DESC:This application claims priority and benefit of following Indian provisional patent application no. 202021003087, filed on January 23, 2020 and Indian provisional patent application no. 202021005070, filed on February 5, 2020.

FIELD OF THE INVENTION
The present invention relates to the solid forms of Baloxavir marboxil and processes for the preparation thereof.
BACKGROUND OF THE INVENTION
Baloxavir marboxil is an antiviral PA endonuclease inhibitor and sold under the brand name XOFLUZA, the chemical name of baloxavir marboxil is ({(12aR)-12-[(11S)-7,8-Difluoro-6,11-dihydrodibenzo[b,e]thiepin- 11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate represented by the following formula I.

Formula I
US patent no 8,987,441 discloses substituted 3-hydroxy-4-pyridone derivatives, prodrug and process for the preparation thereof.
US patent no 10,392,406 discloses Baloxavir marboxil and process for the prepartion thereof.
US patent no 10759814 discloses Baloxavir marboxil form I, Baloxavir marboxil form II, Baloxavir marboxil form III and processes for the preparation thereof.
SUMMARY OF THE INVENTION
The present invention relates to crystalline Baloxavir marboxil form-L, crystalline Baloxavir marboxil form-M and an amorphous Baloxavir marboxil and processes for the preparation thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 depicts an X-ray powder diffraction pattern of crystalline Baloxavir marboxil form-L.
Figure 2 depicts a characteristic FT-IR spectrum of crystalline Baloxavir marboxil form-L.
Figure 3 depicts a characteristic DSC thermogram of crystalline Baloxavir marboxil form-L.
Figure 4 depicts an X-ray powder diffraction pattern of an amorphous Baloxavir marboxil.
Figure 5 depicts an X-ray powder diffraction pattern of crystalline Baloxavir marboxil form-M.
Figure 6 depicts a characteristic FT-IR spectrum of crystalline Baloxavir marboxil form-M.
Figure 7 depicts a characteristic DSC thermogram of crystalline Baloxavir marboxil form-M.
DETAILED DESCRIPTION OF THE INVENTION
One aspect of the present invention relates to crystalline Baloxavir marboxil form-L.
Yet another aspect of the present invention relates to crystalline Baloxavir marboxil form-L, having X-ray powder diffraction pattern peaks at about 5.0°, 8.6°,10.1°, 11.2°, 12.3°, 13.4°, 15.1°, 18.3°, 19.4°, 19.6°, 22.1°, 26.4°, 31.9 and 32.8° (± 0.2) 2? values.

Table 1 provides the d-spacing values (°A), the corresponding 2? values, and the relative intensity of crystalline Baloxavir marboxil form-L.


Table 1
Position(± 0.2° 2 ?) d-spacing(°A) Relative Intensity (%)
5.07 17.419 100
8.64 10.223 24.3
10.14 8.722 5.46
11.24 7.869 9.17
12.33 7.173 18.16
13.41 6.598 15.67
15.14 5.852 41.78
16.59 5.342 10.80
17.61 5.034 8.63
18.30 4.846 24.48
18.93 4.687 10.97
19.48 4.555 43.21
19.64 4.519 45.09
20.78 4.274 8.76
21.52 4.127 7.90
21.76 4.083 7.90
22.18 4.007 18.98
23.17 3.838 12.58
24.39 3.648 11.03
26.46 3.368 18.97
31.99 2.797 6.97
32.82 2.728 5.21

According to present invention, crystalline Baloxavir marboxil form-L is characterized by an infrared (IR) absorption spectrum with characteristic peaks expressed in cm-1 at about 3446, 3066, 2999, 2852, 1759, 1682, 1621, 1543, 1501, 1479, 1464, 1446, 1435, 1424, 1385, 1363, 1342, 1306, 1262, 1218, 1190, 1155, 1127, 1103, 1079, 1050, 1030, 955, 913, 862, 837, 816, 795, 776, 750, 741, 721, 672 and 659 cm-1.
According to present invention, crystalline Baloxavir marboxil form-L having a powder X-ray diffraction pattern comprising peaks at a diffraction angles (2?) essentially the same as shown in Figure 1, crystalline Baloxavir marboxil form-L having an infrared (IR) absorption spectrum with characteristic peaks essentially the same as shown in Figure 2 and DSC thermogram substantially as depicted in Figure 3.
Another aspect of the present invention provides a process for the preparation of crystalline Baloxavir marboxil form-L comprising the steps of:
a) dissolving Baloxavir marboxil in organic solvent,
b) heating the reaction mass,
c) optionally, cooling the reaction mass,
d) optionally, adding solution obtained in step c to precooled second solvent, and
e) isolating crystalline Baloxavir marboxil form-L.

According to the present invention, organic solvent is selected from alcohol such as methanol, ethanol, isopropanol, n-propanol, tertiary-butyl alcohol; ketone solvents such as acetone, methyl isobutyl ketone, methyl ethyl ketone; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride; esters such as methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, polar aprotic solvents such as 1,4-dioxane, nitromethane, dimethyl acetamide, dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrolidone, nitriles such as acetonitrile, butyronitrile, isobutyronitrile, second solvent is selected from ether solvents such as tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether,water or a mixture thereof.
Another aspect of the present invention relates to provide crystalline Baloxavir marboxil form-M.
Yet another aspect of the present invention relates to provide crystalline Baloxavir marboxil form -M, having X-ray powder diffraction pattern peaks at about 7.4°, 9.6°,12.0°, 13.4°, 14.4°, 15.2°, 16.1°, 17.3°, 18.5°, 19, 19.4°, 19.9°, 20.6, 21.4, 22.6, 24.4, 26.1°, 26.8° and 27.2 (± 0.2) 2? values.

Table 2 provides the d-spacing values (°A), the corresponding 2? values, and the relative intensity of crystalline Baloxavir marboxil form-M.
Table 2
Position(± 0.2° 2 ?) d-spacing(°A) Relative Intensity (%)
7.4 11.906 100
9.6 9.197 17.42
12.0 7.329 14.51
13.4 6.599 26.56
14.4 6.147 26.23
15.2 5.810 24.20
16.1 5.473 11.86
17.3 5.100 23.53
18.5 4.775 34.92
19 4.660 21.86
19.4 4.572 51.86
19.9 4.452 23.40
20.6 4.303 14.17
21.4 4.152 22.19
22.6 3.926 41.16
24.4 3.645 49.26
26.1 3.408 38.98
26.8 3.324 14.36
27.2 3.267 14.60

According to present invention, crystalline Baloxavir marboxil form-M is characterized by an infrared (IR) absorption spectrum with characteristic peaks expressed in cm-1 at about 3436, 3070, 2970, 2946, 2864, 1859, 1769, 1753, 1686, 1675, 1610, 1583, 1531, 1500, 1476, 1464, 1437, 1403, 1385, 1363, 1350, 1301, 1287, 1275, 1263, 1220, 1188, 1173, 1151, 1134, 1106, 1079, 1047, 1033, 1005, 968, 952, 938, 930, 912, 842, 831, 817, 805, 795, 774, 763, 757, 740, 721, 673 and 656 cm-1.
According to present invention, crystalline Baloxavir marboxil form-M having a powder X-ray diffraction pattern comprising peaks at a diffraction angles (2?) essentially the same as shown in Figure 5, crystalline Baloxavir marboxil form-M having an infrared (IR) absorption spectrum with characteristic peaks essentially the same as shown in Figure 6 and DSC thermogram substantially as depicted in Figure 7.
Another aspect of the present invention relates to a process for the preparation of crystalline Baloxavir marboxil form-M comprising the steps of:
a) dissolving Baloxavir marboxil in organic solvent,
b) heating the reaction mass,
c) optionally, cooling the reaction mass, and
d) isolating crystalline Baloxavir marboxil form-M.

Yet another aspect of the present invention provides a process for the preparation of Baloxavir marboxil crystalline form-M comprising the steps of:
a) dissolving Baloxavir marboxil in organic solvent,
b) optionally, heating the reaction mass,
c) cooling the reaction mass,
d) optionally, adding solution obtained in step c to precooled second solvent,
e) removing the solvent, and
f) isolating Baloxavir marboxil crystalline form- M.

According to the present invention, organic solvent is selected from alcohol such as methanol, ethanol, isopropanol, n-propanol, tertiary-butyl alcohol; ketone solvents such as acetone, methyl isobutyl ketone, methyl ethyl ketone; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride; esters such as methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; polar aprotic solvents such as 1,4-Dioxane, Nitromethane, dimethyl acetamide, dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrolidone, nitriles such as acetonitrile, butyronitrile, isobutyronitrile, water or a mixture thereof, second solvent is selected from ether solvents such as tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether.
Another aspect of the present invention relates to an amorphous Baloxavir marboxil.
Yet another aspect of the present invention relates to an amorphous Baloxavir marboxil having PXRD, essentially the same as shown in Figure 4.
Another aspect of the present invention provides a process for the preparation of an amorphous Baloxavir marboxil comprising the steps of:
a) dissolving Baloxavir marboxil in organic solvent,
b) adding pre-prepared premixing agent or pharmaceutically acceptable excipient(s),
c) optionally, heating the reaction mass,
d) removing the organic solvent, and
e) isolating an amorphous Baloxavir marboxil.

According to the present invention, the suitable premixing agent or pharmaceutically acceptable excipient(s) discussed in the specification includes but not limited to diluents, lubricants, disintegrants, glidants, stabilizers and surface active agents or mixtures thereof. The premixing agents include but are not limited to polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, sodium starch glycolate, colloidal silicon dioxide, hydroxypropyl methylcellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethylcellulose, polyvinyl acetate, cyclodextrins, gelatins, hypromellose phthalate, corn starch, sugars, poly methyl acrylate polymers such as but not limited to Eudragit S 100, Eudragit S 12.5, Eudragit L 100, Eudragit L 12.5, Eudragit E 100 or combinations comprising one or more of the premixing agent or pharmaceutically acceptable excipient(s).

According to the present invention, organic solvent is selected from alcohol such as methanol, ethanol, isopropanol, n-propanol, tertiary-butyl alcohol; ketone solvents such as acetone, methyl isobutyl ketone, methyl ethyl ketone; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride; esters such as methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; ether solvents such as tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether; nitriles such as acetonitrile, butyronitrile, isobutyronitrile, polar aprotic solvents such as dimethyl acetamide, dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrolidone,water or a mixture thereof.
According to the present invention, wherein the solid is isolated by removal of solvent by using suitable techniques such as distillation, distillation by using a rotational distillation device for example rotavapor (Buchi), distillation under vacuum, filtration, filtration under vacuum, decantation, centrifugation, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), or any other suitable technique known in the art.
Experimental Method:
1) HPLC Instrument and method details:
Instrument : HPLC equipped with Pump, injector, UV detector and Recorder.
Column : Zorbax SB-Aq (4.6 x 250mm), 5µm.
Wavelength : UV Detector 215 nm
Flow rate : 1.5mL/min
Injection volume : 5?L.
Auto sampler temperature: 10°C
Column oven temperature: 20°C.
2) Powder diffraction pattern Instrument and method details:
The X-ray powder diffraction pattern was recorded at room temperature using PANalytical X’Pert PRO diffractogram with Cu Ka radiation (? = 1.540 Å), running at 45 kV and 40 mA.
3) Differential Scanning Calorimetry:
Differential scanning calorimetry was performed using a Diamond DSC PERKIN ELMER differential instrument 2-3mg samples were placed in crimped aluminum pans and heated from 30°C to 250°C in a dry nitrogen atmosphere at a heating rate of 10°C/minute.
4) Infra-red spectroscopy:
The IR spectroscopy was performed using a spectrum 400 using a neat liquid sample or dispersion of solid sample material in KBr.
Following examples are set forth to aid in the understanding of the invention, and are not intended and should not be interpreted as a limitation thereon. Modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention.
Examples:
Example 1
Process for the preparation of crystalline Baloxavir marboxil form-L.
Baloxavir marboxil (0.4 g) was suspend in methyl ethyl ketone (10 ml) at room temperature and heated the mass to 80°C. Reaction mass was cooled and stirred at -20°C. Methyl tertiary butyl ether (15ml) was added at -20, stirred the reaction mass and filter the mass to give the title compound.

Example 2
Process for the preparation of crystalline Baloxavir marboxil form-L
Baloxavir marboxil (1 g) was suspend in dichloromethane (3ml) at room temperature, heat the reaction mass to dissolve the solid, cooled the reaction mass. In a separate reactor charged methyl tertiary butyl ether (30 ml) and cool the solvent, dichloromethane solution of API added slowly in methyl tertiary butyl ether solution and stirred the reaction mass, filter the mass to give the title compound.

Example 3
Process for the preparation of crystalline Baloxavir marboxil form-L.
Baloxavir marboxil (1 g) was suspend in nitromethane (2ml) at room temperature, heat the reaction mass to dissolve the solid, cooled the reaction mass. In a separate small reactor charged methyl tertiary butyl ether (30 ml) and cool the solvent, nitromethane solution of API added slowly in methyl tertiary butyl ether solution and stirred the reaction mass, filter the mass to give the title compound.

Example 4
Process for the preparation of crystalline Baloxavir marboxil form-L.
Baloxavir marboxil (1 g) was suspend in acetonitrile (5 ml) at room temperature, heat the reaction mass to dissolve the solid, cool the reaction mass. In a separate small reactor charged methyl tertiary butyl ether (30 ml) and cool the solvent, acetonitrile solution of API added slowly in methyl tertiary butyl ether solution and stirred the reaction mass, filter the mass to give the title compound.

Example 5
Process for the preparation of an amorphous Baloxavir marboxil.
Baloxavir marboxil (0.5 g) was dissolve in dichloromethane (10 ml) in a conical flask. In another conical flask dissolved Eudragit S-100 (1.0 g) in methanol (30ml). Both the solution mixed at room temperature and stir the reaction mass. Filtered the reaction mass and collected the filtrate and removed solvent by using rotavapor at 60°C. The obtained solid dried to give the title compound.

Example 6
Process for the preparation of crystalline Baloxavir marboxil form-M.
Baloxavir marboxil (0.4 g) was suspend in N-methyl-2-pyrrolidone (1.2 ml) at room temperature and heated the mass to 80°C. Reaction mass was cooled and stirred the reaction mass. Filter the mass and dried the solid to give the title compound.

Example 7
Process for the preparation of crystalline Baloxavir marboxil form-M.
Baloxavir marboxil (0.4 g) was suspend in N-methyl-2-pyrrolidone (1.2 ml) at room temperature and heated the mass to 80°C. Reaction mass was cooled and stirred for 30 min. Added pre-cooled methyl tertiary butyl ether (15ml) at -20°C, stirred the reaction mass and filter the mass to give the title compound.
,CLAIMS:WE CLAIM:

1. Crystalline Baloxavir marboxil form-L.

2. Crystalline Baloxavir marboxil form-L having X-ray powder diffraction pattern peaks at about 5.0°, 8.6°,10.1°, 11.2°, 12.3°, 13.4°, 15.1°, 18.3°, 19.4°, 19.6°, 22.1°, 26.4°, 31.9 and 32.8° (± 0.2) 2? values.

3. A process for the preparation of crystalline Baloxavir marboxil form-L comprising the steps of:
a) dissolving Baloxavir marboxil in organic solvent,
b) heating the reaction mass,
c) optionally, cooling the reaction mass,
d) optionally, adding solution obtained in step c to precooled second solvent, and
e) isolating crystalline Baloxavir marboxil Form-L.

4. Crystalline Baloxavir marboxil form-L, characterized by data selected from one or more of the following:
a) crystalline Baloxavir marboxil form-L having a powder X-ray diffraction pattern comprising peaks at a diffraction angles (2?) essentially the same as shown in Figure 1, b) crystalline Baloxavir marboxil form-L having an infrared (IR) absorption spectrum with characteristic peaks essentially the same as shown in Figure 2, and c) crystalline Baloxavir marboxil form-L having DSC thermogram substantially as depicted in Figure 3.

5. Crystalline Baloxavir marboxil form-M

6. Crystalline Baloxavir marboxil form-M having X-ray powder diffraction pattern peaks at about 7.4°, 9.6°,12.0°, 13.4°, 14.4°, 15.2°, 16.1°, 17.3°, 18.5°, 19, 19.4°, 19.9°, 20.6, 21.4, 22.6, 24.4, 26.1°, 26.8° and 27.2 (± 0.2) 2? values.

7. A process for the preparation of crystalline Baloxavir marboxil form-M comprising the steps of:
a) dissolving Baloxavir marboxil in organic solvent,
b) heating the reaction mass,
c) optionally, cooling the reaction mass, and
d) isolating crystalline Baloxavir marboxil form-M.

8. A process for the preparation of crystalline Baloxavir marboxil form-M comprising the steps of:
a) dissolving Baloxavir marboxil in organic solvent,
b) optionally, heating the reaction mass,
c) cooling the reaction mass,
d) optionally, adding solution obtained in step c to precooled second solvent,
e) removing the solvent, and
f) isolating Baloxavir marboxil crystalline form- M.

9. Crystalline Baloxavir marboxil form-M, characterized by data selected from one or more of the following:
a) crystalline Baloxavir marboxil form-M having a powder X-ray diffraction pattern comprising peaks at a diffraction angles (2?) essentially the same as shown in Figure 5, b) crystalline Baloxavir marboxil form-L having an infrared (IR) absorption spectrum with characteristic peaks essentially the same as shown in Figure 6, and c) crystalline Baloxavir marboxil form-L having DSC thermogram substantially as depicted in Figure 7.
10. A process for the preparation of crystalline Baloxavir marboxil form-L or crystalline Baloxavir marboxil form-L according to claim 3, claim 7 or claim 8 wherein, organic solvent is selected from methanol, ethanol, isopropanol, n-propanol, tertiary-butyl alcohol; ketone solvents such as acetone, methyl isobutyl ketone, methyl ethyl ketone; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride; esters such as methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, polar aprotic solvents such as 1,4-dioxane, nitromethane, dimethyl acetamide, dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrolidone, nitriles such as acetonitrile, butyronitrile, isobutyronitrile, second solvent is selected from ether solvents such as tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether,water or a mixture thereof.

11. Amorphous Baloxavir marboxil.

12. Amorphous Baloxavir marboxil having a powder X-ray diffraction pattern essentially same as shown in Figure 4.

13. A process for the preparation of an amorphous Baloxavir marboxil comprising the steps of:
a. dissolving Baloxavir marboxil in organic solvent,
b. adding pre-prepared excipient solution,
c. optionally, heating the reaction mass,
d. removing the organic solvent, and
e. isolating an amorphous Baloxavir marboxil.

14. A process for the preparation of an amorphous Baloxavir marboxil according to claim 13 wherein, organic solvent is selected from selected from alcohol such as methanol, ethanol, isopropanol, n-propanol, tertiary-butyl alcohol; ketone solvents such as acetone, methyl isobutyl ketone, methyl ethyl ketone; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride; esters such as methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; ether solvents such as tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether; nitriles such as acetonitrile, butyronitrile, isobutyronitrile, polar aprotic solvents such as dimethyl acetamide, dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrolidone,water or a mixture thereof; and excipients are selected from polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, sodium starch glycolate, colloidal silicon dioxide, hydroxypropyl methylcellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethylcellulose, polyvinyl acetate, cyclodextrins, gelatins, hypromellose phthalate, corn starch, sugars, poly methyl acrylate polymers such as but not limited to Eudragit S 100, Eudragit S 12.5, Eudragit L 100, Eudragit L 12.5, Eudragit E 100 or its combinations.