DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
CRYSTALLINE FORMS OF IDELALISIB AND PREPARATION THEREOF

FIELD OF THE INVENTION
The present application relates to crystalline polymorphic forms of Idelalisib, methods for their preparation and pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION
The drug compound having the adopted name Idelalisib (GS-1101, CAL-101) has a chemical name (S)-2-(1-(9H-purin-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one and is represented by structure of formula I.

Idelalisib is an inhibitor of phosphatidylinositol 3-kinase, PI3Kd and is indicated for the treatment of relapsed chronic lymphocytic leukemia (CLL), relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic lymphoma (SLL).
US Patent No. US 7932260 B2 (US ‘260) discloses Idelalisib, related compounds, and their pharmaceutical compositions. Further, it describes a process for the preparation of Idelalisib but does not provide the details of the isolated product.
International Publication No. WO 2013/134288 A1 (WO ‘288) describes two anhydrous crystalline polymorphic forms of idelalisib (Form I and Form II), and five solvates of idelalisib (Form III, IV, V, VI and Form VII).
International Publication No. WO 2015/014315 A1 (WO ‘315) describes nine crystalline polymorphic forms of idelalisib.
Polymorphism, the occurrence of different crystal forms, is a phenomenon of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties. Polymorphs in general will have different melting points, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), X-ray powder diffraction (XRPD or powder XRD) pattern, infrared absorption fingerprint, and solid state nuclear magnetic resonance (NMR) spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
Discovering new polymorphic forms, hydrates and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional solid state forms of idelalisib.

SUMMARY OF THE INVENTION
The present application provides novel crystalline forms of idelalisib, processes for preparing them, and pharmaceutical compositions containing them. The present application also encompasses the use of novel crystalline forms of idelalisib provided herein, for the preparation of other solid state forms of idelalisib and formulations thereof.
In one embodiment the present application provides a crystalline Form of idelalisib, designated as Form V1. Form V1 can be characterized by an X-ray powder diffraction pattern having peaks at about 9.40, 14.91, 17.23, and 18.65 ± 0.2 degrees two theta.
In another embodiment, the present invention provides a process for preparation of crystalline Form V1 of idelalisib, comprising:
(a) providing a solution of idelalisib in a solvent or a mixture of solvents,
(b) optionally stirring the solution of step (a),
(c) evaporating the solvent, and
(d) isolating crystalline idelalisib Form V1.
In another embodiment the present invention provides a crystalline Form of idelalisib, designated as Form V2. Form V2 can be characterized by an X-ray powder diffraction pattern having peaks at about 9.31, 11.20, 14.81, 16.58 and 18.53 ± 0.2 degrees two theta.
In another embodiment, the present invention provides a process for preparation of crystalline Form V2 of idelalisib, comprising:
(a) providing a slurry of idelalisib in a solvent,
(b) stirring the slurry of step (a), and
(c) isolating crystalline idelalisib Form V2.
In another embodiment the present invention provides a crystalline Form of idelalisib, designated as Form V3. Form V3 can be characterized by an X-ray powder diffraction pattern having peaks at about 4.72, 9.30, 9.59, 18.86, 19.54 and 20.16 ± 0.2 degrees two theta.
In another embodiment, the present invention provides a process for preparation of crystalline Form V3 of idelalisib, comprising:
(a) providing a mixture containing idelalisib, propylene glycol and one or more solvents,
(b) adding cyclopentyl methyl ether to the mixture of step (a),
(c) adding one or more anti-solvents to the mixture of step (b),
(d) optionally stirring the mixture obtained in step (c), and
(e) isolating crystalline idelalisib Form V3.
The present application also encompasses the use of any one of the novel solid state forms of idelalisib disclosed herein for the preparation of a medicament, preferably for the treatment of cancer, particularly for the treatment of cancers mediated by epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) tyrosine kinases, e.g., solid tumors including NSCLC, breast, head and neck cancer, and a variety of other cancers mediated by EGFR or HER2 tyrosine kinases. The present invention further provides a pharmaceutical composition comprising any one of the idelalisib crystalline forms of the present invention and at least one pharmaceutically acceptable excipient.
The present application also provides a method of treating cancer, comprising administering a therapeutically effective amount of at least one of the idelalisib novel solid state forms of the present application, or at least one of the above pharmaceutical compositions to a person suffering from cancer, particularly a person suffering from a cancer mediated by epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) tyrosine kinases, e.g., solid tumors including but not limited to NSCLC, breast, head and neck cancer, and a variety of other cancers mediated by EGFR or HER2 tyrosine kinases.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows an X-ray powder diffractogram of idelalisib Form V1 prepared according to the process exemplified in example-1.
Figure 2 shows an X-ray powder diffractogram of idelalisib Form V2 prepared according to the process exemplified in example-2.
Figure 3 shows an X-ray powder diffractogram of idelalisib Form V3 prepared according to the process exemplified in example-4.

DETAILED DESCRIPTION
Idelalisib which may be used as the input in the process for preparation of the solid states of the present application can be prepared by any process known in the art.
In one embodiment the present invention provides a crystalline Form of idelalisib, designated as Form V1. Form V1 can be characterized by an X-ray powder diffraction pattern having peaks at about 9.40, 14.91, 17.23, and 18.65 ± 0.2 degrees two theta.
In another embodiment, the crystalline Form V1 of idelalisib can further be characterized by X-ray powder diffraction pattern having peaks at about 11.31, 20.42, and 21.13 ± 0.2 degrees two theta.
In another embodiment, crystalline Form V1 of idelalisib can be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 1.
In another embodiment, the present invention provides a process for preparation of crystalline Form V1 of idelalisib, comprising:
(a) providing a solution of idelalisib in a solvent or a mixture of solvents,
(b) optionally stirring the solution of step (a),
(c) evaporating the solvent, and
(d) isolating crystalline idelalisib Form V1.
Providing a solution of idelalisib in step a) includes:
a) direct use of a reaction mixture containing idelalisib that is obtained in the course of its synthesis; or
b) any physical form of idelalisib can be utilized for providing the solution of idelalisib.
Suitable solvents which can be used for dissolving idelalisib include but are not limited to: halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and the like; ethers such as diethyl ether, dimethyl ether, di-isopropyl ether, 1,4-dioxane, 1,2-dimethoxy ethane and the like; and any mixtures of two or more thereof.
The solvent or a mixture of the solvents can be taken in the ratio of 1:1 to 1:20 by volume to the weight of idelalisib. After adding idelalisib to the solvent or a mixture of solvents, the obtained mixture may optionally be heated to get a clear solution.
The obtained solution may be optionally filtered to remove any insoluble particles. Suitable techniques to remove insoluble particles are filtration, centrifugation, decantation, and any other known techniques in the art. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as Celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature precipitation of solid.
The step (b) involves optionally stirring the solution of the step (a). The solution of step (a) may optionally be stirred at about 25°C for about 30 minutes to about 10 hours or longer.
The step (c) involves evaporating the solvent at about 25°C. The solution obtained from step (a) or step (b) can be kept for slow solvent evaporation at about 25°C.
The step (d) involves isolating crystalline idelalisib Form V1. The crystalline idelalisib Form V1 can be isolated by the solvent evaporation of step (c).
The resulting crystalline idelalisib Form V1 in step (d) may optionally be further dried. Drying can be carried out in an air tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 80°C, less than about 70°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the idelalisib is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
In another embodiment the present invention provides a crystalline Form of idelalisib, designated as Form V2. Form V2 can be characterized by an X-ray powder diffraction pattern having peaks at about 9.31, 11.20, 14.81, 16.58 and 18.53 ± 0.2 degrees two theta.
In another embodiment, the crystalline Form V2 of idelalisib can further be characterized by X-ray powder diffraction pattern having peaks at about 15.81, and 20.29 ± 0.2 degrees two theta.
In another embodiment, crystalline Form V2 of idelalisib can be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 2.
In another embodiment, the present invention provides a process for preparation of crystalline Form V2 of idelalisib, comprising:
(a) providing a slurry of idelalisib in a solvent,
(b) stirring the slurry of step (a), and
(c) isolating crystalline idelalisib Form V2.
Providing a slurry of idelalisib in step a) includes:
a) direct use of a reaction mixture containing idelalisib that is obtained in the course of its synthesis; or
b) any physical form of idelalisib can be utilized for providing the slurry of idelalisib.
Suitable solvents which can be used for slurrying idelalisib include but are not limited to: ethers such as diethyl ether, dimethyl ether, di-isopropyl ether, 1,4-dioxane, cyclopentyl methyl ether and the like; halogenated hydrocarbon solvents such as dichloromethane, dichloethane, and the like, and any mixtures of two or more thereof.
The solvent or a mixture of the solvents can be taken in the ratio of 1:1 to 1:50 by volume to the weight of idelalisib.
The step (b) involves stirring the slurry of the step (a). The slurry of step (a) is stirred at about 25°C for about 30 minutes to about 10 hours.
The step (c) involves isolating crystalline idelalisib Form V2. The crystalline idelalisib Form V2 can be isolated from the slurry of step (b) by filtration.
The resulting crystalline idelalisib Form V2 may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 60°C, less than about 50°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the idelalisib is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
Alternatively, the crystalline idelalisib Form V2 can be prepared by the process comprising:
(a) providing a solution of idelalisib in dichloromethane,
(b) adding diethyl ether to the solution of step (a),
(c) optionally stirring the mixture obtained in step (b), and
(d) isolating crystalline idelalisib Form V2.
Providing a solution of idelalisib in step a) includes:
a) direct use of a reaction mixture containing idelalisib that is obtained in the course of its synthesis; or
b) any physical form of idelalisib can be utilized for providing the solution of idelalisib.
Dichloromethane can be taken in the ratio of 1:1 to 1: 50 to the weight of idelalisib. After adding idelalisib to the solvent or a mixture of solvents, the obtained mixture may optionally be heated to get a clear solution.
The obtained solution may be optionally filtered to remove any insoluble particles. Suitable techniques to remove insoluble particles are filtration, centrifugation, decantation, and any other known techniques in the art. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as Celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature precipitation of solid.
The step (b) involves adding diethyl ether to the solution obtained in step (a).
The step (c) involves optionally stirring the mixture obtained in step (b). The mixture of step (b) may optionally be stirred at about 25°C for about 30 minutes to about 10 hours or more.
The step (d) involves isolating crystalline idelalisib Form V2. The crystalline idelalisib Form V2 is isolated from the mixture of step (b) or step (c) by filtration of the mixture.
The resulting crystalline idelalisib Form V2 in step (d) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 60°C, less than about 50°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the idelalisib is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
In another embodiment the present application provides a crystalline Form of idelalisib, designated as Form V3. Form V3 can be characterized by an X-ray powder diffraction pattern having peaks at about 4.72, 9.30, 9.59, 18.86, 19.54 and 20.16 ± 0.2 degrees two theta.
In another embodiment, the crystalline Form V3 of idelalisib can further be characterized by X-ray powder diffraction pattern having peaks at about 10.84, 12.44, 13.60, 15.15, 15.72, 16.41, 17.90 and 21.88 ± 0.2 degrees two theta.
In another embodiment, crystalline Form V3 of idelalisib can be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 3.
In another embodiment, the present invention provides a process for preparation of crystalline Form V3 of idelalisib, comprising:
(a) providing a mixture containing idelalisib, propylene glycol and one or more solvents,
(b) adding cyclopentyl methyl ether to the mixture of step (a),
(c) adding one or more anti-solvents to the mixture of step (b),
(d) optionally stirring the mixture obtained in step (c), and
(e) isolating crystalline idelalisib Form V3.
A reaction mixture containing idelalisib that is obtained in the course of its synthesis; or any physical form of idelalisib can be utilized. Propylene glycol and one more solvents are added to the solution to get the mixture of the step (a). The propylene glycol may be racemic or (S)-isomer or (R)-isomer. The propylene glycol can be taken in the ratio of 1:0.1 to 1: 2 by volume to the weight of idelalisib.
Suitable solvents which can be used for dissolving idelalisib include but are not limited to: halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and the like; an ether solvent such as diethyl ether, dimethyl ether, di-isopropyl ether, 1,4-dioxane and the like; and any mixtures of two or more thereof.
The solvent or a mixture of the solvents can be taken in the ratio of 1:1 to 1: 20 by volume to the weight of idelalisib. After adding idelalisib to the solvent or a mixture of solvents, the obtained mixture may optionally be heated to get a clear solution.
The obtained solution may be optionally filtered to remove any insoluble particles. Suitable techniques to remove insoluble particles are filtration, centrifugation, decantation, and any other known techniques in the art. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as Celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature precipitation of solid.
The step (b) involves adding cyclopentyl methyl ether to the mixture of step (a). Cyclopentyl methyl ether can be taken in the ratio of 1:1 to 1: 20 by volume to the weight of idelalisib. After adding cyclopentyl methyl ether to the mixture of step (a)., the resultant mixture may be stirred for about 5 minutes to about 1 hour.
The step (c) involves adding one or more anti-solvents to the mixture of step (a). Suitable anti-solvents which can be used include but are not limited to hydrocarbon solvents such as n-hexane, cyclohexane, toluene and the like; and mixtures thereof.
The step (d) involves optionally stirring the mixture obtained in step (c). The mixture of step (c) may optionally be stirred at about 25°C for about 30 minutes to about 10 hours or more.
The step (e) involves isolating crystalline idelalisib Form V3. The crystalline idelalisib Form V3 is isolated from the mixture of step (b) or step (c) by filtration of the mixture.
The resulting crystalline idelalisib Form V3 in step (d) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the idelalisib is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
In another embodiment, the crystalline idelalisib Form V3 exists as a propylene glycol solvate.
The crystalline Form V3 of Idelalisib is stable for 6 months in ICH storage conditions i.e. (i) 25°C ± 2°C and 60%RH ± 5RH (ii) 40°C±2°C and 75%RH ± 5RH and (ii) 2°C - 8°C. Packing conditions used for idelalisib Form V3 are incorporated below.
Packing method-1: Take the sample in LDPE bag and tie it with thread/plastic strip by twisting after removing air. Keep the bag in triple laminated bag and seal it with VNS Sealer, finally keep in HDPE drum.
Packing method-2: Take the sample in LDPE bag and tie it with thread/plastic strip by twisting after removing air. Keep the bag in triple laminated bag with a silica bag and seal it with VNS Sealer, finally keep in HDPE drum.
Form V3 of Idelalisib of the present application was found to be stable under mechanical stress such as grinding and milling and stable under hygroscopic conditions such as higher relative humidity conditions of more than 60% RH.
The above crystalline forms of idelalisib can be used to prepare other idelalisib solid state forms and pharmaceutical formulations.
The present invention further encompasses 1) a pharmaceutical composition comprising any one of idelalisib crystalline forms, as described above, and at least one pharmaceutically acceptable excipient; and 2) the use of any one or combination of the above-described crystalline forms of idelalisib, in the manufacture of a pharmaceutical composition, and 3) a method of treating a solid tumor such as NSCLC, breast, head and neck cancer, and a variety of other cancers, comprising administration of an effective amount of a pharmaceutical composition comprising any one or more of the forms of idelalisib described herein.
The crystalline forms of idelalisib of the present application are characterized by its PXRD pattern. All PXRD data reported herein were obtained using Cu Ka radiation, having the wavelength 1.541 A, and were obtained using a PanAlytical, Powder X-ray Diffractometer.
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
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 1 1 , 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 .
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, isopentane, neopentane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, 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, methylcyclohexane, cycloheptane, petroleum ethers, 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, cyclopentyl methyl 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.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, “comprising” means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range “between” two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
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. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

EXAMPLES
Example 1: Preparation of crystalline idelalisib Form V1
Idelalisib (500 mg) and 1:1 mixture of dichloromethane and 1, 2-Dimethoxy ethane (1.0 mL) was charged into a test tube at 25 °C, and cyclomixed well for 10 minutes. The resultant clear solution was kept for slow solvent evaporation in a beaker. The solid was dried at 100 °C in ATD for 30 minutes, and then the solid was dried in VTD at 65 °C for 18 hours to get crystalline idelalisib Form V1.
Powder X-Ray diffractogram is shown in Figure 1.
Example 2: Preparation of crystalline idelalisib Form V2
Idelalisib (2.0 gm) and diethyl ether (40 mL) were charged into a 100 mL easymax reactor at 25 °C. The resultant suspension was stirred for 10 hours at 25 °C. The precipitate was filtered under vacuum. The solid was dried under vacuum at 50 °C for 6 hours to get crystalline idelalisib Form V2.
Powder X-Ray diffractogram is shown in Figure 2.
Example 3: Preparation of crystalline idelalisib Form V2
Idelalisib (1.2 gm) and dichloromethane (4 mL) were charged into a 100 mL easymax reactor at 25 °C. Diethyl ether (20 mL) was added and the resultant suspension was stirred for 1.5 hours at 25 °C. Added diethyl ether (20 mL) to it and the resultant suspension was stirred for 12 hours at 25 °C. The precipitate was filtered under vacuum. The solid was dried under vacuum at 50 °C for 6 hours to get crystalline idelalisib Form V2.
Powder X-Ray diffractogram is same as shown in Figure 2.
Example 4: Preparation of crystalline idelalisib Form V3
Idelalisib (500 mg) and dichloromethane (1.0 mL) were charged into a 25 mL round bottom flask at 25 °C. Propylene glycol (0.2 mL) was added to the solution. Cyclopentyl methyl ether (5.0 mL) was added to the solution and stirred the resultant mixture for 10 minutes. Cyclohexane (5 mL) was added to the solution and the resultant precipitate was stirred for 10 hours at 25 °C. The precipitate was filtered under vacuum. The solid was dried under vacuum at 50 °C for 6 hours to get crystalline idelalisib propylene glycol solvate.
Powder X-Ray diffractogram is shown in Figure 3.
Example 5: Preparation of crystalline idelalisib Form V3
Idelalisib (500 mg) and dichloromethane (1.0 mL) were charged into a 25 mL round bottom flask at 25 °C. (R)-(-)-propylene glycol (0.2 mL) was added to the solution. Cyclopentyl methyl ether (5.0 mL) was added to the solution and stirred the resultant mixture for 10 minutes. Cyclohexane (5 mL) was added to the solution and the resultant mixture was kept for 10 hours at 25 °C. Cyclohexane (5 mL) was added to the reaction mixture and the resultant mixture was stirred for 1 hour at 25 °C. The precipitate was filtered under vacuum to get crystalline idelalisib (R)-(-)-propylene glycol solvate.
Powder X-Ray diffractogram is same as shown in Figure 3.
,CLAIMS:CLAIMS
We Claim:
1. A process for preparation of crystalline Form V1 of Idelalisib characterized by an X-ray powder diffraction having peaks at about 9.40, 14.91, 17.23, and 18.65 ± 0.2 degrees two theta, comprising:
(a) providing a solution of idelalisib in a solvent or a mixture of solvents,
(b) optionally stirring the solution of step (a),
(c) evaporating the solvent, and
(d) isolating crystalline idelalisib Form V1.
2. A process for preparation of crystalline Form V2 of Idelalisib characterized by an X-ray powder diffraction having peaks at about 9.31, 11.20, 14.81, 16.58 and 18.53 ± 0.2 degrees two theta, comprising:
(a) providing a solution of idelalisib in dichloromethane,
(b) adding diethyl ether to the solution of step (a),
(c) optionally stirring the mixture obtained in step (b), and
(d) isolating crystalline idelalisib Form V2.
3. Crystalline Form V3 of Idelalisib characterized by an X-ray powder diffraction having peaks at about 4.72, 9.30, 9.59, 18.86, 19.54 and 20.16 ± 0.2 degrees two theta.
4. The crystalline Form V3 of claim 3 is characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 3.
5. A process for preparation of crystalline Form V3 of idelalisib, comprising:
(a) providing a mixture containing idelalisib, propylene glycol and one or more solvents,
(b) adding one or more anti-solvents to the mixture of step (a),
(c) optionally stirring the mixture obtained in step (b), and
(d) isolating crystalline idelalisib Form V3.
6. Idelalisib propylene glycol solvate.
7. A pharmaceutical composition comprising idelalisib crystalline Form V3 and one or more pharmaceutically acceptable carriers.
8. A pharmaceutical composition comprising idelalisib propylene glycol solvate and one or more pharmaceutically acceptable carriers.
9. A pharmaceutical composition comprising idelalisib crystalline Form V3 prepared by the process of claim 5 and one or more pharmaceutically acceptable carriers.