WO2017175184A1

WO2017175184A1 - Process for preparation of amorphous form of idelalisib

Info

Publication number: WO2017175184A1
Application number: PCT/IB2017/052002
Authority: WO
Inventors: Nagaraju MEKALA; Srinivasa Rao BUDDEPU; Rajesh EDUPUGANTI; Sanjay Kumar Dehury; Ram Thaimattam; Venkata Sunil Kumar Indukuri
Original assignee: Laurus Labs Limited
Priority date: 2016-04-07
Filing date: 2017-04-07
Publication date: 2017-10-12

Abstract

The present invention generally relates to processes for preparation of amorphous form of Idelalisib and pharmaceutical composition comprising the same.

Description

"PROCESS FOR PREPARATION OF AMORPHOUS FORM OF IDELALISIB"

PRIORITY

This application claims the benefit under Indian Provisional Application No. 201641012262 filed on 07 Apr, 2016 entitled "Process for preparation of amorphous form of Idelalisib", the contents of which is incorporated by reference herein.

FIELD OF THE INVENTION The present invention generally relates to processes for preparation of amorphous form of Idelalisib and pharmaceutical composition comprising the same.

BACKGROUND OF THE INVENTION Idelalisib, also known as 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino) propyl] quinazolin-4(3H)-one (GS-11 I:

Formula I Idelalisib is marketed by Gilead Sciences under the trade name Zydelig for the treatment of relapsed chronic lymphocytic leukemia (CLL), relapsed follicular B-cell non-hodgkin lymphoma (FL) and relapsed small lymphocytic lymphoma (SLL). The substance acts as a phosphoinositide 3-kinase inhibitor; more specifically, it blocks PI 105, the delta isoform of the enzyme phosphoinositide 3-kinase.

U.S. Patent No. RE44638 ("the '638 patent") discloses Idelalisib and process for preparation thereof. The '638 patent process involves purification of Idelalisib as a solid by flash chromatography using 4% methanol/ methylene chloride as solvent system and the obtained solid product was dissolved in ethanol and concentrated under vacuum to obtain Idelalisib as a light yellow solid. However, the '638 patent does not disclose any polymorphic information on resulted Idelalisib. On repetition of the '638 patent process, the present inventors have found that Idelalisib obtained as an amorphous form and the same was characterized by XRD. U.S. Patent No. 8,865,730 ("the '730 patent") discloses crystalline forms including solvates of Idelalisib such as Form I, Form II, Form III (isopropyl alcohol: water solvate), Form IV (dimethylformamide solvate), Form V (dimethylsulfoxide solvate), Form VI and Form VII (water: ethanol solvate) and its characterization data by XRD,

DSC and TGA. Further, the '730 patent discloses amorphous form of Idelalisib as an intermediate stage during the transmission of Form I to Form II.

PCT Publication No. 2015/014315 ("the '315 publication) discloses crystalline forms including solvates of Idelalisib such as Form II (anhydrous), Form III (anhydrous), Form IV (anhydrous), Form V (tetrahydrofuran solvate), Form VI (hydrate), Form VII (tert-butyl ester solvate), Form VIII (anhydrous), Form IX (hydrate) and Form X (dioxane solvate) and its characterization data by XRD, DSC and TGA. PCT Publication No. 2015/092810 ("the '810 publication) discloses amorphous form of Idelalisib and its process for preparation by spray-dry method.

Patent Publication No. CN104892612A ("the '612 publication) discloses amorphous form of Idelalisib and its process for preparation from a set of solvents like tetrahydrofuran/n-heptane, methylene chloride/n-heptane, dimethylformamide/water or methanol/water.

Patent Publication No. CN106146501A ("the '501 publication) discloses preparation of amorphous form of Idelalisib by solvent and anti-solvent method from a set of solvents such as methanol/water and dimethylformamide/water.

PCT Publication No. 2015/095605 ("the '605 publication) discloses crystalline forms of Idelalisib hydrochloride salt including solvates such as Form I to Form XIII, Pattern 1 (propyl acetate solvate), Pattern 2 (isopropyl acetate solvate), Pattern 3 (1,2- dimethoxyethane solvate), Pattern 4 (isopropyl alcohol solvate), Pattern 9 (propyl acetate solvate), pattern 9', 2 -methyl- 1 -prop anol solvate, 1,4-dioxane solvate and toluene solvates and its characterization data by XRD, DSC and TGA.

PCT Publication No. 2016/188506 ("the '506 publication) discloses crystalline forms of Idelalisib crystal modification 1 and crystal modification 2 and its characterization data by XRD, DSC, TGA and Raman spectra. This publication also discloses preparation of amorphous form of Idelalisib by dissolving Idelalisib in a solvent such as methylene chloride, tetrahydrofuran, chloroform and evaporating the solution or by cooling the reaction mixture.

PCT Publication No. 2016/157136 ("the ' 136 publication) discloses crystalline forms of Idelalisib methyl-tert-butyl ether solvate (Form Ml) and its de-solvated form (Form M2) and its characterization data by XRD, DSC and TGA. PCT Publication No. 2016/147206 ("the '206 publication) discloses preparation of Idelalisib by solvent and anti- solvent method from a set of solvents such as n- propanol/water, isopropanol/water, dimethylformamide/water, dimethylacetamide/ water, dimethylsulfoxide/water and formic acid/water. PCT Publication No. 2016/097314 ("the '314 publication) discloses crystalline forms of Idelalisib solvates such as tert-butanol solvate, dimethylformamide solvate and tetrahydrofuran solvate and its characterization data by XRD, DSC and TGA. This publication also discloses preparation of amorphous form of Idelalisib by desolvation of the above idelalisib solvate.

Idelalisib amorphous form of the reported processes contains high levels of residual solvents with low purity and assay. Further to obtain amorphous form, spray drying is used as one of the method which is not industrially viable and solvent-antisolvent methods used as an alternate approach, which produces the product with high levels of residual solvents. To overcome these disadvantages, there is a need to develop a process for preparing amorphous form of Idelalisib. The present inventors have found processes to prepare amorphous form of Idelalisib having high purity and low levels of residual solvents. SUMMARY OF THE INVENTION

The present invention encompasses processes for the preparation of amorphous from of Idelalisib with high product yield and quality, and greater stability.

In accordance with one embodiment, the present invention provides a process for preparation of amorphous form of Idelalisib, comprising:

a) providing a solution of Idelalisib in one or more organic solvents,

b) optionally, concentrating the solution,

c) adding a suitable antisolvent to the step a) or step b) (or);

d) adding step a) or step b) solution to suitable antisolvent; and

e) isolating the amorphous form; wherein the one or more organic solvents are selected from the group consisting of diols, ketones, sulfoxides, esters, nitriles and the like and mixtures thereof; wherein the suitable antisolvent is selected from the group consisting of water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like and mixtures thereof.

In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of Idelalisib, comprising:

a) providing a solution of Idelalisib in a ketone solvent,

b) optionally, concentrating the solution,

c) adding a suitable antisolvent to the step a) or step b) (or);

d) adding step a) or step b) solution to suitable antisolvent; and

e) isolating the amorphous form;

wherein the ketone solvent is selected form the group consisting of acetone, methylisobutylketone, methylethylketone and the like; and suitable antisolvent is selected from the group consisting of water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like and mixtures thereof.

In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of Idelalisib, comprising: a) providing a solution of Idelalisib in acetone,

b) adding the solution of step a) into water or vice- versa; and

c) isolating the amorphous form.

a) providing a solution of Idelalisib in 1-propanol,

b) adding the solution of step a) into water or vice- versa; and

c) filtering the solid Idelalisib,

d) drying the solid Idelalisib at a temperature of about 25 °C to 35°C to obtain crystalline Idelalisib, and

e) drying the crystalline Idelalisib at a temperature of about 45°C to 85°C to obtain amorphous form of Idelalisib.

In accordance with another embodiment, the present invention provides crystalline Idelalisib, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 5, a differential scanning calorimetry (DSC) substantially in accordance with Figure 6 and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 7. In accordance with another embodiment, the present invention provides crystalline Idelalisib characterized by a PXRD pattern having peaks at about: 8.3, 9.5, 10.9, 11.2, 12.2, 12.5, 12.9, 13.8, 16.1, 16.4, 16.8, 17.1, 18.0, 19.1, 20.3, 21.2, 21.6, 22.0, 22.4, 23.0, 23.1, 23.3, 23.9, 24.8, 25.0, 26.1, 26.4, 26.8, 27.8, 28.1, 28.8, 30.0, 31.0, 32.6, 33.8 and 34.3°± 0.2° 2Θ.

In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of Idelalisib, comprising: drying crystalline Idelalisib at a temperature of about 45°C to about 85°C, wherein the crystalline Idelalisib characterized by an XRPD pattern substantially in accordance with Fig. 5.

In accordance with another embodiment, the present invention provides an amorphous form of Idelalisib having a HPLC purity of about 99.5% or more as determined by high performance liquid chromatography (HPLC). In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising amorphous form of Idelalisib 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 amorphous

Idelalisib prepared according to reference examples [i] to [iv].

Figure 2 is the characteristic powder X-ray diffraction (XRD) pattern of amorphous Idelalisib prepared according to example- 1.

Figure 3 is the characteristic differential scanning calorimetric (DSC) thermogram of amorphous Idelalisib prepared according to example- 1.

Figure 4 is the characteristic thermo gravimetric analysis (TGA) of amorphous Idelalisib prepared according to example- 1.

Figure 5 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline Idelalisib prepared according to example-6. Figure 6 is the characteristic differential scanning calorimetric (DSC) thermogram of crystalline Idelalisib prepared according to example-6.

Figure 7 is the characteristic thermo gravimetric analysis (TGA) of crystalline Idelalisib prepared according to example-6.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for the preparation of amorphous from of Idelalisib and pharmaceutical compositions containing the same.

The amorphous from of Idelalisib of the present invention obtained by process of the present invention are characterized by one or more analytical methods such as X-ray powder diffraction (XRPD) patterns, differential scanning calorimetry (DSC) curves and thermo gravimetric analysis (TGA).

The X-Ray powder diffraction can be measured using PANalytical X'per pro X-ray powder Diffractometer equipped with a Cu-anode ([λ] =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°20; step size=0.01°; and Time per step=43 sec.

All DSC data reported herein were analyzed in hermitically sealed aluminium pan, with a blank 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 with an Indium standard.

All TGA data reported herein were analyzed using TGA Q500 V 20.13 build 39 in platinum pan with a temperature rise of about 10°C/min in the range of about 30°C to about 250°C. In one embodiment, the present invention provides a process for preparation of amorphous form of Idelalisib, comprising:

a) providing a solution of Idelalisib in one or more organic solvents,

b) optionally, concentrating the solution,

c) adding a suitable antisolvent to the step a) or step b) (or),

d) adding step a) or step b) solution to suitable antisolvent; and

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

The step of providing a solution of Idelalisib may include dissolving any form of Idelalisib, in one or more organic solvents. The organic solvents include, but are not limited to diols, ketones, sulfoxides, esters, nitriles and the like and mixtures thereof. The diols include, but are not limited to ethylene glycol, propylene glycol, 2-methyl- 1,2-propane-diol, 1,2-butanediol, 2,3-butanediol, 1,4-butanediol, 1,5-pentanediol, 1,6- hexanediol, 1,7-heptandiol and the like; ketones include, but are not limited to acetone, methylisobutylketone, methylethylketone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide, diethyl sulfoxide and the like; esters include, but are not limited to methyl acetate, ethyl acetate, isopropyl acetate and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like and mixture thereof; preferably acetone, 1,2-butanediol, 2,3-butanediol, propylene glycol or diethyl sulfoxide and mixture thereof. In order to form a solution of step a), the contents may be heated to a suitable temperature. The temperature suitable for dissolving Idelalisib depends on the solvent used and the amount of Idelalisib in the solution. Typically, the solution is heated at a temperature of at least about 30°C to about reflux. The solution may be prepared at other suitable temperatures as long as the Idelalisib is sufficiently dissolved. Increasing the amount of Idelalisib would generally require the use of higher temperatures. Routine experimentation will provide the approximate range of suitable temperatures for a given solvent and amount of Idelalisib; preferably at about 35°C to about 75°C. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. Step b) of the aforementioned process involves optionally concentrating the solution obtained in step a) partially by removal of solvent from the solution by evaporation. Evaporation can be achieved by a distillation, rotational drying (such as with the Buchi Rotavapor), fluid bed drying, flash drying, spin flash drying, agitated thin-film drying and the like. Preferably, the solvent may be evaporated partially by distillation under vacuum at a temperature of about 25°C to about 90°C; preferably at about 45°C to about 60°C.

The aforementioned process involves precipitation of amorphous form of Idelalisib by either addition of suitable antisolvent to the Idelalisib solution obtained from step a) or step b), (or) addition of Idelalisib solution obtained from step a) or step b) into a suitable antisolvent. The suitable antisolvent 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 tetrahydrofuran, 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. The addition may be carried out at a temperature of less than about 25°C, preferably, less than about 15°C. The resultant amorphous Form of Idelalisib can be recovered by any conventional techniques known in the art, for example filtration. Typically, if stirring is involved, the temperature during stirring can range from about -10°C to about 10°C, preferably at about -5°C to 5°C.

The amorphous Form of Idelalisib obtained by the above process may be dried in, for example, a Vacuum Tray Dryer, Rotocon Vacuum Dryer, Vacuum Paddle Dryer or pilot plant Rota vapor. In a specific embodiment, the present invention provides a process for preparation of amorphous form of Idelalisib, comprising:

a) providing a solution of Idelalisib in acetone,

b) adding the solution of step a) into water or vice- versa; and

c) isolating the amorphous form.

The step of providing a solution of Idelalisib may include dissolving any form of Idelalisib in acetone. In order to form a solution of step a), the contents may be heated to a suitable temperature. Typically, the solution is heated at a temperature of at least about 30°C to about reflux; preferably at about 45°C to about 65°C.

Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques.

Further, the aforementioned process involves concentrating the solution obtained in step a) partially by removal of solvent from the solution by evaporation. Evaporation can be achieved by a distillation, rotational drying (such as with the Buchi Rotavapor), fluid bed drying, flash drying, spin flash drying, agitated thin-film drying and the like. Preferably, the solvent may be evaporated partially upto below 20 volumes solvent remains in the reaction flask by distillation at a temperature of about 25°C to about 55°C.

Step b) of the aforementioned process involves addition of Idelalisib solution obtained from step a) into water or water may be added in to step a) solution.

The addition may be carried out at a temperature of less than about 25 °C to obtain the amorphous Idelalisib, preferably, less than about 15°C. The amorphous Form of Idelalisib can be recovered by any conventional techniques known in the art, for example filtration. Typically, if stirring is involved, the temperature during stirring can range from about -10°C to about 10°C, preferably at about -5°C to 5°C. The amorphous Form of Idelalisib obtained by the above process may be further dried in, for example, a Vacuum Tray Dryer, Rotocon Vacuum Dryer, Vacuum Paddle Dryer or pilot plant Rota vapor.

In another embodiment, the present invention provides an amorphous form of Idelalisib, characterized by one or more techniques selected from a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 2, a differential scanning calorimetry (DSC) substantially in accordance with Figure 3 and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 4. In another embodiment, the present invention provides a process for preparation of amorphous form of Idelalisib, comprising:

a) providing a solution of Idelalisib in 1-propanol,

b) adding the solution of step a) into water or vice- versa; and

c) filtering the solid Idelalisib,

e) drying the crystalline Idelalisib at a temperature of about 45°C to 85°C to obtain amorphous form of Idelalisib. The Idelalisib in the step a) may be any crystalline or other form of Idelalisib, including various solvates, hydrates, salts and cocrystals as long as amorphous Idelalisib is produced during the process of the invention or Idelalisib obtaining as existing solution from a previous processing step. The step of providing a solution of Idelalisib may include dissolving any form of Idelalisib in 1-propanol at a temperature of about 25°C to about reflux temperature; preferably at about 35°C to about 75°C.

Step b) of the aforementioned process involves addition of Idelalisib solution obtained from step a) into water or water may be added in to step a) solution. The addition may be carried out at less than 25°C to obtain the solid Idelalisib, preferably, less than about 10°C. The solid Idelalisib can be recovered by any conventional techniques known in the art, for example filtration. Step d) of the aforementioned process involves drying the above obtained solid Idelalisib in, for example, a Vacuum Tray Dryer, Rotocon Vacuum Dryer, Vacuum Paddle Dryer or pilot plant Rota vapor at a temperature of about 25 °C to 35°C to obtain crystalline Idelalisib. The crystalline Idelalisib obtained by the above process may be dried in, for example, a Vacuum Tray Dryer, Rotocon Vacuum Dryer, Vacuum Paddle Dryer or pilot plant Rota vapor at a temperature of about 45°C to 85°C to obtain amorphous form of Idelalisib. In another embodiment, the present invention provides crystalline Idelalisib, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 5.

In another embodiment, the present invention provides crystalline Idelalisib characterized by a PXRD pattern having peaks at about: 8.3, 9.5, 10.9, 11.2, 12.2, 12.5, 12.9, 13.8, 16.1, 16.4, 16.8, 17.1, 18.0, 19.1, 20.3, 21.2, 21.6, 22.0, 22.4, 23.0, 23.1, 23.3, 23.9, 24.8, 25.0, 26.1, 26.4, 26.8, 27.8, 28.1, 28.8, 30.0, 31.0, 32.6, 33.8 and 34.3°± 0.2° 2Θ. In another embodiment, the present invention provides crystalline Idelalisib, characterized by a differential scanning calorimetry (DSC) substantially in accordance with Figure 6.

In another embodiment, the present invention provides crystalline Idelalisib, characterized by a thermo gravimetric analysis (TGA) substantially in accordance with Figure 7.

In another embodiment, the present invention provides crystalline Idelalisib, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 5, a differential scanning calorimetry (DSC) substantially in accordance with Figure 6 and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 7.

In another embodiment, crystalline Idelalisib of the present invention may be 1- propanol solvate.

In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of Idelalisib, comprising: drying crystalline Idelalisib obtained in accordance with the above embodiment at a temperature of about 45 °C to about 85°C, wherein the crystalline Idelalisib characterized by an XRPD pattern substantially in accordance with Fig. 5.

Idelalisib amorphous form can be prepared by drying the crystalline Idelalisib obtained by the process described as above. Preferably the drying is carried out at a temperature of about 45°C-85°C; preferably at about 70°C to 75°C under vacuum, for a period of about 2 hours to about 10 hours under vacuum.

In another embodiment, the present invention provides an amorphous form of Idelalisib having a HPLC purity of about 99.5% or more as determined by high performance liquid chromatography (HPLC).

In another embodiment, the present invention provided a pharmaceutical composition comprosing an amorphous form of Idelalisib preparaed by the process described above, together with one or more pharmaceutically acceptable excipients. Such pharmaceutical composition may be administered to a mammalian patient in any dosage form, e.g., solid, liquid, powder, injectable solution, etc.

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.

REFERENCE EXAMPLE: Preparation of amorphous form of Idelalisib

The following examples were carried out following the teaching of example-9, compound- 107 of USRE44638 (methanol + methylene chloride; and ethanol) [i] Idelalisib (2 g) was dissolved in a mixture of 4% methanol in methylene chloride (50 mL) at room temperature. The solvent was distilled completely at 30°C under vacuum in a Buchi Rotavapor. The obtained solids were dried at 40°C under vacuum. Yield: 2.1 g. [ii] Idelalisib (2 g) was dissolved in a mixture of 4% methanol in methylene chloride (100 mL) at room temperature. The solvent was distilled completely at 30°C under vacuum in a Buchi Rotavapor. The obtained solids were dried at 40°C under vacuum. Yield: 2.1 g.

[iii] Idelalisib (2 g) was dissolved in a mixture of 4% methanol in methylene chloride (200 mL) at room temperature. The solvent was distilled completely at 30°C under vacuum in a Buchi Rotavapor. The obtained solids were dried at 40°C under vacuum. Yield: 2.2 g.

[iv] The above obtained amorphous Idelalisib (1 g) was dissolved in ethanol (35 mL) at room temperature. The solvent was distilled completely at 50°C under vacuum in a Buchi Rotavapor. The obtained solids were dried at 50°C under vacuum. Yield: 1.2 g-

Amorphous Form obtained according to the reference examples [i] to [iv] was analyzed by PXRD and is represented according to Fig. 1.

EXAMPLE 1;

Preparation of amorphous form of Idelalisib (Acetone + water) Idelalisib (10 g) and acetone (800 mL) were combined in a flask and stirred for clear solution at 50-55°C. The reaction mass was concentrated up to 100 mL solvent remains in the flask at below 50-55°C. The reaction solution was added to precooled water at 5-10°C over a period of 10 min and stirred for 45 min at same temperature. Precipitated solid was filtered and washed with water (100 mL) and dried at 60-65°C under vacuum for 12 hrs to obtain Idelalisib amorphous form. Yield: 8.5 g; HPLC Purity: 99.8%; PXRD: Fig. 2; DSC: Fig. 3; TGA: Fig. 4.

EXAMPLE 2: Preparation of amorphous form of Idelalisib (1,2-butanediol + water)

Idelalisib (0.25 g) was dissolved in 1,2-butanediol (2.5 mL) at 65°C. The reaction mass was cooled to 0-5°C. To the reaction mass chilled water (10 mL) was added at 0- 5°C and stirred for 30 min at same temperature. The precipitated solid was filtered, washed with water (5 mL) and dried under vacuum at room temperature for 2 hrs to obtain Idelalisib amorphous form. Yield: 0.17 g.

EXAMPLE 3: Preparation of amorphous form of Idelalisib (2,3-butanediol + water)

Idelalisib (0.25 g) was dissolved in 2,3-butanediol (2 mL) at 65°C. The reaction mass was cooled to 0-5°C. To the reaction mass chilled water (10 mL) was added at 0-5°C and stirred for 30 min at same temperature. The precipitated solid was filtered, washed with water (5 mL) and dried under vacuum at room temperature for 2 hrs to obtain

Idelalisib amorphous form. Yield: 0.18 g. EXAMPLE 4: Preparation of amorphous form of Idelalisib (propylene glycol + water)

Idelalisib (0.25 g) was dissolved in propylene glycol (5 mL) at 65°C. The reaction mass was cooled to 0-5°C. To the reaction mass chilled water (10 mL) was added at 0- 5°C and stirred for 30 min at same temperature. The precipitated solid was filtered, washed with water (5 mL) and dried under vacuum at room temperature for 2 hrs to obtain Idelalisib amorphous form. Yield: 0.1 g.

EXAMPLE 5: Preparation of amorphous form of Idelalisib (dimethylsulfoxide + water)

Idelalisib (1 g) was dissolved in dimethylsulfoxide (2 mL) at 50°C. The reaction mass was cooled to 25-30°C. The dimethyl sulfoxide solution was added to pre-cooled water (50 mL) at 0-5°C. The resultant suspension was stirred for 30 min at 0-5°C. The precipitated solid was filtered, washed with chilled water (20 mL) and dried under vacuum at 50-55°C for 12 hrs to yield 0.96 g of title compound. 500 mg of this material was further dried at 70-75°C for 16 hrs to obtain Idelalisib amorphous form. Yield: 480 mg. EXAMPLE 6:

Preparation of crystalline Idelalisib

Idelalisib (1 g) was dissolved in 1-propanol (15 mL) at 65 °C. The reaction mass was cooled to 25-30°C. To the reaction mass water (50 mL) was added at 25-30°C and stirred for 30 min at same temperature. The precipitated solid was filtered, washed with water (10 mL) and dried under vacuum at room temperature for 16 hrs to obtain crystalline Idelalisib. Yield: 1 g; PXRD: Fig. 5; DSC: Fig. 6; TGA: Fig. 7. EXAMPLE 7:

Preparation of amorphous form of Idelalisib (from crystalline Idelalisib)

Crystalline Idelalisib (500 mg) as obtained in accordance with example-6 was dried in a tray dryer under vacuum at 70-75°C for 3 hrs to obtain Idelalisib amorphous form. Yield: 0.43 g; PXRD: Fig. 5.

EXAMPLE 8:

Preparation of amorphous form of Idelalisib Idelalisib (25 g) was dissolved in methanol (100 mL) at 25-35°C. To the reaction mass trifluoro acetic acid (50 mL) was added at 25-35°C and stirred for 2 hrs at same temperature. The precipitated solid was filtered, washed with methanol (25 mL) and suck dried under vacuum. The obtained solid was dissolved in methylene chloride (2 lit) and water (250 mL) at 15-20°C. The pH of the reaction mass was adjusted to 7-7.5 with sodium bicarbonate solution at 15-20°C and the product containing organic layer was separated. To the organic layer methanol (125 mL) was added and followed by distilled under vacuum at below 45°C to obtain a residue. The obtained residue was dissolved in acetone (2 lit) and heated to 50-55°C. The reaction mass was concentrated up to 250 mL solvent remains in the flask at below 50-55°C. Water (1 lit) was cooled to 5-10°C in another 2-L reaction flask. Then the above acetone solution was added to the water at 5-10°C over a period of 10 min and stirred for 45 min at same temperature. Precipitated solid was filtered and washed with water (250 mL) and dried at 60-65°C under vacuum for 12 hrs to obtain Idelalisib amorphous form. Yield: 10 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

Claim 1: A process for preparation of amorphous form of Idelalisib, comprising: a) providing a solution of Idelalisib in one or more organic solvents,

b) optionally, concentrating the solution,

c) adding a suitable antisolvent to the step a) or step b) (or);

d) adding step a) or step b) solution to suitable antisolvent; and

e) isolating the amorphous form; wherein the one or more organic solvents are selected from the group consisting of diols, ketones, esters, nitriles and the like and mixtures thereof; wherein the suitable antisolvent is selected from the group consisting of water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like and mixtures thereof.

Claim 2: The process of claim 1, wherein the one or more organic solvents are selected from the group consisting of ethylene glycol, propylene glycol, 2-methyl-l,2- propane-diol, 1,2-butanediol, 2,3-butanediol, 1,4-butanediol, 1,5-pentanediol, 1,6- hexanediol, 1,7-heptandiol, acetone, methylisobutylketone, methylethylketone, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, propionitrile and mixtures thereof. Claim 3: The process of claim 2, wherein the organic solvent is acetone, 1,2- butanediol, 2,3-butanediol or propylene glycol.

Claim 4: The process of claim 1, wherein the antisolvent is selected from the group consisting of water, tetrahydrofuran, 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 mixtures thereof.

Claim 5: The process of claim 4, wherein the antisolvent is water.

Claim 6: The process of claim 1, wherein the step a) is carried out at a temperature of about 30°C to reflux.

Claim 7: The process of claim 1, wherein the concentration of the solution is carried out by distillation under vacuum at a temperature of about 25 °C to 90°C.

Claim 8: The process of claim 1, wherein the step c) or step d) is carried out at a temperature of less than about 25 °C. Claim 9: A process for preparation of amorphous form of Idelalisib, comprising: a) providing a solution of Idelalisib in acetone,

b) adding the solution of step a) into water or vice- versa; and

c) isolating the amorphous form. Claim 10: The process of claim 9, wherein the step a) is carried out at a temperature of about 30°C to reflux.

Claim 11: The process of claim 9, wherein the step b) is carried out at a temperature of less than about 25 °C.

Claim 12: A process for preparation of amorphous form of Idelalisib, comprising: a) providing a solution of Idelalisib in 1-propanol,

b) adding the solution of step a) into water or vice- versa; and

c) filtering the solid Idelalisib,

d) drying the solid Idelalisib at a temperature of about 25°C to 35°C to obtain crystalline Idelalisib, and

e) drying the crystalline Idelalisib at a temperature of about 45°C to 85°C to obtain amorphous form of Idelalisib; wherein the crystalline Idelalisib is characterized by a powder X-ray diffraction pattern substantially in accordance with Fig. 5.

Claim 13: The process of claim 12, wherein the step a) is carried out at a temperature of about 30°C to reflux. Claim 14: The process of claim 12, wherein the step b) is carried out at a temperature of less than 30°C.

Claim 15: The process of claim 12, wherein the drying is carried out at a temperature of about 70°C to 75°C under vacuum.

Claim 16: The process of claim 12, wherein the drying is carried out in a tray dryer.

Claim 17: A process for preparation of amorphous form of Idelalisib, comprising: drying crystalline Idelalisib at a temperature of about 45°C to 85°C to obtain amorphous form of Idelalisib; wherein the crystalline Idelalisib is characterized by a powder X-ray diffraction pattern substantially in accordance with Fig. 5.

Claim 18: The process of claim 17, wherein the drying is carried out at a temperature of about 70°C to 75°C under vacuum.

Claim 19: The process of claim 17, wherein the drying is carried out in a tray dryer. Claim 20: A pharmaceutical composition comprising amorphous form of Idelalisib according to claim 1-19 and at least one pharmaceutically acceptable excipient.