liquidity Description 1.00-1.11 The liquidity is very good. 1.12-1.18 Good liquidity 1.19-1.25 Good or moderate liquidity 1.26-1.34 Liquidity is acceptable 1.35-1.45 Poor liquidity 1.46-1.59 Very poor liquidity >1.60 Liquidity is extremely poor.

[0095] The above specific embodiments further illustrate the purpose, technical solution and beneficial effects of this application. It should be understood that the above are only specific embodiments of this application and are not intended to limit the scope of protection of this application. Any modifications, equivalent substitutions, improvements, etc., made on the basis of the technical solution of this application should be included within the scope of protection of this application.

Claims

1. 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole crystal form F, characterized in that... It has the structure shown in Equation I. Its X-ray powder diffraction pattern shows diffraction peaks at 2θ values ​​of 12.0°, 14.0°, 16.5°, 20.3°, 21.7°, 23.9°, 24.5°, 28.0°, 28.8° and 30.1°, with an error range of ±0.2° for the 2θ values.

2. The crystal form F of 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole according to claim 1, characterized in that, The X-ray powder diffraction pattern obtained using Cu-Kα radiation is shown in Figure 1.

3. The crystal form F of 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole according to claim 1, characterized in that, The differential scanning calorimetry curve is shown in Figure 2.

4. The crystal form F of 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole according to claim 1, characterized in that, Its thermogravimetric analysis curve is shown in Figure 3.

5. A method for preparing crystal form F of 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole according to any one of claims 1-4, characterized in that, The process includes the following steps: (a) adding the solid of compound I to tetrahydrofuran; (b) heating to 40–45°C and stirring to dissolve the solid, then adding n-heptane and stirring to crystallize, then cooling to 25–30°C and stirring; (c) post-treatment to obtain crystal form F of compound I.

6. The method according to claim 5, characterized in that, The solid form of the compound of formula I is a type I crystal of the compound of formula I, a type II crystal of the compound of formula I, or a hydrate of the compound of formula I.

7. A pharmaceutical composition comprising crystal form F of 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole as described in any one of claims 1-4, and a pharmaceutically permissible carrier.

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