DESC:FIELD OF THE INVENTION

The present invention generally relates to novel crystalline polymorphic forms of venetoclax and its processes for preparation thereof. The present invention also relates to processes for preparation of amorphous form of venetoclax and pharmaceutical composition containing the same.

BACKGROUND OF THE INVENTION

Venetoclax, also known as 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4yl-methyl)-amino]-phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide)of Formula I:

Formula I

Venetoclax is marketed by Abbvie under the trade name Venclexta®in US and Venclyxto®in EP for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA approved test, who have received at least one prior therapy.

U.S. Patent No. 8,546,399 (“the ‘399 patent”) discloses venetoclax and process for preparation thereof. The ‘399 patent process involves purification of venetoclax as a solid by column chromatography using a mixture of 25-100% ethyl acetate/hexanes and then with a mixture of 10% methanol/ethyl acetate with 1% acetic acid to obtain venetoclax as a white solid. However, the ‘399 patent does not disclose any polymorphic information on resulted venetoclax. Repetition of the ‘399 patent process by the present inventors and found that venetoclax obtained as an amorphous form.

U.S. Patent No.8,722,657(“the ‘657 patent”) discloses crystalline forms including solvates of venetoclax such as anhydrate Pattern A, anhydrate Pattern B, hydrate pattern C, hydrate pattern D, methylene chloride solvate (pattern E), ethyl acetate solvate (pattern F), acetonitrile solvate (pattern G & I), acetone solvate (pattern J), tetrahydrofuran solvate (pattern N), and venetoclax salts such as crystalline venetoclax HCl salt (pattern K), HCl hydrate (pattern L), sulfate salt (pattern M) and its characterization data by PXRD.

PCT publication No. 2017/063572(“the ‘572 publication”) discloses crystalline forms of venetoclax such as Form B, Form D, Form F, Form G and its process for preparation.

PCT publication No. 2017/156398(“the ‘398 publication”) discloses crystalline forms and solvates of venetoclax such as Form 1 (MIBK mono solvate), Form 2 (anhydrous), Form 2A (cyclohexane solvate), Form 3 (toluene mono solvate), Form 4, Form 5 (anhydrous), Form 6 (MIBK hemisolvate), Form 7 (n-propyl acetate mono solvate), Form 8 (anhydrous), Form 9 (dimethyl carbamate solvate), Form 10 (dioxane solvate), Form 11 (isobutyl acetate solvate), Form 12, Form 13 (dimethyl carbonate solvate), Form 14, Form 15 (methyl ethyl ketone solvate) and its process for preparation.

PCT publication No. 2017/212431(“the ‘431 publication”) discloses crystalline forms of venetoclax such as Form RT1, Form RT2, Form RT3, Form RT4 and Form RT5. The ‘431 publication also discloses a process for preparation of amorphous form of venetoclax from dichloromethane and from a mixture of dichloromethane/methanol, and dimethylsulfoxide/ water.

PCT publication No. 2017/029711(“the ‘711 publication”) discloses a process for preparation of amorphous form of venetoclax from acetonitrile.

PCT publication No. 2018/049634 (“the ‘634 publication”) discloses a crystalline form of venetoclax hydrochloride salt and its hydrate form.
PCT publication No. 2018/069941 (“the ‘941 publication”) discloses crystalline forms and solvates of venetoclax such as Form M1 (isobutyl acetate solvate), Form M2, Form M3 (acetonitrile solvate), Form M4 (toluene solvate), Form M5 (3-pentanone solvate), Form M6 (dimethylformamide solvate), Form M7 (methyl ethyl ketone solvate), Form M8 (acetonitrile solvate), Form M9 (anhydrous), Form M10 (anhydrous), Form M11 (n-butyl acetate solvate), Form M12 (n-propyl acetate solvate), Form M13 (1-pentanol solvate), Form M14 (2-butanol solvate), Form M15 (2-pentanone solvate), Form M16 (chlorobenzene solvate), Form M17 (propionitrile solvate), Form M18 (butyronitrile solvate), Form M19 (isobutyronitrile solvate), Form M20, Form M21 (anhydrous) and Form M22 and its process for preparation.

PCT publication No. 2018157803 (“the ‘803 publication”) discloses crystalline forms of venetoclax and its preparation process such as Form CS1 (from tetrahydrofuran and isopropyl acetate), Form CS2 (from tetrahydrofuran and 1,4-dioxane), Form CS3 (from tetrahydrofuran), Form CS4, Form CS5 and Form CS6 (from methyl isobutyl ketone).

PCT publication No. 2019/135253 (“the ‘253 publication”) discloses crystalline forms of venetoclax and its preparation process such as Form M23 (unsolvated form) and Form M24 (n-butyl acetate solvate). The ‘253 publication further covers process for preparation of amorphous venetoclax by desaltification of venetoclax hydrochloride salt with aqueous base.

PCT publication No. 2019/150253 (“the ‘0253 publication”) discloses process for preparation of amorphous form of Venetoclax by formation of venetoclax formate salt and followed by basification with a suitable base.

PCT publication No. 2019/171222 (“the ‘1222 publication”) discloses crystalline forms of venetoclax and its preparation process such as Form a, Form ß, Form ?, Form d, Form e & Form ?.

Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms and solvates, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms and solvates of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms and solvates of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products.

The discovery of new crystalline polymorphic forms and solvates of a pharmaceutically useful compound, like venetoclax, may provide a new opportunity to improve the performance characteristics of a pharmaceutical product. It also adds to the material that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.

Venetoclax is one of the important drug available in the market for the treatment of chronic lymphocytic leukemia (CLL) in those with a specific chromosomal abnormality. Hence, it’s important to discover new polymorphic forms of venetoclax, which may provide a new opportunity to improve the performance characteristics of a pharmaceutical product. Hence the main object of the present invention is to provide novel polymorphic forms of venetoclax.

Further, the present invention relates to methods of producing amorphous form of venetoclax, which is commercially feasible in large scale production with greater yield, higher purity and good stability.

SUMMARY OF THE INVENTION

The present invention encompasses novel crystalline polymorphic forms of venetoclax, process for their preparation and pharmaceutical composition comprising one or more of the novel polymorphic forms of venetoclax. The present invention also encompasses processes for the preparation of amorphous form of venetoclax with high product yield and quality, and greater stability.

In accordance with one embodiment, the present invention provides novel crystalline polymorphic form of venetoclax; which are designated herein as venetoclax Form-L1, venetoclax Form-L2, venetoclax Form-L3, venetoclax Form-L4, venetoclax Form-L5, venetoclax Form-L6, venetoclax Form-L7, venetoclax Form-L8 and venetoclax Form-L9.

In accordance with another embodiment, venetoclax Form-L1of the present invention is an anisole solvate.

In accordance with another embodiment, the present invention provides venetoclax Form-L1 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 1.

In accordance with another embodiment, the present invention provides venetoclax Form-L1 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 3.7, 5.1, 5.7, 5.9, 6.8, 7.1, 7.5, 8.3, 8.6, 9.9, 10.4, 11.5, 12.8, 13.4, 13.7, 14.2, 14.4, 14.7, 15.3, 15.7, 17.1, 17.7, 18, 18.6, 19.1, 19.9, 21, 22, 22.3, 22.7, 23.2, 24.1, 24.6, 25.1, 25.5, 26.2, 27, 27.7, 30.4, 31.3 and 32.1 ±0.2° 2?.

In accordance with another embodiment, the present invention provides venetoclax Form-L1 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 2.

In accordance with another embodiment, the present invention provides venetoclax Form-L1 characterized by X-Ray powder diffraction (XRD) peaks at about 3.7, 5.1, 5.7, 5.9, 6.8, 7.1, 7.5, 8.3, 8.6, 9.9, 10.4, 11.5, 12.8, 13.4, 13.7, 14.2, 14.4, 14.7, 15.3, 15.7, 17.1, 17.7, 18, 18.6, 19.1, 19.9, 21, 22, 22.3, 22.7, 23.2, 24.1, 24.6, 25.1, 25.5, 26.2, 27, 27.7, 30.4, 31.3 and 32.1 ±0.2° 2? and X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 1 and a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 2.

In accordance with another embodiment, venetoclax Form-L2 of the present invention is an anisole solvate.

In accordance with another embodiment, the present invention provides venetoclax Form-L2 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 3.

In accordance with another embodiment, the present invention provides venetoclax Form-L2 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 5.4,7.5, 8.4, 8.9, 9.7, 10.7, 11.2, 11.9, 13, 14.7, 16.6, 17.7, 19.4, 19.9, 20.4, 21, 22.5, 24.5, 25.6 and 29.4 ±0.2° 2?.

In accordance with another embodiment, the present invention provides venetoclax Form-L2 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 4.

In accordance with another embodiment, the present invention provides venetoclax Form-L2 characterized by X-Ray powder diffraction (XRD) peaks at about 5.4,7.5, 8.4, 8.9, 9.7, 10.7, 11.2, 11.9, 13, 14.7, 16.6, 17.7, 19.4, 19.9, 20.4, 21, 22.5, 24.5, 25.6 and 29.4 ±0.2° 2?, X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 3 and a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 4.

In accordance with another embodiment, venetoclax Form-L3 of the present invention is an anisole solvate.

In accordance with another embodiment, the present invention provides venetoclax Form-L3 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 5.

In accordance with another embodiment, the present invention provides venetoclax Form-L3 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 3.7, 5.1, 5.3, 5.7, 6.3, 7.4, 7.9, 8.3, 8.5, 9.2, 9.5, 9.8, 11.5, 12.8, 13.4, 13.7, 13.9, 14.4, 14.7, 15.3, 15.6, 16, 16.4, 17.2, 17.9, 18.2, 18.4, 19.5, 20.2, 21.2, 21.5, 22.3, 22.6, 23.3, 23.7, 24.8, 25.5, 26.1 and 29.8 ±0.2° 2?.

In accordance with another embodiment, the present invention provides venetoclax Form-L3 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 6.

In accordance with another embodiment, the present invention provides venetoclax Form-L3 characterized by X-Ray powder diffraction (XRD) peaks at about 3.7, 5.1, 5.3, 5.7, 6.3, 7.4, 7.9, 8.3, 8.5, 9.2, 9.5, 9.8, 11.5, 12.8, 13.4, 13.7, 13.9, 14.4, 14.7, 15.3, 15.6, 16, 16.4, 17.2, 17.9, 18.2, 18.4, 19.5, 20.2, 21.2, 21.5, 22.3, 22.6, 23.3, 23.7, 24.8, 25.5, 26.1 and 29.8 ±0.2° 2?, X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 5 and a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 6.

In accordance with another embodiment, the present invention provides a process for the preparation of crystalline form of venetoclax Form L1, Form L2 or Form L3, comprising:
a) providing a solution of venetoclax in anisole at room temperature to reflux temperature,
b) cooling the solution to below 45°C,
c) optionally adding a suitable solvent to step b) reaction mass, and
d) isolating venetoclax Form L1, Form L2 or Form L3.

In accordance with another embodiment, the present invention provides a process for the preparation of crystalline form of venetoclax Form L1, Form L2 and Form L3, comprising:
a) providing a solution of venetoclax in anisole at room temperature to reflux temperature,
b) cooling the solution to below 45°C,
c) optionally adding a suitable solvent to step b) reaction mass, and
d) isolating venetoclax;
wherein the venetoclax Form L1 is obtained by cooling step b) solution to below 30°C and adding a suitable solvent to step b) reaction mass;
wherein the venetoclax Form L2 is obtained by cooling step b) solution to between 35°C to 45°C and adding a suitable solvent to step b) reaction mass;
wherein the Form L3 is obtained by cooling the step b) solution below 30°C.

In accordance with another embodiment, venetoclax Form-L4 of the present invention is anhydrous crystalline form.

In accordance with another embodiment, the present invention provides a process for the preparation of venetoclax Form-L4, comprising: heating venetoclax Form-L1 or venetoclax Form-L3 at about 75°C to about 110°C, wherein the venetoclax Form-L1 is characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 1; and venetoclax Form-L3 is characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 5.

In accordance with another embodiment, the present invention provides venetoclax Form-L4 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 7.

In accordance with another embodiment, the present invention provides venetoclax Form-L4 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 5.1, 5.5, 6.2, 6.4, 6.8, 8.5, 9.6, 9.8, 10.8, 11.7, 13.5, 14.2, 15.2, 15.9, 16.4, 16.9, 17.9, 18.4, 18.9, 21.3, 22.7, 24.9 and 26.4 ±0.2° 2?.

In accordance with another embodiment, the present invention provides venetoclax Form-L4 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 8.

In accordance with another embodiment, the present invention provides venetoclax Form-L4 characterized by X-Ray powder diffraction (XRD) peaks at about 5.1, 5.5, 6.2, 6.4, 6.8, 8.5, 9.6, 9.8, 10.8, 11.7, 13.5, 14.2, 15.2, 15.9, 16.4, 16.9, 17.9, 18.4, 18.9, 21.3, 22.7, 24.9 and 26.4 ±0.2° 2?, X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 7 and a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 8.

In accordance with another embodiment, the present invention provides a process for the preparation of venetoclax Form-L4, comprising: heating venetoclax Form-L1 or venetoclax Form-L3 at about 75°C to about 110°C, wherein the venetoclax Form-L1 is characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 1; and venetoclax Form-L3is characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 5.

In accordance with another embodiment, venetoclax Form-L5 of the present invention is anhydrous crystalline form.

In accordance with another embodiment, the present invention provides venetoclax Form-L5 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 9.

In accordance with another embodiment, the present invention provides venetoclax Form-L5 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about
5,7.9,8.1,8.8,9.3,10.5,10.8,11.1,12.2,13.1,13.4,13.9,14.5,15.1,15.6,15.9,16.3,16.5,17,17.2,17.7,18.6,19,19.5,19.8,20.2,20.6,21,21.7,21.8,22.3,23.2,23.8,24.4,25.3,25.8,26.5,27,27.6,28.1,29,29.8,30.2,31.4,32.8,33.9,35.8 and 37.5 ±0.2° 2?.

In accordance with another embodiment, the present invention provides venetoclax Form-L5 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 10.

In accordance with another embodiment, the present invention provides venetoclax Form-L5 characterized by X-Ray powder diffraction (XRD) peaks at about 5,7.9,8.1,8.8,9.3,10.5,10.8,11.1,12.2,13.1,13.4,13.9,14.5,15.1,15.6,15.9,16.3,16.5,17,17.2,17.7,18.6,19,19.5,19.8,20.2,20.6,21,21.7,21.8,22.3,23.2,23.8,24.4,25.3,25.8,26.5,27,27.6,28.1,29,29.8,30.2,31.4,32.8,33.9,35.8 and 37.5 ±0.2° 2?, X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 9 and a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 10.

In accordance with another embodiment, the present invention provides a process for the preparation of venetoclax Form-L5, comprising:
a) suspending venetoclax Form-L1 or venetoclax Form-L3 in n-heptane at a temperature of 30°C to reflux,
b) cooling the step a) suspension to below 30°C; and
c) isolating venetoclax Form-L5.

In accordance with another embodiment, venetoclax Form-L6 of the present invention is an anhydrous crystalline form.

In accordance with another embodiment, the present invention provides venetoclax Form-L6 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 11.

In accordance with another embodiment, the present invention provides venetoclax Form-L6 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 5.4, 8.6, 8.9, 9.7, 10.7, 11.2, 11.9, 13, 14.7, 14.9, 15.6, 16.6, 17.7, 19.4, 19.9, 20.4, 21, 24.5, 25.3, 25.7, 27, 29.4, 33.9 and 36.3 ±0.2° 2?.

In accordance with another embodiment, the present invention provides venetoclax Form-L6 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 12.

In accordance with another embodiment, the present invention provides venetoclax Form-L6 characterized by X-Ray powder diffraction (XRD) peaks at about 5.4, 8.6, 8.9, 9.7, 10.7, 11.2, 11.9, 13, 14.7, 14.9, 15.6, 16.6, 17.7, 19.4, 19.9, 20.4, 21, 24.5, 25.3, 25.7, 27, 29.4, 33.9 and 36.3 ±0.2° 2?, X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 11 and a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 12.

In accordance with another embodiment, the present invention provides a process for the preparation of venetoclax Form-L6, comprising: heating venetoclax Form-L2 at about 80°C to about 100°C, wherein the venetoclax Form-L2 is characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 3.

In accordance with another embodiment, the present invention provides a process for the preparation of venetoclax Form-L6, comprising:
a) suspending venetoclax Form-L2 in n-heptane at a temperature of 30°C to reflux,
b) cooling the step a) suspension to below 30°C; and
c) isolating venetoclax Form-L6.

In accordance with another embodiment, venetoclax Form-L7 of the present invention is dimethyl acetamide solvate.

In accordance with another embodiment, the present invention provides venetoclax Form-L7 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 13.

In accordance with another embodiment, the present invention provides venetoclax Form-L7 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 5, 5.8, 7.4, 8, 10.2, 11.2, 11.9, 12.4, 13.5, 14.1, 14.6, 15, 15.3, 16.1, 17.1, 17.5, 18, 19.2, 20, 20.6, 21.5, 22.1, 23.6, 24.7, 25, 25.7, 27.7, 28.9, 29.6, 31.3 and 35.6 ±0.2° 2?.

In accordance with another embodiment, the present invention provides venetoclax Form-L7 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 14.

In accordance with another embodiment, the present invention provides venetoclax Form-L7 characterized by X-Ray powder diffraction (XRD) peaks at about 5, 5.8, 7.4, 8, 10.2, 11.2, 11.9, 12.4, 13.5, 14.1, 14.6, 15, 15.3, 16.1, 17.1, 17.5, 18, 19.2, 20, 20.6, 21.5, 22.1, 23.6, 24.7, 25, 25.7, 27.7, 28.9, 29.6, 31.3 and 35.6 ±0.2° 2?, X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 13 and a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 14.

In accordance with another embodiment, venetoclax Form-L8 of the present invention is dimethyl acetamide solvate.

In accordance with another embodiment, the present invention provides venetoclax Form-L8 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 15.

In accordance with another embodiment, the present invention provides venetoclax Form-L8 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 5.7, 7.4, 7.9, 9.7, 10.1, 11.1, 12.4, 12.8, 13.4, 14, 14.9, 15.9, 17, 17.4, 17.9, 19.1, 19.9, 20.6, 22, 23.6, 24.6, 24.9, 25.6, 26.5, 27.6, 28.9, 29.5 and 31.2 ±0.2° 2?.

In accordance with another embodiment, the present invention provides venetoclax Form-L8 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 16.

In accordance with another embodiment, the present invention provides venetoclax Form-L8 characterized by X-Ray powder diffraction (XRD) peaks at about 5.7, 7.4, 7.9, 9.7, 10.1, 11.1, 12.4, 12.8, 13.4, 14, 14.9, 15.9, 17, 17.4, 17.9, 19.1, 19.9, 20.6, 22, 23.6, 24.6, 24.9, 25.6, 26.5, 27.6, 28.9, 29.5 and 31.2 ±0.2° 2?, X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 15 and a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 16.

In accordance with another embodiment, venetoclax Form-L9 of the present invention isdimethyl acetamide solvate.

In accordance with another embodiment, the present invention provides venetoclax Form-L9 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 17.

In accordance with another embodiment, the present invention provides venetoclax Form-L9 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 5, 5.9, 7.4, 8.1, 10.1, 11.4, 11.7, 13.4, 14.2, 14.9, 15.1, 16.1, 16.3, 17.5, 17.9, 18.1, 19.6, 20.1, 21.8, 22.3, 24, 24.8, 25.6, 27.8, 28.4, 30.1, 31.4 and 35.3 ±0.2° 2?.

In accordance with another embodiment, the present invention provides venetoclax Form-L9 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 18.

In accordance with another embodiment, the present invention provides venetoclax Form-L9 characterized by X-Ray powder diffraction (XRD) peaks at about 5, 5.9, 7.4, 8.1, 10.1, 11.4, 11.7, 13.4, 14.2, 14.9, 15.1, 16.1, 16.3, 17.5, 17.9, 18.1, 19.6, 20.1, 21.8, 22.3, 24, 24.8, 25.6, 27.8, 28.4, 30.1, 31.4 and 35.3 ±0.2° 2?, X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 17 and a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 18.

In accordance with another embodiment, the present invention provides a process for the preparation of crystalline form of venetoclax Form L7, Form L8 or Form L9 comprising:
a) providing a solution of venetoclax in dimethylacetamide at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding acetone, acetonitrile or 1,4-dioxane to the step b) solution,
d) adding water to the step c) solution or vice-versa; and
e) isolating venetoclax;
wherein the venetoclax Form L7 is obtained when the solvent used in step c) is acetone;
wherein the venetoclax Form L8 is obtained when the solvent used in step c) is acetonitrile;
wherein the venetoclax Form L9 is obtained when the solvent used in step c) is 1,4-dioxane.

In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of venetoclax, comprising:
a) providing a solution of venetoclax in one or more solvents,
b) adding a suitable anti-solvent to the step a) solution or vice-versa; and
c) isolating the amorphous form;
wherein the one or more solvents are selected from dimethyl acetamide, N-methyl pyrrolidinone, methyl tetrahydrofuran, acetic acid, anisole, tert-butanol, waterand the like and mixtures thereof; wherein the suitable anti-solvent is selected from water, heptanes and mixtures thereof.

In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of venetoclax, comprising:
a) providing a solution of venetoclax in one or more solvents; and
b) spray-drying the solvent to isolate amorphous venetoclax.
wherein the one or more solvents are selected from alcohols, ethers, esters, acetic acid, water and mixtures thereof.

In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising novel crystalline forms of venetoclax or amorphous form of venetoclax prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.

Figure 1 is the characteristic powder X-ray diffraction (XRD) pattern of venetoclax Form-L1.

Figure 2 is the characteristic differential scanning calorimetric (DSC) thermogram of venetoclax Form-L1.

Figure 3 is the characteristic powder X-ray diffraction (XRD) pattern of venetoclax Form-L2.

Figure 4 is the characteristic differential scanning calorimetric (DSC) thermogram of venetoclax Form-L2.

Figure 5 is the characteristic powder X-ray diffraction (XRD) pattern of venetoclax Form-L3.

Figure 6 is the characteristic differential scanning calorimetric (DSC) thermogram of venetoclax Form-L3.

Figure 7 is the characteristic powder X-ray diffraction (XRD) pattern of venetoclax Form-L4.

Figure 8 is the characteristic differential scanning calorimetric (DSC) thermogram of venetoclax Form-L4.

Figure 9 is the characteristic powder X-ray diffraction (XRD) pattern of venetoclax Form-L5.

Figure 10 is the characteristic differential scanning calorimetric (DSC) thermogram of venetoclax Form-L5.

Figure 11 is the characteristic powder X-ray diffraction (XRD) pattern of a venetoclax Form-L6.

Figure 12 is the characteristic differential scanning calorimetric (DSC) thermogram of venetoclax Form-L6.

Figure 13 is the characteristic powder X-ray diffraction (XRD) pattern of venetoclax Form-L7.

Figure 14 is the characteristic differential scanning calorimetric (DSC) thermogram of venetoclax Form-L7.

Figure 15 is the characteristic powder X-ray diffraction (XRD) pattern of venetoclax Form-L8.

Figure 16 is the characteristic differential scanning calorimetric (DSC) thermogram of venetoclax Form-L8.

Figure 17 is the characteristic powder X-ray diffraction (XRD) pattern of venetoclax Form-L9.

Figure 18 is the characteristic differential scanning calorimetric (DSC) thermogram of venetoclax Form-L9.

Figure 19 is the characteristic powder X-ray diffraction (XRD) pattern of amorphous venetoclax.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel crystalline polymorphic forms of venetoclax, process for their preparation and pharmaceutical composition comprising one or more of the novel polymorphic forms of venetoclax. The present invention also provides a process for the preparation of amorphous from of venetoclax and pharmaceutical compositions containing the same.

The novel crystalline polymorphic forms of venetoclax, its solvates and amorphous form of the present invention have advantageous properties selected from at least one of: bulk properties - such as particle size, moisture content, chemical purity, flowability, solubility, morphology or crystal habit, stability - such as storage stability, stability to dehydration, stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents.

The polymorphic forms if venetoclax of the present invention are characterized by one or more analytical methods such as X-ray powder diffraction (XRPD) pattern, Differential scanning calorimetric (DSC) and Thermo gravimetric analysis (TGA).
The X-Ray powder diffraction can be measured using PANalytical X’per3pro X-ray powder Diffractometer equipped with a Cu-anode ([?] =1.54 Angstrom), X-ray source operated at 45kV, 40 mA. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=3-45°2?; step size=0.01°; and Time per step=50 sec.

All DSC data reported herein were analyzed in hermitically sealed aluminium pan, with an empty hermitically sealed aluminium pan as the reference and were obtained using DSC (DSC Q200, TA instrumentation, Waters) at a scan rate of 10°C per minute in the range of 50 to 250°C.

All TGA data reported herein were analyzed using TGA Q500 in platinum pan with a temperature rise of about 10°C/min in the range of about room temperature to about 250°C.

As used herein in this specification, unless otherwise specified, venetoclax, which is used as a starting material is known in the art and can be prepared by the process described in the present specification or may be any methods known in art, for example venetoclax may be synthesized as disclosed in U.S. Patent No. 8,546,399. The starting venetoclax may be in any form such as crude obtained directly from the reaction mass, crystalline, amorphous or other forms of venetoclax, including various solvates and hydrates known in the art as well as the novel crystalline forms described herein the present invention.

In one embodiment, the present invention provides novel crystalline polymorphic form of venetoclax; which are designated herein as venetoclax Form-L1, venetoclax Form-L2, venetoclax Form-L3, venetoclax Form-L4, venetoclax Form-L5, venetoclax Form-L6, venetoclax Form-L7, venetoclax Form-L8 and venetoclax Form-L9.

In another embodiment, the present invention provides venetoclax Form-L1.

In another embodiment, venetoclax Form-L1 of the present invention is anisole solvate.

In another embodiment, the present invention provides venetoclax Form-L1 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 1.

In another embodiment, the present invention provides venetoclax Form-L1 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 3.7, 5.1, 5.7, 5.9, 6.8, 7.1, 7.5, 8.3, 8.6, 9.9, 10.4, 11.5, 12.8, 13.4, 13.7, 14.2, 14.4, 14.7, 15.3, 15.7, 17.1, 17.7, 18, 18.6, 19.1, 19.9, 21, 22, 22.3, 22.7, 23.2, 24.1, 24.6, 25.1, 25.5, 26.2, 27, 27.7, 30.4, 31.3 and 32.1±0.2° 2?.

In another embodiment, the present invention provides venetoclax Form-L1 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 2.

In another embodiment, the present invention provides venetoclax Form-L1 characterized by X-Ray powder diffraction (XRD) peaks at about 3.7, 5.1, 5.7, 5.9, 6.8, 7.1, 7.5, 8.3, 8.6, 9.9, 10.4, 11.5, 12.8, 13.4, 13.7, 14.2, 14.4, 14.7, 15.3, 15.7, 17.1, 17.7, 18, 18.6, 19.1, 19.9, 21, 22, 22.3, 22.7, 23.2, 24.1, 24.6, 25.1, 25.5, 26.2, 27, 27.7, 30.4, 31.3 and 32.1 ±0.2° 2?, X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 1 and a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 2.

In another embodiment, the present invention provides venetoclax Form-L2.

In another embodiment, venetoclax Form-L2 of the present invention is anisole solvate.

In another embodiment, the present invention provides venetoclax Form-L2 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 3.

In another embodiment, the present invention provides venetoclax Form-L2 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 5.4,7.5, 8.4, 8.9, 9.7, 10.7, 11.2, 11.9, 13, 14.7, 16.6, 17.7, 19.4, 19.9, 20.4, 21, 22.5, 24.5, 25.6 and 29.4 ±0.2° 2?.

In another embodiment, the present invention provides venetoclax Form-L2 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 4.

In another embodiment, the present invention provides venetoclax Form-L2 characterized by X-Ray powder diffraction (XRD) peaks at about 5.4,7.5, 8.4, 8.9, 9.7, 10.7, 11.2, 11.9, 13, 14.7, 16.6, 17.7, 19.4, 19.9, 20.4, 21, 22.5, 24.5, 25.6 and 29.4 ±0.2° 2?, X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 3 and a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 4.

In another embodiment, the present invention provides venetoclax Form-L3.

In another embodiment, venetoclax Form-L3 of the present invention is anisole solvate.

In another embodiment, the present invention provides venetoclax Form-L3 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 5.

In another embodiment, the present invention provides venetoclax Form-L3 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 3.7, 5.1, 5.3, 5.7, 6.3, 7.4, 7.9, 8.3, 8.5, 9.2, 9.5, 9.8, 11.5, 12.8, 13.4, 13.7, 13.9, 14.4, 14.7, 15.3, 15.6, 16, 16.4, 17.2, 17.9, 18.2, 18.4, 19.5, 20.2, 21.2, 21.5, 22.3, 22.6, 23.3, 23.7, 24.8, 25.5, 26.1 and 29.8 ±0.2° 2?.

In another embodiment, the present invention provides venetoclax Form-L3 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 6.

In another embodiment, the present invention provides venetoclax Form-L3 characterized by X-Ray powder diffraction (XRD) peaks at about 3.7, 5.1, 5.3, 5.7, 6.3, 7.4, 7.9, 8.3, 8.5, 9.2, 9.5, 9.8, 11.5, 12.8, 13.4, 13.7, 13.9, 14.4, 14.7, 15.3, 15.6, 16, 16.4, 17.2, 17.9, 18.2, 18.4, 19.5, 20.2, 21.2, 21.5, 22.3, 22.6, 23.3, 23.7, 24.8, 25.5, 26.1 and 29.8 ±0.2° 2?, X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 5 and a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 6.

In another embodiment, the present invention provides a process for the preparation of crystalline form of venetoclax Form L1, Form L2 or Form L3, comprising:
a) providing a solution of venetoclax in anisole at room temperature to reflux temperature,
b) cooling the solution to below 45°C,
c) optionally adding a suitable solvent to step b) reaction mass, and
d) isolating venetoclax Form L1, Form L2 or Form L3.

In another embodiment, the present invention provides a process for the preparation of crystalline form of venetoclax Form L1, Form L2 and Form L3, comprising:
a) providing a solution of venetoclax in anisole at room temperature to reflux temperature,
b) cooling the solution to below 45°C,
c) optionally adding a suitable solvent to step b) reaction mass, and
d) isolating venetoclax;
wherein the venetoclax Form L1 is obtained by cooling step b) solution to below 30°C and adding a suitable solvent to step b) reaction mass;
wherein the venetoclax Form L2 is obtained by cooling step b) solution to between 35°C to 45°C and adding a suitable solvent to step b) reaction mass;
wherein the Form L3 is obtained by cooling the step b) solution below 30°C.

In a specific embodiment, the present invention provides a process for the preparation of venetoclax Form-L1, comprising:
a) providing a solution of venetoclax in anisoleat 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding a suitable solvent to step b) reaction mass, and
d) isolating venetoclax Form-L1.

The aforementioned process of providing a solution of venetoclax includes first suspending or mixing venetoclax in anisoleat about 30°C to about 35°C and then the suspension may be heated to about 50°C to about reflux temperature; preferably at about 65°C to about 80°C to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C.

The step c) of aforementioned process involves, adding a suitable solvent to the step b) reaction mass at below 30°C. The suitable solvent include, but are not limited to ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like and mixtures thereof. The ethers include, but are not limited to dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; aliphatic hydrocarbons include, but are not limited to hexane, heptane, propane and the like; alicyclic hydrocarbons include, but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and the like and mixture thereof; preferably dimethyl ether, hexane, heptane, cyclohexane, cycloheptane and mixture thereof; more preferably hexane.

Then the venetoclax Form-L1 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 25°C to about 30°C for sufficient period of time; preferably for a period of about 14 to about 18 hours.

In a specific embodiment, the present invention provides a process for the preparation of venetoclax Form-L2, comprising:
a) providing a solution of venetoclax in anisole at 25°C to reflux temperature,
b) cooling the solution to between 35°C and45°C,
c) adding a suitable solvent to the step b) solution or vice-versa; and
d) isolating venetoclax Form-L2.

The aforementioned process of providing a solution of venetoclax includes first suspending or mixing venetoclax in anisole at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution. Then, the resultant reaction solution can be cooled to between 35°C and45°C.

Step c) of the aforementioned process involves precipitation of venetoclax Form-L2 of venetoclax by either addition of suitable solvent to the venetoclax solution of step b) or addition of step b) solution of venetoclax into a suitable solvent. The suitable solvent include, but are not limited to ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like and mixtures thereof. The ethers include, but are not limited to dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; aliphatic hydrocarbons include, but are not limited to hexane, heptane, propane and the like; alicyclic hydrocarbons include, but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and the like and mixture thereof; preferablyhexane, heptane, cyclohexane, cycloheptane and mixture thereof; more preferably heptane.

Then the venetoclax Form-L2 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 25°C to about 30°Cfor sufficient period of time; preferably for a period of about 30 min to about 3 hours.

In a specific embodiment, the present invention provides a process for the preparation of venetoclax Form-L3, comprising:
a) providing a solution of venetoclax in anisoleat 30°C to reflux temperature,
b) cooling the solution to below 30°C; and
c) isolating venetoclax Form-L3.

The aforementioned process of providing a solution of venetoclax includes suspending or mixing venetoclax in anisole at about 30°C to about 35°C and then the suspension may be heated to about 50°C to about reflux temperature; preferably to about 60°C to about 85°C to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C and stirring the reaction mass for sufficient period of time to precipitate venetoclax Form-L3. Then the venetoclax Form-L3 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 25°C to about 30°C for sufficient period of time; preferably for a period of about 2 hours to about 4 hours.

In another embodiment, the present invention provides venetoclax Form-L4.

In another embodiment, venetoclax Form-L4 of the present invention is an anhydrous crystalline form.

In another embodiment, the present invention provides venetoclax Form-L4 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 7.

In another embodiment, the present invention provides venetoclax Form-L4 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 5.1, 5.5, 6.2, 6.4, 6.8, 8.5, 9.6, 9.8, 10.8, 11.7, 13.5, 14.2, 15.2, 15.9, 16.4, 16.9, 17.9, 18.4, 18.9, 21.3, 22.7, 24.9 and 26.4±0.2° 2?.

In another embodiment, the present invention provides venetoclax Form-L4characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 8.

In another embodiment, the present invention provides venetoclax Form-L4 characterized by X-Ray powder diffraction (XRD) peaks at about 5.1, 5.5, 6.2, 6.4, 6.8, 8.5, 9.6, 9.8, 10.8, 11.7, 13.5, 14.2, 15.2, 15.9, 16.4, 16.9, 17.9, 18.4, 18.9, 21.3, 22.7, 24.9 and 26.4 ±0.2° 2?, X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 7 and a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 8.

In another embodiment, the present invention provides a process for the preparation of venetoclax Form-L4, comprising: heating venetoclax Form-L1 or venetoclax Form-L3 at about 75°C to about 110°C, wherein the venetoclax Form-L1 is characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 1; and venetoclax Form-L3 is characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 5.

Venetoclax Form-L4 can be prepared by drying the venetoclax Form-L1 or venetoclax Form-L3 obtained by the process described as above. Preferably the drying is carried out at a temperature of about 80°C to about 100°C for a period of about 10 min to about 24 hours in hot air oven.

In another embodiment, the present invention provides venetoclax Form-L5.

In another embodiment, venetoclax Form-L5 of the present invention is an anhydrous crystalline form.

In another embodiment, the present invention provides venetoclax Form-L5 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 9.

In another embodiment, the present invention provides venetoclax Form-L5 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 5,7.9,8.1,8.8,9.3,10.5,10.8,11.1,12.2,13.1,13.4,13.9,14.5,15.1,15.6,15.9,16.3,16.5,17,17.2,17.7,18.6,19,19.5,19.8,20.2,20.6,21,21.7,21.8,22.3,23.2,23.8,24.4,25.3,25.8,26.5,27,27.6,28.1,29,29.8,30.2,31.4,32.8,33.9,35.8 and 37.5 ±0.2° 2?.

In another embodiment, the present invention provides venetoclax Form-L5 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 10.

In another embodiment, the present invention provides venetoclax Form-L5 characterized by X-Ray powder diffraction (XRD) peaks at about 5,7.9,8.1,8.8,9.3,10.5,10.8,11.1,12.2,13.1,13.4,13.9,14.5,15.1,15.6,15.9,16.3,16.5,17,17.2,17.7,18.6,19,19.5,19.8,20.2,20.6,21,21.7,21.8,22.3,23.2,23.8,24.4,25.3,25.8,26.5,27,27.6,28.1,29,29.8,30.2,31.4,32.8,33.9,35.8 and 37.5 ±0.2° 2?; X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 9 and a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 10.

In another embodiment, the present invention provides a process for the preparation of venetoclax Form-L5, comprising:
a) suspending venetoclax Form-L1 or venetoclax Form-L3 in n-heptane at a temperature of 30°C to reflux,
b) cooling the step a) suspension to below 30°C; and
c) isolating venetoclax Form-L5.

The starting material venetoclax Form-L1 is characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 1; and venetoclax Form-L3 is characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 5 and prepared by the process described as above.

The aforementioned process of suspending venetoclax From-L1 or venetoclax Form-L3 includes mixing venetoclax From-L1 or venetoclax Form-L3 in n-heptane at a temperature about 30°C to about 35°C and then the suspension may be heated to about 50°C to about reflux temperature; preferably to about 70°C to about 80°C.Then, the resultant reaction mass can be cooled to below 30°C and stirring the reaction mass for sufficient period of time; preferably for about 10 hours to about 16 hours.

Then the venetoclax Form-L5 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 35°C to about 65°C for sufficient period of time.

In another embodiment, the present invention provides venetoclax Form-L6.

In another embodiment, venetoclax Form-L6 of the present invention is an anhydrous crystalline form.

In another embodiment, the present invention provides venetoclax Form-L6 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 11.

In another embodiment, the present invention provides venetoclax Form-L6 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 5.4, 8.6, 8.9, 9.7, 10.7, 11.2, 11.9, 13, 14.7, 14.9, 15.6, 16.6, 17.7, 19.4, 19.9, 20.4, 21, 24.5, 25.3, 25.7, 27, 29.4, 33.9 and 36.3 ±0.2° 2?.

In another embodiment, the present invention provides venetoclax Form-L6 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 12.

In another embodiment, the present invention provides venetoclax Form-L6 characterized by X-Ray powder diffraction (XRD) peaks at about 5.4, 8.6, 8.9, 9.7, 10.7, 11.2, 11.9, 13, 14.7, 14.9, 15.6, 16.6, 17.7, 19.4, 19.9, 20.4, 21, 24.5, 25.3, 25.7, 27, 29.4, 33.9 and 36.3 ±0.2° 2?, X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 11 and a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 12.

In another embodiment, the present invention provides a process for the preparation of venetoclax Form-L6, comprising: heating venetoclax Form-L2 at about 80°C to about 100°C,wherein the venetoclax Form-L2 is characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 3.

Venetoclax Form-L6 can be prepared by drying the venetoclax Form-L2 obtained by the process described as above. Preferably the drying is carried out at a temperature of about 80°C to about 100°C for a period of about 10 min to about 24 hours in hot air oven.

In another embodiment, the present invention provides a process for the preparation of venetoclax Form-L6, comprising:
a) suspending venetoclax Form-L2 in n-heptane at a temperature of 30°C to reflux,
b) cooling the step a) suspension to below 30°C; and
c) isolating venetoclax Form-L6.

The aforementioned process of suspending venetoclax From-L2 includes mixing venetoclax From-L2 in n-heptane at a temperature about 30°C to about 35°C and then the suspension may be heated to about 50°C to about reflux temperature; preferably to about 65°C to about 80°C. Then, the resultant reaction mass can be cooled to below 30°C and stirring the reaction mass for sufficient period of time. Then the venetoclax Form-L6 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 35°C to about 65°C for sufficient period of time; preferably for about 8 hours to about 15 hours.

In another embodiment, the present invention provides venetoclax Form-L7.

In another embodiment, venetoclax Form-L7 of the present invention is a dimethylacetamide solvate.

In another embodiment, the present invention provides venetoclax Form-L7 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 13.

In another embodiment, the present invention provides venetoclax Form-L7 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about5, 5.8, 7.4, 8, 10.2, 11.2, 11.9, 12.4, 13.5, 14.1, 14.6, 15, 15.3, 16.1, 17.1, 17.5, 18, 19.2, 20, 20.6, 21.5, 22.1, 23.6, 24.7, 25, 25.7, 27.7, 28.9, 29.6, 31.3 and 35.6±0.2° 2?.

In another embodiment, the present invention provides venetoclax Form-L7 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 14.

In another embodiment, the present invention provides venetoclax Form-L7 characterized by X-Ray powder diffraction (XRD) peaks at about 5, 5.8, 7.4, 8, 10.2, 11.2, 11.9, 12.4, 13.5, 14.1, 14.6, 15, 15.3, 16.1, 17.1, 17.5, 18, 19.2, 20, 20.6, 21.5, 22.1, 23.6, 24.7, 25, 25.7, 27.7, 28.9, 29.6, 31.3 and 35.6 ±0.2° 2?, X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 13 and a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 14.

In another embodiment, the present invention provides venetoclax Form-L8.

In another embodiment, venetoclax Form-L8 of the present invention is a dimethylacetamide solvate.
In another embodiment, the present invention provides venetoclax Form-L8 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 15.

In another embodiment, the present invention provides venetoclax Form-L8 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 5.7, 7.4, 7.9, 9.7, 10.1, 11.1, 12.4, 12.8, 13.4, 14, 14.9, 15.9, 17, 17.4, 17.9, 19.1, 19.9, 20.6, 22, 23.6, 24.6, 24.9, 25.6, 26.5, 27.6, 28.9, 29.5 and 31.2 ±0.2° 2?.

In another embodiment, the present invention provides venetoclax Form-L8 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 16.

In another embodiment, the present invention provides venetoclax Form-L8 characterized by X-Ray powder diffraction (XRD) peaks at about 5.7, 7.4, 7.9, 9.7, 10.1, 11.1, 12.4, 12.8, 13.4, 14, 14.9, 15.9, 17, 17.4, 17.9, 19.1, 19.9, 20.6, 22, 23.6, 24.6, 24.9, 25.6, 26.5, 27.6, 28.9, 29.5 and 31.2 ±0.2° 2?, X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 15 and a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 16.

In another embodiment, the present invention provides venetoclax Form-L9.

In another embodiment, venetoclax Form-L9 of the present invention is a dimethylacetamide solvate.

In another embodiment, the present invention provides venetoclax Form-L9 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 17.

In another embodiment, the present invention provides venetoclax Form-L9 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 5, 5.9, 7.4, 8.1, 10.1, 11.4, 11.7, 13.4, 14.2, 14.9, 15.1, 16.1, 16.3, 17.5, 17.9, 18.1, 19.6, 20.1, 21.8, 22.3, 24, 24.8, 25.6, 27.8, 28.4, 30.1, 31.4 and 35.3 ±0.2° 2?.

In another embodiment, the present invention provides venetoclax Form-L9 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 18.

In another embodiment, the present invention provides venetoclax Form-L9 characterized by X-Ray powder diffraction (XRD) peaks at about 5, 5.9, 7.4, 8.1, 10.1, 11.4, 11.7, 13.4, 14.2, 14.9, 15.1, 16.1, 16.3, 17.5, 17.9, 18.1, 19.6, 20.1, 21.8, 22.3, 24, 24.8, 25.6, 27.8, 28.4, 30.1, 31.4 and 35.3 ±0.2° 2?, X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 17 and a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 18.

In another embodiment, the present invention provides a process for the preparation of crystalline form of venetoclax Form L7, Form L8 or Form L9 comprising:
a) providing a solution of venetoclax in dimethylacetamide at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding acetone, acetonitrile or 1,4-dioxane to the step b) solution,
d) adding water to the step c) solution or vice-versa; and
e) isolating venetoclax;
wherein the venetoclax Form L7 is obtained when the solvent used in step c) is acetone;
wherein the venetoclax Form L8 is obtained when the solvent used in step c) is acetonitrile;
wherein the venetoclax Form L9 is obtained when the solvent used in step c) is 1,4-dioxane.

In a specific embodiment, the present invention provides a process for the preparation of venetoclax Form-L7, comprising:
a) providing a solution of venetoclax in dimethylacetamide at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding acetone to the step b) solution,
d) adding a suitable anti-solvent to the step c) solution or vice-versa; and
e) isolating venetoclax Form-L7.
The aforementioned process of providing a solution of venetoclax includes suspending or mixing venetoclax in dimethylacetamide at a temperature about 30°C to about 35°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution; preferably to about 55°C to about 70°C.Then, the resultant reaction solution can be cooled to below 30°C.

Step c) of the aforementioned process involves adding acetone to the step b) solution at below 30°C. Then venetoclax Form-L7 may be precipitated by either addition of suitable anti-solvent to the venetoclax solution of step c) or addition of step c) solution of venetoclax into a suitable anti-solvent. The suitable anti-solvent include, but are not limited to water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like and mixtures thereof. The ethers include, but are not limited to dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; aliphatic hydrocarbons include, but are not limited to hexane, heptane, propane and the like; alicyclic hydrocarbons include, but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and the like; water and mixture thereof; preferably water. Then the venetoclax Form-L7 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 25°C to about 35°C for sufficient period of time; preferably for about 10 hours to 20 hours.

In a specific embodiment, the present invention provides a process for the preparation of venetoclax Form-L8, comprising:
a) providing a solution of venetoclax in dimethylacetamide at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding acetonitrile to the step b) reaction mass,
d) adding a suitable anti-solvent to the step c) reaction mass or vice-versa; and
e) isolating venetoclax Form-L8.

The aforementioned process of providing a solution of venetoclax includes suspending or mixing venetoclaxin dimethylacetamide at a temperature about 30°C to about 35°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution; preferably to about 55°C to about 70°C. Then, the resultant reaction solution can be cooled to below 30°C.

Step c) of the aforementioned process involves adding acetonitrile to the step b) reaction mass at below 30°C. Then venetoclax Form-L8 may be precipitated by either addition of suitable anti-solvent to the venetoclax solution of step c) or addition of step c) solution in to a suitable anti-solvent. The suitableanti-solvent include, but are not limited to water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like and mixtures thereof. The ethers include, but are not limited to dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; aliphatic hydrocarbons include, but are not limited to hexane, heptane, propane and the like; alicyclic hydrocarbons include, but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and the like; water and mixture thereof; preferably water. Then the venetoclax Form-L8 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 25°C to about 35°C for sufficient period of time; preferably for about 10 hours to about 20 hours.

In a specific embodiment, the present invention provides a process for the preparation of venetoclax Form-L9, comprising:
a) providing a solution of venetoclax in a mixture of dimethylacetamide and dioxane at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding a suitable anti-solvent to the step b) solution or vice-versa; and
d) isolating venetoclax Form-L9.

The aforementioned process of providing a solution of venetoclax includes suspending or mixing venetoclax in a mixture of dimethylacetamide and dioxane at a suitable temperature, for example at about 25°C to about 35°C and then the suspension may be heated to about 50°C to about reflux temperature; preferably to about 55°C to about 70°C to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C.

Step c) of the aforementioned process involves precipitation of venetoclax Form-L9 of venetoclax by either addition of suitable anti-solvent to the venetoclax solution of step b) or addition of step b) solution of venetoclax into a suitable anti-solvent. The suitable anti-solvent include, but are not limited to water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like and mixtures thereof. The ethers include, but are not limited to dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; aliphatic hydrocarbons include, but are not limited to hexane, heptane, propane and the like; alicyclic hydrocarbons include, but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and the like; water and mixture thereof; preferably 1,4-dioxane, hexane, heptane, water and mixture thereof; more preferably a mixture of 1,4-dioxane and water. Then the venetoclax Form-L9 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 35°C to about 65°C for sufficient period of time; preferably for about 8 hours to about 20 hours.

In another embodiment, the present invention provides a pharmaceutical composition comprising at least one of the novel crystalline forms of venetoclax described above and at least one or more pharmaceutically acceptable excipients.

In another embodiment, the novel crystalline forms of venetoclax of the present invention may be used as an intermediate in the preparation of other polymorphic forms including amorphous form of venetoclax.

In another embodiment, the present invention provides a process for the preparation of amorphous from of venetoclax and pharmaceutical compositions containing the same.

In another embodiment, the present invention provides a process for preparation of amorphous form of venetoclax, comprising:
a) providing a solution of venetoclax in one or more solvents,
b) adding a suitable anti-solvent to the step a) solution or vice-versa; and
c) isolating the amorphous form.
wherein the one or more solvents are selected from dimethyl acetamide, N-methyl pyrrolidinone, methyl tetrahydrofuran, acetic acid, anisole, tert-butanol, water and the like and mixtures thereof; wherein the suitable anti-solvent is selected from water, heptanes and the like and mixtures thereof.

The starting venetoclax used herein in step a) may be any crystalline or other form of venetoclax, including various solvates, hydrates, salts, cocrystals and novel crystalline forms described herein the present invention as long as amorphous venetoclax is produced during the process of the invention or venetoclax obtaining as existing solution from a previous processing step.

Step a) of providing a solution of venetoclax may include dissolving any form of venetoclax in one or more solvents. The one or more solvents include, but are not limited to dimethyl acetamide, N-methyl pyrrolidone, methyl tetrahydrofuran, acetic acid, anisole, tert-butanol, water and the like and mixtures thereof.

The step a) reaction may optionally be heated to dissolve all solids in one or more solvents. The dissolution temperature for the venetoclax may range from about 20° C to reflux temperature of the solvent used; preferably from about 50°C to about 80°C.

Step b) of the aforementioned process involves precipitation of amorphous form of venetoclax by either addition of suitable anti-solvent to the venetoclax solution of step a) or addition of step a) solution of venetoclax into a suitable anti-solvent. The step b) is carried out at a temperature of about 0°C to about 35°C.

The suitable anti-solvent include, but are not limited to water, heptanes and the like and mixtures thereof.

The isolation of the resultant product is accomplished by removal of solvent from the solution by, for example, substantially complete evaporation of the solvent, concentrating the solution, cooling to obtain amorphous form and filtering the solid under inert atmosphere; preferably isolated by filtration. Alternatively, the solvent may also be removed by evaporation. Evaporation can be achieved at sub-zero temperatures by the lyophilisation or freeze-drying technique, a rotational drying (such as with the Buchi Rotavapor), spray drying, fluid bed drying, flash drying, spin flash drying and thin-film drying.

The resultant product may optionally be further dried for about 2 hours to 20 hours. Drying can be suitably carried at a suitable temperature out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like.

In another embodiment, the present invention provides a process for preparation of amorphous form of venetoclax, comprising:
a) providing a solution of venetoclax in one or more solvents; and
b) spray-drying the solvent to isolate amorphous venetoclax.
wherein the one or more solvents are selected from alcohols, ethers, esters, acetic acid, water and mixtures thereof.

The starting venetoclax used herein in step a) may be any crystalline or other form of venetoclax, including various solvates, hydrates, salts, cocrystals and novel crystalline forms described herein the present invention as long as amorphous venetoclax is produced during the process of the invention or venetoclax obtaining as existing solution from a previous processing step.

Step a) of providing a solution of venetoclax may include dissolving any form of venetoclax in one or more solvents at a suitable temperature. The one or more solvents include, but are not limited to alcohols, ethers, esters, polar protic solvent like acetic acid, water or mixtures thereof. The alcohols include, but are not limited to methanol, ethanol, propanol, isopropanol and the like; ethers include, but are not limited to methyl ethyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,1,4-dioxane, cyclopentyl methyl ether, dimethoxymethane, di-tert-butyl ether, methoxyethane and the like; esters include, but are not limited to ethyl acetate, propyl acetate and the like; acetic acid; water or mixtures thereof; preferably methanol, tetrahydrofuran, ethyl acetate, acetic acid, water and mixtures thereof.

Then removing the solvent from step a) solution to isolate amorphous venetoclax is carried out by using spray-dryer such as LAB ULTIMA LU228 with following parameters: inlet temperature: 120°C; outlet temperature: 110°C; flow rate: 10-20 m/min; solution temperature: 55°C; Nitrogen pressure: 0.8-1.8 kg/cm2.

The resultant product may optionally be further dried for about 2 hours to 20 hours. Drying can be suitably carried out at a suitable temperature in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like.

The venetoclax recovered using the process of the present invention is in the form of substantially pure amorphous form.

In another embodiment, the present invention provides amorphous form of venetoclax prepared by the process herein above is characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 19.

The amorphous form of venetoclax is believed to be stable during storage. This property is important and advantageous for the desired use of venetoclax in pharmaceutical product formulations.

The amorphous form of venetoclax of the present invention has commercially acceptable pharmacokinetic characteristics, solubility, flow properties, stability, and the like. The products may optionally be milled to get the desired particle size distributions. Milling or micronization may be performed prior to drying, or after the completion of drying of the products.

The present invention further provides novel crystalline forms of venetoclax or an amorphous form of venetoclax prepared by the processes described above, having a chemical purity of 98% or more as measure by HPLC, preferably 99% or more, more preferably 99.8% or more. Moreover, the venetoclax may be obtained substantially free of any unknown impurity, e.g., a content of less than about 0.1% of impurities.

The present invention also encompasses a pharmaceutical composition comprising novel crystalline forms of venetoclax or amorphous form of venetoclax prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.

EXAMPLES

The following non limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way.

EXAMPLE-1: Preparation of venetoclax Form-L1

Venetoclax (2 gm) and anisole (16 mL) were added in to a round bottom flask at 25°C to 30°C, heated the reaction mass to 70°C to 75°C and stirred for clear solution at same temperature. Then the reaction mass temperature was cool to 25°C to 30°C and stirred for about 1 to 1.5 hours at this temperature. n-hexane (48 mL) was added to the heterogeneous mixture at 25°C to 30°C and stirred for about 2 hours at same temperature, precipitated solids was filtered and washed with n-heptane (10 mL), dried the solid under vacuum at 25°C to 30°C for about 16 hours to obtain the title compound. Yield: 2.1 gm; PXRD-Fig. 1; DSC- Fig. 2, TGA weight loss: 11% w/w and Anisole solvent content by NMR: 11.3%.

EXAMPLE-2: Preparation of venetoclax Form-L2

Venetoclax (1.5 gm) and anisole (12 mL) were added in to a round bottom flask at 25°C to 30°C, heated the reaction mass to 70°C to 75°C and stirred for clear solution at same temperature. Then the reaction mass temperature was cool to 40°C to 45°C. To the clear solution n-heptane (20 mL) was added at 40-41°C for about 6 min. After completion of addition, temperature was further cool to 25°C to 30°C and stirred for 16 hours at same temperature. Precipitated solid was filtered and washed with n-heptane (7.5 mL), dried the solid under vacuum at 25°C to 30°C for about 2 hours to obtain the title compound. Yield: 1.5 gm; PXRD-Fig. 3; DSC- Fig. 4, TGA weight loss: 13% w/w and Anisole solvent content by NMR: 14.8%.

EXAMPLE-3: Preparation of venetoclax Form-L2

Venetoclax (1.5 gm) and anisole (12 mL) were added in to a round bottom flask at 25°C to 30°C, heated the reaction mass to 70°C to 75°C and stirred for clear solution at same temperature. Then the reaction mass temperature was cool to 25°C to 30°C and stirred for about 48 hours at this temperature. Precipitated solid was filtered and washed with anisole (1.5 mL), dried the solid under vacuum at 25°C to 30°C for about 2 hours to obtain the title compound. Yield: 1.25 gm.

EXAMPLE-4: Preparation of venetoclax Form-L3

Venetoclax (1.5 gm) and anisole (12 mL) were added in to a round bottom flask at 25°C to 30°C, heated the reaction mass to 70°C to 75°C and stirred for clear solution at same temperature. Then the reaction mass temperature was cool to 25°C to 30°C and stirred for about 16 hours at this temperature. Precipitated solid was filtered and washed with anisole (3 mL), dried the solid under vacuum at 25°C to 30°C for about 3 hours to obtain the title compound. Yield: 1.39 gm; PXRD-Fig. 5; DSC- Fig. 6, TGA weight loss: 13% w/w and Anisole solvent content by NMR: 14.8%.

EXAMPLE-5: Preparation of venetoclax Form-L4

Venetoclax Form-L1 (501.5 mg) was dryed in vacuum oven at 90°C for 20 hours to obtain venetoclax Form-L4. Yield: 437.8 mg; PXRD-Fig. 7; DSC- Fig. 8,TGA weight loss: 0.5% w/w and Anisole solvent content by NMR: 0.4%.

EXAMPLE-6: Preparation of venetoclax Form-L4

Venetoclax Form-L3 (502.7 mg) was dryed in vacuum oven at 90°C for 14 hours to obtain venetoclax Form-L4. Yield: 424.8 mg.

EXAMPLE-7: Preparation of venetoclax Form-L5

Venetoclax Form-L1 (or Form-L3) (503 mg) and n-heptane (5 mL) were added in to a round bottom flask at 25°C to 30°C, heated the reaction mass to 70°C to 75°C and stirred for 6 hours at same temperature. Then the temperature was allowed to cool to 25°C to 30°C. Filtered the reaction mass and washed with n-heptane (2.5 mL), dried the solid under vacuum at 50°C for about 14 hours to obtain the title compound. Yield: 284.3 mg; PXRD-Fig. 9; DSC- Fig. 10,TGA weight loos: No weight loss reported and Anisole solvent content by NMR: Not detected.

EXAMPLE-8: Preparation of venetoclax Form-L6
Venetoclax Form-L2 (501.6 mg) was dryed in vacuum oven at 90°C for 15 hours to obtain venetoclax Form-L6. Yield: 472.1 mg; PXRD-Fig. 11; DSC- Fig. 12, TGA weight loos: No weight loss reported and Anisole solvent content by NMR: 0.2%.

EXAMPLE-9: Preparation of venetoclax Form-L6

Venetoclax Form-L2 (or Form-L3) (503.2 mg) and n-heptane (5 mL) were added in to a round bottom flask at 25°C to 30°C, heated the reaction mass to 70°C to 75°C and stirred for 6 hours at same temperature. Then the temperature was allowed to cool to 25°C to 30°C. Filtered the reaction mass and washed with n-heptane (5 mL), dried the solid under vacuum at 50°C to 55°C for about 12 hours to obtain the title compound. Yield: 352.2 mg.

EXAMPLE-10: Preparation of venetoclax Form-L7

Venetoclax (1 gm) and dimethyl acetamide (3 mL) were added in to a round bottom flask at 25°C to 30°C, heated the reaction mass to 60°C to 65°C and stirred for clear solution at same temperature. Then the temperature was allowed to cool to 25°C to 30°C. To the clear solution acetone (10 mL) and water (20 mL) was added at 25°C to 30°C and allowed to stir for 1 hour at same temperature. Precipitated solid was filtered and washed with water (3 mL), dried the solid under vacuum at 25°C to 30°C for about 14 hours to obtain the title compound. Yield: 947.2mg; PXRD-Fig. 13; DSC- Fig. 14, TGA weight loss: 4% w/w and dimethyl acetamide solvent content by NMR: 5.7%.

EXAMPLE-11: Preparation of venetoclax Form-L8

Venetoclax (1 gm) and dimethyl acetamide (3 mL) were added in to a round bottom flask at 25°C to 30°C, heated the reaction mass to 60°C to 65°C and stirred for clear solution at same temperature. Then the temperature was allowed to cool to 25°C to 30°C. To the clear solution acetonitrile (10 mL) and water (20 mL) was added at 25°C to 30°C and allowed to stir for 1 hour at same temperature. Precipitated solids was filtered and washed with water (3 mL), dried the solid under vacuum at 25°C to 30°C for about 14 hours to obtain the title compound. Yield: 955mg; PXRD-Fig. 15; DSC- Fig. 16, TGA weight loss: 3% w/w and dimethyl acetamide solvent content by NMR: 4.8%.

EXAMPLE-12: Preparation of venetoclax Form-L9

Venetoclax (1 gm), dimethyl acetamide (3.5 mL) and dioxane (5 mL) were added in to a round bottom flask at 25°C to 30°C, heated the reaction mass to 60°C to 65°C and stirred for clear solution at same temperature. Then the temperature was allowed to cool to 25°C to 30°C. To the clear solution a mixture of dioxane and water (10 mL: 20 mL) was added at 25°C to 30°C and allowed to stir for 2 hour at same temperature. Precipitated solids was filtered and washed with water (3 mL), dried the solid under vacuum at 55°C for about 13 hours to obtain the title compound. Yield: 950.5mg; PXRD-Fig. 17; DSC- Fig. 18, TGA weight loss: 7.3% w/w and dimethyl acetamide solvent content by NMR: 1.4%.

EXAMPLE-13: Preparation of amorphous form of venetoclax (DMAc/water)

Venetoclax (1 gm) and dimethyl acetamide (3 mL) were added in to a round bottom flask at 25°C to 35°C, heated the reaction mass to 65°C to 70°C and stirred for clear solution at same temperature. Then the temperature was allowed to cool to 25°C to 30°C and the resulting solution was added to water (15 mL) at 25°C to 30°C. Stirred for about 1 hour at this temperature and the precipitated solid was filtered and washed with water (1 mL), dried the solid in an oven under vacuum at 50°C to 55°C for about 18 hours. Yield: 0.9 g; PXRD-Fig.19.

EXAMPLE-14: Preparation of amorphous form of venetoclax (2-MeTHF/NPM/heptane)

Venetoclax (1 gm), 2-methyl tetrahydrofuran (10 mL) and N-methyl pyrrolidone (0.1 mL) were added in to a round bottom flask at 25°C to 35°C, heated the reaction mass to 65°C to 70°C and stirred for clear solution at same temperature. Then the temperature was allowed to cool to 25°C to 30°C and the resulting solution was added to pre cooled n-heptane (50 mL) at 0°C to 5°C. Stirred for about 30 min at this temperature and the precipitated solid was filtered and washed with n-heptane (10 mL), dried the solid in an oven under vacuum at 60°C to 65°C for about 12 hours. Yield: 0.84 g.

EXAMPLE-15: Preparation of amorphous form of venetoclax (2-MeTHF/AcOH/heptane)
Venetoclax (1 gm), 2-methyl tetrahydrofuran (10 mL) and acetic acid (0.5 mL) were added in to a round bottom flask at 25°C to 35°C, heated the reaction mass to 65°C to 70°C and stirred for clear solution at same temperature. Then the temperature was allowed to cool to 25°C to 30°C and the resulting solution was added to pre cooled n-heptane (50 mL) at 0°C to 5°C.Stirred for about 30 min at this temperature and the precipitated solid was filtered and washed with n-heptane (10 mL), dried the solid in an oven under vacuum at 60°C to 65°C for about 12 hours. Yield: 0.85 g.

EXAMPLE-16: Preparation of amorphous form of venetoclax (2-MeTHF/water/heptane)

Venetoclax (1 gm), 2-methyl tetrahydrofuran (10 mL) and water (0.5 mL) were added in to a round bottom flask at 25°C to 35°C, heated the reaction mass to 65°C to 70°C and stirred for clear solution at same temperature. Then the temperature was allowed to cool to 25°C to 30°C and the resulting solution was added to pre cooled n-heptane (50 mL) at 0°C to 5°C. Stirred for about 30 min at this temperature and the precipitated solid was filtered and washed with n-heptane (10 mL), dried the solid in an oven under vacuum at 60°C to 65°C for about 12 hours. Yield: 0.92 g.

EXAMPLE-17: Preparation of amorphous form of venetoclax (2-MeTHF/AcOH/water)

Venetoclax (2 gm), 2-methyl tetrahydrofuran (5 mL) and acetic acid (5 mL) were added in to a round bottom flask at 25°C to 35°C, heated the reaction mass to 65°C to 70°C and stirred for clear solution at same temperature. Then the temperature was allowed to cool to 25°C to 30°C and the resulting solution was added to pre cooled water (60 mL) at 0°C to 5°C. Stirred for about 30 min at this temperature and the precipitated solid was filtered and washed with chilled water (10 mL), dried the solid in an oven under vacuum at 60°C to 65°C for about 12 hours. Yield: 1.5 g.

EXAMPLE-18: Preparation of amorphous form of venetoclax (Anisole/AcOH/heptane)

Venetoclax (2 gm), anisole (10 mL) and acetic acid (0.9 mL) were added in to a round bottom flask at 25°C to 35°C, heated the reaction mass to 65°C to 70°C and stirred for clear solution at same temperature. Then the temperature was allowed to cool to 25°C to 30°C and the resulting solution was added to pre cooled n-heptane (100 mL) at 0°C to 5°C.Stirred for about 30 min at this temperature and the precipitated solid was filtered and washed with n-heptane (10 mL), dried the solid in an oven under vacuum at 60°C to 65°C for about 12 hours. Yield: 1.8 g.

EXAMPLE-19: Preparation of amorphous form of venetoclax (AcOH/water)

Venetoclax (0.5 gm) and acetic acid (1 mL) were added in to a round bottom flask at 25°C to 35°C, heated the reaction mass to 65°C to 70°C and stirred for clear solution at same temperature. Then the temperature was allowed to cool to 25°C to 30°C and the resulting solution was added to water (15 mL) at 25°C to 30°C. Stirred for about 45 min at this temperature and the precipitated solid was filtered and washed with water (5 mL), dried the solid in an oven under vacuum at 60°C to 65°C for about 13 hours. Yield: 0.39 g.

EXAMPLE-20: Preparation of amorphous form of venetoclax (AcOH/t-BuOH/heptane)

Venetoclax (0.5 gm), t-butanol (1.25 mL) and acetic acid (1.25 mL) were added in to a round bottom flask at 25°C to 35°C, heated the reaction mass to 65°C to 70°C and stirred for clear solution at same temperature. Then the temperature was allowed to cool to 25°C to 30°C and the resulting solution was added to pre cooled water (100 mL) at 0°C to 5°C. Stirred for about 45 min at this temperature and the precipitated solid was filtered and washed with water (5 mL), dried the solid in an oven under vacuum at 60°C to 65°C for about 13 hours. Yield: 0.4 g.

EXAMPLE-21: Preparation of amorphous form of venetoclax

Venetoclax (10 gm) was dissolved in a mixture of ethyl acetate (400 mL), acetic acid (2 mL) and methanol (0.5 mL) at 70°C to 75°C. The solution was spray-dried using LAB ULTIMA LU228 spray dryer and dryed the material under vacuum at 50°C to 55°C for 12 hours. Yield: 3.4 g.

EXAMPLE-22: Preparation of amorphous form of venetoclax
Venetoclax (10 gm) was dissolved in a mixture of 2-methyl tetrahydrofuran (200 mL) and water (2.5 mL) at 70°C to 75°C. The solution was spray-dried using LAB ULTIMA LU228 spray dryer and dryed the material under vacuum at 50°C to 55°C for 12 hours. Yield: 4.78 g.

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be constructed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.
,CLAIMS:We Claim:

1. Crystalline form of venetoclax, characterized by X-Ray diffraction (XRD) pattern peaks having one or more peaks selected from the group consisting of:
a) 3.7, 5.1, 5.7, 5.9, 6.8, 7.1, 7.5, 8.3, 8.6, 9.9, 10.4, 11.5, 12.8, 13.4, 13.7, 14.2, 14.4, 14.7, 15.3, 15.7, 17.1, 17.7, 18, 18.6, 19.1, 19.9, 21, 22, 22.3, 22.7, 23.2, 24.1, 24.6, 25.1, 25.5, 26.2, 27, 27.7, 30.4, 31.3 and 32.1 ±0.2° 2? (Form L1);
b) 5.4, 7.5, 8.4, 8.9, 9.7, 10.7, 11.2, 11.9, 13, 14.7, 16.6, 17.7, 19.4, 19.9, 20.4, 21, 22.5, 24.5, 25.6 and 29.4 ±0.2° 2? (Form L2); and
c) 3.7, 5.1, 5.3, 5.7, 6.3, 7.4, 7.9, 8.3, 8.5, 9.2, 9.5, 9.8, 11.5, 12.8, 13.4, 13.7, 13.9, 14.4, 14.7, 15.3, 15.6, 16, 16.4, 17.2, 17.9, 18.2, 18.4, 19.5, 20.2, 21.2, 21.5, 22.3, 22.6, 23.3, 23.7, 24.8, 25.5, 26.1 and 29.8 ±0.2° 2? (Form L3).

2. A process for the preparation of crystalline form of venetoclax as claimed according to claim 1, comprising:
a) providing a solution of venetoclax in anisole at room temperature to reflux temperature,
b) cooling the solution to below 45°C,
c) optionally adding a suitable solvent to step b) reaction mass, and
d) isolating venetoclax;
wherein when the venetoclax Form L1 is obtained by cooling step b) solution to below 30°C and adding a suitable solvent to step b) reaction mass;
wherein when the venetoclax Form L2 is obtained by cooling step b) solution to between 35°C to 45°C and adding a suitable solvent to step b) reaction mass;
wherein when the Form L3 is obtained by cooling the step b) solution below 30°C.

3. The process as claimed in claim 2, wherein the step c) solvent is selected from the group consisting of dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, hexane, heptane, propane, cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and mixture thereof.

4. Crystalline venetoclax Form-L4 characterized by X-Ray diffraction pattern having one or more peaks at about 5.1, 5.5, 6.2, 6.4, 6.8, 8.5, 9.6, 9.8, 10.8, 11.7, 13.5, 14.2, 15.2, 15.9, 16.4, 16.9, 17.9, 18.4, 18.9, 21.3, 22.7, 24.9 and 26.4 ±0.2° 2?.

5. A process for the preparation of crystalline venetoclax Form-L4, comprising: heating venetoclax Form-L1 or venetoclax Form-L3 at about 75°C to about 110°C, wherein the venetoclax Form-L1 is characterized by X-Ray diffraction pattern having one or more peaks at about 3.7, 5.1, 5.7, 5.9, 6.8, 7.1, 7.5, 8.3, 8.6, 9.9, 10.4, 11.5, 12.8, 13.4, 13.7, 14.2, 14.4, 14.7, 15.3, 15.7, 17.1, 17.7, 18, 18.6, 19.1, 19.9, 21, 22, 22.3, 22.7, 23.2, 24.1, 24.6, 25.1, 25.5, 26.2, 27, 27.7, 30.4, 31.3 and 32.1 ±0.2° 2?; and venetoclax Form-L3 is characterized by X-Ray diffraction pattern having one or more peaks at about 3.7, 5.1, 5.3, 5.7, 6.3, 7.4, 7.9, 8.3, 8.5, 9.2, 9.5, 9.8, 11.5, 12.8, 13.4, 13.7, 13.9, 14.4, 14.7, 15.3, 15.6, 16, 16.4, 17.2, 17.9, 18.2, 18.4, 19.5, 20.2, 21.2, 21.5, 22.3, 22.6, 23.3, 23.7, 24.8, 25.5, 26.1 and 29.8 ±0.2° 2?.

6. Crystalline venetoclax Form-L5, characterized by X-Ray diffraction pattern having one or more peaks at about 5,7.9,8.1,8.8,9.3,10.5,10.8,11.1,12.2,13.1,13.4,13.9,14.5,15.1,15.6,15.9,16.3,16.5,17,17.2,17.7,18.6,19,19.5,19.8,20.2,20.6,21,21.7,21.8,22.3,23.2,23.8,24.4,25.3,25.8,26.5,27,27.6,28.1,29,29.8,30.2,31.4,32.8,33.9,35.8 and 37.5 ±0.2° 2?.

7. A process for the preparation of crystalline venetoclax Form-L5, comprising:
a) suspending venetoclax Form-L1 or venetoclax Form-L3 in n-heptane at a temperature of 30°C to reflux,
b) cooling the step a) suspension to below 30°C; and
c) isolating venetoclax Form-L5.
wherein the venetoclax Form-L1 is characterized by X-Ray diffraction pattern having one or more peaks at about 3.7, 5.1, 5.7, 5.9, 6.8, 7.1, 7.5, 8.3, 8.6, 9.9, 10.4, 11.5, 12.8, 13.4, 13.7, 14.2, 14.4, 14.7, 15.3, 15.7, 17.1, 17.7, 18, 18.6, 19.1, 19.9, 21, 22, 22.3, 22.7, 23.2, 24.1, 24.6, 25.1, 25.5, 26.2, 27, 27.7, 30.4, 31.3 and 32.1 ±0.2° 2?; and venetoclax Form-L3 is characterized byX-Ray diffraction pattern having one or more peaks at about 3.7, 5.1, 5.3, 5.7, 6.3, 7.4, 7.9, 8.3, 8.5, 9.2, 9.5, 9.8, 11.5, 12.8, 13.4, 13.7, 13.9, 14.4, 14.7, 15.3, 15.6, 16, 16.4, 17.2, 17.9, 18.2, 18.4, 19.5, 20.2, 21.2, 21.5, 22.3, 22.6, 23.3, 23.7, 24.8, 25.5, 26.1 and 29.8 ±0.2° 2?.

8. Crystalline venetoclax Form-L6, characterized by X-Ray diffraction pattern having one or more peaks at about 5.4, 8.6, 8.9, 9.7, 10.7, 11.2, 11.9, 13, 14.7, 14.9, 15.6, 16.6, 17.7, 19.4, 19.9, 20.4, 21, 24.5, 25.3, 25.7, 27, 29.4, 33.9 and 36.3 ±0.2° 2?.

9. A process for the preparation of crystalline venetoclax Form-L6, comprising:
A) heating venetoclax Form-L2 at about 80°C to about 100°C, or
B) suspending venetoclax Form-L2 in n-heptane at a temperature of 30°C to reflux, cooling the step a) suspension to below 30°C; and isolating venetoclax Form-L6; wherein the venetoclax Form-L2 is characterized by X-Ray diffraction pattern having one or more peaks at about 5.4, 7.5, 8.4, 8.9, 9.7, 10.7, 11.2, 11.9, 13, 14.7, 16.6, 17.7, 19.4, 19.9, 20.4, 21, 22.5, 24.5, 25.6 and 29.4 ±0.2° 2?.

10. Crystalline form of venetoclax, characterized by X-Ray diffraction (XRD) pattern peaks having one or more peaks selected from the group consisting of:
a) 5, 5.8, 7.4, 8, 10.2, 11.2, 11.9, 12.4, 13.5, 14.1, 14.6, 15, 15.3, 16.1, 17.1, 17.5, 18, 19.2, 20, 20.6, 21.5, 22.1, 23.6, 24.7, 25, 25.7, 27.7, 28.9, 29.6, 31.3 and 35.6 ±0.2° 2? (Form L7);
b) 5.7, 7.4, 7.9, 9.7, 10.1, 11.1, 12.4, 12.8, 13.4, 14, 14.9, 15.9, 17, 17.4, 17.9, 19.1, 19.9, 20.6, 22, 23.6, 24.6, 24.9, 25.6, 26.5, 27.6, 28.9, 29.5 and 31.2 ±0.2° 2? (Form L8); and
c) 5, 5.9, 7.4, 8.1, 10.1, 11.4, 11.7, 13.4, 14.2, 14.9, 15.1, 16.1, 16.3, 17.5, 17.9, 18.1, 19.6, 20.1, 21.8, 22.3, 24, 24.8, 25.6, 27.8, 28.4, 30.1, 31.4 and 35.3 ±0.2° 2? (Form L9).

11. A process for the preparation of crystalline form of venetoclax as claimed according to claim 10, comprising:
a) providing a solution of venetoclax in dimethylacetamide at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding acetone, acetonitrile or 1,4-dioxane to the step b) solution,
d) adding water to the step c) solution or vice-versa; and
e) isolating venetoclax;
wherein the venetoclax Form L7 is obtained when the solvent used in step c) is acetone;
wherein the venetoclax Form L8 is obtained when the solvent used in step c) is acetonitrile;
wherein the venetoclax Form L9 is obtained when the solvent used in step c) is 1,4-dioxane.

12. A process for preparation of amorphous form of venetoclax, comprising:
a) providing a solution of venetoclax in one or more solvents,
b) adding a suitable anti-solvent to the step a) solution or vice-versa; and
c) isolating the amorphous form;
wherein the one or more solvents are selected from dimethyl acetamide, N-methyl pyrrolidinone, methyl tetrahydrofuran, acetic acid, anisole, tert-butanol, water and the like and mixtures thereof; wherein the suitable anti-solvent is selected from water, heptanes and the like and mixtures thereof.

13. The process as claimed in claim 12, wherein the step a) is carried out at a temperature of about 50°C to about 80°C; and the step b)is carried out at a temperature of about0°C to about 35°C.

14. A process for preparation of amorphous form of venetoclax, comprising:
a) providing a solution of venetoclax in one or more solvents; and
b) spray-drying the solvent to isolate amorphous venetoclax; wherein the one or more solvents are selected from alcohols, ethers, esters, acetic acid, water and mixtures thereof.

15. The process as claimed in claim 14, wherein the step a) solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, methyl ethyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, dimethoxymethane, di-tert-butyl ether, methoxyethane, ethyl acetate, propyl acetate, acetic acid, water and mixtures thereof.