DESC:INTRODUCTION
Aspects of the present application relates to processes for the preparation of amorphous Venetoclax and amorphous solid dispersion of Venetoclax.
The drug compound having the adopted name “Venetoclax” has chemical name: 4-(4-{[2-(4-chlorophenyl)-4,4dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide) as below.

Venetoclax is a selective and orally bioavailable small-molecule inhibitor of BCL-2, an anti-apoptotic protein. Overexpression of BCL-2 has been demonstrated in CLL cells where it mediates tumor cell survival and has been associated with resistance to chemotherapeutics. Venetoclax helps restore the process of apoptosis by binding directly to the BCL-2 protein, displacing pro-apoptotic proteins like BIM, triggering mitochondrial outer membrane permeabilization and the activation of caspases. In nonclinical studies, Venetoclax has demonstrated cytotoxic activity in tumor cells that overexpress BCL-2.
Venetoclax is approved in US as VENCLEXTA tablet for oral administration for the treatment of patients with chronic lymphocytic leukemia with 17p deletion, as detected by an FDA approved test, who have received at least one prior therapy. This indication is approved under accelerated approval based on overall response rate. VENCLEXTA is available as 10, 50 and 100 mg tablets with dosage of 20 mg once daily for 7 days, followed by a weekly ramp-up dosing schedule to the recommended daily dose of 400 mg.
US 8546399 B2 discloses Venetoclax and its pharmaceutical compositions. US 8546399 B2 illustrates the usefulness of Venetoclax as an inhibitor of BCL-2 protein.
WO 2012121758 A1 and WO 2012058392 A1 describe the solid dispersions of various BCL-2 protein inhibitors with atleast one water soluble polymer and atleast one surfactant in essentially non-crystalline form including Venetoclax.
US 8722657 B2 describes various crystalline forms A to N of Venetoclax including solvated and non-solvated forms and salts of Venetoclax including hydrochloride and sulfate.
US 8722657 B2 discloses that Venetoclax is obtained in amorphous state through the synthesis disclosed therein. Further, it indicates that amorphous form of Venetoclax may not be suitable as an active pharmaceutical ingredient for various types of downstream formulations. Also, it discloses that it is difficult and expensive to purify amorphous form of Venetoclax, which can present process control problems.
Amorphous form of a drug may exhibit a higher bioavailability than its crystalline counterparts, which leads to the selection of the amorphous form as the final drug substance for pharmaceutical dosage form development. Additionally, the solubility of crystalline form is lower than its amorphous form in some instances, particularly aqueous solubility, which may result in the difference in their in-vivo bioavailability. Therefore, it is desirable to have an amorphous form of a drug to meet the needs of drug development which is stable and also a reproducible process for their preparation. Hence, it is desirable to provide a stable amorphous Venetoclax or its solid dispersion.
SUMMARY
In another aspect, the present application provides process for the preparation of amorphous form of Venetoclax comprising:
a) providing a solution of Venetoclax in acid;
b) contacting the solution of step a) with aqueous base; and
c) isolating the amorphous form of Venetoclax.

In another aspect, the present application provides process for the preparation of amorphous form of Venetoclax comprising:
a) providing a solution of Venetoclax in acetic acid;
b) contacting the solution of step a) with aqueous ammonia; and
c) isolating the amorphous form of Venetoclax.

An 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 solvent;
b) contacting the solution of step a) with an anti-solvent at high temperature; and
c) isolating the amorphous form of Venetoclax.

An 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 solvent selected from DMSO, acetic acid, N-methyl-2-pyrrolidone (NMP), dimethylformamide (DMF);
b) contacting the solution of step a) with ethyl acetate;
c) contacting the solution of step b) with an anti-solvent; and
d) isolating the amorphous form of Venetoclax.

In another aspect, the present application provides a process for the preparation of amorphous solid dispersion of Venetoclax with syloid, comprising the steps of:
a) providing a solution of Venetoclax in a suitable solvent;
b) contacting the solution of step a) with mixture of anti-solvent and syloid; and
c) isolating the amorphous solid dispersion of Venetoclax with syloid.

In another aspect, the present application provides a process for the preparation of amorphous solid dispersion of Venetoclax with syloid, comprising the steps of:
a) providing a solution of Venetoclax and syloid in a suitable solvent; and
b) isolating the amorphous solid dispersion of Venetoclax with syloid using agitated thin film dryer (ATFD) or spray dryer.

In another aspect, the present application provides a process for the preparation of amorphous solid dispersion of Venetoclax with soluplus, comprising the steps of:
a) providing a solution of Venetoclax and soluplus in acetone; and
b) isolating the amorphous solid dispersion of Venetoclax with soluplus.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of amorphous form of Venetoclax prepared by the method of Example No 2.
Figure 2 is an illustrative X-ray powder diffraction pattern of amorphous form of Venetoclax prepared by the method of Example No 3.
Figure 3 is an illustrative X-ray powder diffraction pattern of amorphous form of Venetoclax prepared by the method of Example No 4.
Figure 4 is an illustrative X-ray powder diffraction pattern of amorphous form of Venetoclax prepared by the method of Example No 5.
Figure 5 is an illustrative X-ray powder diffraction pattern of amorphous form of Venetoclax prepared by the method of Example No 7.
Figure 6 is an illustrative X-ray powder diffraction pattern of amorphous form of Venetoclax prepared by the method of Example No 6.
Figure 7 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Venetoclax with soluplus prepared by the method of Example No 15.
Figure 8 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Venetoclax with syloid prepared by the method of Example No 14.
Figure 9 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Venetoclax with syloid prepared by the method of Example No 11.
Figure 10 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Venetoclax with syloid prepared by the method of Example No 12.
Figure 11 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Venetoclax with syloid prepared by the method of Example No 13.
Figure 12 is an illustrative X-ray powder diffraction pattern of amorphous form of Venetoclax prepared by the method of Example No 8.
Figure 13 is an illustrative X-ray powder diffraction pattern of amorphous form of Venetoclax prepared by the method of Example No 9.
Figure 14 is an illustrative X-ray powder diffraction pattern of amorphous form of Venetoclax prepared by the method of Example No 10.
Figure 15 is an illustrative X-ray powder diffraction pattern of amorphous form of Venetoclax prepared by the method of Example No 1.

DETAILED DESCRIPTION
In another aspect, the present application provides process for the preparation of amorphous form of Venetoclax comprising:
a) providing a solution of Venetoclax in acid;
b) contacting the solution of step a) with aqueous base; and
c) isolating the amorphous form of Venetoclax.
In an embodiment, suitable acid used in step a) include, but are not limited to acetic acid, formic acid, methanoic acid, benzoic acid, hydrofluoric acid, nitrous acid, phosphoric acid, sulfurous acid, oxalic acid, hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, perchloric acid, chloric acid and the like.
In an embodiment, providing a solution at step a) may be carried out by dissolving Venetoclax in a suitable acid or by taking the reaction mixture containing Venetoclax directly. In an embodiment, a solution of Venetoclax can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature. Stirring and heating may be used to reduce the time required for the dissolution process.
In an embodiment, a solution of Venetoclax may be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, the solution of Venetoclax of step a) may be optionally cooled to a suitable temperature before or after contacting it with aqueous base.
In an embodiment, the aqueous base may be contacted at suitable temperature and concentration for the nucleation of amorphous form. In a specific embodiment, the aqueous base may be contacted at about 20oC.
The aqueous base may be contacted in sufficient volume to complete the formation of solids.
In an embodiment, aqueous base may be contacted in any of the modes such as addition of aqueous base to the solution of step a) or addition of solution of step a) to the aqueous base.
In an embodiment, base 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.
In an embodiment, suitable base used in step b) include, but are not limited to ammonia, trimethyl ammonia, pyridine, ammonium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and 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 water.
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.

In another aspect, the present application provides process for the preparation of amorphous form of Venetoclax comprising:
a) providing a solution of Venetoclax in acetic acid;
b) contacting the solution of step a) with aqueous ammonia; and
c) isolating the amorphous form of Venetoclax.
In an embodiment, providing a solution at step a) may be carried out by dissolving Venetoclax in acetic acid or by taking the reaction mixture containing Venetoclax directly. In an embodiment, a solution of Venetoclax can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature. Stirring and heating may be used to reduce the time required for the dissolution process.
In an embodiment, acetic acid solution of Venetoclax may be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, the acetic acid solution of Venetoclax of step a) may be optionally cooled to a suitable temperature before or after contacting it with aqueous ammonia.
In an embodiment, the aqueous ammonia may be contacted at suitable temperature and concentration for the nucleation of amorphous form. In a specific embodiment, the aqueous ammonia may be contacted at about 20oC.
The aqueous ammonia may be contacted in sufficient volume to complete the formation of solids.
In an embodiment, aqueous ammonia may be contacted in any of the modes such as addition of aqueous ammonia to the solution of step a) or addition of solution of step a) to the aqueous ammonia.
In an embodiment, aqueous ammonia may be contacted with acetic acid solution of Venetoclax of step a) either by gradual addition or in single short addition such as dumping of one into the other.
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 water.
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.

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 solvent;
b) contacting the solution of step a) with an anti-solvent at high temperature; and
c) isolating the 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 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, 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 at suitable temperature and concentration for the nucleation of amorphous form. In an specific embodiment, the anti-solvent may be contacted at 50-70oC
The anti- solvent may be contacted in sufficient volume to complete the formation of solids.
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.

An 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 solvent selected from DMSO, acetic acid, N-methyl-2-pyrrolidone (NMP), dimethylformamide (DMF);
b) contacting the solution of step a) with ethyl acetate;
c) contacting the solution of step b) with an anti-solvent; and
d) isolating the amorphous form of Venetoclax.
In an embodiment, step a) may be carried out by dissolving Venetoclax in a suitable solvent selected from DMSO, acetic acid, N-methyl-2-pyrrolidone (NMP), dimethylformamide (DMF).
In an embodiment, ethyl acetate may be useful as bridging solvent and the ratio of solvent to bridging solvent is about 1:0.1 to 1:20. The bridging solvent is useful for the formation spherical agglomeration of amorphous Venetoclax. This agglomeration is resulted in improved filtration rate characterized by an improvement in cake resistance value. The study has resulted in identifying novel approaches to overcome criticalities in amorphous precipitation processes & develop a robust scalable process.
In an embodiment, the Venetoclax may be dissolved in the solvent selected from DMSO, acetic acid, N-methyl-2-pyrrolidone (NMP), dimethylformamide (DMF), 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 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.
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, 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.

In another aspect, the present application provides a process for the preparation of amorphous solid dispersion of Venetoclax with syloid, comprising the steps of:
a) providing a solution of Venetoclax in a suitable solvent;
b) contacting the solution of step a) with mixture of anti-solvent and syloid; and
c) isolating the amorphous solid dispersion of Venetoclax with syloid.
In an embodiment, a solution of Venetoclax may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In an embodiment, a solution of Venetoclax may be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
Suitable solvent may include, but not limited to: dimethyl sulfoxide, dimethyl formamide or the like.
In an embodiment, the solution of Venetoclax of step a) may be optionally cooled to a suitable temperature before or after contacting it with mixture of anti-solvent and syloid.
In an embodiment, the mixture of anti-solvent and syloid may be contacted at suitable temperature and concentration for the nucleation of amorphous form.
In an embodiment, mixture of anti-solvent and syloid may be contacted in any of the modes such as addition of mixture of anti-solvent and syloid to the solution of step a) or addition of solution of step a) to the mixture of anti-solvent and syloid.
In an embodiment, mixture of anti-solvent and syloid 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 solid dispersion of Venetoclax with syloid 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 solid dispersion of Venetoclax with syloid 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 solid dispersion of Venetoclax with syloid, comprising the steps of:
a) providing a solution of Venetoclax and syloid in a suitable solvent;
b) isolating the amorphous solid dispersion of Venetoclax with syloid using agitated thin film dryer (ATFD) or spray dryer.
In an embodiment, suitable solvent at step a) of this aspect may be selected from C1-C6 alcohols, C3-C6 ketones, C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, C2-C6 aliphatic or cyclic ethers, C2-C6 nitriles, halogenated hydrocarbons or mixtures thereof.
In preferred embodiment, the suitable solvent may be selected from the group comprising of alcohol solvents such as methanol, ethanol, 2-propanol, 1-butanol, 2- butanol, 1-pentanol, 2-pentanol, 3-pentanol; dichloro methane; tetrahydrofuran; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; esters solvents such as methyl acetate, ethyl acetate, isopropyl acetate and mixtures thereof.
In an embodiment, a solution of Venetoclax and syloid may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In an embodiment, a solution of Venetoclax and syloid may be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, removal of solvent at step b) may be carried out by agitated thin film dryer or spray dryer.
In an embodiment, the solvent may be removed under reduced pressures, at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures. In preferred embodiment, the solvent may be removed under reduced pressures, at temperature range from about 40°C to 80°C.
In an embodiment, drying amorphous solid dispersion of Venetoclax with syloid 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 solid dispersion of Venetoclax with soluplus, comprising the steps of:
a) providing a solution of Venetoclax and soluplus in acetone;
b) isolating the amorphous solid dispersion of Venetoclax with soluplus.
In an embodiment, a solution of Venetoclax and soluplus may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In an embodiment, a solution of Venetoclax and soluplus may be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, removal of solvent at step b) may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using buchi rotavapor, spray drying, freeze drying, agitated thin film drying and the like.
In an embodiment, the solvent may be removed under reduced pressures, at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures. In preferred embodiment, the solvent may be removed under reduced pressures, at temperature range about 40°C to 80°C.
In an embodiment, drying amorphous solid dispersion of Venetoclax with soluplus 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.
Amorphous form of Venetoclax or its solid dispersion may be obtained alternatively either by employing a melt-extrusion technique or by combining a solution of Venetoclax as obtained any of the aspects of present application with a suitable anti-solvent. In embodiment, amorphous product may be obtained by employing suitable melt-extrusion conditions or any of the procedures known in the art for obtaining amorphous product by melt-extrusion technique. In embodiment, solution of Venetoclax may be combined with the anti-solvent at suitable temperature and for sufficient time to obtain amorphous product. Suitable anti-solvent is a solvent, wherein Venetoclax has low solubility and it may include, but not limited to aliphatic or cyclic ethers solvents, aliphatic or aromatic hydrocarbons or the like.
The present application provides amorphous Venetoclax, its solid dispersion or pharmaceutical composition comprising Venetoclax having a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.
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 terms “amorphous form of Venetoclax" and “amorphous Venetoclax” indicate that the Venetoclax is present in substantially amorphous state in the composition (e.g. solid dispersion, adsorbate or pharmaceutical composition). "Substantially" amorphous denotes that 90 %, preferably 95 % or 99 %, more preferably all of the Venetoclax being present in the solid dispersion, on the adsorbate or in the pharmaceutical composition is amorphous. In other words, an "amorphous" Venetoclax composition denotes a Venetoclax-containing composition, which does not contain substantial amounts, preferably does not contain noticeable amounts, of crystalline portions of Venetoclax e.g. measurable upon X-ray powder diffraction analysis.
The term "solid dispersion" when used in the present application, denotes a state where most of the Venetoclax, preferably 90%, 95% or all of the Venetoclax of the solid dispersion, is homogeneously molecularly dispersed in a solid polymer matrix. Preferably solid dispersion, relates to a molecular dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a non-ordered way. In other words, in a solid dispersion, the two components (polymer and API) form a homogeneous one-phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size. In a preferred embodiment, in the solid dispersion according to the present invention no chemical bonds can be detected between the API and the polymer. In order to arrive at such a solid dispersion, preferably solid solution, it is required to have a substantial amount of API dissolved in a suitable solvent at least at one time point during preparation of said solid dispersion.
The term "adsorbate" when used in the present application, specifies that the Venetoclax is, preferably evenly, and preferably homogeneously, distributed on the inner and/or outer surface of the particulate substrate.
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, 2-nitroethanol,2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 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-C8aliphatic 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-C6esters” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl 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-C6Nitriles” include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.
A “soluplus” also referred commercially as Soluplus® is an excipient available from BASF Global.
EXAMPLES
Example-1: Preparation of Amorphous form of Venetoclax
Venetoclax (20 g) was dissolved in acetic acid (80 mL) at 45°C and filtered the solution to make it particle free. The clear solution was added to aqueous ammonia (136 mL in 1200 mL water) at 20oC. The reaction mixture was stirred for 10 minutes at 20oC. The resulted suspension was filtered and washed with water (400 mL). The solid was dried under reduced pressure initially followed by drying in vacuum tray drier at 70°C for 5 hours to obtain the title compound. Yield: 17.1g; HPLC purity: 98.921%
Example-2: Preparation of amorphous form of Venetoclax
Venetoclax (10 g) was dissolved in DMSO (35 mL) at 45°C and filtered the solution to make it particle free. The filtrate was added to water (500 mL) at 52°C and stirred for 20 minutes at the same temperature. The resulted suspension was filtered and washed with water (200 mL). The solid was dried under reduced pressure initially followed by drying in vacuum tray drier at 80°C for 7 hours to obtain the title compound.
Example-3: Preparation of amorphous form of Venetoclax
Venetoclax (40 g) was dissolved in DMSO (120 mL) at 45°C and filtered the solution to make it particle free. The filtrate was added to water (600 mL) at 63°C and stirred for 40 minutes at the same temperature. The reaction mass was cooled to 15°C and stirred for 60 minutes. The resulted suspension was filtered and washed with water (80 mL). The solid was dried under reduced pressure initially followed by drying in vacuum tray drier at 80°C for 8 hours to obtain the title compound.
Example-4: Preparation of amorphous form of Venetoclax
Venetoclax (5 g) was dissolved in DMSO (22.5 mL) at 45°C and filtered the solution to make it particle free. The filtrate was added to water (250 mL) at 68°C and stirred for 30 minutes at the same temperature. The resulted suspension was filtered and washed with water (100 mL). The solid was dried under reduced pressure initially followed by drying in vacuum tray drier at 80°C for 8 hours to obtain the title compound. Yield: 4.5g
Example-5: Preparation of amorphous form of Venetoclax
Venetoclax (1 g) was dissolved in acetic acid (5 mL) at 45°C. The clear solution was added to water (50 mL) and stirred for 10 minutes. The resulted suspension was filtered and dried under reduced pressure to obtain the title compound.
Example-6: Preparation of amorphous form of Venetoclax
Venetoclax (1 g) was dissolved in N-methyl-2-pyrrolidone (10 mL) at 45°C. The clear solution was added to water (50 mL) and stirred for 30 minutes. The resulted suspension was filtered and dried under reduced pressure to obtain the title compound.
Example-7: Preparation of amorphous form of Venetoclax
Venetoclax (1 g) was dissolved in DMF (4 mL) at 45°C. The clear solution was added to water (50 mL) and stirred for 30 minutes. The resulted suspension was filtered and dried under reduced pressure to obtain the title compound.
Example-8: Preparation of amorphous form of Venetoclax
Venetoclax (4 g) was dissolved in DMSO (18 mL) and ethyl acetate (2 mL) at 45°C. The solution was added to water (200 mL) and stirred for 30 minutes. The resulted suspension was filtered and washed with water (80 mL). The solid was dried under reduced pressure initially followed by drying in vacuum tray drier at 79°C for 6 hours to obtain the title compound.
Example-9: Preparation of amorphous form of Venetoclax
Venetoclax (5 g) was dissolved in DMSO (22.5 mL) and ethyl acetate (15 mL) at 45°C. The solution was added to water (250 mL) and stirred for 30 minutes. The resulted suspension was filtered and washed with water (100 mL). The solid was dried under reduced pressure initially followed by drying in vacuum tray drier at 80°C for 8 hours to obtain the title compound.
Example-10: Preparation of amorphous form of Venetoclax
Venetoclax (5 g) was dissolved in DMSO (22.5 mL) and ethyl acetate (2.5 mL) at 45°C. The solution was added to water (250 mL) at 3°C and stirred for 30 minutes. The resulted suspension was filtered and washed with water (100 mL). The solid was dried under reduced pressure initially followed by drying in vacuum tray drier at 70°C for 7 hours to obtain the title compound.
Example-11: Preparation of amorphous solid dispersion of Venetoclax with syloid 244 NF
Venetoclax (3 g) was dissolved in DMSO (10.5 mL) at 45°C and filtered the solution to make it particle free. The filtrate was added to mixture of syloid 244 NF (9 g) and water (150 mL). The resulted suspension was filtered and washed with water (60 mL). The solid was dried under reduced pressure initially followed by drying in vacuum tray drier at 90°C for 2 hours to obtain the title compound.
Example-12: Preparation of amorphous solid dispersion of Venetoclax with syloid 244 NF
Venetoclax (5 g) was dissolved in dichloromethane (667 mL) and filtered the solution to make it particle free. Syloid 244 NF (28 g) was added to the filtrate. The resulted suspension was dried using ATFD to obtain the title compound. The feed rate is 15 ml/min (temperature 40°C/ vacuum 200 mmHg) while maintaining the dispersion by magentic stirring at 500 rpm.
Example-13: Preparation of amorphous solid dispersion of Venetoclax with syloid 244 NF
Venetoclax (4.4 g) was dissolved in dichloromethane (667 mL) and filtered the solution to make it particle free. Syloid 244 NF (24.64 g) was added to the filtrate. The resulted suspension was dried using ATFD to obtain the title compound. The feed rate is 15 ml/min (temperature 80°C/ vacuum 200 mmHg) while maintaining the dispersion by magentic stirring at 500 rpm.
Example-14: Preparation of amorphous solid dispersion of Venetoclax with syloid 244 NF
Venetoclax (1.5 g) was dissolved in dichloromethane (200 mL) and filtered the solution to make it particle free. Syloid 244 NF (8.5 g) was added to the filtrate. The resulted suspension was spray dried using procept spray dryer at 60°C and 5g/minutes to obtain the title compound. Yield: 6.62g
Example-15: Preparation of amorphous solid dispersion of Venetoclax with soluplus

Venetoclax (2.5 g) was dissolved in acetone (200 mL) at 40°C. The mixture of soluplus (5 g) and acetone (100 mL) was added to the clear solution. The resulted solution was evaporated at 50°C to obtain the title compound. Yield:5g
,CLAIMS:We claim:
1. A process for the preparation of amorphous form of Venetoclax comprising:
a) providing a solution of Venetoclax in an acid;
b) contacting the solution of step a) with an aqueous base; and
c) isolating the amorphous form of Venetoclax;
wherein the acid is selected from one or more of acetic acid, formic acid, methanoic acid, benzoic acid, hydrofluoric acid, nitrous acid, phosphoric acid, sulfurous acid, oxalic acid, hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, perchloric acid or chloric acid; and wherein the base is selected from one or more of ammonia, trimethyl ammonia, pyridine, ammonium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
2. The process for the preparation of amorphous form of Venetoclax as claimed in claim 1 comprising:
a) providing a solution of Venetoclax in acetic acid;
b) contacting the solution of step a) with aqueous ammonia; and
c) isolating the amorphous form of Venetoclax.
3. A process for the preparation of amorphous form of Venetoclax, comprising the steps of: a) providing a solution of Venetoclax in a suitable solvent;
b) contacting the solution of step a) with an anti-solvent at a temperature between 50oC to 70oC; and
c) isolating the amorphous form of Venetoclax;
wherein the solvent is selected from dimethyl sulfoxide, dimethyl formamide or mixture thereof; and wherein the anti-solvent is selected from water, n- hexane, n- heptane, cyclohexane , diethyl ether, di isopropyl ether or methyl tert-butyl ether.
4. A process for the preparation of amorphous form of Venetoclax, comprising the steps of: a) providing a solution of Venetoclax in a suitable solvent selected from one or more of DMSO, acetic acid, N-methyl-2-pyrrolidone (NMP), dimethylformamide (DMF);
b) contacting the solution of step a) with ethyl acetate;
c) contacting the solution of step b) with an anti-solvent; and
d) isolating the amorphous form of Venetoclax;
wherein the anti-solvent is selected from water, n- hexane, n-heptane, cyclohexane, diethyl ether, di isopropyl ether or methyl tert-butyl ether.
5. A process for the preparation of amorphous solid dispersion of Venetoclax with syloid, comprising the steps of:
a) providing a solution of Venetoclax in a suitable solvent;
b) contacting the solution of step a) with a mixture of an anti-solvent and syloid; and
c) isolating the amorphous solid dispersion of Venetoclax with syloid;
wherein the solvent is selected from dimethyl sulfoxide, dimethyl formamide or mixture thereof; and wherein the anti-solvent is selected from water, n- hexane, n- heptane, cyclohexane, diethyl ether, di isopropyl ether or methyl tert- butyl ether.
6. A process for the preparation of amorphous solid dispersion of Venetoclax with syloid, comprising the steps of:
a) providing a solution of Venetoclax and syloid in a suitable solvent; and
b) isolating the amorphous solid dispersion of Venetoclax with syloid using agitated thin film dryer (ATFD) or spray dryer;
wherein the solvent is selected from methanol, ethanol, 2-propanol, 1-butanol, 2- butanol, 1-pentanol, 2-pentanol, 3-pentanol; dichloro methane; tetrahydrofuran; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; esters solvents such as methyl acetate, ethyl acetate, isopropyl acetate and mixtures thereof.
7. A process for the preparation of amorphous solid dispersion of Venetoclax with soluplus, comprising the steps of:
a) providing a solution of Venetoclax and soluplus in acetone; and
b) isolating the amorphous solid dispersion of Venetoclax with soluplus.