Novel crystal form of dotenorad and application thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and relates to a novel crystal form of dotenorad and application thereof, in particular to a crystal form B, a crystal form C, a crystal form D, a crystal form E, a crystal form G, a crystal form J and a crystal form K. The dotenomer crystal form B disclosed by the invention is radiated by Cu-Ka, and has characteristic peaks at 6.9 + / -0.2 degrees, 13.9 + / -0.2 degrees, 21.5 + / -0.2 degrees and 26.9 + / -0.2 degrees in X-ray powder diffraction represented by a 2 theta angle. The dotenomer crystal form J provided by the invention has characteristic peaks at 5.30 + / -0.2 degrees, 15.90 + / -0.2 degrees, 23.65 + / -0.2 degrees, 23.95 + / -0.2 degrees and 27.36 + / -0.2 degrees in an X-ray powder diffraction pattern which is radiated by Cu-Ka and is expressed by a 2 theta angle. The various novel crystal forms provided by the invention can be used for preparing medicinal dotenorad.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to various new crystal forms of dotinurad and their uses. Background Art

[0002] Dotinurad, with the English name Dotinurad and the chemical name: 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxido-2,3-dihydro-1,3-benzothiazole. Dotinurad has a significant effect of promoting uric acid excretion. The structural formula of dotinurad is as follows:

[0003]

[0004] Patent CN110914246A describes crystal form I, crystal form II, hydrates and various solvates of dotinurad. Summary of the Invention

[0005] In the first aspect of the present invention, a crystal form B of dotinurad is provided. Using Cu-Kα radiation, X-ray powder diffraction (X-RPD) expressed in 2θ angle has characteristic peaks at 6.9±0.2°, 13.9±0.2°, 21.5±0.2°, and 26.9±0.2°.

[0006] For the crystal form B of dotinurad of the present invention, in some preferred embodiments, using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angle has characteristic peaks at 6.9±0.2°, 13.9±0.2°, 21.5±0.2°, 23.5±0.2°, 26.2±0.2°, and 26.9±0.2°.

[0007] For the crystal form B of dotinurad of the present invention, in some other preferred embodiments, using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angle has characteristic peaks at 6.9±0.2°, 13.9±0.2°, 15.0±0.2°, 16.1±0.2°, 21.5±0.2°, 22.7±0.2°, 23.5±0.2°, 25.4±0.2°, 26.2±0.2°, 26.9±0.2°, 28.1±0.2°, and 29.4±0.2°.

[0008] In still some other preferred embodiments, the crystal form B has an X-ray powder diffraction pattern as Figure 1 shown.

[0009] In the second aspect of the present invention, there is provided a polymorph C of dolutegravir, and the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 11.29 ± 0.2°, 15.54 ± 0.2°, 21.85 ± 0.2°, 22.75 ± 0.2°, 25.39 ± 0.2° when using Cu-Kα radiation.

[0010] In some preferred embodiments of the polymorph C of dolutegravir of the present invention, the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 11.29 ± 0.2°, 15.54 ± 0.2°, 18.45 ± 0.2°, 18.67 ± 0.2°, 21.85 ± 0.2°, 22.75 ± 0.2°, 25.39 ± 0.2°, 28.98 ± 0.2° when using Cu-Kα radiation.

[0011] In other preferred embodiments of the polymorph C of dolutegravir of the present invention, the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 11.29 ± 0.2°, 14.11 ± 0.2°, 15.54 ± 0.2°, 16.06 ± 0.2°, 16.27 ± 0.2°, 18. 45 ± 0.2°, 18.67 ± 0.2°, 21.29 ± 0.2°, 21.85 ± 0.2°, 22.75 ± 0.2°, 25.39 ± 0.2°, 26.27 ± 0.2°, 28.98 ± 0.2° when using Cu-Kα radiation.

[0012] In still other preferred embodiments, the polymorph C has an X-ray powder diffraction pattern as Figure 2 shown.

[0013] In some preferred embodiments of the polymorph C of dolutegravir of the present invention, endothermic peaks appear in the ranges of 75 - 105 °C and 205 - 225 °C respectively in its differential scanning calorimetry (DSC) pattern, and exothermic peaks appear in the ranges of 105 - 125 °C and 165 - 190 °C respectively. Preferably, the peak values of the endothermic peaks in the DSC pattern of the polymorph C appear at 99.9 ± 2 °C and 211.7 ± 2 °C respectively, and the peak values of the exothermic peaks appear at 113.4 ± 2 °C and 177.7 ± 2 °C respectively. More preferably, the polymorph C has a DSC pattern as Figure 3 shown.

[0014] In some preferred embodiments of the polymorph C of dolutegravir of the present invention, weight loss occurs in the range of 34 - 130 °C in its thermogravimetric analysis (TGA) pattern, and the mass fraction of the weight loss is 4.7%. Preferably, the polymorph C has a TGA pattern as Figure 3 shown.

[0015] The third aspect of the present invention provides a polymorph D of dolutegravir, and the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 10.67±0.2°, 15.75±0.2°, 18.02±0.2°, 22.08±0.2°, 26.39±0.2° when using Cu-Kα radiation.

[0016] In some preferred embodiments of the polymorph D of dolutegravir of the present invention, the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 10.67±0.2°, 15.75±0.2°, 18.02±0.2°, 20.36±0.2°, 22.08±0.2°, 25.39±0.2°, 25.70±0.2°, 26.39±0.2° when using Cu-Kα radiation.

[0017] In some other preferred embodiments, the polymorph D has an X-ray powder diffraction pattern as Figure 4 shown.

[0018] For the polymorph D of dolutegravir of the present invention, an endothermic peak appears in the differential scanning calorimetry (DSC) pattern in the range of 205-225°C, and an exothermic peak appears in the range of 155-195°C. Preferably, the peak value of the endothermic peak in the DSC pattern of the polymorph D appears at 214.1±2°C, and the peak value of the exothermic peak appears at 178.7±2°C. More preferably, the polymorph D has a TGA-DSC pattern as Figure 5 shown.

[0019] The fourth aspect of the present invention provides a polymorph E of dolutegravir, and the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 7.68±0.2°, 15.49±0.2°, 16.93±0.2°, 23.10±0.2°, 23.44±0.2° when using Cu-Kα radiation.

[0020] In some preferred embodiments of the polymorph E of dolutegravir of the present invention, the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 7.68±0.2°, 15.49±0.2°, 16.05±0.2°, 16.93±0.2°, 18.11±0.2°, 22.34±0.2°, 23.10±0.2°, 23.44±0.2° when using Cu-Kα radiation.

[0021] In some other preferred embodiments, for polymorph E of dolutegravir of the present invention, using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 7.68±0.2°, 14.19±0.2°, 15.49±0.2°, 16.05±0.2°, 16.93±0.2°, 18.11±0.2°, 22.34±0.2°, 23.10±0.2°, 23.44±0.2°, 25.32±0.2°, 25.90±0.2°, 26.10±0.2°.

[0022] In still some other preferred embodiments, Figure 6 the polymorph E has the X-ray powder diffraction pattern as shown.

[0023] The fifth aspect of the present invention provides a polymorph G of dolutegravir. Using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 6.40±0.2°, 21.82±0.2°, 24.44±0.2°, 24.83±0.2°.

[0024] For polymorph G of dolutegravir of the present invention, in some preferred embodiments, using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 6.40±0.2°, 17.67±0.2°, 21.55±0.2°, 21.82±0.2°, 22.52±0.2°, 24.44±0.2°, 24.83±0.2°.

[0025] In some other preferred embodiments, Figure 7 the polymorph G has the X-ray powder diffraction pattern as shown.

[0026] For polymorph G of dolutegravir of the present invention, in some preferred embodiments, in its differential scanning calorimetry (DSC) pattern, endothermic peaks appear in the ranges of 65-85°C, 185-192°C, 205-225°C, and an exothermic peak appears in the range of 192-201°C. Preferably, the peak values of the endothermic peaks in the DSC pattern of the polymorph G appear at 71.9±2°C, 190.2±2°C, 213.6±2°C respectively, and the peak value of the exothermic peak appears at 192.9±2°C. More preferably, the polymorph G has the DSC pattern as shown in Figure 8 the figure.

[0027] For polymorph G of dolutegravir of the present invention, in some preferred embodiments, in its thermogravimetric analysis (TGA) pattern, weight loss occurs in the ranges of 35-130°C and 130-205°C, and the mass fractions of the weight loss are 3.8% and 0.6% respectively. Preferably, the polymorph G has the TGA pattern as shown in Figure 8 the figure.

[0028] The sixth aspect of the present invention provides a polymorph J of dolutegravir, and the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 5.30±0.2°, 15.90±0.2°, 23.65±0.2°, 23.95±0.2°, 27.36±0.2° when using Cu-Kα radiation.

[0029] For the polymorph J of dolutegravir of the present invention, in some preferred embodiments, the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 5.30±0.2°, 15.09±0.2°, 15.90±0.2°, 16.86±0.2°, 22.27±0.2°, 23.65±0.2°, 23.95±0.2°, 27.36±0.2° when using Cu-Kα radiation.

[0030] For the polymorph J of dolutegravir of the present invention, in some other preferred embodiments, the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 5.30±0.2°, 12.26±0.2°, 14.60±0.2°, 15.09±0.2°, 15.90±0.2°, 16.86±0.2°, 18.11±0.2°, 20.76±0.2°, 22.27±0.2°, 23.65±0.2°, 23.95±0.2°, 27.36±0.2°, 29.32±0.2° when using Cu-Kα radiation.

[0031] In still some other preferred embodiments, the polymorph J has an X-ray powder diffraction pattern as Figure 9 shown.

[0032] In some preferred embodiments, the differential scanning calorimetry (DSC) pattern of the polymorph J shows endothermic peaks in the ranges of 99-120°C and 135-240°C respectively. Preferably, the peak values of the endothermic peaks in the DSC pattern of the polymorph J appear at 108.5±2°C and 189.3±2°C respectively. More preferably, the polymorph J has a TGA-DSC pattern as Figure 10 shown.

[0033] The seventh aspect of the present invention provides a polymorph K of dolutegravir, and the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 7.03±0.2°, 21.78±0.2°, 23.52±0.2°, 26.49±0.2° when using Cu-Kα radiation.

[0034] For polymorph K of dutinore, in some preferred embodiments, the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 7.03 ± 0.2°, 14.12 ± 0.2°, 14.48 ± 0.2°, 21.36 ± 0.2°, 21.78 ± 0.2°, 23.52 ± 0.2°, 26.49 ± 0.2° when using Cu-Kα radiation.

[0035] For polymorph K of dutinore, in some other preferred embodiments, the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 7.03 ± 0.2°, 11.46 ± 0.2°, 14.12 ± 0.2°, 14.48 ± 0.2°, 16.55 ± 0.2°, 21.36 ± 0.2°, 21.78 ± 0.2°, 23.12 ± 0.2°, 23.52 ± 0.2°, 25.86 ± 0.2°, 26.49 ± 0.2° when using Cu-Kα radiation.

[0036] In still some other preferred embodiments, the polymorph K has an X-ray powder diffraction pattern as Figure 11 shown.

[0037] The eighth aspect of the present invention provides the use of the polymorph as described in any one of the above in the preparation of a drug for promoting uric acid excretion, reducing blood uric acid level, and for treating hyperuricemia, gout, urinary calculi, obesity, hyperlipidemia, dyslipidemia, impaired glucose tolerance, diabetes, metabolic syndrome, kidney disease and / or cardiovascular disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 is the X-ray powder diffraction pattern of polymorph B of dutinore.

[0039] Figure 2 is the X-ray powder diffraction pattern of polymorph C of dutinore.

[0040] Figure 3 is the TGA-DSC thermal spectrum of polymorph C of dutinore.

[0041] Figure 4 is the X-ray powder diffraction pattern of polymorph D of dutinore.

[0042] Figure 5 is the TGA-DSC thermal spectrum of polymorph D of dutinore.

[0043] Figure 6 is the X-ray powder diffraction pattern of polymorph E of dutinore.

[0044] Figure 7 is the X-ray powder diffraction pattern of polymorph G of dutinore.

[0045] Figure 8 It is the TGA-DSC thermal spectrum of polymorph G of dolutegravir.

[0046] Figure 9 It is the X-ray powder diffraction pattern of polymorph J of dolutegravir.

[0047] Figure 10 It is the TGA-DSC thermal spectrum of polymorph J of dolutegravir.

[0048] Figure 11 It is the X-ray powder diffraction pattern of polymorph K of dolutegravir. Detailed implementation manners

[0049] The above content of the present invention will be further described in detail through specific implementation manners below, but this should not be construed as any limitation to the protection subject matter of the present invention. Any technical solution implemented based on the above content of the present invention falls within the scope of the present invention. The present invention generally and / or specifically describes the materials and test methods used in the experiments.

[0050] Example 1 Preparation of polymorph B of dolutegravir

[0051] 0.12 g of dolutegravir and 1.0 mL of THF were added to a sample bottle, and the heating temperature was raised to 65 °C and stirred until dissolved. It was filtered into a sample bottle containing 10.0 mL of isopropanol, and the isopropanol was kept stirred during the filtration process. After stirring at room temperature for 1 h, suction filtration was carried out to obtain polymorph B of dolutegravir. The X-ray powder diffraction pattern of the obtained polymorph B of dolutegravir is shown in Figure 1 .

[0052] Example 2 Preparation of polymorph C of dolutegravir

[0053] 0.51 g of dolutegravir was added to a sample bottle, 1.0 mL of ethanol was added, and stirring was started. A 10% aqueous solution of Na2CO3 was slowly added dropwise within 0.5 h until it became clear. After becoming clear, the temperature was lowered to 15 °C, and it was kept warm for 0.5 h. The pH was adjusted to about 2 with dilute hydrochloric acid, crystallization was carried out for 4 h, suction filtration was carried out, and the wet product was left to dry at room temperature for 24 h to obtain polymorph C of dolutegravir. The X-ray powder diffraction pattern of the obtained polymorph C of dolutegravir is shown in Figure 2 , and the TGA / DSC spectrum is shown in Figure 3 . The TGA weight loss was 4.7%, and the theoretical mass fraction of 1 equivalent of water was 4.8%. It is speculated that polymorph C is a monohydrate.

[0054] Example 3 Preparation of polymorph D of dolutegravir

[0055] Polymorph C of dolutegravir was placed in a vacuum drying oven at 50 °C for 4 h to obtain polymorph D of dolutegravir. The X-ray powder diffraction pattern of the obtained polymorph D of dolutegravir is shown in Figure 4 , and the TGA / DSC spectrum is shown in Figure 5。The weight loss of TGA is small, and it is speculated that crystal form D is the anhydrous form.

[0056] Preparation of Dorzolamide Crystal Form D in Example 4

[0057] 10.2 mg of dorzolamide was added to a sample bottle, and then 2.5 mL of methanol was added. The mixture was stirred at room temperature until dissolved. After the solution became clear, it was filtered into a new sample bottle, sealed with a sealing film, and 5 small holes were pricked. It was slowly volatilized at room temperature for 7 days. Dorzolamide crystal form D was obtained. The X-ray powder diffraction pattern of the obtained dorzolamide crystal form D is shown in Figure 4 。

[0058] Preparation of Dorzolamide Crystal Form E in Example 5

[0059] 12.0 mg of dorzolamide was added to a sample bottle, and then 5.0 mL of dichloromethane was added. The mixture was stirred at room temperature until dissolved. After it became clear, it was filtered into a new sample bottle. It was sealed with a sealing film, 5 small holes were pricked, and it was slowly volatilized at room temperature to obtain dorzolamide crystal form E. The X-ray powder diffraction pattern of the obtained dorzolamide crystal form E is shown in Figure 6 。

[0060] Preparation of Dorzolamide Crystal Form G in Example 6

[0061] 11.6 mg of dorzolamide was added to a sample bottle, and then 2.0 mL of ethyl acetate was added. The mixture was stirred until dissolved. After it became clear, it was filtered into a new sample bottle. It was sealed with a sealing film, 5 small holes were pricked, and it was slowly volatilized at room temperature to obtain the X-ray powder diffraction pattern of dorzolamide crystal form G as shown in Figure 7 , and the TGA / DSC pattern is shown in Figure 8 。

[0062] Preparation of Dorzolamide Crystal Form J in Example 7

[0063] 0.44 g of dorzolamide and 3.0 mL of dimethyl sulfoxide (DMSO) were added to a sample bottle and stirred at room temperature until dissolved. It was filtered into a new sample bottle, and 3.0 mL of purified water was slowly added dropwise over 0.5 h. After the addition was complete, it was kept warm for 1 h, cooled to 15 °C slowly over 0.5 h, kept warm and stirred for 12 h, filtered, and dried under vacuum at room temperature for 24 h to obtain dorzolamide crystal form J. The X-ray powder diffraction pattern of the obtained dorzolamide crystal form J is shown in Figure 9 , and the TGA / DSC pattern is shown in Figure 10 。The weight loss of TGA is 18.6%, and the theoretical mass fraction of 1 equivalent of DMSO is 4.8%. It is speculated that crystal form J is a DMSO solvate.

[0064] The results of the influencing factor tests for crystal form J and crystal form II are as follows:

[0065]

[0066] Crystal form J has excellent chemical stability.

[0067] Example 8 Preparation of Polytinol Form K

[0068] 0.12 g of polytinol and 1.0 mL of THF were added to a sample bottle and heated to 65°C. Stirring was performed until dissolved. Filtered and quickly added dropwise to 4.0 mL of n-heptane. Solid precipitated to obtain polytinol Form K. The X-ray powder diffraction pattern of the obtained polytinol Form K is shown in FIG. Figure 11 .

Claims

1. A polymorphic form B of dolutegravir, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (X-RPD) expressed in terms of 2θ angle has characteristic peaks at 6.9±0.2°, 13.9±0.2°, 21.5±0.2°, 26.9±0.2°; Preferably, using Cu-Kα radiation, the X-ray powder diffraction expressed in terms of 2θ angle has characteristic peaks at 6.9±0.2°, 13.9±0.2°, 21.5±0.2°, 23.5±0.2°, 26.2±0.2°, 26.9±0.2°; More preferably, using Cu-Kα radiation, the X-ray powder diffraction expressed in terms of 2θ angle has characteristic peaks at 6.9±0.2°, 13.9±0.2°, 15.0±0.2°, 16.1±0.2°, 21.5±0.2°, 22.7±0.2°, 23.5±0.2°, 25.4±0.2°, 26.2±0.2°, 26.9±0.2°, 28.1±0.2°, 29.4±0.2°; Most preferably, the crystal form B has an X-ray powder diffraction pattern as shown in Figure 1.

2. A crystal form C of dolutegravir, the X-ray powder diffraction pattern expressed in terms of 2θ angle using Cu-Kα radiation has characteristic peaks at 11.29±0.2°, 15.54±0.2°, 21.85±0.2°, 22.75±0.2°, 25.39±0.2°; Preferably, the X-ray powder diffraction pattern expressed in terms of 2θ angle using Cu-Kα radiation has characteristic peaks at 11.29±0.2°, 15.54±0.2°, 18.45±0.2°, 18.67±0.2°, 21.85±0.2°, 22.75±0.2°, 25.39±0.2°, 28.98±0.2°; More preferably, the X-ray powder diffraction pattern expressed in terms of 2θ angle using Cu-Kα radiation has characteristic peaks at 11.29±0.2°, 14.11±0.2°, 15.54±0.2°, 16.06±0.2°, 16.27±0.2°, 18.45±0.2°, 18.67±0.2°, 21.29±0.2°, 21.85±0.2°, 22.75±0.2°, 25.39±0.2°, 26.27±0.2°, 28.98±0.2°; Most preferably, the crystal form C has an X-ray powder diffraction pattern as shown in Figure 2.

3. The polymorphic form C of dolutegravir according to claim 2, wherein, Its differential scanning calorimetry (DSC) pattern shows endothermic peaks in the ranges of 75-105°C and 205-225°C respectively, and exothermic peaks in the ranges of 105-125°C and 165-190°C respectively; preferably, the peak values of the endothermic peaks of the DSC pattern of the crystal form C appear at 99.9±2°C and 211.7±2°C respectively, and the peak values of the exothermic peaks appear at 113.4±2°C and 177.7±2°C respectively; more preferably, the crystal form C has a DSC pattern as shown in Figure 3, The thermogravimetric analysis (TGA) spectrum of the crystalline form C shows a weight loss in the range of 34 to 130 °C, and the mass fraction of the weight loss is 4.7%; preferably, the crystalline form C has a TGA spectrum as shown in Figure 3.

4. A polymorph D of dolutegravir, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction spectrum expressed in 2θ angle has characteristic peaks at 10.67 ± 0.2°, 15.75 ± 0.2°, 18.02 ± 0.2°, 22.08 ± 0.2°, 26.39 ± 0.2°. Preferably, using Cu-Kα radiation, the X-ray powder diffraction spectrum expressed in 2θ angle has characteristic peaks at 10.67 ± 0.2°, 15.75 ± 0.2°, 18.02 ± 0.2°, 20.36 ± 0.2°, 22.08 ± 0.2°, 25.39 ± 0.2°, 25.70 ± 0.2°, 26.39 ± 0.2°. Most preferably, the crystalline form D has an X-ray powder diffraction spectrum as shown in Figure 4. The differential scanning calorimetry (DSC) spectrum of the crystalline form D shows an endothermic peak in the range of 205 to 225 °C and an exothermic peak in the range of 155 to 195 °C; preferably, the peak value of the endothermic peak of the DSC spectrum of the crystalline form D appears at 214.1 ± 2 °C, and the peak value of the exothermic peak appears at 178.7 ± 2 °C; more preferably, the crystalline form D has a TGA-DSC spectrum as shown in Figure 5.

5. A polymorph E of dolutegravir, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction spectrum expressed in 2θ angle has characteristic peaks at 7.68 ± 0.2°, 15.49 ± 0.2°, 16.93 ± 0.2°, 23.10 ± 0.2°, 23.44 ± 0.2°. Preferably, using Cu-Kα radiation, the X-ray powder diffraction spectrum expressed in 2θ angle has characteristic peaks at 7.68 ± 0.2°, 15.49 ± 0.2°, 16.05 ± 0.2°, 16.93 ± 0.2°, 18.11 ± 0.2°, 22.34 ± 0.2°, 23.10 ± 0.2°, 23.44 ± 0.2°. Further preferably, using Cu-Kα radiation, the X-ray powder diffraction spectrum expressed in 2θ angle has characteristic peaks at 7.68 ± 0.2°, 14.19 ± 0.2°, 15.49 ± 0.2°, 16.05 ± 0.2°, 16.93 ± 0.2°, 18.11 ± 0.2°, 22.34 ± 0.2°, 23.10 ± 0.2°, 23.44 ± 0.2°, 25.32 ± 0.2°, 25.90 ± 0.2°, 26.10 ± 0.2°. Most preferably, the crystalline form E has an X-ray powder diffraction spectrum as shown in Figure 6.

6. A polymorphic form G of dolutegravir, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction spectrum expressed in 2θ angle has characteristic peaks at 6.40 ± 0.2°, 21.82 ± 0.2°, 24.44 ± 0.2°, 24.83 ± 0.2°. Further preferably, using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in 2θ angle has characteristic peaks at 6.40±0.2°, 17.67±0.2°, 21.55±0.2°, 21.82±0.2°, 22.52±0.2°, 24.44±0.2°, 24.83±0.2°; Most preferably, the crystal form G has an X-ray powder diffraction pattern as shown in Figure 7.

7. The polymorphic form G of dolutegravir according to claim 6, wherein Its differential scanning calorimetry (DSC) pattern shows endothermic peaks in the ranges of 65-85°C, 185-192°C, 205-225°C respectively, and an exothermic peak in the range of 192-201°C; preferably, the peak values of the endothermic peaks of the DSC pattern of the crystal form G appear at 71.9±2°C, 190.2±2°C, 213.6±2°C respectively, and the peak value of the exothermic peak appears at 192.9±2°C; more preferably, the crystal form G has a DSC pattern as shown in Figure 8, The thermogravimetric analysis (TGA) pattern of the crystal form G shows weight loss in the ranges of 35-130°C and 130-205°C, and the mass fractions of weight loss are 3.8% and 0.6%; preferably, the crystal form G has a TGA pattern as shown in Figure 8.

8. A polymorph J of dolutegravir, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in 2θ angle has characteristic peaks at 5.30±0.2°, 15.90±0.2°, 23.65±0.2°, 23.95±0.2°, 27.36±0.2°; Preferably, using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in 2θ angle has characteristic peaks at 5.30±0.2°, 15.09±0.2°, 15.90±0.2°, 16.86±0.2°, 22.27±0.2°, 23.65±0.2°, 23.95±0.2°, 27.36±0.2°; Further preferably, using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in 2θ angle has characteristic peaks at 5.30±0.2°, 12.26±0.2°, 14.60±0.2°, 15.09±0.2°, 15.90±0.2°, 16.86±0.2°, 18.11±0.2°, 20.76±0.2°, 22.27±0.2°, 23.65±0.2°, 23.95±0.2°, 27.36±0.2°, 29.32±0.2°; Most preferably, the crystal form J has an X-ray powder diffraction pattern as shown in Figure 9, In some preferred embodiments, the differential scanning calorimetry (DSC) pattern of the crystal form J shows endothermic peaks in the ranges of 99-120°C and 135-240°C respectively; preferably, the peak values of the endothermic peaks of the DSC pattern of the crystal form J appear at 108.5±2°C and 189.3±2°C respectively; more preferably, the crystal form J has a TGA-DSC pattern as shown in Figure 10.

9. A polymorphic form K of dolutegravir, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 7.03 ± 0.2°, 21.78 ± 0.2°, 23.52 ± 0.2°, 26.49 ± 0.2°; Preferably, using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 7.03 ± 0.2°, 14.12 ± 0.2°, 14.48 ± 0.2°, 21.36 ± 0.2°, 21.78 ± 0.2°, 23.52 ± 0.2°, 26.49 ± 0.2°; More preferably, using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 7.03 ± 0.2°, 11.46 ± 0.2°, 14.12 ± 0.2°, 14.48 ± 0.2°, 16.55 ± 0.2°, 21.36 ± 0.2°, 21.78 ± 0.2°, 23.12 ± 0.2°, 23.52 ± 0.2°, 25.86 ± 0.2°, 26.49 ± 0.2°; Most preferably, the crystalline form K has the X-ray powder diffraction pattern shown in Figure 11.

10. Use of the crystalline form according to any one of claims 1-9 in the preparation of a medicament for promoting uric acid excretion, reducing blood uric acid level, and for treating hyperuricemia, gout, urinary calculi, obesity, hyperlipidemia, dyslipidemia, impaired glucose tolerance, diabetes, metabolic syndrome, kidney disease and / or cardiovascular disease.

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