Crystal forms of cabotegravir sodium

Abstract

The present invention relates to crystalline forms of cabotegravir sodium, and processes for their preparation. Furthermore, the present invention relates to pharmaceutical compositions, which contain one of said crystalline forms of cabotegravir sodium, preferably in a predetermined and / or effective amount, and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions of the present invention are useful as medicaments, in particular for the treatment and / or prevention of viral infections, such as HIV infections.

Description

[0001] The applicant filed PCT application PCT / EP2018 / 051819 on January 25, 2018, entitled "Crystal Form of Sodium Cabotevir". This PCT application entered the Chinese national phase on October 16, 2019, with application number 201880025341.0. This application is a divisional application of that Chinese application. Technical Field

[0002] This invention relates to the crystalline form of cabotegravir sodium and its preparation method. Furthermore, this invention relates to pharmaceutical compositions comprising one of the said crystalline forms of cabotegravir sodium (preferably a predetermined and / or effective amount) and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions of this invention can be used as medicines, particularly for the treatment and / or prevention of viral infections such as HIV infection. Background Technology

[0003] Cabotevir is an integrase strand transfer inhibitor (INSTI) of human immunodeficiency virus type 1 (HIV-1) currently under development for use in combination with other antiretroviral drugs to treat HIV-1 infection. Chemically, it is designated as (3... S ,11a R )- N -[2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2- a ]pyrido[1,2- d Pyrazine-8-carboxamide, and can be represented by the chemical structure of formula (I) below: (I).

[0004] The preparation method of cabotevir sodium is disclosed in Example Z-9 of WO 2006 / 116764 A1, wherein cabotevir is prepared in ethanol using 1 N Sodium hydroxide treatment followed by the addition of ether. In Example Ae of WO 2010 / 068253 A1, cabotevir was dissolved in aqueous ethanol and reacted with 1... NThe sodium hydroxide aqueous solution reacts to the corresponding sodium salt. The solution is cooled, then filtered, washed with ethanol, and dried to obtain cabotevir sodium as crystals. In Johns BA et al., Carbamoyl Pyridone HIV-1 Integrase Inhibitors 3. A Diastereomeric Approach to Chiral Nonracemic Tricyclic Ring Systems and the Discovery of Dolutegravir (S / GSK1349572) and (S / GSK1265744) (J. Med. Chem. 2013, 56, 5901-5916), cabotevir was used with 1 N Sodium hydroxide aqueous solution was treated in ethanol to give sodium cabotevir as a white solid. In Example 17 of WO 2015 / 177537 A1, it was obtained by treating with methanol using 2 N Cabotevir was prepared by treating cabotevir with an aqueous sodium hydroxide solution.

[0005] The inventors of this invention repeat the prior art embodiments listed above (see Reference Examples 1-4 in the text). According to powder X-ray diffraction, the same crystal form of sodium cabotevir was obtained in all cases. This form is designated as "Form A" in the text.

[0006] Different solid forms of active pharmaceutical ingredients (APIs) typically possess different properties. Differences in the physicochemical properties of solid forms can be important for improving pharmaceutical compositions; for example, an improved solid form of the API may result in a pharmaceutical formulation with an improved solubility profile, stability, or shelf life. The handling or manipulation of the API during formulation can also be improved. Therefore, new solid forms of APIs may possess desired handling properties. Compared to previously known solid forms, they may be easier to handle, better suited for storage, and / or ensure better purification.

[0007] Furthermore, the sudden appearance or disappearance of metastable polymorphs can cause problems in drug development. Similarly, if transformation occurs in the dosage form, such as once stored, serious pharmaceutical consequences can result. Therefore, there is a need for the use of stable polymorphs of the active pharmaceutical ingredient, such as kinetically stable polymorphs or preferably the most thermodynamically stable polymorphs, in the preparation of pharmaceutical products. Therefore, there is an urgent need to provide a solid form of cabotevir sodium that is stable, for example, thermodynamically stable, and does not undergo phase transformation during production, drug processing, or storage. There is also an urgent need to provide pharmaceutical compositions containing a solid form of cabotevir sodium that is stable under the conditions typically encountered during drug processing and storage. Polymorphs that are kinetically more stable than existing polymorphs, and thermodynamically most stable solid forms, in particular, can ensure reliable efficacy and safety of the pharmaceutical composition throughout its shelf life. Summary of the Invention

[0008] The inventors of this invention have surprisingly discovered that polymorphs of sodium cabotevir are thermodynamically more stable at room temperature and elevated temperatures than prior art "Form A". Hereinafter, these forms will be referred to as "Form B" and "Form C". Aspects, advantageous features, and preferred embodiments of the invention are summarized in the following entries: 1) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, it has a powder X-ray diffraction pattern containing reflections at 2-θ angles of (6.8 ± 0.2)°, (18.5 ± 0.2)°, and (23.7 ± 0.2)°.

[0009] 2) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.8 ± 0.2)°, (18.5 ± 0.2)°, (20.3 ± 0.2)°, and (23.7 ± 0.2)°.

[0010] 3) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.8 ± 0.2)°, (18.5 ± 0.2)°, (18.9 ± 0.2)°, (20.3 ± 0.2)°, and (23.7 ± 0.2)°.

[0011] 4) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.8 ± 0.2)°, (18.5 ± 0.2)°, (18.9 ± 0.2)°, (20.3 ± 0.2)°, (22.8 ± 0.2)°, and (23.7 ± 0.2)°.

[0012] 5) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.8 ± 0.2)°, (18.5 ± 0.2)°, (18.9 ± 0.2)°, (20.3 ± 0.2)°, (22.8 ± 0.2)°, (23.2 ± 0.2)°, and (23.7 ± 0.2)°.

[0013] 6) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.8 ± 0.2)°, (17.7 ± 0.2)°, (18.5 ± 0.2)°, (18.9 ± 0.2)°, (20.3 ± 0.2)°, (22.8 ± 0.2)°, (23.2 ± 0.2)°, and (23.7 ± 0.2)°.

[0014] 7) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.8 ± 0.2)°, (17.7 ± 0.2)°, (18.5 ± 0.2)°, (18.9 ± 0.2)°, (20.3 ± 0.2)°, (20.6 ± 0.2)°, (22.8 ± 0.2)°, (23.2 ± 0.2)°, and (23.7 ± 0.2)°.

[0015] 8) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.8 ± 0.2)°, (17.7 ± 0.2)°, (18.5 ± 0.2)°, (18.9 ± 0.2)°, (20.3 ± 0.2)°, (20.6 ± 0.2)°, (22.8 ± 0.2)°, (23.2 ± 0.2)°, (23.7 ± 0.2)°, and (28.6 ± 0.2)°.

[0016] 9) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.8 ± 0.2)°, (14.6 ± 0.2)°, (17.7 ± 0.2)°, (18.5 ± 0.2)°, (18.9 ± 0.2)°, (20.3 ± 0.2)°, (20.6 ± 0.2)°, (22.8 ± 0.2)°, (23.2 ± 0.2)°, (23.7 ± 0.2)°, and (28.6 ± 0.2)°.

[0017] 10) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.8 ± 0.2)°, (14.6 ± 0.2)°, (17.7 ± 0.2)°, (18.5 ± 0.2)°, (18.9 ± 0.2)°, (20.3 ± 0.2)°, (20.6 ± 0.2)°, (22.8 ± 0.2)°, (23.2 ± 0.2)°, (23.7 ± 0.2)°, (27.3 ± 0.2)°, and (28.6 ± 0.2)°.

[0018] 11) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, it has a powder X-ray diffraction pattern containing reflections at 2-θ angles of (6.8 ± 0.1)°, (18.5 ± 0.1)°, and (23.7 ± 0.1)°.

[0019] 12) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.8 ± 0.1)°, (18.5 ± 0.1)°, (20.3 ± 0.1)°, and (23.7 ± 0.1)°.

[0020] 13) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.8 ± 0.1)°, (18.5 ± 0.1)°, (18.9 ± 0.1)°, (20.3 ± 0.1)°, and (23.7 ± 0.1)°.

[0021] 14) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.8 ± 0.1)°, (18.5 ± 0.1)°, (18.9 ± 0.21)°, (20.3 ± 0.1)°, (22.8 ± 0.1)°, and (23.7 ± 0.1)°.

[0022] 15) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.8 ± 0.1)°, (18.5 ± 0.1)°, (18.9 ± 0.1)°, (20.3 ± 0.1)°, (22.8 ± 0.1)°, (23.2 ± 0.1)°, and (23.7 ± 0.1)°.

[0023] 16) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.8 ± 0.1)°, (17.7 ± 0.1)°, (18.5 ± 0.1)°, (18.9 ± 0.1)°, (20.3 ± 0.1)°, (22.8 ± 0.1)°, (23.2 ± 0.1)°, and (23.7 ± 0.1)°.

[0024] 17) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.8 ± 0.1)°, (17.7 ± 0.1)°, (18.5 ± 0.1)°, (18.9 ± 0.1)°, (20.3 ± 0.1)°, (20.6 ± 0.1)°, (22.8 ± 0.1)°, (23.2 ± 0.1)°, and (23.7 ± 0.1)°.

[0025] 18) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.8 ± 0.1)°, (17.7 ± 0.1)°, (18.5 ± 0.1)°, (18.9 ± 0.1)°, (20.3 ± 0.1)°, (20.6 ± 0.1)°, (22.8 ± 0.1)°, (23.2 ± 0.1)°, (23.7 ± 0.1)°, and (28.6 ± 0.1)°.

[0026] 19) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.8 ± 0.1)°, (14.6 ± 0.1)°, (17.7 ± 0.1)°, (18.5 ± 0.1)°, (18.9 ± 0.1)°, (20.3 ± 0.1)°, (20.6 ± 0.1)°, (22.8 ± 0.1)°, (23.2 ± 0.1)°, (23.7 ± 0.1)°, and (28.6 ± 0.1)°.

[0027] 20) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.8 ± 0.1)°, (14.6 ± 0.1)°, (17.7 ± 0.1)°, (18.5 ± 0.1)°, (18.9 ± 0.1)°, (20.3 ± 0.1)°, (20.6 ± 0.1)°, (22.8 ± 0.1)°, (23.2 ± 0.1)°, (23.7 ± 0.1)°, (27.3 ± 0.1)°, and (28.6 ± 0.1)°.

[0028] 21) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurement, it has a basic similarity to the present invention. Figure 1 The same powder X-ray diffraction pattern is shown.

[0029] 22) A composition containing the sodium cabotevir crystal form according to any of the preceding entries, wherein the composition is substantially free of any other physical form of sodium cabotevir.

[0030] 23) A composition comprising a sodium cabotevir crystal form according to any one of Clauses 1-21, characterized in that, based on the weight of the composition, it contains up to 20% by weight of any other physical form of sodium cabotevir.

[0031] 24) A composition comprising a sodium cabotevir crystal form according to any one of Clauses 1-21, characterized in that, based on the weight of the composition, it contains up to 10% by weight of any other physical form of sodium cabotevir.

[0032] 25) A composition comprising a sodium cabotevir crystal form according to any one of Clauses 1-21, characterized in that, based on the weight of the composition, it contains up to 5% by weight of any other physical form of sodium cabotevir.

[0033] 26) A composition comprising a sodium cabotevir crystal form according to any one of Clauses 1-21, characterized in that, based on the weight of the composition, it contains up to 2% by weight of any other physical form of sodium cabotevir.

[0034] 27) A composition comprising a sodium cabotevir crystal form according to any one of Clauses 1-21, characterized in that, based on the weight of the composition, it contains up to 1% by weight of any other physical form of sodium cabotevir.

[0035] 28) The composition according to any one of clauses 22-27, wherein the other physical form of sodium cabotevir is form A, characterized by being prepared by using Cu-Kα with a wavelength of 0.15419 nm at a temperature of 20-30 °C. 1,2 During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (5.4 ± 0.2)°, (12.8 ± 0.2)°, (13.1 ± 0.2)°, (23.9 ± 0.2)°, and (24.4 ± 0.2)°.

[0036] 29) The composition according to any one of Clauses 22-27, wherein any other physical form of sodium cabotevir is amorphous.

[0037] 30) A method for preparing the crystalline form of sodium cabotevir as defined in any of Clauses 1-21 or the composition as defined in any of Clauses 22-29, comprising: (i) Providing sodium cabotevir in crystalline form (form A), characterized by being obtained by reacting Cu-Kα with a wavelength of 0.15419 nm at a temperature of 20–30 °C. 1,2 When measuring radiation, it has a PXRD containing reflections at 2-θ angles of (5.4 ± 0.2)°, (12.8 ± 0.2)°, (13.1 ± 0.2)°, (23.9 ± 0.2)° and (24.4 ± 0.2)°.

[0038] (ii) In a solvent, the crystalline form of cabotevir sodium provided in step (i) is pulped, the solvent being selected from cyclic ethers, C3-C4 ketones and methyl acetate or mixtures thereof, wherein the pulping continues for a period of time sufficient to convert the cabotevir sodium (form A) into the crystalline form of cabotevir sodium as defined in any of Articles 1-21 or the composition as defined in any of Articles 22-29.

[0039] 31) The method of Section 30, wherein the cyclic ethers are selected from 1,4-dioxane and tetrahydrofuran.

[0040] 32) The method of Article 30, wherein the C3-C4 ketones are selected from acetone and 2-butanone.

[0041] 33) The method according to any one of Clauses 30-32, wherein the sodium cabotevir concentration of the suspension provided in step (ii) is 5-80 g / L.

[0042] 34) The method according to any one of Clauses 30-32, wherein the sodium cabotevir concentration of the suspension provided in step (ii) is 5 to 50 g / L.

[0043] 35) The method according to any one of Clauses 30-32, wherein the sodium cabotevir concentration of the suspension provided in step (ii) is 5-25 g / L.

[0044] 36) The method according to any one of Clauses 30-32, wherein the sodium cabotevir concentration of the suspension provided in step (ii) is 10 g / L.

[0045] 37) The pulping is carried out according to the method of any one of Clauses 30-36, wherein the pulping is carried out at a temperature of 20-30 °C.

[0046] 38) The pulping is carried out according to any one of Clauses 30-36, wherein the pulping is carried out at a temperature of 40-80 °C.

[0047] 39) The pulping is carried out according to the method of any one of clauses 30-36, wherein the pulping is carried out at a temperature of 40-60 °C.

[0048] 40) The method of any one of Clauses 30-39, wherein pulping is carried out for at least 24 hours.

[0049] 41) The method according to Article 40, wherein pulping is carried out for at least 120 hours.

[0050] 42) The method according to any one of Clauses 30-41 further comprises step (iii), separating at least a portion of the crystals obtained in step (ii) from the mother liquor.

[0051] 43) The method according to Clause 42, wherein crystals are separated from the mother liquor by filtration, centrifugation, decantation or solvent evaporation.

[0052] 44) The method according to Clause 42, wherein crystals are separated from the mother liquor by filtration or centrifugation.

[0053] 45) The method according to Article 42, wherein crystals are separated from the mother liquor by filtration.

[0054] 46) The method according to any one of paragraphs 42-45 further includes step (iv) rinsing the separated crystals obtained in step (iii).

[0055] 47) The method according to Clause 46, wherein the crystals are rinsed with an organic solvent and / or water.

[0056] 48) The method according to Clause 47, wherein the organic solvent is selected from 1,4-dioxane, tetrahydrofuran, acetone, 2-butanone and methyl acetate or mixtures thereof.

[0057] 49) The method according to any one of Articles 30-48 further includes step (v) drying the crystal obtained in any one of steps (ii) to (iv).

[0058] 50) The method according to Clause 49, wherein drying is carried out at a temperature of 150 °C or lower.

[0059] 51) The method according to Clause 49, wherein drying is carried out at a temperature of 100 °C or lower.

[0060] 52) The method according to Clause 49, wherein drying is carried out at a temperature of 60 °C or lower.

[0061] 53) The method according to Clause 49, wherein drying is carried out at a temperature of 40 °C or lower.

[0062] 54) The method according to Article 49, wherein drying is carried out at a temperature of 20 ℃ to 30 ℃.

[0063] 55) The method of any one of Clauses 49-54, wherein the drying is carried out for a period of 1 to 72 hours.

[0064] 56) The method of any one of Clauses 49-54, wherein the drying is carried out for a period of 2 to 48 hours.

[0065] 57) The method of any one of Clauses 49-54, wherein the drying is carried out for a period of 4 to 24 hours.

[0066] 58) The method of any one of Clauses 49-54, wherein the drying is carried out for a period of 6 to 18 hours.

[0067] 59) Use of the crystalline form of cabotevir sodium as defined in any of Clauses 1-21 for the preparation of pharmaceutical compositions.

[0068] 60) Use of the crystalline form of cabotevir sodium obtained by any of the methods in Sections 30-58 for the preparation of pharmaceutical compositions.

[0069] 61) Use of any of the compositions defined in Sections 22-29 for the preparation of pharmaceutical compositions.

[0070] 62) Use of a composition obtained according to any one of the methods in Sections 30-58 for the preparation of a pharmaceutical composition.

[0071] 63) The pharmaceutical composition is prepared by dry or wet processing methods according to any of the uses in Sections 59-62.

[0072] 64) According to the use of Section 63, the wet processing method includes wet granulation.

[0073] 65) According to the use of Section 63, the dry processing method includes dry granulation or dry compaction.

[0074] 66) A pharmaceutical composition comprising a crystalline form of cabotevir sodium as defined in any one of Sections 1-21 or a composition as defined in any one of Sections 22-29, and at least one pharmaceutically acceptable excipient.

[0075] 67) A pharmaceutical composition according to section 66, comprising a predetermined amount and / or an effective amount of a crystalline form of cabotevir sodium as defined in any one of sections 1-21 or a composition as defined in any one of sections 22-29, and at least one pharmaceutically acceptable excipient.

[0076] 68) A pharmaceutical composition of section 66 or 67 or a pharmaceutical composition of section 137, wherein at least one pharmaceutically acceptable excipient is selected from carriers, fillers, diluents, lubricants, sweeteners, stabilizers, solubilizers, antioxidants and preservatives, flavoring agents, binders, colorants, penetrants, buffers, surfactants, disintegrants, granulators, coating materials, and combinations thereof.

[0077] 69) A pharmaceutical composition according to any one of Sections 66-68 or a pharmaceutical composition according to Section 137, wherein at least one pharmaceutically acceptable excipient is selected from mannitol, microcrystalline cellulose, povidone, sodium starch glycolate and sodium stearoyl fumarate.

[0078] 70) A pharmaceutical composition according to any one of Sections 66-69 or a pharmaceutical composition according to Section 137, comprising one or more other pharmaceutically active ingredients.

[0079] 71) A pharmaceutical composition according to Section 70, wherein the one or more other pharmaceutically active ingredients are selected from entry / fusion inhibitors, reverse transcriptase inhibitors (RTIs), integrase strand transfer inhibitors (INSTIs), maturation inhibitors, protease inhibitors (PIs), or any combination thereof.

[0080] 72) A pharmaceutical composition according to section 71, wherein the entry / fusion inhibitor is selected from entfuvirtide, maraviro, vicriviroc, cenicriviroc, ibalizumab, and fostemsavir, or a mixture thereof.

[0081] 73) A pharmaceutical composition according to section 71, wherein the reverse transcriptase inhibitor (RTI) is selected from abacavir, didanosine, emtricitabine, lamivudine, stavudine, zidovudine, amdoxovir, aritabine, censavudine, elvucitabine, racivir, stampidine, zalcitabine, tenofovir disoproxil, tenofovir alafenamide, efavirenz, nevirapine, delavirdine, etravirine, rilpivirine, doravirine, or a mixture thereof.

[0082] 74) A pharmaceutical composition according to section 71, wherein the integrase strand transfer inhibitor (INSTI) is selected from dulutegravir, elvitegravir, raltegravir and bictegravir or a mixture thereof.

[0083] 75) A pharmaceutical composition according to section 71, wherein the protease inhibitors (PIs) are selected from ampranasvir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, atazanavir, darunavir, tipranavir, or mixtures thereof.

[0084] 76) A pharmaceutical composition according to section 70, wherein one or more other pharmaceutical active ingredients are rilpivirine.

[0085] 77) A pharmaceutical composition according to section 70, wherein the one or more other active pharmaceutical ingredient is rilpivirine in the form of hydrochloride.

[0086] 78) A pharmaceutical composition according to Section 70, wherein one or more other pharmaceutical active ingredients are abacavir and / or lamivudine.

[0087] 79) The pharmaceutical composition according to any one of clauses 66-78 is an oral solid dosage form.

[0088] 80) A pharmaceutical composition according to section 79, wherein the oral solid dosage form is a tablet or capsule.

[0089] 81) A pharmaceutical composition according to any one of Sections 66-80, wherein the crystalline form of cabotevir sodium as defined in any one of Sections 1-21 is present in an amount selected from 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg and 90 mg, calculated as cabotevir.

[0090] 82) A pharmaceutical composition according to section 81, wherein the crystalline form of cabotevir sodium as defined in any one of sections 1-21 or any one of sections 88-97 is present in an amount of 30 mg, calculated as cabotevir.

[0091] 83) The pharmaceutical composition according to any one of Clauses 66-82 shall be administered once daily.

[0092] 84) A pharmaceutical composition according to any one of clauses 66-83, which is used as a medicine.

[0093] 85) A pharmaceutical composition according to any one of Sections 66-83, used for the treatment and / or prevention of viral infections.

[0094] 86) A pharmaceutical composition pursuant to Section 85, wherein the viral infection is caused by a DNA virus, RNA virus, herpesvirus, retrovirus, hepadnavirus, papillomavirus, hantavirus, adenovirus and HIV.

[0095] 87) The crystal form of sodium cabotevir as defined in any of entries 1-21 is characterized by a powder X-ray diffraction pattern having a reflection of a 2-θ angle not including (5.4 ± 0.2)° 2-θ.

[0096] 88) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C with Cu-Kα at a wavelength of 0.15419 nm. 1,2 During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.2 ± 0.2)°, (17.3 ± 0.2)°, and (23.2 ± 0.2)°.

[0097] 89) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.2 ± 0.2)°, (17.3 ± 0.2)°, (21.7 ± 0.2)°, and (23.2 ± 0.2)°.

[0098] 90) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.2 ± 0.2)°, (17.3 ± 0.2)°, (21.7 ± 0.2)°, (23.2 ± 0.2)°, and (25.1 ± 0.2)°.

[0099] 91) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.2 ± 0.1)°, (17.3 ± 0.1)°, and (23.2 ± 0.1)°.

[0100] 92) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.2 ± 0.1)°, (17.3 ± 0.1)°, (21.7 ± 0.1)°, and (23.2 ± 0.1)°.

[0101] 93) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20-30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.2 ± 0.1)°, (17.3 ± 0.1)°, (21.7 ± 0.1)°, (23.2 ± 0.1)°, and (25.1 ± 0.1)°.

[0102] 94) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (6.2 ± 0.1)°, (9.1 ± 0.1)°, (17.3 ± 0.1)°, (21.7 ± 0.1)°, (23.2 ± 0.1)°, and (25.1 ± 0.1)°.

[0103] 95) The crystal form of sodium cabotevir as defined in any of clauses 88-94 is characterized by a powder X-ray diffraction pattern having a reflection of a 2-θ angle not including (5.4 ± 0.2)° 2-θ.

[0104] 96) The crystal form of sodium cabotevir as defined in any of clauses 88-95 is characterized by a powder X-ray diffraction pattern having a reflection of a 2-θ angle not including (6.8 ± 0.2)° 2-θ.

[0105] 97) The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 When measuring radiation, it has basic and Figure 5 The same powder X-ray diffraction pattern shown.

[0106] 98) A composition containing the crystalline form of sodium cabotevir according to any one of clauses 88-97, wherein the composition is substantially free of any other physical form of sodium cabotevir.

[0107] 99) A composition containing the crystalline form of sodium cabotevir according to any one of clauses 88-97, characterized in that, based on the weight of the composition, it contains up to 20% by weight of any other physical form of sodium cabotevir.

[0108] 100) A composition containing the crystalline form of sodium cabotevir according to any one of clauses 88-97, characterized in that, based on the weight of the composition, it contains up to 10% by weight of any other physical form of sodium cabotevir.

[0109] 101) A composition containing the crystalline form of sodium cabotevir according to any one of clauses 88-97, characterized in that, based on the weight of the composition, it contains up to 5% by weight of any other physical form of sodium cabotevir.

[0110] 102) A composition containing the crystalline form of sodium cabotevir according to any one of clauses 88-97, characterized in that, based on the weight of the composition, it contains up to 2% by weight of any other physical form of sodium cabotevir.

[0111] 103) A composition containing the crystalline form of sodium cabotevir according to any one of clauses 88-97, characterized in that, based on the weight of the composition, it contains up to 1% by weight of any other physical form of sodium cabotevir.

[0112] 104) The composition according to any one of clauses 98-103, wherein the other physical form of sodium cabotevir is form A, characterized by being prepared by using Cu-Kα with a wavelength of 0.15419 nm at a temperature of 20-30 °C. 1,2 During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (5.4 ± 0.2)°, (12.8 ± 0.2)°, (13.1 ± 0.2)°, (23.9 ± 0.2)°, and (24.4 ± 0.2)°.

[0113] 105) The composition according to any one of Clauses 98-103, wherein the other physical form of sodium cabotevir is amorphous.

[0114] 106) A method for preparing the sodium cabotevir crystal form as defined in any one of Clauses 88-97 or the composition as defined in any one of Clauses 98-105, comprising: (i) Providing sodium cabotevir in crystalline form (form A), characterized by being crystalline when heated to a temperature of 20–30 °C with Cu-Kα having a wavelength of 0.15419 nm. 1,2 During radiation measurements, PXRDs with reflections included at 2-θ angles of (5.4 ± 0.2)°, (12.8 ± 0.2)°, (13.1 ± 0.2)°, (23.9 ± 0.2)°, and (24.4 ± 0.2)° are used.

[0115] (ii) In a solvent containing methyl isobutyl ketone, the crystals of cabotevir sodium provided in step (i) are pulped, wherein the pulping continues for a period of time sufficient to convert the cabotevir sodium (form A) into the crystalline form of cabotevir sodium as defined in any of Articles 88-97 or the composition as defined in any of Articles 98-103.

[0116] 107) The method according to any of the provisions of 106, wherein the sodium cabotevir concentration of the suspension provided in step (ii) is 5 to 80 g / L.

[0117] 108) The method according to any one of Clauses 106-107, wherein the sodium cabotevir concentration of the suspension provided in step (ii) is 5 to 50 g / L.

[0118] 109) The method according to any one of Clauses 106-108, wherein the sodium cabotevir concentration of the suspension provided in step (ii) is 5 to 25 g / L.

[0119] 110) The method according to any one of Clauses 106-108, wherein the sodium cabotevir concentration of the suspension provided in step (ii) is 10 g / L.

[0120] 111) The method according to any one of Clauses 106-110, wherein pulping is carried out at a temperature of 20-30 °C.

[0121] 112) The method according to any one of Clauses 106-110, wherein pulping is carried out at a temperature of 40 to 80 °C.

[0122] 113) The method according to any one of Clauses 106-110, wherein pulping is carried out at a temperature of 40 to 60 °C.

[0123] 114) The method of any one of Clauses 106-113, wherein pulping is carried out for at least 24 hours.

[0124] 115) The method according to Article 114, wherein pulping is carried out for at least 120 hours.

[0125] 116) The method according to any one of Articles 106-115 further comprises step (iii) separating at least a portion of the crystals obtained in step (ii) from the mother liquor.

[0126] 117) The method according to Clause 116, wherein crystals are separated from the mother liquor by filtration, centrifugation, decantation or solvent evaporation.

[0127] 118) The method according to Article 116, wherein crystals are separated from the mother liquor by filtration or centrifugation.

[0128] 119) The method according to Article 116, wherein crystals are separated from the mother liquor by filtration.

[0129] 120) The method according to any one of Articles 106-119 further includes step (iv) rinsing the separated crystals obtained in step (iii).

[0130] 121) The method according to Section 120, wherein the crystals are rinsed with methyl isobutyl ketone and / or water.

[0131] 122) The method according to Articles 98-121 further includes step (v) drying the crystal obtained in any of steps (ii) to (iv).

[0132] 123) The method according to Clause 122, wherein drying is carried out at a temperature of 150 °C or lower.

[0133] 124) The method according to Clause 122, wherein drying is carried out at a temperature of 100 °C or lower.

[0134] 125) The method according to Clause 122, wherein drying is carried out at a temperature of 60 °C or lower.

[0135] 126) The method according to Clause 122, wherein drying is carried out at a temperature of 40 °C or lower.

[0136] 127) The method according to Clause 122, wherein drying is carried out at a temperature of 20 °C to 30 °C.

[0137] 128) The method of any one of Clauses 122-127, wherein the drying is carried out for a period of 1 to 72 hours.

[0138] 129) The method of any one of Clauses 122-127, wherein the drying is carried out for a period of 2 to 48 hours.

[0139] 130) The method of any one of Clauses 122-127, wherein the drying is carried out for a period of 4 to 24 hours.

[0140] 131) The method according to any one of Clauses 122-127, wherein the drying is carried out for a period of 6 to 18 hours.

[0141] 132) Use of the crystalline form of cabotevir sodium as defined in any of Articles 88-97 for the preparation of pharmaceutical compositions.

[0142] 133) Use of any of the compositions defined in Articles 98-103 for the preparation of pharmaceutical compositions.

[0143] 134) The pharmaceutical composition is prepared by wet or dry processing methods according to any of the uses in Sections 132-133.

[0144] 135) According to the use of Section 134, the wet processing method includes wet granulation.

[0145] 136) According to the use of Section 134, the dry processing method includes dry granulation or dry compaction.

[0146] 137) A pharmaceutical composition comprising a crystalline form of cabotevir sodium as defined in any one of Sections 88-97 or a composition as defined in any one of Sections 98-103, and at least one pharmaceutically acceptable excipient.

[0147] definition

[0148] The term “cabotway” as used in this text refers to (3) according to formula (I) disclosed above. S ,11a R )- N -[2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2- a ]pyrido[1,2- d Pyrazine-8-carboxamide.

[0149] The term "cabotvir sodium" as used in this text refers to the sodium salt of cabbotvir with the chemical structure in which approximately 1 mole of cabbotvir and 1 mole of sodium are deprotonated and reacted with Na. + The ions bind together. Cabotevir sodium can be represented by its chemical structure according to formula (II) below.

[0150] The term "cabotevidin sodium form A" as used herein refers to the crystalline form of cabotevir sodium, which is intrinsically disclosed, for example, in Example Z-9 of WO 2006 / 116764 A1, Example Ae of WO 2010 / 068253 A1, and Example 17 of WO 2015 / 177537 A1. Cabotevir sodium form A is characterized by the following: when precipitated at a temperature of 20–30 °C using Cu-Kα with a wavelength of 0.15419 nm... 1,2 During radiation measurements, it has powder X-ray diffraction patterns containing reflections at 2-θ angles of (5.4 ± 0.2)°, (12.8 ± 0.2)°, (13.1 ± 0.2)°, (23.9 ± 0.2)°, and (24.4 ± 0.2)°.

[0151] As used herein, the term "measured at a temperature of 20–30 °C" refers to measurement under standard conditions. Generally, standard conditions mean a temperature of 20–30 °C, i.e., room temperature. Standard conditions may also mean a temperature of approximately 22 °C. Standard conditions may also further mean measurements at relative humidity of 20–80%, preferably 30–70%, more preferably 40–60%, and most preferably 50%.

[0152] In powder X-ray diffraction, the term "reflection" as used herein refers to peaks in an X-ray diffraction pattern, which are generated at a specific diffraction angle (Bragg angle) by constructive interference of X-rays scattered from parallel planes of atoms in a solid material distributed in an ordered and repetitive manner along long-range positions. The solid material is classified as crystalline; however, amorphous materials are defined as solid materials that lack long-range order and exhibit only short-range order, thus producing broad scattering. According to the literature, long-range order extends, for example, over approximately 100–1000 atoms, while short-range order extends only over a few atoms (see [reference needed]). Vitalij K. "Fundamentals of Powder Diffraction and Structural Characterization of Materials", Kluwer Academic Publishers, 2003 (Page 3).

[0153] As used in this text, the term "amorphous" refers to the solid form of a compound that is not crystalline. Amorphous compounds do not possess long-range order and do not exhibit definite X-ray diffraction patterns with reflection.

[0154] The term "substantially identical" in powder X-ray diffraction means taking into account the variability of reflection position and relative reflection intensity. For example, the typical accuracy of 2-θ values ​​is ±0.2° 2-θ, preferably ±0.1° 2-θ. Therefore, on most X-ray diffractometers, reflections that typically occur at 6.8° 2-θ under standard conditions may occur at 6.6°–7.0° 2-θ, preferably 6.7°–6.9° 2-θ. Furthermore, those skilled in the art should understand that relative reflection intensity will exhibit variability between instruments, as well as variability in crystallinity, preferred orientation, sample preparation, and other factors known to those skilled in the art, and should be used only as a qualitative measurement.

[0155] As used herein, the term “substantially no other physical form” in relation to compositions containing a specific physical form of sodium cabotevir means, based on the weight of the composition, that the composition comprises up to 20% by weight, preferably up to 10% by weight, more preferably up to 5% by weight, even more preferably up to 2% by weight, and most preferably up to 1% by weight of any other physical form of sodium cabotevir.

[0156] The term "physical form" as used in this article refers to any crystalline and / or amorphous phase of the compound.

[0157] The term "anhydrous form" or "anhydrous material" as used herein refers to a crystalline solid in which no water is introduced into the crystal structure. The anhydrous form may also contain residual water, which is not part of the crystal structure but may be adsorbed on the surface of the crystal or into disordered regions. Typically, based on the weight of the crystal form, the anhydrous form contains no more than 1.0 w-%, preferably no more than 0.5 w-%, and most preferably no more than 0.1 w-%. The water content can be determined by the Karl Fischer coulomb method and / or thermogravimetric analysis (TGA), for example by measuring the weight loss at a heating rate of 10 K / min at 25–200 °C.

[0158] When discussing crystalline solids, the term "unsolvated" as used herein means that no organic solvent is introduced into the crystal structure. The unsolvated form may also contain residual organic solvents that are not part of the crystal structure but can be adsorbed on the crystal surface or into disordered regions. Typically, based on the weight of the crystal form, the unsolvated form contains no more than 1.0 w-%, preferably no more than 0.5 w-%, and most preferably no more than 0.1 w-%. The organic solvent content can be determined by thermogravimetric analysis (TGA), for example, by measuring the weight loss at a heating rate of 10 K / min at 25–200 °C.

[0159] The crystal form of sodium cabotevir can be described herein by reference to the powder X-ray diffraction pattern shown in Figure "". Those skilled in the art will understand that factors such as variations in instrument type, response and sample directivity, sample concentration, sample purity, sample history, and sample preparation can cause variations, such as those related to precise reflection position and intensity. However, the comparison of the spectral data in this paper with spectral data generated from unknown physical forms, and the confirmation of two sets of spectral data related to the same crystal form, are within the knowledge of those skilled in the art.

[0160] As used in this text, the term "mother liquor" refers to the solution remaining after a solid has crystallized from the solution.

[0161] For cabotevir sodium, the term “predetermined amount” as used herein refers to the initial amount of cabotevir sodium used to prepare a pharmaceutical composition containing a desired dose strength of cabotevir.

[0162] For cabotevir sodium, the term "effective amount" as used herein includes the amount of cabotevir sodium that produces the desired therapeutic and / or preventative effect.

[0163] As used herein, the term "approximately" refers to a range of values ​​that are statistically significant. This range can be within an order of magnitude, typically within 10%, more typically within 5%, even more typically within 1%, and most typically within 0.1% of the value or range indicated. Sometimes, the range may lie within the typical experimental error range of the standard methods used for measuring and / or determining a given value or range. Attached Figure Description

[0164] Figure 1 This section explains the representative powder X-ray diffraction pattern of sodium cabotevir form B of the present invention. The x-axis shows the scattering angle in °2-θ, and the y-axis shows the intensity of the X-ray scattered beam as measured by a photon counter.

[0165] Figure 2 The following describes the representative powder X-ray diffraction pattern of sodium cabotevir, form A, prepared according to Reference Example 1 in this document. The x-axis shows the scattering angle in °2-θ, and the y-axis shows the intensity of the X-ray scattered beam as detected by a photon counter.

[0166] Figure 3 This section explains a comparison between a representative powder X-ray diffraction pattern (bottom) of sodium cabotevir form B prepared according to Reference Example 1 of this document and a representative powder X-ray diffraction pattern (top) of sodium cabotevir form A prepared according to Reference Example 1 of this document. The x-axis shows the scattering angle expressed in °2-θ. The powder X-ray diffraction pattern of form A is shifted along the y-axis to separate the diffraction pattern for clarity. Therefore, the y-axis is subjective and unlabeled.

[0167] Figure 4 This section explains the representative powder X-ray diffraction pattern of the Caboteve crystal prepared according to Example D of WO 2011 / 119566 A1. The x-axis shows the scattering angle in °2-θ, and the y-axis shows the intensity of the X-ray scattered beam as detected by a photon counter.

[0168] Figure 5 This section explains the representative powder X-ray diffraction pattern of sodium cabotevir form C of the present invention. The x-axis shows the scattering angle in °2-θ, and the y-axis shows the intensity of the X-ray scattered beam as detected by a photon counter.

[0169] Figure 6 This section explains a comparison of a representative powder X-ray diffraction pattern (bottom) of sodium cabotevir crystal form C of the present invention with a representative powder X-ray diffraction pattern (top) of sodium cabotevir form A prepared according to Reference Example 1 described herein. The x-axis shows the scattering angle expressed in °2-θ. The powder X-ray diffraction pattern of form A is shifted along the y-axis to separate the diffraction pattern for clarity. Therefore, the y-axis is subjective and unlabeled.

[0170] Figure 7 This section explains and compares representative powder X-ray diffraction (PXRD) patterns of sodium cabotevir crystal form C (bottom), sodium cabotevir crystal form B (middle), and sodium cabotevir form A prepared according to Reference Example 1 (top). The x-axis shows the scattering angle expressed in °2-θ. The PXRD patterns of forms A and B are shifted along the y-axis to separate the diffraction patterns for clarity. Therefore, the y-axis is subjective and unlabeled.

[0171] Figure 8 This section explains the representative thermogravimetric analysis (TGA) curves of sodium cabotevir crystal form A prepared according to Reference Example 1 in this document. The x-axis shows the temperature in degrees Celsius (°C), and the y-axis shows the sample mass (weight loss) in weight percentage (w-%).

[0172] Figure 9 This section explains the representative thermogravimetric analysis (TGA) curves of sodium cabotevir crystal form B according to the present invention. The x-axis shows the temperature in degrees Celsius (°C), and the y-axis shows the sample mass (weight loss) in weight percentage (w-%).

[0173] Figure 10 This section explains the representative thermogravimetric analysis (TGA) curves of sodium cabotevir crystal C according to the present invention. The x-axis shows the temperature in degrees Celsius (°C), and the y-axis shows the sample mass (weight loss) in weight percentage (w-%). Invention Details

[0175] This invention provides new sodium cabotevir crystal forms, also referred to herein as "Form B" and "Form C".

[0176] The inventors have surprisingly discovered that, in the presence of certain organic solvents, at least at room temperature and elevated temperatures, forms B and C of the present invention are thermodynamically more stable than prior art form A. Modifications providing thermodynamic stability to cabotevir sodium are urgently needed due to the fact that phase transitions (which can occur during the production and / or storage of pharmaceuticals, such as polymorphic transformations and / or amorphization) can occur. These transitions often have serious consequences for the safety and efficacy of pharmaceuticals. Therefore, forms B and C of the present invention are advantageous solid forms of cabotevir sodium to be used in the preparation of pharmaceuticals. This is because the application of form B or form C ensures the reliable safety and efficacy properties of pharmaceuticals containing form B or form C throughout the entire storage period.

[0177] Cabotevir sodium can be represented by the following chemical structure according to formula (II): (II).

[0178] Cabotevir sodium is characterized by the following molar ratio of cabotevir to sodium: preferably 1.0 : 0.7 to 1.0 : 1.3, more preferably 1.0 : 0.8 to 1.0 : 1.2, even more preferably 1.0 : 0.9 to 1.0 : 1.1, and particularly a molar ratio of 1.0 : 1.0.

[0179] On one hand, the present invention relates to the crystal form of sodium cabotevir, designated as "Form B".

[0180] The cabotevir sodium form B of the present invention may be characterized by any one or a combination of two or more of the following embodiments.

[0181] Therefore, the present invention relates to the crystalline form (form B) of sodium cabotevir, characterized by being prepared at a temperature of 20-30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, a powder X-ray diffraction pattern is obtained that includes reflections at angles of 2-θ: (6.8 ± 0.2)°, (18.5 ± 0.2)°, and (23.7 ± 0.2)°; or (6.8 ± 0.2)°, (18.5 ± 0.2)°, (20.3 ± 0.2)° and (23.7 ± 0.2)°; or (6.8 ± 0.2)°, (18.5 ± 0.2)°, (18.9 ± 0.2)°, (20.3 ± 0.2)°, and (23.7 ± 0.2)°; or (6.8 ± 0.2)°, (18.5 ± 0.2)°, (18.9 ± 0.2)°, (20.3 ± 0.2)°, (22.8 ± 0.2)°, and (23.7 ± 0.2)°; or (6.8 ± 0.2)°, (18.5 ± 0.2)°, (18.9 ± 0.2)°, (20.3 ± 0.2)°, (22.8 ± 0.2)°, (23.2 ± 0.2)°, and (23.7 ± 0.2)°; or (6.8 ± 0.2)°, (17.7 ± 0.2)°, (18.5 ± 0.2)°, (18.9 ± 0.2)°, (20.3 ± 0.2)°, (22.8 ± 0.2)°, (23.2 ± 0.2)° and (23.7 ± 0.2)°; or (6.8 ± 0.2)°, (17.7 ± 0.2)°, (18.5 ± 0.2)°, (18.9 ± 0.2)°, (20.3 ± 0.2)°, (20.6 ± 0.2)°, (22.8 ± 0.2)°, (23.2 ± 0.2)°, and (23.7 ± 0.2)°; or (6.8 ± 0.2)°, (17.7 ± 0.2)°, (18.5 ± 0.2)°, (18.9 ± 0.2)°, (20.3 ± 0.2)°, (20.6 ± 0.2)°, (22.8 ± 0.2)°, (23.2 ± 0.2)°, (23.7 ± 0.2)°, and (28.6 ± 0.2)°; or (6.8 ± 0.2)°, (14.6 ± 0.2)°, (17.7 ± 0.2)°, (18.5 ± 0.2)°, (18.9 ± 0.2)°, (20.3 ± 0.2)°, (20.6 ± 0.2)°, (22.8 ± 0.2)°, (23.2 ± 0.2)°, (23.7 ± 0.2)°, and (28.6 ± 0.2)°; or (6.8 ± 0.2)°, (14.6 ± 0.2)°, (17.7 ± 0.2)°, (18.5 ± 0.2)°, (18.9 ± 0.2)°, (20.3 ± 0.2)°, (20.6 ± 0.2)°, (22.8 ± 0.2)°, (23.2 ± 0.2)°, (23.7 ± 0.2)°, (27.3 ± 0.2)°, and (28.6 ± 0.2)°; In another embodiment, the present invention relates to the crystalline form (form B) of sodium cabotevir, characterized by being prepared at a temperature of 20-30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, a powder X-ray diffraction pattern is obtained that includes reflections at angles of 2-θ: (6.8 ± 0.1)°, (18.5 ± 0.1)°, and (23.7 ± 0.1)°; or (6.8 ± 0.1)°, (18.5 ± 0.1)°, (20.3 ± 0.1)° and (23.7 ± 0.1)°; or (6.8 ± 0.1)°, (18.5 ± 0.1)°, (18.9 ± 0.1)°, (20.3 ± 0.1)°, and (23.7 ± 0.1)°; or (6.8 ± 0.1)°, (18.5 ± 0.1)°, (18.9 ± 0.1)°, (20.3 ± 0.1)°, (22.8 ± 0.1)°, and (23.7 ± 0.1)°; or (6.8 ± 0.1)°, (18.5 ± 0.1)°, (18.9 ± 0.1)°, (20.3 ± 0.1)°, (22.8 ± 0.1)°, (23.2 ± 0.1)°, and (23.7 ± 0.1)°; or (6.8 ± 0.1)°, (17.7 ± 0.1)°, (18.5 ± 0.1)°, (18.9 ± 0.1)°, (20.3 ± 0.1)°, (22.8 ± 0.1)°, (23.2 ± 0.1)°, and (23.7 ± 0.1)°; or (6.8 ± 0.1)°, (17.7 ± 0.1)°, (18.5 ± 0.1)°, (18.9 ± 0.1)°, (20.3 ± 0.1)°, (20.6 ± 0.1)°, (22.8 ± 0.1)°, (23.2 ± 0.1)°, and (23.7 ± 0.1)°; or (6.8 ± 0.1)°, (17.7 ± 0.1)°, (18.5 ± 0.1)°, (18.9 ± 0.1)°, (20.3 ± 0.1)°, (20.6 ± 0.1)°, (22.8 ± 0.1)°, (23.2 ± 0.1)°, (23.7 ± 0.1)°, and (28.6 ± 0.1)°; or (6.8 ± 0.1)°, (14.6 ± 0.1)°, (17.7 ± 0.1)°, (18.5 ± 0.1)°, (18.9 ± 0.1)°, (20.3 ± 0.1)°, (20.6 ± 0.1)°, (22.8 ± 0.1)°, (23.2 ± 0.1)°, (23.7 ± 0.1)°, and (28.6 ± 0.1)°; or (6.8 ± 0.1)°, (14.6 ± 0.1)°, (17.7 ± 0.1)°, (18.5 ± 0.1)°, (18.9 ± 0.1)°, (20.3 ± 0.1)°, (20.6 ± 0.1)°, (22.8 ± 0.1)°, (23.2 ± 0.1)°, (23.7 ± 0.1)°, (27.3 ± 0.1)°, and (28.6 ± 0.1)°; In another embodiment, the present invention relates to the crystalline form (form B) of sodium cabotevir, characterized by being prepared at a temperature of 20-30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurement, it has the characteristics of the present invention. Figure 1 The powder X-ray diffraction patterns shown are essentially the same.

[0182] The powder X-ray diffraction pattern of sodium cabotevir form B of this invention is clearly distinguishable from that of form A in the prior art (see also the text). Figure 3 (As shown in the overlapping display). Form B shows, for example, reflection at (6.8 ± 0.2)° 2-θ, while form A shows no reflection in the same range. On the other hand, form B shows no reflection at (5.4 ± 0.2)° 2-θ, while form A has characteristic reflection in the aforementioned range. Therefore, the crystal form B of sodium cabotevir is also characterized by having the powder X-ray diffraction pattern described above, but not including diffraction at the 2-θ angle of (5.4 ± 0.2)° 2-θ.

[0183] The powder X-ray diffraction pattern of sodium cabotevir in form B of this invention can also be clearly distinguished from the powder X-ray diffraction pattern of form C of this invention (see also the text). Figure 7(The overlapping is shown). As mentioned above, form B shows reflection at (6.8 ± 0.2)° 2-θ, while form C does not show reflection in the same range. On the other hand, form B does not show reflection at (6.2 ± 0.2)° 2-θ, while form C has characteristic reflection in the same range. Therefore, the crystal form B of sodium cabotevir is also characterized by having the powder X-ray diffraction pattern described above, but not including diffraction at the 2-θ angle of (6.2 ± 0.2)° 2-θ. The crystal form B of sodium cabotevir is also characterized by having the powder X-ray diffraction pattern described above, but not including reflection at the 2-θ angles of (5.4 ± 0.2)° and (6.2 ± 0.2)° 2-θ. In one aspect, the present invention relates to compositions containing sodium cabotevir form B of the present invention, which are substantially free of any other physical form of sodium cabotevir. For example, based on the weight of the composition, a composition containing cabotevir sodium form B of the present invention comprises up to 20% by weight, preferably up to 10% by weight, more preferably up to 5% by weight, even more preferably up to 2% by weight, and most preferably up to 1% by weight of any other physical form of cabotevir sodium. Preferably, any other physical form of cabotevir sodium is form A as defined herein, or it is form C as defined herein, or it is amorphous cabotevir sodium. More preferably, a composition containing cabotevir sodium form B comprises up to 2% by weight of a combination of cabotevir sodium form A as defined herein, cabotevir sodium form C as defined herein, and amorphous cabotevir sodium.

[0184] On the other hand, the present invention relates to a method for preparing cabotevir sodium crystal form B or a composition containing cabotevir sodium form B as defined above, comprising: (i) Providing sodium cabotevir in crystalline form (form A), characterized by being obtained by reacting Cu-K with a wavelength of 0.15419 nm at a temperature of 20–30 °C. 1,2 During radiation measurement, it has the characteristics contained in 2- PXRD of reflections at angles of (5.4 ± 0.2)°, (12.8 ± 0.2)°, (13.1 ± 0.2)°, (23.9 ± 0.2)° and (24.4 ± 0.2)°; (ii) In a solvent, the crystalline form (form A) of cabotevir sodium provided in step (i) is pulped, the solvent being selected from cyclic ethers, C3-C4 ketones and methyl acetate or mixtures thereof, wherein the pulping continues for a period of time sufficient to allow cabotevir sodium (form A) to be transformed into the crystalline form B of cabotevir sodium of the present invention; (iii) Optionally, at least a portion of the crystals obtained in step (ii) is separated from its mother liquor; (iv) Optionally rinse the separated crystals obtained in step (iii); (v) Optionally dry the crystal obtained in any of steps (ii) to (iv); The sodium form A of cabotevir used as a raw material in the above method can be prepared according to Example Z-1 of WO 2006 / 116764 A1, Example Ae of WO 2010 / 068253 A, Example 17 of WO 2015 / 177537 A1, or according to the method of J. Med. Chem. 2013, 56, 5901-5916.

[0185] Solvent-mediated conversion of cabotevir sodium form A to cabotevir sodium form B can be achieved by applying the conditions defined below.

[0186] Suitable solvents that can be used in step (ii) of the above method may be selected from cyclic ethers, C3-C4 ketones, and methyl acetate, or mixtures thereof. In a preferred embodiment, the cyclic ethers are selected from tetrahydrofuran and 1,4-dioxane, and the C3-C4 ketones are selected from acetone and 2-butanone. The solvent or solvent mixture may contain other organic solvents and / or water. However, most preferably, the only solvent present in the slurry is selected from tetrahydrofuran, 1,4-dioxane, acetone, 2-butanone, and methyl acetate.

[0187] The concentration of cabotevir sodium in the suspension is preferably about 5 to 80 g / L, more preferably about 5 to 50 g / L, and most preferably about 5 to 25 g / L, for example, a concentration of about 10 g / L.

[0188] Preferably, pulping is carried out at room temperature, but depending on the concentration used, pulping can also be carried out at elevated temperatures, such as about 40 to 80 °C, preferably about 40 to 60 °C.

[0189] Slurrying includes any kind of movement of solid matter suspended in a solvent, caused by, but not limited to, oscillation, stirring, mixing, shaking, vibration, ultrasonication, wet milling, etc.

[0190] The pulping process is carried out for a sufficient period of time to convert at least the majority, preferably all, of form A into form B. Preferably, the pulping process takes place for a period of several hours to several days. The pulping process can, for example, take for a period of 6 hours to 14 days or longer. Technicians can monitor the conversion of cabotevir sodium from form A to form B by extracting samples from the pulp and analyzing the samples by powder X-ray diffraction.

[0191] Once cabotevir sodium form B is obtained, or preferably obtained in substantially pure form, at least some crystals are optionally separated from its mother liquor. Preferably, the crystals are separated from its mother liquor by any conventional method such as filtration, centrifugation, solvent evaporation or decantation, more preferably by filtration or centrifugation, and most preferably by filtration.

[0192] Optionally, in a further step, the separated crystals are washed with a suitable solvent, such as an organic solvent and / or water. Suitable organic solvents include, but are not limited to, tetrahydrofuran, 1,4-dioxane, acetone, 2-butanone, and methyl acetate. Most preferably, the solvent applied in step (ii) of the method as defined above is also used for washing.

[0193] The resulting crystals can then be optionally dried. Drying can be carried out at a temperature of about 150 °C or lower, preferably about 100 °C or lower, more preferably about 60 °C or lower, and most preferably about 40 °C or lower. Typically, drying is carried out at room temperature. Drying can be carried out for a period of about 1 to 72 hours, preferably 2 to 48 hours, more preferably 4 to 24 hours, and most preferably 6 to 18 hours. Drying can be carried out under ambient pressure and / or reduced pressure. Preferably, drying is carried out under a pressure of about 100 mbar or lower, more preferably about 50 mbar or lower, and most preferably about 30 mbar or lower, for example, under a vacuum of about 20 mbar or lower.

[0194] In another aspect, the present invention relates to the crystalline form of sodium cabotevir designated as "Form C".

[0195] The cabotevir sodium form C of the present invention may be characterized by any one or a combination of two or more of the following embodiments.

[0196] Therefore, the present invention relates to the crystalline form (form C) of sodium cabotevir, characterized by being prepared at a temperature of 20-30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, a powder X-ray diffraction pattern is obtained that includes reflections at angles of 2-θ: (6.2 ± 0.2)°, (17.3 ± 0.2)°, and (23.2 ± 0.2)°; or (6.2 ± 0.2)°, (17.3 ± 0.2)°, (21.7 ± 0.2)°, and (23.2 ± 0.2)°; or (6.2 ± 0.2)°, (17.3 ± 0.2)°, (21.7 ± 0.2)°, (23.2 ± 0.2)°, and (25.1 ± 0.2)°; or (6.2 ± 0.2)°, (9.1 ± 0.2)°, (17.3 ± 0.2)°, (21.7 ± 0.2)°, (23.2 ± 0.2)°, and (25.1 ± 0.2)°; or (6.2 ± 0.2)°, (9.1 ± 0.2)°, (11.7 ± 0.2)°, (17.3 ± 0.2)°, (21.7 ± 0.2)°, (23.2 ± 0.2)°, and (25.1 ± 0.2)°; or (6.2 ± 0.2)°, (9.1 ± 0.2)°, (11.7 ± 0.2)°, (13.6 ± 0.2)°, (17.3 ± 0.2)°, (21.7 ± 0.2)°, (23.2 ± 0.2)° and (25.1 ± 0.2)°.

[0197] In another embodiment, the present invention relates to the crystalline form (form C) of sodium cabotevir, characterized in that it is prepared at a temperature of 20-30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2 During radiation measurements, a powder X-ray diffraction pattern is obtained that includes reflections at angles of 2-θ: (6.2 ± 0.1)°, (17.3 ± 0.1)°, and (23.2 ± 0.1)°; or (6.2 ± 0.1)°, (17.3 ± 0.1)°, (21.7 ± 0.1)°, and (23.2 ± 0.1)°; or (6.2 ± 0.1)°, (17.3 ± 0.1)°, (21.7 ± 0.1)°, (23.2 ± 0.1)°, and (25.1 ± 0.1)°; or (6.2 ± 0.1)°, (9.1 ± 0.1)°, (17.3 ± 0.1)°, (21.7 ± 0.1)°, (23.2 ± 0.1)°, and (25.1 ± 0.1)°; or (6.2 ± 0.1)°, (9.1 ± 0.1)°, (11.7 ± 0.1)°, (17.3 ± 0.1)°, (21.7 ± 0.1)°, (23.2 ± 0.1)°, and (25.1 ± 0.1)°; or (6.2 ± 0.1)°, (9.1 ± 0.1)°, (11.7 ± 0.1)°, (13.6 ± 0.1)°, (17.3 ± 0.1)°, (21.7 ± 0.1)°, (23.2 ± 0.1)° and (25.1 ± 0.1)°.

[0198] In another embodiment, the present invention relates to the crystalline form (form C) of sodium cabotevir, characterized by being prepared at a temperature of 20-30 °C using Cu-Kα with a wavelength of 0.15419 nm. 1,2During radiation measurement, it has the characteristics of the present invention. Figure 5 The powder X-ray diffraction patterns shown are essentially the same.

[0199] The powder X-ray diffraction pattern of sodium cabotevir form C of this invention is clearly distinguishable from a prior art form A (see also the text). Figure 6 (The overlapping display is shown). Form C shows, for example, reflection at (6.2 ± 0.2)° 2-θ, while form A shows no reflection in the same range. On the other hand, form C shows no reflection at (5.4 ± 0.2)° 2-θ, while form A has characteristic reflection in the range described above. Therefore, the crystal form C of sodium cabotevir is also characterized by having the powder X-ray diffraction pattern described above, but without including reflection at the 2-θ angle of (5.4 ± 0.2)° 2-θ.

[0200] As mentioned above, the powder X-ray diffraction pattern of sodium cabotevir form C of the present invention can also be clearly distinguished from the powder X-ray diffraction pattern of form B of the present invention (see also the text). Figure 7 (As shown in the overlapping display). Form C, for example, shows reflection at 2-θ of (6.2 ± 0.2)°, while form B does not show reflection in the same range. On the other hand, form C does not show reflection at 2-θ of (6.8 ± 0.2)°, while form B has characteristic reflection in the same range. Therefore, the crystal form C of sodium cabotevir is also characterized by having the powder X-ray diffraction pattern described above, but does not include reflection at the 2-θ angle of (6.8 ± 0.2)°.

[0201] The crystalline form of sodium cabotevir is also characterized by having the powder X-ray diffraction pattern described above, but without the reflections at 2-θ angles of (5.4 ± 0.2)° and (6.8 ± 0.2)° 2-θ.

[0202] On the other hand, the present invention relates to compositions containing cabotevir sodium form C of the present invention, which are substantially free of any other physical form of cabotevir sodium. For example, based on the weight of the composition, the composition containing cabotevir sodium form C of the present invention comprises up to 20% by weight, preferably up to 10% by weight, more preferably up to 5% by weight, even more preferably up to 2% by weight, and most preferably up to 1% by weight of any other physical form of cabotevir sodium. Preferably, any other physical form of cabotevir sodium is form A as defined herein, or is form B as defined herein, or is amorphous cabotevir sodium. More preferably, the composition containing cabotevir sodium form C comprises up to 2% by weight of a combination of cabotevir sodium form A as defined herein, cabotevir sodium form B as defined herein, and amorphous cabotevir sodium.

[0203] On the other hand, the present invention relates to a method for preparing cabotevir sodium crystal form C or a composition containing cabotevir sodium form C as defined above, comprising: (i) Providing a crystalline form (form A) of sodium cabotevir, said crystalline form being characterized by its crystallization at a temperature of 20–30 °C using Cu-K with a wavelength of 0.15419 nm. 1,2 During radiation measurement, it has the characteristics contained in 2- PXRD of reflections at angles of (5.4 ± 0.2)°, (12.8 ± 0.2)°, (13.1 ± 0.2)°, (23.9 ± 0.2)° and (24.4 ± 0.2)°; (ii) In methyl isobutyl ketone, the crystalline form (form A) of cabotevir sodium provided in step (i) is pulped, wherein the pulping continues for a period of time sufficient to achieve the transformation of cabotevir sodium (form A) into the crystalline form C of cabotevir sodium of the present invention, and wherein the pulping is stopped before the obtained crystalline form C is further transformed into the crystalline form B of cabotevir sodium as defined above. (iii) Optionally, at least a portion of the crystals obtained in step (ii) is separated from its mother liquor; (iv) Optionally rinse the separated crystals obtained in step (iii); (v) Optionally dry the crystal obtained in any of steps (ii) to (iv); The sodium form A of cabotevir used as a raw material in the above method can be prepared according to Example Z-1 of WO 2006 / 116764 A1, Example Ae of WO 2010 / 068253 A, Example 17 of WO 2015 / 177537 A1, or according to the method of J. Med. Chem. 2013, 56, 5901-5916.

[0204] Solvent-mediated conversion of cabotevir sodium form A to cabotevir sodium form C can be achieved by applying the conditions defined below.

[0205] A suitable solvent that can be used in step (ii) of the above method is methyl isobutyl ketone. In addition to methyl isobutyl ketone, the solvent may contain other organic solvents and / or water. However, most preferably, methyl isobutyl ketone is the only solvent present in the slurry.

[0206] The concentration of cabotevir sodium in the suspension is preferably about 5 to 80 g / L, more preferably about 5 to 50 g / L, and most preferably about 5 to 25 g / L, for example, a concentration of about 10 g / L.

[0207] Pulping is carried out at room temperature, but it can also be carried out at elevated temperatures. Preferably, pulping is carried out at a temperature of about 40 to 80 °C, or even more preferably about 40 to 60 °C.

[0208] Slurrying includes any kind of movement of solid matter suspended in a solvent, caused by, but not limited to, oscillation, stirring, mixing, shaking, vibration, ultrasonication, wet milling, etc.

[0209] The pulping process is carried out for a sufficient period of time, at least substantially all of form A, to be converted to form C, and is stopped before form C is further converted to form B. Depending on the temperature used, the pulping process can last from several hours to several days, with the pulping time decreasing as the temperature increases. For example, at 60 °C, pulping can be carried out for approximately 2 days, or at room temperature for approximately 10 days. Technicians can monitor the conversion of cabotevir sodium from form A to form B by extracting samples from the pulp and analyzing them by powder X-ray diffraction. Preferably, pulping is stopped once most, preferably all, of form A has been converted to form C to avoid further conversion to form B.

[0210] Once cabotevir sodium form C is obtained, or preferably obtained in substantially pure form, at least some crystals are optionally separated from its mother liquor. Preferably, the crystals are separated from its mother liquor by any conventional method such as filtration, centrifugation, solvent evaporation or decantation, more preferably by filtration or centrifugation, and most preferably by filtration.

[0211] Optionally, in a further step, the separated crystals are washed with a suitable solvent, such as an organic solvent, and / or water. A suitable organic solvent is, for example, methyl isobutyl ketone.

[0212] The resulting crystals can then be optionally dried. Drying can be carried out at a temperature of about 150 °C or lower, preferably about 100 °C or lower, more preferably about 60 °C or lower, and most preferably about 40 °C or lower. Typically, drying is performed at room temperature. Drying can be carried out for a period of about 1 to 72 hours, preferably 2 to 48 hours, more preferably 4 to 24 hours, and most preferably 6 to 18 hours. Drying can be performed under ambient pressure and / or reduced pressure. Preferably, drying is carried out under a pressure of about 100 mbar or lower, more preferably about 50 mbar or lower, and most preferably about 30 mbar or lower, for example, under a vacuum of about 20 mbar or lower.

[0213] The inventors have surprisingly discovered that when slurryed for a sufficiently long time in the presence of a suitable organic solvent, sodium cabotevir in its prior art form A undergoes a solvent-mediated phase transition, becoming a more stable modified form, namely form B of this invention. This indicates that, under the test conditions, sodium cabotevir crystal form B is a thermodynamically more stable solid form (see also Example 1 and Reference Example 1 herein).

[0214] Furthermore, it was found that when slurryed for a sufficiently long time in the presence of methyl isobutyl ketone, the prior art form A of cabotevir sodium undergoes a solvent-mediated phase transition to become another more stable modification, namely form C of the present invention. This indicates that cabotevir sodium form C is a thermodynamically more stable form under the specific test conditions stated herein (see also Examples 2 and 3 in the text).

[0215] The precise conditions used for the pulping tests are described in more detail in Examples 1-3 of this document. A summary of the completed pulping tests is provided in Table 1 below:

[0216] Table 1: Overview of the completed pulping tests

[0217] Under given conditions, form A is transformed into forms B and C, respectively, indicating that the two modifications of the present invention are thermodynamically more stable than the prior art form A, at least under the test conditions. Competitive slurry tests performed with equal amounts of form A and form B further confirm that form B is thermodynamically more stable than form A (see also Example 5 in the text).

[0218] The thermodynamically most stable polymorph, or at least kinetically stable, is preferred for pharmaceutical development because metastable polymorphs can transform into more stable forms during drug processing and / or once stored. Such phase transitions can cause formulation problems such as physical instability of solid dosage forms and changes in bioavailability. The application of the thermodynamically most stable form, or at least kinetically stable, is highly recommended because it generally minimizes the risk of polymorphic transformation and provides a medicine with consistent therapeutic and efficacy outcomes. Therefore, cabotevir sodium forms B and C of the present invention are superior to form A because they ensure a safe and effective medicine for patients.

[0219] Therefore, on the other hand, the present invention relates to the use of cabotevir sodium form B or form C as defined above for the preparation of pharmaceutical compositions.

[0220] The pharmaceutical compositions of the present invention can be prepared by wet or dry processing methods. In some embodiments, the pharmaceutical compositions are prepared by wet processing, such as, but not limited to, wet granulation. Suitable wet granulation methods include high-shear granulation or fluidized bed granulation. In another embodiment, the pharmaceutical compositions are prepared by dry processing methods, such as, but not limited to, direct compression or dry granulation. An example of dry granulation is roller compaction. The pharmaceutical compositions obtained by dry or wet processing methods can be compressed into tablets, capsules, or sachets.

[0221] On the other hand, the present invention relates to pharmaceutical compositions preferably containing, in effective and / or predetermined amounts, cabotevir sodium form B or form C as defined above, and at least one pharmaceutically acceptable excipient and optionally one or more other pharmaceutically active ingredients. Most preferably, the pharmaceutical compositions of the present invention are oral solid dosage forms, such as tablets or capsules. Preferably, the pharmaceutical compositions of the present invention are tablets. In a preferred embodiment, the tablets are film-coated with a coating material comprising polyvinyl alcohol (e.g., partially hydrolyzed), iron oxide (e.g., yellow), talc, and titanium dioxide.

[0222] At least one pharmaceutically acceptable excipient included in the pharmaceutical composition of the present invention is preferably selected from carriers, fillers, diluents, lubricants, sweeteners, stabilizers, solubilizers, antioxidants and preservatives, flavoring agents, binders, colorants, penetrants, buffers, surfactants, disintegrants, granulators, coating materials, and combinations thereof.

[0223] In a preferred embodiment, the at least one pharmaceutically acceptable excipient is selected from mannitol, microcrystalline cellulose, povidone, sodium starch glycolate, and sodium stearoyl fumarate. In a preferred embodiment, the pharmaceutical composition of the present invention comprises all of the aforementioned pharmaceutically acceptable excipients.

[0224] In another preferred embodiment, the one or more other active ingredients are selected from entry / fusion inhibitors, reverse transcriptase inhibitors (RTIs), integrase strand transfer inhibitors (INSTIs), maturation inhibitors, protease inhibitors (PIs), or mixtures thereof. In another preferred embodiment, the entry / fusion inhibitor is selected from entfuviride, maraviro, velivirol, cenicriviroc, and fostamsavir, or mixtures thereof; the reverse transcriptase inhibitors (RTIs) are selected from abacavir, norinosine, emtricitabine, lamivudine, stavudine, zidovudine, amadoxovir, aripipridine, censavudine, lavatabine, racivir, stampidine, zalcitabine, tenofovir disoproxil fumarate, tenofovir alafenamide, and efavirenz. The following are included: virex, nevirapine, deraviridine, ectavirine, rilpivirine, doravirine, or mixtures thereof; integrase strand transfer inhibitors (INSTIs) selected from dulutegravir, ertigvir, ritigvir, and bictegravir, or mixtures thereof; maturation inhibitors are bevirimat; and protease inhibitors (PIs) selected from ampravir, furazonavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, atazanavir, darunavir, telanavir, or mixtures thereof.

[0225] In a particularly preferred embodiment, the one or more other pharmaceutically active ingredients are selected from rilpivirine and lamivudine, and most preferably, the one or more other pharmaceutically active ingredients are rilpivirine, for example, in its hydrochloride form.

[0226] Preferably, the present invention relates to the pharmaceutical composition described above, wherein the predetermined and / or effective amount of cabotevir sodium is selected from 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, and 90 mg, calculated in cabotevir. Most preferably, the present invention relates to the above-described pharmaceutical composition, wherein the predetermined and / or effective amount of cabotevir sodium is 30 mg, calculated in cabotevir.

[0227] Preferably, the present invention relates to the pharmaceutical composition described above, wherein the pharmaceutical composition is to be administered orally once daily.

[0228] On the other hand, the present invention relates to the pharmaceutical composition described above, which is used as a medicine.

[0229] In another aspect, the present invention relates to the pharmaceutical compositions described above for the treatment or prevention of viral infections caused by DNA viruses, RNA viruses, herpesviruses (e.g., CMV, HSV 1, HSV 2, VZV), retroviruses, hepatotropic viruses (e.g., HBV), papillomaviruses, hantaviruses, adenoviruses, and HIV.

[0230] In a particular embodiment, the present invention relates to the pharmaceutical composition described above for the treatment or prevention of HIV-1 infection.

[0231] On the other hand, the present invention relates to the pharmaceutical composition described above for treating HIV-1 infection, in combination with one or more other pharmaceutically active ingredients selected from entry / fusion inhibitors, reverse transcriptase inhibitors (RTIs), integrase strand transfer inhibitors (INSTIs), maturation inhibitors, protease inhibitors (PIs), or mixtures thereof. In another preferred embodiment, the entry / fusion inhibitor is selected from emfuviride, maraviro, velivirol, cenicriviroc, ipalizumab, and fostamsavir, or mixtures thereof; the reverse transcriptase inhibitor (RTI) is selected from abacavir, norinosine, emtricitabine, lamivudine, stavudine, zidovudine, amadoxovir, aripipridine, censavudine, lavatabine, racivir, stampidine, zalcitabine, tenofovir disoproxil fumarate, and tenofovir disoproxil fumarate. Viagra, efavirenz, nevirapine, deraviridine, ectrevirine, rilpivirine, doravirine, or mixtures thereof; integrase strand transfer inhibitor (INSTI) selected from dulutegravir, ertigvir, ritigvir, and bictegravir, or mixtures thereof; maturation inhibitor is bevirimilamide; and protease inhibitors (PIs) selected from ampravir, furazonavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, atazanavir, darunavir, telanavir, or mixtures thereof.

[0232] Treatment in combination with one or more other pharmaceutical active ingredients may refer to the administration of a pharmaceutical dosage form containing the cabotevir sodium form B of the present invention and one or more other pharmaceutical active ingredients in the same dosage form, such as a fixed-dose combination product.

[0233] Alternatively, treatment in combination with one or more other pharmaceutically active ingredients may refer to the administration of separate pharmaceutical dosage forms, one of which contains cabozantvir sodium form B of the present invention, and the other contains one or more other pharmaceutically active ingredients. Typically, in said combination treatment, instructions are provided for use of a pharmaceutical dosage form containing cabozantvir sodium form B of the present invention in combination with the separate dosage forms for the effective treatment of viral infections such as HIV-1 infection. Detailed Implementation

[0234] Example

[0235] The following non-limiting embodiments are illustrative of this disclosure and should not be construed as limiting the scope of the invention in any way.

[0236] Example 1: Preparation of Cabotevir sodium form B

[0237] Cabotevir sodium form A (approximately 50 mg, prepared according to Reference Example 1 in this text) was suspended in an organic solvent (5 mL) according to Table 2 and vigorously stirred with a magnetic stirrer at room temperature. After 7 days, the solids were collected by filtration, dried under vacuum (30 mbar) at room temperature for 20 hours, and analyzed by PXRD. The results are shown in Table 2.

[0238]

[0239] Table 2: Overview of Equilibrium Slurry Tests Starting with Cabotevir Sodium Form A

[0240] Using a goniometer equipped with a conductive geometry θ / θ coupling and a Cu-Kα with a focusing lens 1，2 PXRD was performed using a PANalytical X'Pert PRO diffractometer with a radiation source (wavelength 0.15419 nm) and a solid-state PIXcel detector. Under ambient conditions, diffraction patterns were recorded at 40 s per step (255 channels) with a step size of 0.013° 2-θ in the 2°–40° 2-θ angle range, using a tube voltage of 45 kV and a tube current of 40 mA. The classical accuracy of the 2-θ values ​​is within ±0.2° 2-θ, preferably ±0.1° 2-θ. Therefore, a cabotevir sodium form B diffraction peak appearing, for example, at 6.8° 2-θ under standard conditions will appear in the range of 6.6–7.0° 2-θ on most diffractometers, preferably in the range of 6.7–6.9° 2-θ.

[0241] A representative diffraction pattern of cabotevir sodium form B is shown in the text. Figure 1 The corresponding reflection list is provided in Table 3 below.

[0242]

[0243] Table 3: PXRD reflection and corresponding relative intensity of cabotevir sodium form B in the 2-θ range of 2~30°; the classical accuracy of the 2-θ value is in the range of ±0.2° 2-θ, preferably in the range of ±0.1° 2-θ.

[0244] Example 2: Preparation of Cabotevir sodium form C

[0245] Cabotevir sodium form A (25 mg, prepared according to Reference Example 1 in this text) was suspended in methyl isobutyl ketone (2.5 mL) and heated to reflux temperature, resulting in incomplete dissolution, but the mixture remained in suspension. The suspension was cooled to room temperature and vigorously stirred at room temperature using a magnetic stirrer. After 7 days, the solids were collected by filtration, dried under vacuum (30 mbar) at room temperature for 20 hours, and analyzed by PXRD.

[0246] Using a goniometer coupled with a focusing lens and a Cu-Kα lens with a conductive geometry θ / θ coupling. 1，2 PXRD was performed using a PANalytical X'Pert PRO diffractometer with radiation (wavelength 0.15419 nm) and a solid-state PIXcel detector. Under ambient conditions, diffraction patterns were recorded at 40 s per step (255 channels) with a step size of 0.013° 2-θ in the 2°–40° 2-θ angle range, using a tube voltage of 45 kV and a tube current of 40 mA. The classical accuracy of the 2-θ values ​​is within ±0.2° 2-θ, preferably ±0.1° 2-θ. Therefore, a C diffraction peak in the cabotevir sodium form appearing under standard conditions, for example at 6.2° 2-θ, will appear in the range of 6.0–6.4° 2-θ on most diffractometers, preferably in the range of 6.1–6.3° 2-θ.

[0247] The representative diffraction pattern of cabotevir sodium form C is shown in the text. Figure 5 The corresponding reflection list is provided in Table 4 below.

[0248]

[0249] Table 4: PXRD reflection and corresponding relative intensity of cabotevir sodium form C in the 2-θ range of 2~30°; the classical accuracy of the 2-θ value is in the range of ±0.2° 2-θ, preferably in the range of ±0.1° 2-θ.

[0250] Example 3: Preparation of Cabotevir sodium form C

[0251] Cabotevir sodium form A (204 mg, prepared according to Reference Example 1 in this text) was suspended in methyl isobutyl ketone (20 mL) and heated to 60 °C. The suspension was vigorously stirred at 60 °C using a magnetic stirrer. After 2 days, the solids were collected by filtration, dried under vacuum (30 mbar) at room temperature for 20 hours, and confirmed as form C by PXRD analysis.

[0252] Example 4: Thermogravimetric analysis (TGA) of cabotevir sodium forms A, B, and C

[0253] TGA was performed on a Mettler TGA / DSC 1 instrument. Samples (3.82 mg form A, 4.79 mg form B, 7.07 mg form C) were heated in a 100 microL aluminum pot sealed with an aluminum lid; for this purpose, the lid was automatically perforated at the start of the measurement. Samples were heated from 25 °C to 380 °C at a rate of 10 K / min. Nitrogen gas (fill rate 50 mL / min) was used as the filling gas.

[0254] At temperatures reaching approximately 200 °C, the text... Figure 8 , 9 The TGA curves for forms A, B, and C shown in Figure 10 show no significant mass loss (≤ 0.1 wt%), confirming the presence of the unsolvated and anhydrous forms.

[0255] Example 5: Competitive pulping test of form A and form B

[0256] Competitive slurry formation tests in 2-butanone were conducted by suspending equal amounts of form A (approximately 50 mg, prepared according to Reference Example 1) and form B (approximately 50 mg, prepared according to Example 1) in 4 mL of 2-butanone and vigorously stirring the resulting suspensions with a magnetic stirrer at 20 °C, 40 °C, 60 °C, and 80 °C, respectively. The results of the slurry formation tests are summarized in Table 5 below.

[0257]

[0258] Table 5: Overview of the competitive pulping tests completed using Form A and Form B

[0259] The fact that form A completely transforms into form B in all experiments indicates that form B is thermodynamically more stable than form A.

[0260] Reference Example 1: Repeated experiment of the last step of Example Z-9

[0261] Cabotevir (278 mg, 0.66 mmol, prepared, for example, according to the steps disclosed in Example Z-9, which is based on Example Z-1 of WO 2006 / 116764 A1) was dissolved in ethanol (10 mL) and 1 N The sample was treated with sodium hydroxide (aq) (0.66 mL, 0.66 mmol). The resulting suspension was stirred at room temperature for 30 minutes. Ether was added, and the solid was collected by filtration. The resulting white solid was observed by PXRD and found to be crystalline. In the context of this invention, the crystalline substance is designated as form A.

[0262] Using a goniometer equipped with a conductive geometry θ / θ coupling and a Cu-Kα with a focusing lens 1，2 PXRD was performed using a PANalytical X'Pert PRO diffractometer with radiation (wavelength 0.15419 nm) and a solid-state PIXcel detector. Diffraction patterns were recorded under ambient conditions at 40 s per step (255 channels), with a step size of 0.013° 2-θ in the 2°–40° 2-θ angle range, using a tube voltage of 45 kV and a tube current of 40 mA.

[0263] A representative diffraction pattern of cabotevir sodium form A is shown in the text. Figure 2 The corresponding reflection list is provided in Table 6 below.

[0264]

[0265] Table 6: PXRD reflections and corresponding relative intensities of cabotevir sodium form A in the 2-θ range of 2 to 30°; the classical accuracy of the 2-θ values ​​is within ±0.2° 2-θ, preferably within ±0.1° 2-θ.

[0266] Reference Example 2: Repeat experiment of Example Ae of WO 2010 / 068253 A1

[0267] Cabotevir (254 mg, 0.60 mmol, prepared, for example, according to Examples Aa to Ad of WO 2010 / 068253 A1) was dissolved in ethanol (40 mL) and water (10 mL) by heating, followed by filtration. At 75 °C, 1 N Sodium hydroxide (aq) (0.61 mL, 0.61 mmol). The solution was gradually cooled to room temperature. Filtered, washed with ethanol (1.25 mL), and dried to obtain dolutegravir sodium crystals. The crystals were analyzed by PXRD and classified as form A.

[0268] Reference Example 3: Repeated Experiments in J. Med. Chem. 2013, 56, 5901-5916

[0269] Cabotevir (385 mg, 0.95 mmol) was dissolved in 1.0 mL of ethanol (15 mL). N Treatment with sodium hydroxide (aq) (0.95 mL, 0.95 mmol) yielded sodium cabotevir as a white solid (380 mg, theoretical yield 93%). The substance was analyzed by PXRD and classified as form A.

[0270] Reference Example 4: Salt Formation in Methanol

[0271] Cabotevir (1002 mg, 2.47 mmol) was dissolved in methanol (60 mL) at 60 °C using 2.0 mL of water. N The mixture was treated with sodium hydroxide (aq) (1.25 mL, 2.50 mmol), and the reaction mixture was stirred for another 1 hour. The reaction mixture was cooled to room temperature and stirred for another 1 hour. The solids were separated by filtration, washed with methanol, and dried. The substance obtained was analyzed by PXRD and classified as form A.

Claims

1. The crystalline form of sodium cabotevir, characterized by its crystal structure when heated to 20–30 °C using Cu-K with a wavelength of 0.15419 nm. 1,2 During radiation measurement, it has the following 2- Powder X-ray diffraction pattern reflected at the corner: (6.8 ± 0.2)°, (18.5 ± 0.2)°, and (23.7 ± 0.2)°; or (6.8 ± 0.2)°, (18.5 ± 0.2)°, (20.3 ± 0.2)° and (23.7 ± 0.2)°; or (6.8 ± 0.2)°, (18.5 ± 0.2)°, (18.9 ± 0.2)°, (20.3 ± 0.2)° and (23.7 ± 0.2)°.

2. The crystalline form of claim 1, characterized by a powder X-ray diffraction pattern substantially the same as shown in Figure 1 when measured at a temperature of 20-30 °C using Cu-Ka radiation of wavelength 0.15419 nm. 1,2 When measured using Cu-Ka radiation of wavelength 0.15419 nm, it has a powder X-ray diffraction pattern substantially the same as shown in Figure 1.

3. A composition comprising the crystalline form according to claim 1, and, based on the weight of the composition, up to 20% by weight, 10% by weight, 5% by weight, 2% by weight, or 1% by weight of any other physical form of sodium cabotevir.

4. The composition according to claim 3, wherein the other physical form of sodium cabotevir is form A, characterized in that when at a temperature of 20-30 °C, it is reacted with Cu-K having a wavelength of 0.15419 nm. 1,2 During radiation measurement, it has the following 2- Powder X-ray diffraction patterns of reflected light at angles of (5.4 ± 0.2)°, (12.8 ± 0.2)°, (13.1 ± 0.2)°, (23.9 ± 0.2)° and (24.4 ± 0.2)°.

5. The composition of claim 3, wherein the other physical form of sodium cabotevir is amorphous sodium cabotevir.

6. The method for preparing sodium cabotevir crystals as defined in claim 1, comprising: (i) providing Form A of cabotegravir sodium characterized by having a PXRD comprising reflections at 2-theta angles (5.4 ± 0.2)°, (12.8 ± 0.2)°, (13.1 ± 0.2)°, (23.9 ± 0.2)° and (24.4 ± 0.2)° when measured at temperatures of 20 to 30 °C with Cu-Ka radiation of 0.15419 nm wavelength 1,2 when measured at temperatures of 20 to 30 °C with Cu-Ka radiation of 0.15419 nm wavelength (ii) In a solvent, the crystalline form (form A) of cabotevir sodium provided in step (i) is pulped, the solvent being selected from cyclic ethers, C3-C4 ketones and methyl acetate or mixtures thereof, wherein the pulping is carried out for a period of 6 hours to 14 days or longer to achieve the transformation of cabotevir sodium (form A) into the crystalline form of cabotevir sodium as described in claim 1.

7. The method of claim 6, wherein the cyclic ether is selected from 1,4-dioxane and tetrahydrofuran, and the C3-C4 ketone is selected from acetone and 2-butanone.

8. The method of claim 6, further comprising step (iii) separating at least a portion of the crystals obtained in step (ii) from the mother liquor.

9. The method of claim 8, further comprising step (iv) rinsing the separated crystals obtained in step (iii).

10. The method of claim 6, further comprising step (v) drying the crystal obtained in step (ii).

11. A method for preparing a pharmaceutical composition comprising a crystalline form of cabotevir sodium, said crystalline form being characterized by reacting Cu-K with a wavelength of 0.15419 nm at a temperature of 20–30 °C. 1,2 During radiation measurement, it has the following 2- Powder X-ray diffraction pattern reflected at the corner: (6.8 ± 0.2)°, (18.5 ± 0.2)°, and (23.7 ± 0.2)°; or (6.8 ± 0.2)°, (18.5 ± 0.2)°, (20.3 ± 0.2)° and (23.7 ± 0.2)°; or (6.8 ± 0.2)°, (18.5 ± 0.2)°, (18.9 ± 0.2)°, (20.3 ± 0.2)° and (23.7 ± 0.2)°; and containing up to 20% by weight of any other physical form of sodium cabotevir based on the weight of the composition; and pharmaceutically acceptable excipients.

12. The method of claim 11, wherein the pharmaceutical composition is a solid oral dosage form, optionally a tablet or capsule.

13. Use of the pharmaceutical composition of claim 11 or 12 in the preparation of a medicament for treating and / or preventing viral infections optionally caused by DNA viruses, RNA viruses, herpesviruses, retroviruses, hepatotropic viruses, papillomaviruses, hantaviruses, adenoviruses, and HIV.

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