DESC:In an aspect, the present application provides acid addition salt of Venetoclax, wherein the acid may be selected from the group comprising of Trifluoro acetic acid (TFA), Oxalic acid, Maleic acid, Isethionic acid, Ortho-phosphoric acid, citric acid, methanesulfonic acid and acetic acid.
In an embodiment, the acid addition salt of this aspect may contain Venetoclax and the acid in any stoichiometric ratio.
In an embodiment, the acid addition salt may be in crystalline or an amorphous form. In preferred embodiment, the acid addition salt may be in crystalline form.
In another aspect, the present application provides a Trifluoro acetic acid (TFA) salt of Venetoclax. In an embodiment, the Trifluoro acetic acid (TFA) salt is a crystalline salt, characterized by a PXRD pattern of figure 1.
In another aspect, the present application provides an Oxalic acid salt of Venetoclax. In an embodiment, the Oxalic acid salt is a crystalline salt, characterized by a PXRD pattern of figure 2.
In another aspect, the present application provides a Maleic acid salt of Venetoclax. In an embodiment, the Maleic acid salt is a crystalline salt, characterized by a PXRD pattern of figure 3.
In another aspect, the present application provides an Isethionic acid salt of Venetoclax. In an embodiment, the Isethionic acid salt is a crystalline salt, characterized by a PXRD pattern of figure 4.
In another aspect, the present application provides an Ortho-phosphoric salt of Venetoclax. In an embodiment, the Ortho-phosphoric acid salt is a crystalline salt, characterized by a PXRD pattern of figure 6.
In another aspect, the present application provides a citric acid salt of Venetoclax. In an embodiment, the citric acid salt is a crystalline salt, characterized by a PXRD pattern of figure 7.
In another aspect, the present application provides a methanesulfonic acid salt of Venetoclax. In an embodiment, the methanesulfonic acid salt is a crystalline salt, characterized by a PXRD pattern of figure 8.
In another aspect, the present application provides an acetic acid salt of Venetoclax. In an embodiment, the acetic acid salt is a crystalline salt, characterized by a PXRD pattern of figure 9.

In another aspect, the present application provides a process for the preparation of salt of Venetoclax comprising the step of contacting an acid with Venetoclax, wherein acid may be selected from the group comprising of Trifluoro acetic acid (TFA), Oxalic acid, Maleic acid, Isethionic acid, Ortho-phosphoric acid, citric acid, methanesulfonic acid and acetic acid.
In an embodiment Venetoclax may be contacted with an acid in a mole ratio of about 1: 0.8 to 1:1.6.
In an embodiment, Venetoclax may be contacted with an acid in a heterogeneous or homogenous phase. In an embodiment, Venetoclax may be contacted with an acid in homogeneous phase. In an embodiment, solution comprising Venetoclax in an inert solvent may be contacted with an acid.
In an embodiment, the acid may be used either in concentrated or diluted form before contacting with Venetoclax.
In an embodiment, Venetoclax may be contacted with an acid at a suitable temperature at about 0°C and above for time sufficient for salt formation. In an embodiment, the reaction mixture comprising Venetoclax and the acid may be stirred for sufficient time and at suitable temperature for the completion of salt formation.
In an embodiment, the reaction mixture comprising Venetoclax and the acid may be concentrated and / or cooled to suitable temperature before isolating the salt of Venetoclax.
In an embodiment, suitable anti-solvent may be added to the reaction mixture comprising Venetoclax and the acid before isolating the salt of Venetoclax.
Isolation of acid addition salt of Venetoclax may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, acid addition salt of Venetoclax may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In an embodiment, drying acid addition salt of Venetoclax may be carried out at temperatures and times sufficient to achieve desired quality of product. Drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In an alternate aspect, the present application provides a Hydrochloride salt of Venetoclax. In an embodiment, the hydrochloride salt is a crystalline salt, characterized by a PXRD pattern of figure 5.
The present application provides a process for the preparation of hydrochloride salt of Venetoclax comprising the step of contacting a hydrochloric acid with Venetoclax. In an embodiment, 0.8 to 1.6.moles of hydrochloric acid may be contacted with Venetoclax may be used either in concentrated or diluted form before contacting with Venetoclax. In an embodiment, solution comprising Venetoclax in an inert solvent may be contacted with an acid. In an embodiment, the acid may be used either in concentrated or diluted form before contacting with Venetoclax.
In an embodiment, hydrochloride salt of Venetoclax may be obtained by any suitable method known in the art or process described or exemplified in the instant application for the preparation of hydrochloride salt or any other salt of Venetoclax.
It is worth noting, that the option of purifying a low soluble drug substances among BCS class II or class IV like Venetoclax, by conventional methods like recrystallization from a solvent or mixture of solvents may not be suitable due to the limited solvents. Therefore, purification of such drug substance through salt formation is a boon to a chemist. Venetoclax may be purified through the formation of a suitable salt followed by its neutralization to free from.
Further, these salts may be optionally purified by any method known in the art including recrystallization, before neutralization, unlike the free forms. The salt forms are generally regarded as superior in terms of solubility compared to respective free forms and may be conveniently recrystallized from suitable solvents according to techniques known in the art such cooling crystallization, anti-solvent addition, or the like.
The present application provides a purification process for Venetoclax, comprising the step of converting a salt of Venetoclax obtained according any of the previous aspects into its free form.
In another aspect, the present application provides a process for the preparation of Venetoclax, comprising the step of converting a salt of Venetoclax into its free form, wherein the salt may be selected from the group comprising of Trifluoro acetic acid (TFA), Oxalic acid, Maleic acid, Isethionic acid, Hydrochloric acid, Ortho-phosphoric acid, citric acid, methanesulfonic acid and acetic acid.
In an embodiment, the salt of Venetoclax may be converted to Venetoclax in free form by neutralization. In an embodiment, the salt may be neutralized in the presence of a suitable base.
Suitable base may include, but not limited to: either an inorganic base like hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide; carbonates such sodium carbonate, potassium carbonate, ammonium carbonate; bicarbonates such as sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, or an organic base like amines such as triethyl amine, diisopropyl amine, diisopropyl ethyl amine; alkoxides such as methoxide, ethoxide, isopropoxide, tert. Butoxide; N-heterocyclic Compounds; tetraalkylammonium and phosphonium hydroxides; Amides; metal silanoates; and the like.
In another embodiment, the salt of Venetoclax may be converted to its free form by subjecting the acid addition salt to suitable conditions which may include, but not limited to: suspending the acid addition salt of Venetoclax in a suitable solvent optionally in the presence of a suitable base and optionally at elevated temperatures.

In another aspect, the present application provides a crystalline Form RT1 of Venetoclax characterized by a PXRD pattern comprising the peaks at about 4.39 and 8.56 ± 0.2° 2?. In an embodiment, the application provides crystalline Form RT1 of Venetoclax, characterized by a PXRD pattern having one or more additional peaks at about 5.91, 16.03, 22.08, 24.90 and 26.46 ±0.2° 2?. In an embodiment, the application provides crystalline Form RT1 of Venetoclax, characterized by a PXRD pattern of figure 10.
In another aspect, the present application provides a crystalline Form RT2 of Venetoclax characterized by a PXRD pattern comprising the peaks at about 6.55, 19.37, 23.07, 26.82 and 28.70 ± 0.2° 2?. In an embodiment, the application provides crystalline Form RT2 of Venetoclax, characterized by a PXRD pattern having one or more- additional peaks at about 11.93, 12.95, 13.46, 14.49, 20.04, 22.50 and 25.86 ±0.2° 2?. In an embodiment, the application provides crystalline Form RT2 of Venetoclax, characterized by a PXRD pattern of figure 11.
In another aspect, the present application provides a crystalline Form RT3 of Venetoclax characterized by a PXRD pattern comprising the peaks at about 6.30, 12.57 and 20.06 ± 0.2° 2?. . In an embodiment, the application provides crystalline Form RT3 of Venetoclax, characterized by a PXRD pattern of figure 12.
In another aspect, the present application provides a process for the preparation of crystalline Form RT1 of Venetoclax, comprising the step of contacting Venetoclax with benzyl alcohol.
In an embodiment, contacting Venetoclax with benzyl alcohol may be carried out by suspending or dissolving Venetoclax in benzyl alcohol, optionally by heating. In an embodiment, Venetoclax may be dissolved in benzyl alcohol at suitable temperature of about 30°C and above. Optionally, the solution may be filtered to make it particle free.
Alternatively, the solution may be provided by taking the reaction mixture containing Venetoclax in benzyl alcohol or a mixture thereof. Optionally, the solution may be filtered to make it particle free.
In an embodiment, the solution of Venetoclax in benzyl alcohol may be cooled to precipitate the solids to a suitable temperature and at which crystalline Form RT1 is formed and / or is stable.
In an embodiment, a solution of Venetoclax in benzyl alcohol may be optionally contacted with an anti-solvent. Anti-solvent is the solvent wherein Venetoclax or its crystalline Form RT1 has very low solubility or is insoluble. Anti-solvent may include, but not limited to hydrocarbons such as n-hexane, n-heptane, cyclohexane or the like; ethers such as diethyl ether, di isopropyl ether, methyl tert-Butyl ether or the like; any mixtures thereof.
In an embodiment, the anti-solvent may be contacted at suitable temperature for the nucleation of solids and for sufficient time for the formation of solids. The anti-solvent may be contacted in sufficient quantity to complete the formation of solids.
In an embodiment, the solution of Venetoclax in benzyl alcohol may be cooled to a suitable temperature before and / or after contacting with anti-solvent.
Isolation of crystalline Form RT1 of Venetoclax may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline Form RT1 of Venetoclax may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In an embodiment, drying crystalline Form RT1 of Venetoclax may be carried out at temperatures and times sufficient to achieve desired quality of product. Drying may be carried out for any time period required for obtaining a desired quality, such as from about 5 minutes to 10 hours or longer.

In another aspect, the present application provides a process for the preparation of crystalline Form RT2 of Venetoclax, comprising the steps of:
a) Dissolving or suspending Venetoclax in methyl isopropyl ketone or a mixture thereof
b) Optionally, contacting the solution of step a) with an anti-solvent
c) Isolating crystalline Form RT2 of Venetoclax
In an embodiment, step a) may be carried out by dissolving or suspending Venetoclax in methyl isopropyl ketone or a mixture of methyl isopropyl ketone and any other solvent. Alternatively, the solution may be provided by taking the reaction mixture containing Venetoclax in methyl isopropyl ketone or a mixture thereof.
In an embodiment, the Venetoclax may be dissolved in methyl isopropyl ketone optionally by heating the mixture to obtain a homogenous solution. The solution may be filtered to make it particle free.
In an embodiment, the solution of Venetoclax in methyl isopropyl ketone may be cooled to precipitate the solids to a suitable temperature and at which crystalline Form RT2 is formed and / or is stable.
In an embodiment, optionally the solution of step a) may be contacted with an anti-solvent. Anti-solvent may include, but not limited to hydrocarbons such as n-hexane, n-heptane, cyclohexane or the like; ethers such as diethyl ether, di isopropyl ether, methyl tert-Butyl ether or the like; water; or any mixtures thereof.
In an embodiment, the anti-solvent may be contacted at suitable temperature for the nucleation of solids and for sufficient time for the formation of solids. The anti-solvent may be contacted in sufficient quantity to complete the formation of solids.
Isolation of crystalline Form RT2 of Venetoclax may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline Form RT2 of Venetoclax may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In an embodiment, drying crystalline Form RT2 of Venetoclax may be carried out at temperatures and times sufficient to achieve desired quality of product. Drying may be carried out for any time period required for obtaining a desired quality, such as from about 5 minutes to 10 hours or longer.

In another aspect, the present application provides a process for the preparation of crystalline Form RT3 of Venetoclax, comprising the steps of:
a) Providing a solution of Venetoclax in a methylene chloride or a mixture thereof
b) Optionally washing the solution of step a) with water
c) Removing the solvent of step a) to obtain crystalline Form RT3 of Venetoclax.
In an embodiment, the solution of Venetoclax of step a) may be provided by dissolving Venetoclax in methylene chloride or a mixture thereof, optionally by heating. Alternatively, the solution may be provided by taking the reaction mixture containing Venetoclax in methylene chloride or a mixture thereof. The solution may be filtered to make it particle free.
In an embodiment, the solution of step a) may be optionally washed with water at a suitable temperature. The water washings may be repeated to attain the desired quality of the product. The washed aqueous layer may be extracted back with methylene chloride, if required and combined with the solution of step a).
In an embodiment, the combined solution of Venetoclax in a methylene chloride may be dried over suitable drying agent such as sodium sulfate or the like to remove the residual traces of water.
In an embodiment, the solution of step a) or b) may be cooled to suitable temperature before the removal of the solvent at step c). In an embodiment, step c) may be carried out by removing the solvent of step a) or b) to obtain crystalline Form RT3 of Venetoclax. Removal of the solvent may be carried out at suitable temperature from freezing point to boiling point of the methylene chloride or mixture thereof.
The solvent of step a) or b) may be removed using suitable techniques known in the art or procedures described or exemplified in the present application. Suitable techniques for the removal of the solvent may include but not limited to evaporation of solvent under atmospheric pressure or reduced pressure; spray drying; sublimation such as freeze drying or lyophilisation; thin film drying such as drying in agitated thin film drier; or the like.
In an embodiment, the solvent may be removed by evaporation under reduced pressure at about 0°C to boiling point of the solvent or mixture thereof.
Isolation of crystalline Form RT3 of Venetoclax may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline Form RT3 of Venetoclax may be isolated by employing any of the techniques, but not limited to: scratching the walls of the container with a spatula, adding solvent to make slurry followed by filtration, decantation, filtration by gravity or suction, centrifugation, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In an embodiment, drying crystalline Form RT3 of Venetoclax may be carried out at temperatures and times sufficient to achieve desired quality of product. Drying may be carried out for any time period required for obtaining a desired quality, such as from about 5 minutes to 10 hours or longer.

In another aspect, the present application provides a process for the preparation of amorphous form of Venetoclax, comprising the steps of:
a) Providing a solution of Venetoclax in a suitable or a mixture thereof.
b) Contacting the solution of step a) with an anti-solvent.
c) Isolating amorphous form of Venetoclax.
In an embodiment, step a) may be carried out by dissolving Venetoclax in a suitable solvent or a mixture thereof. Alternatively, the solution may be provided by taking the reaction mixture containing Venetoclax in solvent or a mixture of solvents.
Suitable solvent may include, but not limited to: dimethyl sulfoxide, dimethyl formamide, tetrahydrofuran or the like
In an embodiment, the Venetoclax may be dissolved in the solvent, optionally under heating to obtain a homogenous solution. The solution may be filtered to make it particle free.
In an embodiment, the solution of Venetoclax of step a) may be optionally cooled to a suitable temperature before or after contacting it with anti-solvent.
In an embodiment, the solution of step a) may be cooled to temperature above the freezing point of the solvent used before contacting it with anti-solvent.
In an embodiment, the anti-solvent may be contacted at suitable temperature and concentration for the nucleation of amorphous form.
The anti-solvent may be contacted in sufficient volume to complete the formation of solids with ratio of solvent to anti-solvent of about 1: 1 to 1: 20.
In an embodiment, anti-solvent may be contacted in any of the modes such as addition of anti-solvent to the solution of step a) or addition of solution of step a) to the anti-solvent.
In an embodiment, the anti-solvent may be contacted for sufficient time, till the amorphous form is stable. In an embodiment, anti-solvent may be contacted with solution of step a) either by gradual addition or in single short addition such as dumping of one into the other.
Anti-solvent may include, but not limited to water; hydrocarbons such as n-hexane, n-heptane, cyclohexane or the like; ethers such as diethyl ether, di isopropyl ether, methyl tert-Butyl ether; or the like.
Isolation of amorphous form of Venetoclax may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, amorphous form of Venetoclax may be isolated by employing any of the techniques, but not limited to: scratching the walls of the container with a spatula, adding solvent to make slurry followed by filtration, decantation, filtration by gravity or suction, centrifugation, or other techniques specific to the equipment used and the like, and optionally washing with an anti-solvent.
In an embodiment, drying amorphous form of Venetoclax may be carried out at temperatures and times sufficient to achieve desired quality of product. Drying may be carried out for any time period required for obtaining a desired quality, such as from about 5 minutes to 10 hours or longer.
Starting materials used for the preparation of crystalline Form RT1, Form RT2, Form RT3 of Venetoclax or acid addition salts thereof according to any of the aspects of the present application may be any crystalline or amorphous in nature. Further, these starting materials may be purified according to any of the method known in the art such as recrystallization, slurrying, acid-base treatment i.e., salt making and breaking, chromatography, fractional distillation or any other separation methods, before using.
In another aspect, the present application provides a pharmaceutical composition comprising the acid addition salts of Venetoclax or solid forms thereof and atleast one additional pharmaceutically acceptable excipient, wherein the acid may be selected from the group comprising of Trifluoro acetic acid (TFA), Oxalic acid, Maleic acid, Isethionic acid, Hydrochloric acid, Ortho-phosphoric acid, citric acid, methanesulfonic acid and acetic acid.
Similar procedures for the preparation of any Venetoclax salts described here may be useful to produce other salts of Venetoclax comprising the acid addition salts such as adipate, alginate, bicarbonate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, formate, fumarate, glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydroiodide, lactobionate, lactate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, pamoate, pectinate, persulfate, picrate, propionate, succinate, tartrate, thiocyanate, trichloroacetic, para-toluenesulfonate, and undecanoate; basic addition salts such as hydroxide, carbonate or bicarbonate of cations such as lithium, sodium, potassium, calcium, and magnesium.
In another aspect, the present application provides a pharmaceutical composition comprising crystalline forms RT1, RT2 & RT3 of Venetoclax and atleast one additional pharmaceutically acceptable excipient.
In another aspect, the present application provides a pharmaceutical composition comprising amorphous form of Venetoclax obtained according the process of instant application and atleast one additional pharmaceutically acceptable excipient.
In another aspect, the present application provides crystalline or amorphous form of Venetoclax or its acid addition salts according to instant application and pharmaceutical compositions thereof, wherein the chemical purity of Venetoclax or acid addition salt 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 crystalline or amorphous form of Venetoclax or its acid addition salts according to instant application and pharmaceutical compositions thereof, wherein particle size (D90) of Venetoclax may be less than 100 microns or less than 50 microns or less than 20 microns.
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.
The term “inert solvent” when used in the present application is a solvent that does not react with the reactants or reagents under conditions that cause the chemical reaction indicated to take place.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include, but are not limited to, methanol, ethanol, ethylene glycol, diethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.
An “aliphatic hydrocarbon” is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called “aromatic.” Examples of “C5-C8 aliphatic or aromatic hydrocarbons” include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or any mixtures thereof.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6 esters” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.
An “ether” is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.
A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6 Nitriles” include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.
EXAMPLES
Example-1: Preparation of Trifluoroacetic acid (TFA) salt of Venetoclax
Venetoclax (500 mg) was dissolved in acetone (10 mL) at 28°C and trifluoroacetic acid (TFA) (0.048 mL) was added at the same temperature. The reaction mixture was stirred for 4 hours at 28°C and filtered the solid. The solid was washed with acetone (10 mL) and dried for 20 hours under reduced pressure at 28°C and for 45 minutes at 50°C to obtain the title compound with melting range of 230-232°C. Yield: 545 mg and HPLC purity: 99.37%

Example-2: Preparation of Oxalic acid salt of Venetoclax
Venetoclax (500 mg) was dissolved in ethanol (10 mL) at 28°C and oxalic acid (57.0 mg in 5 mL of ethanol) was added at the same temperature. The reaction mixture was heated to 90°C and stirred at this temperature for 3 hours. Cooled the reaction mixture to 28°C and stirred for 14 hours at the same temperature. The solid was filtered and washed with ethanol (10 mL). The solid was dried for 24 hours at under reduced pressure at 28°C and at 50°C for 45 minutes to obtain the title compound with melting range of 220-223°C. Yield: 369 mg and HPLC purity: 99.08%

Example-3: Preparation of Maleic acid salt of Venetoclax
Venetoclax (500 mg) was dissolved in acetone (8 mL) at 28°C and maleic acid (73.5 mg in 2 mL of acetone) was added at the same temperature. The reaction mixture was stirred for 17 hours at 28°C and filtered the solid. The solid was washed with acetone (10 mL) and dried for 6 hours at 28°C under reduced pressure and 45 minutes at 50°C under reduced pressure to obtain the title compound with melting range of 204-206°C. Yield: 372 mg and HPLC purity: 99.518%

Example-4: Preparation of Isethionic acid salt of Venetoclax
Venetoclax (500 mg) was dissolved in acetone (10 mL) at 28°C and isethionic acid (0.049 mL) was added at the same temperature. The reaction mixture was stirred for 17 hours at 28°C and filtered the solid. The solid was washed with acetone (10 mL) and dried for 6 hours at 28°C under reduced pressure and 45 minutes at 50°C under reduced pressure to obtain the title compound with melting range of 172-174°C. Yield: 500 mg and HPLC purity: 99.539%

Example-5: Preparation of hydrochloride salt of Venetoclax
Venetoclax (500 mg) was dissolved in acetone (10 mL) at 28°C and hydrochloric acid (0.25 mL of 4 M hydrochloride in 1,4-dioxane) was added at the same temperature. The reaction mixture was stirred for 17 hours at 28°C and filtered the solid. The solid was washed with acetone (10 mL) and dried for 6 hours at 28°C under reduced pressure and 45 minutes at 50°C under reduced pressure to obtain the title compound with melting range of 200-202°C. Yield: 440 mg and HPLC purity: 99.278%

Example-6: Preparation of Ortho-phosphoric acid salt of Venetoclax
Venetoclax (500 mg) was dissolved in acetone (10 mL) at 28°C and ortho-phosphoric acid (0.032 mL) was added at the same temperature. The reaction mixture was stirred for 16.5 hours at 28°C and filtered the solid. The solid was washed with acetone (10 mL) and dried for 6 hours at 28°C under reduced pressure and 45 minutes at 50°C under reduced pressure to obtain the title compound with melting range of 200-202°C. Yield: 400 mg and HPLC purity: 99.165%

Example-7: Preparation of Citric acid salt of Venetoclax
Venetoclax (500 mg) was dissolved in acetone (8 mL) at 28°C and citric acid monohydrate (133 mg in 2 mL of acetone) was added at the same temperature. The reaction mixture was stirred for 18 hours at 28°C and filtered the solid. The solid was washed with acetone (10 mL) and dried for 6 hours at 28°C under reduced pressure and 45 minutes at 50°C under reduced pressure to obtain the title compound with melting range of 168-170°C. Yield: 532 mg and HPLC purity: 98.796%

Example-8: Preparation of Methanesulfonic acid salt of Venetoclax
Venetoclax (500 mg) was dissolved in acetone (10 mL) at 28°C and methanesulfonic acid (0.04 mL) was added at the same temperature. The reaction mixture was stirred for 17 hours at 28°C and filtered the solid. The solid was washed with acetone (10 mL) and dried for 12 hours at 28°C under reduced pressure and 45 minutes at 50°C under reduced pressure to obtain the title compound with melting range of 165-168°C. Yield: 448 mg and HPLC purity: 99.51%

Example-9: Preparation of Acetic acid salt of Venetoclax
Acetic acid (0.036 mL) was added to a mixture of Venetoclax (500 mg) in acetone (10 mL) at 28°C and heated to 60°C. The reaction mixture was stirred for 1 hour at 60°C and cooled to 28°C. The reaction mixture was stirred for 14 hours at the same temperature and filtered. The solid was washed with acetone (10 mL) and dried for 6 hours at 28°C under reduced pressure and 45 minutes at 50°C under reduced pressure to obtain the title compound with melting range of 158-160°C. Yield: 452 mg and HPLC purity: 99.333%

Example-10: Preparation of crystalline Form RT1 of Venetoclax
Venetoclax (1 g) was dissolved in benzyl alcohol (2 mL) at 90°C and cooled the solution to 50°C. n-heptane (18 mL) was added to the solution at 50°C and cooled further to 25°C. Methyl tert. Butyl ether (10 mL) was added to the reaction mixture and stirred for 5 minutes. The solid was filtered under vacuum for about 10 minutes and dried at 50°C for one hour in air tray drier to obtain the title compound.

Example-11: Preparation of crystalline Form RT2 of Venetoclax
A mixture of Venetoclax (1 g) in methyl isopropyl ketone (20 mL) was heated to 45°C and stirred at the same temperature for about 8 hours. Cooled the reaction mixture to 25°C and filtered under vacuum for about 5 minutes. The solid was dried at 45°C for one hour in air tray drier to obtain the title compound.

Example-12: Preparation of crystalline Form RT3 of Venetoclax
Venetoclax (20 g) was dissolved in methylene chloride (1 L) at 28°C and water (400 mL) was added to this solution. The mixture was stirred for 30 minutes at 28°C and separated the organic layer. The aqueous layer was extracted with methylene chloride (300 mL). The combined organic layer was washed with water (400 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated from the organic layer under reduced pressure at 50°C and the solid was dried under reduced pressure for 6 hours at 50°C to obtain the title compound with melting range of 141-146°C. Yield: 19.11 g and HPLC purity: 99.290 %

Example-13: Preparation of amorphous form of Venetoclax
Venetoclax (20 g) was dissolved in DMSO (60 mL) at 90°C and filtered the solution under hot condition. The hot filtrate was added to water (600 mL) at 25°C and stirred for about 10minutes at the same temperature. The solid was filtered and dried under reduced pressure initially followed by drying in air tray drier at 45 °C for 7 hours to obtain the title compound. Yield: 18.5 g
,CLAIMS:1. A process for the preparation of amorphous form of Venetoclax, comprising the steps of:
a) providing a solution of Venetoclax in a suitable solvent or a mixture thereof;
b) contacting the solution of step a) with an anti-solvent;
c) isolating amorphous form of Venetoclax.
2. The process according to claim 1, wherein the solvent is selected from dimethyl sulfoxide, dimethyl formamide, tetrahydrofuran or mixtures thereof.
3. The process according to claim 1, wherein the anti-solvent is selected from water, n-hexane, n-heptane, cyclohexane, di isopropyl ether, methyl tert-Butyl ether or mixtures thereof.
4. A process for the preparation of salt of Venetoclax comprising the step of contacting an acid with Venetoclax, wherein acid is selected from the group comprising of trifluoro acetic acid (TFA), oxalic acid, maleic acid, isethionic acid, ortho-phosphoric acid, citric acid, methanesulfonic acid and acetic acid.
5. A process for the preparation of Venetoclax, comprising the step of converting a salt of Venetoclax into its free form, wherein the salt is selected from the group comprising of trifluoro acetic acid (TFA), oxalic acid, maleic acid, isethionic acid, ortho-phosphoric acid, citric acid, methanesulfonic acid and acetic acid.
6. A crystalline form of Venetoclax that is a:
(a) crystalline Form RT1, that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 4.39 and 8.56 ± 0.2° 2?;
(b) crystalline Form RT3, that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.30, 12.57 and 20.06 ± 0.2° 2?;
(c) crystalline Form RT4, that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 4.55 and 5.10 ± 0.2° 2?;
(d) crystalline Form RT5, that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.51 and 25.00 ± 0.2° 2?.
7. A process for the preparation of crystalline Form RT1 of Venetoclax, comprising the step of contacting Venetoclax with benzyl alcohol.
8. A process for the preparation of crystalline Form RT3 of Venetoclax, comprising the steps of:
a) providing a solution of Venetoclax in methylene chloride or a mixture thereof;
b) optionally washing the solution of step a) with water;
c) removing the solvent of step a) to obtain crystalline Form RT3 of Venetoclax.
9. A process for the preparation of crystalline Form RT4 of Venetoclax, comprising the steps of:
a) dissolving or suspending Venetoclax in methyl iso-butyl Ketone or a mixture thereof;
b) optionally, contacting the solution of step a) with an anti-solvent;
c) isolating crystalline Form RT4 of Venetoclax.
10. A process for the preparation of crystalline Form RT5 of Venetoclax, comprising the steps of:
a) dissolving or suspending Venetoclax in 1,4-dioxane or mixture thereof;
b) optionally, contacting the solution of step a) with an anti-solvent;
c) isolating crystalline Form RT5 of Venetoclax.