Crystalline form of pyrrolopyridine derivatives

Abstract

The present invention relates to a crystal polymorph of a pyrrolopyridine derivative that is a non-catalytic site integrase inhibitor and a method for preparing the same. The novel crystal polymorph of the present invention exhibits excellent non-hygroscopicity and stability, making it suitable for pharmaceutical formulations.

Description

Technology Field

[0001] The present invention relates to a crystalline form of a pyrrolopyridine derivative that is a non-catalytic site integrase inhibitor. Furthermore, the present invention relates to a method for preparing the crystalline form of the said pyrrolopyridine derivative. Background Technology

[0002] Acquired Immunodeficiency Syndrome (AIDS) is caused by infection with the Human Immunodeficiency Virus (HIV). Enzyme inhibitors have been developed for the treatment of AIDS based on the mechanism of action of HIV, and are classified according to their target into nucleoside reverse transcriptase inhibitors (NRTI), protease inhibitors (PI), fusion inhibitors, and integrase inhibitors. Due to problems such as side effects, drug interactions, and the development of drug resistance associated with reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors, the development of integrase inhibitors is actively underway.

[0003] Integrase inhibitors are classified into catalytic site inhibitors and non-catalytic site inhibitors based on their mechanism of action. Raltegravir is a representative drug among catalytic site integrase inhibitors. The mechanism of non-catalytic site integrase inhibition was introduced by Zeger Debyser et al. (Frauke Christ, Zeger Debyser et al., Nature Chemical Biology, 2010, Vol. 6, 442), but no drug has yet been successfully developed.

[0004] However, drug resistance has also been observed with raltegravir, a catalytic site integrase inhibitor. Since latent HIV is reactivated and resistance develops when treatment is discontinued, rendering the current medication ineffective, the development of non-catalytic site integrase inhibitors is being attempted as a treatment to address the issue of drug resistance. In particular, a pyrrolopyridine derivative of the chemical formula I below is known as a non-catalytic site integrase inhibitor.

[0005] [Chemical Formula I]

[0006]

[0007] When designing a suitable dosage form during the drug manufacturing process, the physical state of the drug raw material—namely, whether crystalline or amorphous—is important. However, crystalline raw materials have low solubility, which can lead to reduced bioavailability per unit weight, while amorphous materials are unstable and may present problems such as difficulty in controlling drug release and blood concentration.

[0008] Therefore, it is necessary to develop a new crystalline form of the pyrrolopyridine derivative of Formula I that exhibits excellent physicochemical properties while simultaneously solving these problems. The problem to be solved

[0009] The objective of the present invention is to provide a crystalline form of a pyrrolopyridine derivative having excellent non-hygroscopicity and stability, and capable of improving solubility and bioavailability, and a method for preparing the same. means of solving the problem

[0010] In order to achieve the above objective, the inventors of the present invention, through their research efforts, manufactured crystalline forms A to D mentioned below and confirmed that all of them exhibited excellent effects, thereby completing the present invention.

[0011] Crystalline form A and method of manufacturing the same

[0012] The present invention provides a crystalline form A of a compound represented by the following formula I, having peaks at diffraction angles (2θ±0.2°) of 9.26°, 10.47°, 12.76°, 14.70°, 15.83°, and 16.61° in a powder X-ray diffraction pattern:

[0013] [Chemical Formula I]

[0014] .

[0015] According to a specific embodiment of the present invention, the crystalline form A may further include one or more peaks at diffraction angles (2θ±0.2°) of 17.57°, 18.50°, 20.15°, 21.06°, 22.17°, 23.93°, or 27.05° in the powder X-ray diffraction pattern.

[0016] According to a specific embodiment of the present invention, the crystalline form A may further include one or more peaks at diffraction angles (2θ±0.2°) of 8.02°, 8.39°, 8.72°, 13.92°, 16.40°, 17.80°, 19.33°, 23.38°, 24.36°, 24.90°, 25.59°, 25.99°, 26.70°, 27.85°, 29.37°, 29.98°, 30.77°, or 31.59° in the powder X-ray diffraction pattern.

[0017] According to a specific embodiment of the present invention, the crystalline form A may have a Differential Scanning Calorimetry (DSC) endothermic transition peak at 208 to 215 ℃ when the heating rate is 10 ℃ / min.

[0018] In addition, the present invention provides a method for manufacturing the crystalline form A. Specifically, the manufacturing method may include the following steps:

[0019] (A-1) A step of adding a compound represented by the above chemical formula I to toluene, ethyl acetate, or isopropanol and stirring; and

[0020] (A-2) A step of filtering and drying the generated solid.

[0021] Crystalline form B and method for manufacturing the same

[0022] The present invention provides a crystalline form B of a compound represented by the formula I, having peaks at diffraction angles (2θ±0.2°) of 9.24°, 12.77°, 15.43°, 16.32°, 17.83°, and 19.35° in a powder X-ray diffraction pattern.

[0023] According to a specific embodiment of the present invention, the crystalline form B may further include one or more peaks at diffraction angles (2θ±0.2°) of 20.18°, 23.35°, 23.84°, 24.46°, 26.03°, 29.66°, or 30.54° in the powder X-ray diffraction pattern.

[0024] According to a specific embodiment of the present invention, the crystalline form B may further include one or more peaks at diffraction angles (2θ±0.2°) of 7.94°, 10.03°, 11.65°, 14.63°, 16.80°, 17.55°, 18.63°, 21.58°, 22.67°, 23.62°, 25.29°, 27.15°, 28.13°, 29.38°, 30.68°, 31.61°, 32.05°, 33.04°, 34.41°, 35.50°, or 36.26° in the powder X-ray diffraction pattern.

[0025] According to a specific embodiment of the present invention, the crystalline form B may have a Differential Scanning Calorimetry (DSC) endothermic transition peak at 213 to 218 ℃ when the heating rate is 10 ℃ / min.

[0026] In addition, the present invention provides a method for manufacturing the crystalline form B. Specifically, the manufacturing method may include the following steps:

[0027] (B-1) A step of adding a compound represented by the above chemical formula I to ethanol and stirring; and

[0028] (B-2) A step of filtering and drying the generated solid.

[0029] Crystalline C and method for manufacturing the same

[0030] The present invention provides a crystalline form C of a compound represented by the formula I, having peaks at diffraction angles (2θ±0.2°) of 7.62°, 8.61°, 10.09°, 12.06°, 13.52°, and 15.72° in a powder X-ray diffraction pattern.

[0031] According to a specific embodiment of the present invention, the crystalline form C may further include one or more peaks at diffraction angles (2θ±0.2°) of 17.35°, 18.74°, 19.62°, 22.60°, 23.50°, or 25.57° in the powder X-ray diffraction pattern.

[0032] According to a specific embodiment of the present invention, the crystalline form C may further include one or more peaks at diffraction angles (2θ±0.2°) of 9.23°, 9.73°, 11.36°, 12.85°, 15.37°, 16.16°, 17.85°, 20.34°, 21.00°, 23.96°, 24.37°, 25.21°, 26.24°, 27.33°, 27.84°, 29.70°, 30.32°, 31.08°, 33.94°, or 35.18° in the powder X-ray diffraction pattern.

[0033] According to a specific embodiment of the present invention, the crystalline form C may have Differential Scanning Calorimetry (DSC) endothermic transition peaks at 124 to 143 ℃ and 207 to 213 ℃ when the heating rate is 10 ℃ / min.

[0034] In addition, the present invention provides a method for manufacturing the crystalline form C. Specifically, the manufacturing method may include the following steps:

[0035] (C-1) A step of adding a compound represented by the above chemical formula I to methanol and stirring; and

[0036] (C-2) A step of filtering and drying the generated solid.

[0037] Crystalline form D and method for manufacturing the same

[0038] The present invention provides a crystalline form D of a compound represented by the formula I, having peaks at diffraction angles (2θ±0.2°) of 8.69°, 11.42°, 13.62°, 15.51°, 16.70°, and 21.58° in a powder X-ray diffraction pattern.

[0039] According to a specific embodiment of the present invention, the crystalline form D may further include one or more peaks at diffraction angles (2θ±0.2°) of 7.52°, 9.37°, 9.89°, 18.59°, or 23.84° in the powder X-ray diffraction pattern.

[0040] According to a specific embodiment of the present invention, the crystalline form D may further include one or more peaks at diffraction angles (2θ±0.2°) of 8.25°, 10.72°, 12.02°, 12.38°, 15.01°, 15.93°, 17.95°, 19.91°, 20.62°, 21.29°, 22.71°, or 27.10° in the powder X-ray diffraction pattern.

[0041] According to a specific embodiment of the present invention, the crystalline form D may have a Differential Scanning Calorimetry (DSC) endothermic transition peak at 204 to 209 ℃ when the heating rate is 10 ℃ / min.

[0042] In addition, the present invention provides a method for manufacturing the crystalline form D. Specifically, the manufacturing method may include the following steps:

[0043] (D-1) A step of adding a compound represented by the following chemical formula I to acetone and water and stirring by reflux;

[0044] (D-2) A step of filtering the insoluble matter and adding water and stirring; and

[0045] (D-3) A step of filtering and drying the generated solid. Effects of the invention

[0046] The crystalline form of the present invention has low hygroscopicity, excellent stability under accelerated and long-term storage conditions, and can be maintained stably without changes in content over the long term, making it advantageous for pharmaceutical formulations.

[0047] In addition, the crystalline form of the present invention has high solubility and bioavailability, so it can be usefully used as an active pharmaceutical ingredient. Brief explanation of the drawing

[0048] Figure 1 shows the powder X-ray diffraction analysis (PXRD) results of crystalline form A according to Example 1 of the present invention. Figure 2 shows the differential scanning calorimetry (DSC) thermogram results of crystalline form A according to Example 1 of the present invention. Figure 3 shows the powder X-ray diffraction analysis (PXRD) results of crystalline form B according to Example 2 of the present invention. Figure 4 shows the differential scanning calorimetry (DSC) thermogram results of crystalline form B according to Example 2 of the present invention. Figure 5 shows the powder X-ray diffraction analysis (PXRD) results of crystalline C according to Example 3 of the present invention. Figure 6 shows the differential scanning calorimetry (DSC) thermogram results of crystalline C according to Example 3 of the present invention. Figure 7 shows the powder X-ray diffraction analysis (PXRD) results of crystalline form D according to Example 4 of the present invention. Figure 8 shows the differential scanning calorimetry (DSC) thermogram results of crystalline form D according to Example 4 of the present invention. Specific details for implementing the invention

[0049] Hereinafter, to aid in understanding the present invention, examples and experimental examples will be described in detail. However, the following examples and experimental examples are merely illustrative of the content of the present invention, and the scope of the present invention is not limited to the following examples. The examples and experimental examples of the present invention are provided to more completely explain the present invention to those with average knowledge in the art.

[0050] Unless otherwise noted, the reagents and solvents mentioned below were purchased from Sigma-Aldrich Korea, TCI, and Daejeong Hwakum, and HLPC was measured using the Agilent Technologies 1000 series.

[0051] In addition, the various solid forms of (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazole-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-5-yl)acetic acid prepared according to the following examples were confirmed by X-ray diffraction patterns and DSC patterns by differential scanning calorimetry (DSC).

[0052] Specifically, powder X-ray diffraction analysis was performed using a BRUKER D8 Focus equipped with a rotary meter and a solid-state detector, and measurements were taken using Cu-Kα rays under conditions of an analysis range of 5° to 50°, a step of 0.020°, and a step time of 171.6s. In addition, DSC measurements by differential scanning calorimetry (DSC) were taken using a METTLER TOLEDO DSC3 at a rate of 10°C / min at 50°C to 300°C.

[0053] Preparation Example. Preparation of (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazole-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-5-yl)acetic acid

[0054] [Chemical Formula I]

[0055]

[0056] (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazole-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-5-yl)acetate (13.5 g, 25.8 mmol) was diluted in 108 mL of tetrahydrofuran and 27 mL of methanol. Sodium hydroxide (3.1 g, 77.4 mmol) was added, and the mixture was stirred at 40–45 °C for 4 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and 120 mL of dichloromethane and 60 mL of purified water were added. After cooling to 0–5 °C, the pH was adjusted to 4.5–5.0 with a 2N aqueous hydrochloric acid solution. After separating the organic layer, it was washed with 60 mL of purified water, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 30 mL of acetonitrile was added to the obtained residue, cooled to 5–10 ℃, and stirred for 3 hours. The precipitated crystals were filtered and dried under reduced pressure to obtain the title compound (9.25 g, 72%, ee: 99%) as a milky white solid.

[0057] Example 1. Preparation of Crystalline Form A

[0058] 1 g of (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazole-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-5-yl)acetic acid prepared in the preparation example of the present invention was added to various solvents according to Table 1 below and stirred overnight at room temperature. The resulting solid was filtered and dried in a hot air dryer at 50 ℃ to obtain crystalline form A.

[0059] [Table 1]

[0060]

[0061] Powder X-ray Diffraction Analysis (PXRD) peaks and Differential Scanning Calorimetry (DSC) endothermic peaks for the above solid were analyzed, and the results are as shown in Figures 1 and 2, respectively.

[0062] As confirmed in Figure 1, the solid compound exhibited major peaks at 2θ (±0.2°) values ​​of 9.26°, 10.47°, 12.76°, 14.70°, 15.83°, and 16.61°.

[0063] In addition, as confirmed in Fig. 2, it was found that the solid compound exhibited a differential scanning calorimetry (DSC) endothermic transition peak at 208 to 215 ℃ when the heating rate was 10 ℃ / min.

[0064] Example 2. Preparation of Crystalline Form B

[0065] 1 g of (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazole-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-5-yl)acetic acid prepared in the preparation example of the present invention was added to ethanol (5 mL, 5 V) and stirred overnight at room temperature. The resulting solid was filtered and dried in a hot air dryer at 50 ℃ to obtain crystalline form B (0.71 g, 71%).

[0066] Powder X-ray Diffraction Analysis (PXRD) peaks and Differential Scanning Calorimetry (DSC) endothermic peaks for the above solid were analyzed, and the results are as shown in Figures 3 and 4, respectively.

[0067] As confirmed in Fig. 3, the solid compound exhibited major peaks at 2θ (±0.2°) values ​​of 9.24°, 12.77°, 15.43°, 16.32°, 17.83°, and 19.35°.

[0068] In addition, as confirmed in Fig. 4, it was found that the solid compound exhibited a differential scanning calorimetry (DSC) endothermic transition peak at 213 to 218 ℃ when the heating rate was 10 ℃ / min.

[0069] Example 3. Preparation of crystalline C

[0070] 1 g of (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazole-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-5-yl)acetic acid prepared in the preparation example of the present invention was added to methanol (5 mL, 5 V) and stirred overnight at room temperature. The resulting solid was filtered and dried in a hot air dryer at 50 ℃ to obtain crystalline form C (0.76 g, 76%).

[0071] Powder X-ray diffraction (PXRD) peaks and differential scanning calorimetry (DSC) endothermic peaks for the above solid were analyzed, and the results are as shown in Figures 5 and 6, respectively.

[0072] As confirmed in Fig. 5, the solid compound exhibited major peaks at 2θ (±0.2°) values ​​of 7.62°, 8.61°, 10.09°, 12.06°, 13.52°, and 15.72°.

[0073] In addition, as confirmed in Fig. 6, it was found that the solid compound exhibited a differential scanning calorimetry (DSC) endothermic transition peak at 124 to 143 °C when the heating rate was 10 °C / min. The exothermic peak appearing after the endothermic peak (melting) indicates that crystals have precipitated. After crystal precipitation (exothermic peak), an endothermic peak appeared again at 206 to 213 °C.

[0074] Example 4. Preparation of Crystalline Form D

[0075] 1 g of (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazole-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-5-yl)acetic acid prepared in the preparation example of the present invention was diluted in a mixed solvent of 10 mL of acetone and 0.4 mL of purified water and stirred under reflux for 1 hour. The insoluble material was filtered, and 10 mL of purified water was added dropwise to the filtrate while stirring for 10 minutes. The resulting solid was stirred at room temperature for 30 minutes, filtered, and then dried in a hot air dryer at 50 ℃ to obtain crystalline form D (0.91 g, 91%).

[0076] Powder X-ray Diffraction Analysis (PXRD) peaks and Differential Scanning Calorimetry (DSC) endothermic peaks for the above solid were analyzed, and the results are as shown in Figures 7 and 8, respectively.

[0077] As confirmed in Fig. 7, the solid compound exhibited major peaks at 2θ (±0.2°) values ​​of 8.69°, 11.42°, 13.62°, 15.51°, 16.70°, and 21.58°.

[0078] In addition, as confirmed in Fig. 8, it was found that the solid compound exhibited a differential scanning calorimetry (DSC) endothermic transition peak at 204 to 209 ℃ when the heating rate was 10 ℃ / min.

[0079] Experimental Example 1. Hygroscopicity (DVS) Measurement Experiment

[0080] Hygroscopicity was tested using the crystalline forms prepared in the embodiments of the present invention.

[0081] a. Equipment used in the experiment

[0082] - Model name: DVS Intrinsic (Surface Measurement Systems)

[0083] - Specifications

[0084] Temperature Range: 20 ~ 40℃

[0085] Temperature stability: ±0.2℃

[0086] Humidity range: 0 ~ 98% RH

[0087] RH Accuracy: ±1% RH

[0088] Typical gas (Nitrogen + water vapor) flow rate: 200sccm

[0089] Sample chamber: 40mm wide x 50mm deep x 50mm high

[0090] Heating system: Peltier + Cartridge

[0091] b. Sample Information

[0092] Experiments were performed on the crystal forms of the above examples.

[0093] c. Experimental conditions

[0094] - Temperature: 25 ℃

[0095] - Humidity: Initial 0% Max 95%

[0096] - Solvent: Water

[0097] d. Experimental Method

[0098] A certain amount (10–20 mg) of the crystalline form prepared in the example was placed on a sample pan inside the sample chamber, and nitrogen was flowed through a tube connected to the sample chamber for the first hour to remove moisture from the chamber and the sample. The humidity inside the chamber was controlled by adjusting the water vapor, and the moisture content of the crystalline form was measured by gradually increasing the target relative humidity from 0% to approximately 10% increments. The mass of the sample was measured (from 0% RH to 95% RH), and the trend of weight change of the sample according to the increase or decrease in humidity was graphed.

[0099] The change in moisture content of the crystalline forms according to the example is as shown in Table 2 below.

[0100] [Table 2]

[0101]

[0102] As shown in Table 2 above, the analysis results showed that the crystalline form of the present invention exhibited excellent non-hygroscopicity with almost no change in moisture content. This indicates that the crystalline form of the present invention is pharmaceutically superior throughout the entire process, including the preparation, storage, and formulation of the active ingredient.

[0103] Experimental Example 2. Accelerated Stability Test

[0104] Crystalline powder according to an embodiment of the present invention was double-packaged in a PE bag and tertiarily-packaged in an aluminum bag, and after being left at 40±2 ℃ and RH 75±5% for 0 months and 6 months, impurities were measured using HPLC. The results are shown in Table 3 below.

[0105] [Table 3]

[0106]

[0107] As shown in the results of Table 3 above, no significant changes in the content of the flexible material were observed in the crystalline form of the present invention, and it was confirmed that the crystalline form was maintained. Therefore, it was found that the crystalline form of the present invention can stably maintain high purity for 6 months under accelerated conditions, thus having excellent stability, with almost no change in moisture content and significantly low hygroscopicity.

[0108] Experimental Example 3. Long-term stability test

[0109] Crystalline powder according to an embodiment of the present invention was double-packaged in a PE bag and tertiarily-packaged in an aluminum bag, and after being left at 25±2 ℃ and RH 60±5% for 0 months and 12 months, impurities were measured using HPLC. The results are shown in Table 4 below.

[0110] [Table 4]

[0111]

[0112] As shown in the results of Table 4 above, no significant changes in the content of the crystalline form of the present invention were observed, and it was confirmed that the crystalline form was maintained. Therefore, it was found that the crystalline form of the present invention can stably maintain high purity for 12 months, thus having excellent stability, with almost no change in moisture content and significantly low hygroscopicity.

Claims

Claim 1 Crystalline form A of the compound represented by the following chemical formula I having peaks at diffraction angles (2θ±0.2°) of 9.26°, 10.47°, 12.76°, 14.70°, 15.83°, and 16.61° in the powder X-ray diffraction pattern: [Chemical Formula I] . Claim 2 In claim 1, crystalline form A further comprising one or more peaks at diffraction angles (2θ±0.2°) of 17.57°, 18.50°, 20.15°, 21.06°, 22.17°, 23.93°, or 27.05° in the powder X-ray diffraction pattern. Claim 3 In claim 2, crystalline form A further comprising one or more peaks at diffraction angles (2θ±0.2°) of 8.02°, 8.39°, 8.72°, 13.92°, 16.40°, 17.80°, 19.33°, 23.38°, 24.36°, 24.90°, 25.59°, 25.99°, 26.70°, 27.85°, 29.37°, 29.98°, 30.77°, or 31.59° in the powder X-ray diffraction pattern. Claim 4 In claim 1, crystalline form A having a Differential Scanning Calorimetry (DSC) endothermic transition peak at 208 to 215 ℃ when the heating rate is 10 ℃ / min. Claim 5 (A-1) a step of adding a compound represented by the following chemical formula I to toluene, ethyl acetate, or isopropanol and stirring; and (A-2) a step of filtering and drying the resulting solid; comprising a method for preparing crystalline form A of a compound represented by chemical formula I according to any one of claims 1 to 4: [Chemical Formula I] . Claim 6 Crystalline form B of the compound represented by the following chemical formula I having peaks at diffraction angles (2θ±0.2°) of 9.24°, 12.77°, 15.43°, 16.32°, 17.83°, and 19.35° in the powder X-ray diffraction pattern: [Chemical Formula I] . Claim 7 In claim 6, crystalline form B further comprising one or more peaks at diffraction angles (2θ±0.2°) of 20.18°, 23.35°, 23.84°, 24.46°, 26.03°, 29.66°, or 30.54° in the powder X-ray diffraction pattern. Claim 8 In claim 7, crystalline form B further comprising one or more peaks at diffraction angles (2θ±0.2°) of 7.94°, 10.03°, 11.65°, 14.63°, 16.80°, 17.55°, 18.63°, 21.58°, 22.67°, 23.62°, 25.29°, 27.15°, 28.13°, 29.38°, 30.68°, 31.61°, 32.05°, 33.04°, 34.41°, 35.50°, or 36.26° in the powder X-ray diffraction pattern. Claim 9 In claim 6, crystalline form B having a Differential Scanning Calorimetry (DSC) endothermic transition peak at 213 to 218 ℃ when the heating rate is 10 ℃ / min. Claim 10 (B-1) a step of adding a compound represented by the following chemical formula I to ethanol and stirring; and (B-2) a step of filtering and drying the resulting solid; comprising a method for preparing crystalline form B of a compound represented by chemical formula I according to any one of claims 6 to 9: [Chemical formula I] . Claim 11 delete Claim 12 delete Claim 13 delete Claim 14 delete Claim 15 delete Claim 16 delete Claim 17 delete Claim 18 delete Claim 19 delete Claim 20 delete Claim 21 A pharmaceutical composition for antiviral use comprising crystalline form A according to any one of claims 1 to 4, or crystalline form B according to any one of claims 6 to 9. Claim 22 In claim 21, a pharmaceutical composition for anti-human immunodeficiency virus (HIV).

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