DESC:Aspects of the present application relate to solid form of Sotorasib and pharmaceutical compositions thereof. Specific aspects relate to the crystalline forms Sotorasib and processes for their preparation.
Sotorasib is the adopted name of compound developed by Hanmi pharma having a chemical name: 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2enoyl) piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1H)-one and the structure as below.

Sotorasib is an inhibitor of the RAS GTPase family indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC).
US 10519146 B2 discloses Sotorasib, its pharmaceutically acceptable salts, atropisomer and pharmaceutical formulations.
Further, US2020/0369662A1 discloses crystalline forms and amorphous form of Sotorasib or an atropisomer thereof.
The existence and possible numbers of polymorphic forms for a given compound cannot be predicted, and there are no “standard” procedures that can be used to prepare polymorphic forms of a substance. However, new forms of a pharmaceutically useful compound may provide an opportunity to improve the performance characteristics of pharmaceutical products. Further, discovery of additional polymorphic forms, including solvate polymorphs, may help in the identification of the polymorphic content of a batch of an active pharmaceutical ingredient. For example, in some cases, different forms of the same drug can exhibit very different solubility and different dissolution rates. The discovery of new polymorphic forms enlarges selection of materials with which formulation scientists can design a pharmaceutically acceptable dosage form of a drug with a targeted release profile or other desired characteristics. Therefore, there remains a need for preparing new and stable polymorphic forms of Sotorasib which can overcome the disadvantages of the prior art and their preparation in a more cost effective and industrially viable manner.
SUMMARY
In an aspect, the present application provides a crystalline Form SHM-1 of Sotorasib, characterized by a PXRD pattern comprising the peaks at about 8.9 and 14.8 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form SHM-1 of Sotorasib, further characterized by a PXRD pattern comprising the peaks at about 5.0, 12.3 and 13.1 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form SHM-2 of Sotorasib, characterized by a PXRD pattern comprising the peaks at about 5.6, 7.6 and 21.7± 0.2° 2?.
In another aspect, the present application provides a crystalline Form SHM-2 of Sotorasib, further characterized by a PXRD pattern comprising the peaks at about 11.9, 14.2, 16.0, 17.4, 19.0, 23.9 and 28.7 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form SH4 of Sotorasib, characterized by a PXRD pattern comprising the peaks at about 5.3, 20.4 and 21.7 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form SH4 of Sotorasib, further characterized by a PXRD pattern comprising the peaks at about 7.2, 10.7, 13.6, 15.9, 18.1, 19.3 and 19.7 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ST-1 of Sotorasib, characterized by a PXRD pattern comprising the peaks at about 8.7 and 14.0 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ST-1 of Sotorasib, further characterized by a PXRD pattern comprising the peaks at about 7.2, 10.7, 16.1 and 18.9 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ST-2 of Sotorasib, characterized by a PXRD pattern comprising the peaks at about 10.6 and 21.5 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ST-2 of Sotorasib, further characterized by a PXRD pattern comprising the peaks at about 7.1, 9.2, 14.3, 16.7, 21.0 and 25.3 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ST-3 of Sotorasib, characterized by a PXRD pattern comprising the peaks at about 6.6, 7.6 and 16.9 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ST-3 of Sotorasib, further characterized by a PXRD pattern comprising the peaks at about 4.9, 12.8, 15.8, 17.4 and 21.1 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ST-4 of Sotorasib, characterized by a PXRD pattern comprising the peaks at about 5.0 and 17.0 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ST-4 of Sotorasib, further characterized by a PXRD pattern comprising the peaks at about 10.1, 17.6, 18.9 and 20.4 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline SH4 of Sotorasib, comprising
a) providing a solution or suspending Sotorasib in water; and
b) isolating the crystalline Form SH4 of Sotorasib.
In another aspect, the present application provides a process for the preparation of crystalline Form ST-1 of Sotorasib, comprising
a) providing a solution or suspending Sotorasib in Dimethyl sulfoxide; and
b) isolating the crystalline Form ST-1 of Sotorasib.
In another aspect, the present application provides a process for the preparation of crystalline Form ST-2 of Sotorasib, comprising
a) providing a solution or suspending Sotorasib in Methyl isopropyl ketone; and
b) isolating the crystalline Form ST-2 of Sotorasib.
In another aspect, the present application provides a process for the preparation of crystalline Form ST-3 of Sotorasib, comprising
a) providing a solution or suspending Sotorasib in Propylene glycol or R-Propylene glycol; and
b) isolating the crystalline Form ST-3 of Sotorasib.
In another aspect, the present application provides a process for the preparation of crystalline Form ST-4 of Sotorasib, comprising
a) providing a solution or suspending Sotorasib in tert-Butyl alcohol; and
b) isolating the crystalline Form ST-4 of Sotorasib.
In another aspect, the present application provides pharmaceutical compositions comprising a one or more crystalline forms selected crystalline Form SHM-1, Form SHM-2, Form SH4, Form ST-1, Form ST-2, Form ST-3 and Form ST-4 of Sotorasib and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline Form SH4 of Sotorasib, prepared by the method of Example-1.
Figure 2 is an illustrative X-ray powder diffraction pattern of crystalline Form SHM-1 of Sotorasib, prepared by the method of Example-2.
Figure 3 is an illustrative X-ray powder diffraction pattern of crystalline Form SHM-2 of Sotorasib, prepared by the method of Example-3.
Figure 4 is an illustrative X-ray powder diffraction pattern of crystalline Form ST-1 of Sotorasib, prepared by the method of Example-4.
Figure 5 is an illustrative X-ray powder diffraction pattern of crystalline Form ST-2 of Sotorasib, prepared by the method of Example-5.
Figure 6 is an illustrative X-ray powder diffraction pattern of crystalline Form ST-3 of Sotorasib, prepared by the method of Example-6.
Figure 7 is an illustrative X-ray powder diffraction pattern of crystalline Form ST-4 of Sotorasib, prepared by the method of Example-8.

DETAILED DESCRIPTION
In an aspect, the present application provides a crystalline Form SHM-1 of Sotorasib, characterized by a PXRD pattern comprising the peaks at about 8.9 and 14.8 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form SHM-1 of Sotorasib, further characterized by a PXRD pattern comprising the peaks at about 5.0, 12.3 and 13.1 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form SHM-2 of Sotorasib, characterized by a PXRD pattern comprising the peaks at about 5.6, 7.6 and 21.7± 0.2° 2?.
In another aspect, the present application provides a crystalline Form SHM-2 of Sotorasib, further characterized by a PXRD pattern comprising the peaks at about 11.9, 14.2, 16.0, 17.4, 19.0, 23.9 and 28.7 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form SH4 of Sotorasib, characterized by a PXRD pattern comprising the peaks at about 5.3, 20.4 and 21.7 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form SH4 of Sotorasib, further characterized by a PXRD pattern comprising the peaks at about 7.2, 10.7, 13.6, 15.9, 18.1, 19.3 and 19.7 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ST-1 of Sotorasib, characterized by a PXRD pattern comprising the peaks at about 8.7 and 14.0 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ST-1 of Sotorasib, further characterized by a PXRD pattern comprising the peaks at about 7.2, 10.7, 16.1 and 18.9 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ST-2 of Sotorasib, characterized by a PXRD pattern comprising the peaks at about 10.6 and 21.5 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ST-2 of Sotorasib, further characterized by a PXRD pattern comprising the peaks at about 7.1, 9.2, 14.3, 16.7, 21.0 and 25.3 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ST-3 of Sotorasib, characterized by a PXRD pattern comprising the peaks at about 6.6, 7.6 and 16.9 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ST-3 of Sotorasib, further characterized by a PXRD pattern comprising the peaks at about 4.9, 12.8, 15.8, 17.4 and 21.1 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ST-4 of Sotorasib, characterized by a PXRD pattern comprising the peaks at about 5.0 and 17.0 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ST-4 of Sotorasib, further characterized by a PXRD pattern comprising the peaks at about 10.1, 17.6, 18.9 and 20.4 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline SH4 of Sotorasib, comprising
a) providing a solution or suspending Sotorasib in water; and
b) isolating the crystalline Form SH4 of Sotorasib.
In another aspect, the present application provides a process for the preparation of crystalline Form ST-1 of Sotorasib, comprising
a) providing a solution or suspending Sotorasib in Dimethyl sulfoxide; and
b) isolating the crystalline Form ST-1 of Sotorasib.
In another aspect, the present application provides a process for the preparation of crystalline Form ST-2 of Sotorasib, comprising
a) providing a solution or suspending Sotorasib in Methyl isopropyl ketone; and
b) isolating the crystalline Form ST-2 of Sotorasib.
In another aspect, the present application provides a process for the preparation of crystalline Form ST-3 of Sotorasib, comprising
a) providing a solution or suspending Sotorasib in Propylene glycol or R-Propylene glycol; and
b) isolating the crystalline Form ST-3 of Sotorasib.
In another aspect, the present application provides a process for the preparation of crystalline Form ST-4 of Sotorasib, comprising
a) providing a solution or suspending Sotorasib in tert-Butyl alcohol; and
b) isolating the crystalline Form ST-4 of Sotorasib.
Providing a solution or suspension of Sotorasib includes:
i) direct use of a reaction mixture containing Sotorasib that is obtained in the course of its synthesis; or
ii) dissolving or suspending Sotorasib in a solvent
Any physical form of Sotorasib including solvates, hydrates, anhydrous or amorphous may be utilized for providing solution or suspension of Sotorasib. In embodiments, Sotorasib can be dissolved or suspended in a solvent or mixture of one or more solvents. The dissolution or suspension temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 100°C, less than about 70°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures without affecting its quality.
Isolation of crystalline forms of Sotorasib may involve methods including cooling, concentrating the mass, adding an anti-solvent, adding seed crystals to induce crystallization, or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.
The crystalline forms of Sotorasib may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, agitated nutsche filter & dryer or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, agitated nutsche filter & dryer or the like.
The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the Sotorasib is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved.
The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer milling, and jet milling.
One or more crystalline forms of the present application may be anhydrous or solvates or hydrates or mixtures thereof.
In another aspect, the present application provides crystalline forms of Sotorasib according to instant application and pharmaceutical compositions thereof, wherein the chemical purity of Sotorasib may be more than 99% by HPLC or more than 99.5% by HPLC or more than 99.9% by HPLC.
In another aspect, the present application provides pharmaceutical compositions comprising a one or more crystalline forms selected crystalline Form SHM-1, Form SHM-2, Form SH4, Form ST-1, Form ST-2, Form ST-3 and Form ST-4 of Sotorasib and at least one pharmaceutically acceptable excipient.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
Definitions
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example, "about 10" should be construed as meaning within the range of 9 to 11 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.

EXAMPLES
Example-1: Preparation of crystalline form SH4 of Sotorasib
Sotorasib (50 mg) was suspended in water (2 mL), the resulting slurry was stirred at 30° C for 4 hours. Solid was filtered and dried to afford the title compound.
XRPD: Crystalline form SH4, as depicted in Figure-1.

Example-2: Preparation of crystalline form SHM-1 of Sotorasib
Sotorasib hydrate (100 mg) was dried in vacuum tray drier (VTD) at 80° C for 31 hours to afford the title compound.
XRPD: Crystalline form SHM-1, as depicted in Figure-2.

Example-3: Preparation of crystalline form SHM-2 of Sotorasib
Desolvated the Sotorasib Form SH4 (7.5mg) using TGA (Temperature: 40-80 °C; Ramp of 10° C/minute; Isothermal for 5minutes at 80° C)
XRPD: Crystalline form SHM-2, as depicted in Figure-3.

Example-4: Preparation of crystalline form ST-1 of Sotorasib
Sotorasib (50 mg) was suspended in dimethylsulfoxide (0.1 mL), the resulting slurry was stirred at ambient temperature for 30 minutes. Solid was filtered and dried to afford the title compound.
XRPD: Crystalline form ST-1, as depicted in Figure-4.

Example-5: Preparation of crystalline form ST-2 of Sotorasib
Sotorasib (200 mg) was suspended in methyl isopropyl ketone (1.5 mL), the resulting solution was stirred at ambient temperature for 45 minutes. Separated solid was filtered and dried to afford the title compound.
XRPD: Crystalline form ST-2, as depicted in Figure-5.

Example-6: Preparation of crystalline form ST-3 of Sotorasib
Sotorasib (50 g) was suspended in propylene glycol (0.1 mL), the resulting slurry was stirred at ambient temperature for 1 hour. Solid was filtered and dried to afford the title compound.
XRPD: Crystalline form ST-3, as depicted in Figure-6.

Example-7: Preparation of crystalline form ST-3 of Sotorasib
Sotorasib (50 g) was suspended in R-propylene glycol (0.1 mL), the resulting slurry was stirred at ambient temperature for 1 hour. Solid was filtered and dried to afford the title compound.
XRPD: Crystalline form ST-3, as depicted in Figure-6.

Example-8: Preparation of crystalline form ST-4 of Sotorasib
Sotorasib (300 mg) was suspended in tert-butyl alcohol (0.2 mL), the resulting slurry was stirred at ambient temperature for 5 days. Solid was filtered and dried to afford the title compound.
XRPD: Crystalline form ST-4, as depicted in Figure-7.

,CLAIMS:CLAIMS

1. A crystalline Form SHM-1 of Sotorasib, characterized by a PXRD pattern comprising the peaks at about 8.9 and 14.8 ± 0.2° 2?.

2. A crystalline form SHM-1 according to claim 1, further characterized by a PXRD pattern comprising the peaks at about 5.0, 12.3 and 13.1 ± 0.2° 2?.

3. A crystalline Form ST-2 of Sotorasib, characterized by a PXRD pattern comprising the peaks at about 10.6 and 21.5 ± 0.2° 2?.

4. A crystalline Form ST-2 according to claim 3, further characterized by a PXRD pattern comprising the peaks at about 7.1, 9.2, 14.3, 16.7, 21.0 and 25.3 ± 0.2° 2?.

5. A process for the preparation of crystalline Form ST-2 of Sotorasib according to claim 3, comprising
a) providing a solution or suspending Sotorasib in Methyl isopropyl ketone; and
b) isolating the crystalline Form ST-2 of Sotorasib.