DESC:The following specification describes particularly the invention and in the manner in which it is to be performed:

INTRODUCTION
Aspects of the present application relate to solid state forms of Sotorasib and pharmaceutical compositions thereof. Specific aspects relate to the crystalline forms of 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, US 11,236,091 and WO 2021/236920 A1 discloses amorphous form and various crystalline forms of Sotorasib and processes for their preparation.
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 ST-5 of Sotorasib, characterized by a PXRD pattern comprising the peaks at about 13.4 and 16.4 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ST-5 of Sotorasib, further characterized by a PXRD pattern comprising the peaks at about 8.9, 12.2, 13.8 and 20.2 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ST-6 of Sotorasib, characterized by a PXRD pattern comprising the peaks at about 7.0, 14.0, and 21.3 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ST-6 of Sotorasib, further characterized by a PXRD pattern comprising the peaks at about 15.9, 19.2 and 24.8 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form ST-5 of Sotorasib, comprising
a) providing a solution or suspension of Sotorasib in a solvent selected from methyl isopropyl ketone, methyl tert-butyl ether, 1-Butanol, n-Heptane or mixture thereof
b) optionally adding second solvent to the solution or suspension obtained in step (a) or adding solution or suspension obtained in step (a) to second solvent; and
c) isolating the crystalline Form ST-5 of Sotorasib.
In another aspect, the present application provides a process for the preparation of crystalline Form ST-6 of Sotorasib, comprising
a) providing a solution or suspension of Sotorasib in tert-Butyl alcohol,
b) optionally adding second solvent to the solution or suspension obtained in step (a); and
c) isolating the crystalline Form ST-6 of Sotorasib.
In another aspect, the present application provides pharmaceutical compositions comprising crystalline Form ST-5 or Form ST-6 of Sotorasib and at least one pharmaceutically acceptable excipient or carrier.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline Form ST-5 of Sotorasib.
Figure 2 is an illustrative 13C solid state NMR pattern of crystalline Form ST-5 of Sotorasib.
Figure 3 is differential scanning calorimetry (DSC) thermogram of Form ST-5 of Sotorasib.
Figure 4 is thermogravimetric analysis (TGA) thermogram of Form ST-5 of Sotorasib.
Figure 5 is an illustrative X-ray powder diffraction pattern of crystalline Form ST-6 of Sotorasib, prepared by the method of Example-5.

DETAILED DESCRIPTION
In an aspect, the present application provides a crystalline Form ST-5 of Sotorasib, characterized by a PXRD pattern comprising the peaks at about 13.4 and 16.4 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ST-5 of Sotorasib, further characterized by a PXRD pattern comprising the peaks at about 8.9, 12.2, 13.8 and 20.2 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ST-6 of Sotorasib, characterized by a PXRD pattern comprising the peaks at about 7.0, 14.0, and 21.3 ± 0.2° 2?.
In another aspect, the present application provides a crystalline Form ST-6 of Sotorasib, further characterized by a PXRD pattern comprising the peaks at about 15.9, 19.2 and 24.8 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form ST-5 of Sotorasib, comprising
a) providing a solution or suspension of Sotorasib in a solvent selected from methyl isopropyl ketone, methyl tert-butyl ether, 1-Butanol, n-Heptane or mixture thereof
b) optionally adding second solvent to the solution or suspension obtained in step (a) or adding solution or suspension obtained in step (a) to second solvent; and
c) isolating the crystalline Form ST-5 of Sotorasib.
In another aspect, the present application provides a process for the preparation of crystalline Form ST-6 of Sotorasib, comprising
a) providing a solution or suspension of Sotorasib in tert-Butyl alcohol,
b) optionally adding second solvent to the solution or suspension obtained in step (a); and
c) isolating the crystalline Form ST-6 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.
Suitable second solvent that may be used for preparation of crystalline form ST-5 and ST-6 include but not limited to aliphatic hydrocarbon solvents like n-Heptane, n-Hexane and the like or ether solvents like methyl tert-butyl ether and the like or mixture thereof.
Optionally seed crystals of form ST-5 or ST-6 may be added to the solution obtained in step (a).
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.
Stability of the crystalline form ST-5 is analyzed in different temperature at different humidity conditions and the results indicates that the crystal form remained stable after 3 months in all the conditions. Stability studies details are provided in the below table.

Storage condition Water content (%) % of Related Substances By HPLC XRD
2-8°C (Initial) 0.45 0.46 Form ST-5
2-8°C (1st month) 0.58 0.47 Form ST-5
2-8°C (3rd month) 0.50 0.47 Form ST-5
25°C ±2°C; 60% ± 5%RH
(Initial) 0.45 0.46 Form ST-5
25°C ±2°C; 60% ± 5%RH
(1st month) 0.47 0.47 Form ST-5
25°C ±2°C; 60% ± 5%RH
(3rd month) 0.45 0.50 Form ST-5
40°C ±2°C; 75% ± 5%RH (Initial) 0.45 0.46 Form ST-5
40°C ±2°C; 75% ± 5%RH (1st month) 0.42 0.47 Form ST-5
40°C ±2°C; 75% ± 5%RH
(3rd month) 0.44 0.45 Form ST-5

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 crystalline Form ST-5 or Form ST-6 of Sotorasib and at least one pharmaceutically acceptable excipient or carriers.
Sotorasib together with one or more pharmaceutically acceptable carriers of the present application may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions.
Formulations may be in the forms of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.
Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic, cationic, or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses (HPMC), HPMC-AS, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, and the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
The pharmaceutical dosage form according to the present invention may be coated with one or more coating materials or uncoated. The coating materials are not particularly limited and are known to the person skilled in the art.
The pharmaceutical dosage form according to the present invention can further comprise additional excipients and adjuvants, which are pharmaceutically acceptable and general coating materials, which are preferably applied as a coating to the pharmaceutical dosage form of the present invention. Such further excipients and adjuvants are known to the person skilled in the art.
The pharmaceutical compositions of the present invention are generally administered orally to patients, which include, but are not limited to, mammals, for example, humans, in the form of, for example, a hard or soft gelatin capsule, a tablet, a caplet, pills, granules or a suspension. The pharmaceutical dosage form can be prepared by methods known in the art, such as direct compression or wet granulation or direct compression. The compression of the blend to tablet cores can be carried out using a conventional tableting machine or a rotary compression machine. The tablet cores may vary in shape and can be, for example, round, oval, oblong, cylindrical or any other suitable shape. The cores may also vary in size depending on the concentration of the therapeutic agent.
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 ST-5 of Sotorasib
Sotorasib (1.0 g) was suspended in methyl isopropyl ketone (2 mL), the resulting slurry was stirred at ambient temperature for 30 minutes. n-Heptane (10 mL) was added to the suspension and stirred for 45 minutes at ambient temperature. Solid was filtered and dried to afford the title compound.
XRPD: Crystalline form ST-5, as depicted in Figure-1.
Example-2: Preparation of crystalline form ST-5 of Sotorasib
Sotorasib (5.5 g) and methyl tertiary-butyl ether (55 mL) charged into flask and the resulting slurry was stirred at 30 °C for 2 hours 30 minutes. Solid was filtered, washed with methyl tertiary-butyl ether (20 mL) and dried at 45 °C to afford the title compound.
XRPD: Crystalline form ST-5, as depicted in Figure-1.
Example-3: Preparation of crystalline form ST-5 of Sotorasib
Sotorasib (5.5 g), methyl tertiary-butyl ether (50 mL) and n-heptane (75 mL) charged into flask and the resulting slurry was stirred at 30 °C for 24 hours. Solid was filtered, washed with n-heptane (20 mL) and dried at 60 °C to afford the title compound.
XRPD: Crystalline form ST-5, as depicted in Figure-1.
Purity by HPLC: 99.31%; GC (Residual solvent): methyl tertiary-butyl ether: 4065ppm; n-Heptane: 628ppm.

Example-4: Preparation of crystalline form ST-5 of Sotorasib
Sotorasib (35 g) and 1-Butanol (210 mL) charged into flask, heated to 70 °C and stirred for 15 minutes. The resultant solution was slowly added to the reaction mixture containing methyl tertiary-butyl ether (210 mL), n-heptane (315 mL) and sotorasib form ST-5 seed (100 mg) at 30 °C and stirred at 30 °C for 1 hour. Solid was filtered, washed with mixture of methyl tertiary-butyl ether (MTBE) & n-heptane (250 mL 2:3 ratio) and dried at 65 °C to afford the title compound.
XRPD: Crystalline form ST-5, as depicted in Figure-1.
Purity by HPLC: 99.53%;
Example-5: Preparation of crystalline form ST-6 of Sotorasib
Sotorasib (1.0 g) was suspended in methyl tert-Butyl alcohol (3 mL), the resulting slurry was stirred at ambient temperature for 30 minutes. n-Heptane (10 mL) was added to the suspension and stirred for 30 minutes at ambient temperature. Solid was filtered and dried to afford the title compound.
XRPD: Crystalline form ST-6, as depicted in Figure-2.

Dated: 11th of January 2023.
Signature: _________________
Dr. B. Dinesh Kumar.
Intellectual Property Management,
Dr. Reddy’s Laboratories Limited.
,CLAIMS:CLAIMS

1. A crystalline form ST-5 of Sotorasib, characterized by a powder X-ray diffraction pattern comprising the peaks at about 13.4 and 16.4 ± 0.2° 2?.

2. The crystalline form ST-5 of claim 1, further characterized by a powder X-ray diffraction pattern comprising the peaks at about 8.9, 12.2, 13.8 and 20.2 ± 0.2° 2?.

3. The crystalline form ST-5 of claim 1, having powder X-ray diffraction pattern substantially as depicted in FIG. 1.

4. A process for the preparation of crystalline Form ST-5 of Sotorasib, comprising:
a) providing a solution or suspension of Sotorasib in a solvent selected from methyl isopropyl ketone, methyl tert-butyl ether, 1-Butanol, n-Heptane or mixture thereof
b) optionally adding second solvent to the solution or suspension obtained in step (a) or adding solution or suspension obtained in step (a) to second solvent; and
c) isolating the crystalline Form ST-5 of Sotorasib.

5. The process according to claim 4, wherein the solvent used in step (a) selected from methyl isopropyl ketone, methyl tert-butyl ether, or n-Heptane.

6. The process according to claim 4, wherein the solvent used in step (a) is methyl tert-butyl ether, or mixture of methyl tert-butyl ether and n-Heptane.

7. The process according to claim 4, wherein the solvent used in step (a) is 1-Butanol.

8. The process according to claim 4, wherein the second solvent in step (b) is methyl tert-butyl ether, or mixture of methyl tert-butyl ether and n-Heptane.

9. The process according to claim 4, further comprising addition of seed crystals of form ST-5 in step (b).

10. A pharmaceutical composition comprising sotorasib crystalline form ST-5 of claim 1 and a pharmaceutically acceptable excipient or carrier.