DESC:The following specification particularly describes the invention and the manner in which it is to be performed

CRYSTALLINE FORMS OF CERITINIB

FIELD OF INVENTION
The present application relates to crystalline forms RC1, RC2, RC3, RC4, RC5, RC6 and RC7 of ceritinib.

BACKGROUND OF INVENTION
US Patent Application No. US2013/0274279 A1 discloses two crystalline forms of ceritinib, namely crystalline form A and crystalline form B. The US’279 application further discloses process for preparation of crystalline form A and crystalline form B of ceritinib. IP.Com Journal, Volume 14, Issue 12B, Pages 1-3 discloses another new crystalline form of ceritinib. Moreover, Chinese Patent Application No. CN105061397A teaches crystalline form C of ceritinib. All these crystalline forms are characterized by X-ray powder diffraction pattern.

In general, polymorphism refers to the ability of a substance to exist as two or more crystalline phases that have different spatial arrangements and/or conformations of molecules in their crystal lattices. Thus, “polymorphs” refer to different crystalline forms of the same pure substance in which the molecules have different spatial arrangements of the molecules, atoms, and/or ions forming the crystal. Different polymorphs may have different physical properties such as melting points, solubilities, etc. The variation in solid forms may appreciably influence the pharmaceutical properties, such as bioavailability, handling properties, dissolution rate, and stability, and in turn such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorphic form. For these reasons, regulatory authorities require drug manufacturing companies to put efforts into identifying all polymorphic forms, e.g., crystalline, amorphous, solvates, stable dispersions with a pharmaceutically acceptable carriers, etc., of new drug substances.
The existence and possible numbers of polymorphic forms for a given compound cannot be predicted, and there are no “standard” procedures that can be used to prepare polymorphic forms of a substance. This is well-known in the art, as reported, for example, by A. Goho, “Tricky Business,” Science News, Vol. 166(8), August 2004.

Hence, there remains a need for alternate polymorphic forms of ceritinib and processes for preparing them.

SUMMARY OF INVENTION
First aspect of the present application relates to crystalline form RC1 of ceritinib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 5.01, 9.61, 10.06, 14.47, 15.09 and 21.91 ± 0.2° 2?. In embodiments, the present application provides crystalline form RC1 of ceritinib characterized by its PXRD pattern having additional peaks located at about 12.29, 17.09, 17.89 and 25.83 ± 0.2° 2?.
Second aspect of the present application provides crystalline form RC1 of ceritinib characterized by a PXRD pattern substantially as illustrated in Figure 1.
Third aspect of the present application provides a process for preparing crystalline form RC1 of ceritinib comprising:
a) providing a mixture of ceritinib in an acidic solvent or mixtures thereof;
b) combining an aqueous solution of a suitable base with the mixture of step a); and
c) isolating crystalline form RC1 of ceritinib.
Fourth aspect of the present application relates to a composition comprising crystalline form RC1 of ceritinib and one or more pharmaceutically acceptable excipient.

Fifth aspect of the present application relates to crystalline form RC2 of ceritinib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 5.04, 9.59, 10.09, 13.33, 14.44, 15.09, 17.97 and 24.35 ± 0.2° 2?. In embodiments, the present application provides crystalline form RC2 of ceritinib characterized by its PXRD pattern having additional peaks located at about 7.11, 7.97, 12.31, 17.08, 18.86, 19.24 and 25.81 ± 0.2° 2?.
Sixth aspect of the present application provides crystalline form RC2 of ceritinib characterized by a PXRD pattern substantially as illustrated in Figure 2.
Seventh aspect of the present application provides a process for preparing crystalline form RC2 of ceritinib comprising drying crystalline form RC1 of ceritinib under suitable condition.
Eighth aspect of the present application relates to a composition comprising crystalline form RC2 of ceritinib and one or more pharmaceutically acceptable excipient.

Ninth of the present application relates to crystalline form RC3 of ceritinib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 5.42, 7.08, 9.36, 12.45, 13.23, 16.82 and 25.71 ± 0.2° 2?. In embodiments, the present application provides crystalline form RC3 of ceritinib characterized by its PXRD pattern having additional peaks located at about 15.02, 15.97, 16.39 and 28.46 ± 0.2° 2?.
Tenth aspect of the present application provides crystalline form RC3 of ceritinib characterized by a PXRD pattern substantially as illustrated in Figure 3.
Eleventh aspect of the present application provides a process for preparing crystalline form RC3 of ceritinib comprising drying crystalline form RC1 or crystalline form RC2 or mixtures thereof under suitable condition.
Twelfth aspect of the present application relates to a composition comprising crystalline form RC3 of ceritinib and one or more pharmaceutically acceptable excipient.

Thirteenth of the present application relates to crystalline form RC4 of ceritinib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 7.38, 7.69, 9.92, 13.08, 14.82 and 25.23 ± 0.2° 2?. In embodiments, the present application provides crystalline form RC4 of ceritinib characterized by its PXRD pattern having additional peaks located at about 12.53, 19.04, 19.41 and 20.83 ± 0.2° 2?.
Fourteenth aspect of the present application provides crystalline form RC4 of ceritinib characterized by a PXRD pattern substantially as illustrated in Figure 4.
Fifteenth aspect of the present application provides a process for preparing crystalline form RC4 of ceritinib comprising
a) providing a mixture of ceritinib in an aromatic hydrocarbon solvent or mixtures thereof;
b) combining an aliphatic hydrocarbon solvent with the mixture of step a); and
c) isolating crystalline form RC4 of ceritinib.
Sixteenth aspect of the present application relates to a composition comprising crystalline form RC4 of ceritinib and one or more pharmaceutically acceptable excipient.

Seventeenth aspect of the present application relates to crystalline form RC5 of ceritinib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 7.32, 7.78, 9.78, 9.97, 12.68, 14.66 and 22.06 ± 0.2° 2?. In embodiments, the present application provides crystalline form RC5 of ceritinib characterized by its PXRD pattern having additional peaks located at about 12.32, 17.78 and 18.92 ± 0.2° 2?.
Eighteenth aspect of the present application provides crystalline form RC5 of ceritinib characterized by a PXRD pattern substantially as illustrated in Figure 5.
Nineteenth aspect of the present application provides a process for preparing crystalline form RC5 of ceritinib comprising
a) providing a mixture of ceritinib in an aromatic hydrocarbon solvent or mixtures thereof; and
b) isolating crystalline form RC5 of ceritinib.
Twenty aspect of the present application relates to a composition comprising crystalline form RC5 of ceritinib and one or more pharmaceutically acceptable excipient.
Twenty first aspect of the present application relates to crystalline form RC6 of ceritinib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 7.34, 7.74, 9.84, 10.09, 14.67, 21.56 and 25.13 ± 0.2° 2?. In embodiments, the present application provides crystalline form RC6 of ceritinib characterized by its PXRD pattern having additional peaks located at about 17.91, 20.20 and 28.09 ± 0.2° 2?.
Twenty second of the present application provides crystalline form RC6 of ceritinib characterized by a PXRD pattern substantially as illustrated in Figure 6.
Twenty third aspect of the present application provides a process for preparing crystalline form RC6 of ceritinib comprising
a) providing a mixture of ceritinib in an aromatic hydrocarbon solvent or mixtures thereof; and
b) isolating crystalline form RC6 of ceritinib.
Twenty fourth aspect of the present application relates to a composition comprising crystalline form RC6 of ceritinib and one or more pharmaceutically acceptable excipient.
Twenty fifth aspect of the present application relates to crystalline form RC7 of ceritinib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 4.42, 10.04, 11.78, 12.97, 25.78 and 30.11 ± 0.2° 2?. In embodiments, the present application provides crystalline form RC7 of ceritinib characterized by its PXRD pattern having additional peaks located at about 14.73, 15.52, 17.15, 18.28, 18.86, 22.66 and 24.68 ± 0.2° 2?.
Twenty sixth aspect of the present application provides crystalline form RC7 of ceritinib characterized by a PXRD pattern substantially as illustrated in Figure 7.
Twenty seventh aspect of the present application provides a process for preparing crystalline form RC7 of ceritinib comprising
a) providing a mixture of ceritinib in a mixture of benzyl alcohol and water; and
b) isolating crystalline form RC7 of ceritinib.
Twenty eighth aspect of the present application relates to a pharmaceutical composition comprising crystalline form RC7 of ceritinib and one or more pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustration of a PXRD pattern of crystalline form RC1 of ceritinib.
Figure 2 is an illustration of a PXRD pattern of crystalline form RC2 of ceritinib.
Figure 3 is an illustration of a PXRD pattern of crystalline form RC3 of ceritinib.
Figure 4 is an illustration of a PXRD pattern of crystalline form RC4 of ceritinib.
Figure 5 is an illustration of a PXRD pattern of crystalline form RC5 of ceritinib.
Figure 6 is an illustration of a PXRD pattern of crystalline form RC6 of ceritinib.
Figure 7 is an illustration of a PXRD pattern of crystalline form RC7 of ceritinib.

DETAILED DESCRIPTION OF INVENTION
First aspect of the present application relates to crystalline form RC1 of ceritinib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 5.01, 9.61, 10.06, 14.47, 15.09 and 21.91 ± 0.2° 2?. In embodiments, the present application provides crystalline form RC1 of ceritinib characterized by its PXRD pattern having additional peaks located at about 12.29, 17.09, 17.89 and 25.83 ± 0.2° 2?.
Second aspect of the present application provides crystalline form RC1 of ceritinib characterized by a PXRD pattern substantially as illustrated in Figure 1.
Third aspect of the present application provides a process for preparing crystalline form RC1 of ceritinib comprising:
a) providing a mixture of ceritinib in an acidic solvent or mixtures thereof;
b) combining an aqueous solution of a suitable base with the mixture of step a); and
c) isolating crystalline form RC1 of ceritinib.
The suitable acidic solvent of step a) includes but not limited to formic acid, acetic acid, propionic acid and the like. Specifically, the acidic solvent is acetic acid. The mixture of ceritinib and acidic solvent may be heated to achieve complete dissolution of ceritinib in the acidic solvent.
In one of the embodiments of step a), any physical form of ceritinib may be utilized, which may be crystalline or amorphous, for providing the mixture of ceritinib in a suitable solvent or mixtures thereof. In another embodiment of step a), any physical form of ceritinib may be utilized, which may be anhydrous or hydrate, for providing the mixture of ceritinib in suitable acidic solvent or mixtures thereof.
To the mixture of step a), an aqueous solution of a suitable base may be added. Alternatively, the mixture of step a) may be added to an aqueous solution of a suitable base. The suitable base includes but not limited to hydroxide base such as sodium hydroxide, potassium hydroxide and the like; carbonate base such as sodium carbonate, potassium carbonate and the like; bicarbonate base such as sodium bicarbonate, potassium bicarbonate and the like. Specifically, the suitable base is sodium hydroxide. The resulting mixture of step b) may be stirred for suitable time at a suitable temperature. Specifically, the resulting mixture of step b) may be stirred for about 1 hour to about 5 days at about 0 °C to about boiling point of the solvent. More specifically, the resulting mixture of step b) may be stirred for 10 hours to about 50 hours at about 15 °C to about 50 °C. Most specifically, the resulting mixture of step b) may be stirred for 20 hours to 40 hours at about 25 °C to about 40 °C.
In one embodiment of step a) or step b), the seed crystals of crystalline form RC1 of ceritinib may be optionally added to the mixture of step a) or step b).
Isolation of crystalline form RC1 from the mixture of step b) may be performed by any technique known in the art. Specifically, crystalline form RC1 may be isolated from the mixture of step b) by filtration. Optionally, the crystalline form RC1 may be dried under suitable condition. Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C and most specifically at 40 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 5 minutes to about 24 hours, or longer.
The obtained crystalline form RC1 of ceritinib may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of crystalline form RC1 of ceritinib. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.
The crystalline form RC1 of ceritinib may contain water and typically the water content may vary from about 0.5% to about 15.0% w/w, more specifically from about 1.0% to about 5.0% w/w, and most specifically from about 1.0% to about 3.5% w/w.
The crystalline form RC1 of ceritinib of the present application is stable and has excellent physico-chemical properties. The crystalline form RC1 of ceritinib of the present application may be easily formulated into a pharmaceutical composition comprising ceritinib.
Fourth aspect of the present application relates to a composition comprising crystalline form RC1 of ceritinib and one or more pharmaceutically acceptable excipient.

Fifth aspect of the present application relates to crystalline form RC2 of ceritinib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 5.04, 9.59, 10.09, 13.33, 14.44, 15.09, 17.97 and 24.35 ± 0.2° 2?. In embodiments, the present application provides crystalline form RC2 of ceritinib characterized by its PXRD pattern having additional peaks located at about 7.11, 7.97, 12.31, 17.08, 18.86, 19.24 and 25.81 ± 0.2° 2?.
Sixth aspect of the present application provides crystalline form RC2 of ceritinib characterized by a PXRD pattern substantially as illustrated in Figure 2.
Seventh aspect of the present application provides a process for preparing crystalline form RC2 of ceritinib comprising drying crystalline form RC1 of ceritinib under suitable condition.
In one embodiment, crystalline form RC1 may be dried in an air tray drier or vacuum tray drier for about 30 minutes to about 72 hours at a temperature from about 25 °C to about 100 °C. Specifically, crystalline form RC1 may be dried in an air tray drier for about 30 minutes to 5 hours at a temperature from about 30 °C to about 60 °C. Alternatively, crystalline form RC1 may be dried in a vacuum tray drier for about 24 hours to 72 hours at a temperature from about 25 °C to about 40 °C.
The obtained crystalline form RC2 of ceritinib may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.
The crystalline form RC2 of ceritinib may contain water and typically the water content may vary from about 0.5% to about 10.0% w/w, more specifically from about 0.75% to about 5.0% w/w.
The crystalline form RC2 of ceritinib of the present application is stable and has excellent physico-chemical properties. The crystalline form RC2 of ceritinib of the present application may be easily formulated into a pharmaceutical composition comprising ceritinib.
Eighth aspect of the present application relates to a composition comprising crystalline form RC2 of ceritinib and one or more pharmaceutically acceptable excipient.

Ninth aspect of the present application relates to crystalline form RC3 of ceritinib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 5.42, 7.08, 9.36, 12.45, 13.23, 16.82 and 25.71 ± 0.2° 2?. In embodiments, the present application provides crystalline form RC3 of ceritinib characterized by its PXRD pattern having additional peaks located at about 15.02, 15.97, 16.39 and 28.46 ± 0.2° 2?.
Tenth aspect of the present application provides crystalline form RC3 of ceritinib characterized by a PXRD pattern substantially as illustrated in Figure 3.
Eleventh aspect of the present application provides a process for preparing crystalline form RC2 of ceritinib comprising drying crystalline form RC1 or crystalline form RC2 or mixtures thereof under suitable condition.
In one embodiment, crystalline form RC1 or crystalline form RC2 or mixtures thereof may be dried in an air tray drier for about 5 minutes to about 100 minutes at a temperature from about 60 °C to about 150 °C. Specifically, crystalline form RC1 or crystalline form RC2 may be dried in an air tray drier for about 10 minutes to 20 minutes at a temperature from about 90 °C to about 120 °C.
The obtained crystalline form RC3 of ceritinib may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.
In one embodiment, the crystalline form RC3 of ceritinib may be anhydrous in nature and may contain water below 0.5% and specifically below 0.3 %.
The crystalline form RC3 of ceritinib of the present application is stable and has excellent physico-chemical properties. The crystalline form RC3 of ceritinib of the present application may be easily formulated into a pharmaceutical composition comprising ceritinib.
Twelfth aspect of the present application relates to a composition comprising crystalline form RC3 of ceritinib and one or more pharmaceutically acceptable excipient.

Thirteenth aspect of the present application relates to crystalline form RC4 of ceritinib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 7.38, 7.69, 9.92, 13.07, 14.82 and 25.23 ± 0.2° 2?. In embodiments, the present application provides crystalline form RC4 of ceritinib characterized by its PXRD pattern having additional peaks located at about 12.53, 19.03, 19.41 and 20.83 ± 0.2° 2?.
Fourteenth aspect of the present application provides crystalline form RC4 of ceritinib characterized by a PXRD pattern substantially as illustrated in Figure 4.
Fifteenth aspect of the present application provides a process for preparing crystalline form RC4 of ceritinib comprising
a) providing a mixture of ceritinib in an aromatic hydrocarbon solvent or mixtures thereof;
b) combining an aliphatic hydrocarbon solvent with the mixture of step a); and
c) isolating crystalline form RC4 of ceritinib.
The suitable aromatic hydrocarbon solvent of step a) includes but not limited to toluene, benzene, xylene and the like. Specifically, the aromatic hydrocarbon solvent is toluene. The mixture of ceritinib and aromatic hydrocarbon solvent may be heated to achieve complete dissolution of ceritinib in the solvent.
In one of the embodiments of step a), any physical form of ceritinib may be utilized, which may be crystalline or amorphous, for providing the mixture of ceritinib in a suitable solvent or mixtures thereof. In another embodiment of step a), any physical form of ceritinib may be utilized, which may be anhydrous or hydrate, for providing the mixture of ceritinib in suitable aromatic hydrocarbon solvent or mixtures thereof.
An aliphatic hydrocarbon solvent may be mixed with the solution of step (a). Alternatively, the solution of step (a) may be added to the suitable aliphatic hydrocarbon solvent. The aliphatic hydrocarbon solvent includes but not limited to hexane, heptane, cyclohexane and the like. Specifically, the aliphatic hydrocarbon solvent is hexane. In one embodiment, aliphatic hydrocarbon solvent may be mixed with the solution of step (a) at a temperature of about 0 °C to about boiling point of the solvent. Specifically, aliphatic hydrocarbon solvent may be mixed with the solution of step (a) at a temperature of about 20 °C to about 50 °C.
In one embodiment of step a) or step b), the seed crystals of crystalline form RC4 of ceritinib may be optionally added to the mixture of step a) or step b).
Isolation of crystalline form RC4 from the mixture of step b) may be performed by any technique known in the art. In one embodiment, crystalline form RC4 may be isolated from the mixture of step b) by evaporation. Specifically, crystalline form RC4 may be isolated from the mixture of step b) by filtration. Optionally, the crystalline form RC4 may be dried under suitable condition. Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C and most specifically at 40 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 5 minutes to about 24 hours, or longer.
The obtained crystalline form RC4 of ceritinib may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of crystalline form RC4 of ceritinib. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.
In one embodiment, the crystalline form RC4 of ceritinib may be anhydrous in nature and may contain water below 0.5% and specifically below 0.3%.
The crystalline form RC4 of ceritinib of the present application is stable and has excellent physico-chemical properties. The crystalline form RC4 of ceritinib of the present application may be easily formulated into a pharmaceutical composition comprising ceritinib.
Sixteenth aspect of the present application relates to a composition comprising crystalline form RC4 of ceritinib and one or more pharmaceutically acceptable excipient.

Seventeenth aspect of the present application relates to crystalline form RC5 of ceritinib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 7.32, 7.78, 9.78, 9.97, 12.68, 14.66 and 22.06 ± 0.2° 2?. In embodiments, the present application provides crystalline form RC5 of ceritinib characterized by its PXRD pattern having additional peaks located at about 12.32, 17.78 and 18.92 ± 0.2° 2?.
Eighteenth aspect of the present application provides crystalline form RC5 of ceritinib characterized by a PXRD pattern substantially as illustrated in Figure 5.
Nineteenth aspect of the present application provides a process for preparing crystalline form RC5 of ceritinib comprising
a) providing a mixture of ceritinib in an aromatic hydrocarbon solvent or mixtures thereof; and
b) isolating crystalline form RC5 of ceritinib.
The suitable aromatic hydrocarbon solvent of step a) includes but not limited to toluene, benzene, xylene and the like. Specifically, the aromatic hydrocarbon solvent is xylene. The mixture of ceritinib and aromatic hydrocarbon solvent may be heated to achieve complete dissolution of ceritinib in the solvent.
In one of the embodiments of step a), any physical form of ceritinib may be utilized, which may be crystalline or amorphous, for providing the mixture of ceritinib in a suitable solvent or mixtures thereof. In another embodiment of step a), any physical form of ceritinib may be utilized, which may be anhydrous or hydrate, for providing the mixture of ceritinib in suitable aromatic hydrocarbon solvent or mixtures thereof. In another embodiment, crystalline form RC1 of ceritinib may be used in step a). In another embodiment, crystalline form A of ceritinib, as reported in US2013/0274279 A1 may be used in step a). In yet another embodiment, amorphous ceritinib, as reported in co-pending application, IN6355/CHE/2014 A may be used in step a).
In one embodiment of step a), the seed crystals of crystalline form RC5 of ceritinib may be optionally added to the mixture of step a).
Isolation of crystalline form RC5 obtained in step b) may be performed by any technique known in the art. In one embodiment, crystalline form RC5 may be isolated from the mixture of step b) by evaporation. Specifically, crystalline form RC5 may be isolated from the mixture of step b) by filtration. Optionally, the crystalline form RC5 may be dried under suitable condition. Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C and most specifically at 40 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 5 minutes to about 24 hours, or longer.
The obtained crystalline form RC5 of ceritinib may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of crystalline form RC5 of ceritinib. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.
The crystalline form RC5 of ceritinib of the present application is stable and has excellent physico-chemical properties. The crystalline form RC5 of ceritinib of the present application may be easily formulated into a pharmaceutical composition comprising ceritinib.
Twentieth aspect of the present application relates to a composition comprising crystalline form RC5 of ceritinib and one or more pharmaceutically acceptable excipient.

Twenty first aspect of the present application relates to crystalline form RC6 of ceritinib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 7.34, 7.74, 9.84, 10.09, 14.67, 21.56 and 25.13 ± 0.2° 2?. In embodiments, the present application provides crystalline form RC6 of ceritinib characterized by its PXRD pattern having additional peaks located at about 17.91, 20.20 and 28.09 ± 0.2° 2?.
Twenty second aspect of the present application provides crystalline form RC6 of ceritinib characterized by a PXRD pattern substantially as illustrated in Figure 6.
Twenty third aspect of the present application provides a process for preparing crystalline form RC6 of ceritinib comprising
a) providing a mixture of ceritinib in an aromatic hydrocarbon solvent or mixtures thereof; and
b) isolating crystalline form RC6 of ceritinib.
The suitable aromatic hydrocarbon solvent of step a) includes but not limited to toluene, benzene, xylene, anisole and the like. Specifically, the aromatic hydrocarbon solvent is anisole. The mixture of ceritinib and aromatic hydrocarbon solvent may be heated to achieve complete dissolution of ceritinib in the solvent.
In one of the embodiments of step a), any physical form of ceritinib may be utilized, which may be crystalline or amorphous, for providing the mixture of ceritinib in a suitable solvent or mixtures thereof. In another embodiment of step a), any physical form of ceritinib may be utilized, which may be anhydrous or hydrate, for providing the mixture of ceritinib in suitable aromatic hydrocarbon solvent or mixtures thereof. In another embodiment, crystalline form RC1 of ceritinib may be used in step a). In another embodiment, crystalline form A of ceritinib, as reported in US2013/0274279 A1 may be used in step a). In yet another embodiment, amorphous ceritinib, as reported in co-pending application, IN6355/CHE/2014 A may be used in step a).
In one embodiment of step a), the seed crystals of crystalline form RC6 of ceritinib may be optionally added to the mixture of step a).
Isolation of crystalline form RC6 obtained in step b) may be performed by any technique known in the art. In one embodiment, crystalline form RC6 may be isolated from the mixture of step b) by evaporation. Specifically, crystalline form RC6 may be isolated from the mixture of step b) by filtration. Optionally, the crystalline form RC6 may be dried under suitable condition. Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C and most specifically at 40 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 5 minutes to about 24 hours, or longer.
The obtained crystalline form RC6 of ceritinib may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of crystalline form RC6 of ceritinib. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.
The crystalline form RC6 of ceritinib of the present application is stable and has excellent physico-chemical properties. The crystalline form RC6 of ceritinib of the present application may be easily formulated into a pharmaceutical composition comprising ceritinib.
Twenty fourth aspect of the present application relates to a composition comprising crystalline form RC6 of ceritinib and one or more pharmaceutically acceptable excipient.

Twenty fifth aspect of the present application relates to crystalline form RC7 of ceritinib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 4.42, 10.04, 11.78, 12.97, 25.78 and 30.11 ± 0.2° 2?. In embodiments, the present application provides crystalline form RC7 of ceritinib characterized by its PXRD pattern having additional peaks located at about 14.73, 15.52, 17.15, 18.28, 18.86, 22.66 and 24.68 ± 0.2° 2?.
Twenty sixth aspect of the present application provides crystalline form RC7 of ceritinib characterized by a PXRD pattern substantially as illustrated in Figure 7.
Twenty seventh aspect of the present application provides a process for preparing crystalline form RC7 of ceritinib comprising
a) providing a mixture of ceritinib in a mixture of benzyl alcohol and water; and
b) isolating crystalline form RC7 of ceritinib.
In one of the embodiments of step a), any physical form of ceritinib may be utilized, which may be crystalline or amorphous, for providing the mixture of ceritinib in a mixture of benzyl alcohol and water. In another embodiment of step a), any physical form of ceritinib may be utilized, which may be anhydrous or hydrate, for providing the mixture of ceritinib in a mixture of benzyl alcohol and water. In another embodiment, amorphous form of ceritinib, as reported in the may be used in step a). In another embodiment, crystalline form A of ceritinib, as reported in US2013/0274279 A1 may be used in step a). In yet another embodiment, amorphous ceritinib, as reported in co-pending application, IN6355/CHE/2014 A may be used in step a).
In one embodiment of step a), the seed crystals of crystalline form RC7 of ceritinib may be optionally added to the mixture of step a).
Isolation of crystalline form RC7 obtained in step b) may be performed by any technique known in the art. In one embodiment, crystalline form RC7 may be isolated from the mixture of step b) by evaporation. Specifically, crystalline form RC7 may be isolated from the mixture of step b) by filtration. In one embodiment of step b), the solvent from the reaction mass may be decanted and a suitable non-polar solvent may be added. The suitable non-polar solvent may include but not limited to ether solvent such as diethyl ether, methyl tert-butyl ether and the like; aliphatic hydrocarbon solvent such as n-heptane, n-hexane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; or mixture thereof. Specifically, the suitable non-polar solvent may be a mixture of an ether solvent and an aliphatic hydrocarbon solvent. More specifically, the suitable non-polar solvent may be a mixture of methyl tert-butyl ether and n-heptane.
Optionally, the crystalline form RC7 may be dried under suitable condition. Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C and most specifically at 40 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 5 minutes to about 24 hours, or longer. The obtained crystalline form RC7 of ceritinib may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of crystalline form RC7 of ceritinib. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.
The crystalline form RC7 of ceritinib of the present application is stable and has excellent physico-chemical properties. The crystalline form RC7 of ceritinib of the present application may be easily formulated into a pharmaceutical composition comprising ceritinib.
Twenty eighth aspect of the present application relates to a pharmaceutical composition comprising crystalline form RC7 of ceritinib and one or more pharmaceutically acceptable excipient.

One aspect of the present application provides pharmaceutically acceptable dosage form comprising crystalline form RC1 or crystalline form RC2 or crystalline form RC3 or crystalline form RC4 or crystalline form RC5 or crystalline form RC6 or crystalline form RC7 of ceritinib and one or more pharmaceutically acceptable excipients. Crystalline forms RC1 or RC2 or RC3 or RC4 or RC5 or RC6 or RC7 of ceritinib together with one or more pharmaceutically acceptable excipients of the present application may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.
Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic, cationic, or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, and the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.

The PXRD conditions for the measurement of PXRD peaks of crystalline forms RC1, RC2, RC3, RC4 and RC7 of ceritinib are as follows:
Range: 3° 2? to 40° 2? in conventional reflection mode
Instrument: PANalytical X-ray Diffractometer
Detector: X’celerator
Source: Copper K-alpha radiation (1.5418 Angstrom).
The PXRD conditions for the measurement of PXRD peaks of crystalline forms RC5 and RC6 of ceritinib are as follows:
Range: 3° 2? to 40° 2? in conventional reflection mode
Instrument: Bruker X-ray Diffractometer
Detector: Lynxeye XE detector
Source: Copper K-alpha radiation (1.5418 Angstrom).

DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
The terms "about," "general, ‘generally," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
A name used herein to characterize a crystalline form should not be considered limiting with respect to any other substance possessing similar or identical physical and chemical characteristics, but rather it should be understood that these designations are mere identifiers that should be interpreted according to the characterization information also presented herein.
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, the terms “comprising” and “comprises” mean 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.
The term “optional” or “optionally” is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
In general, a diffraction angle (2?) in powder X-ray diffractometry may have an error in the range of ± 0.2o. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2o. Accordingly, the present application includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ± 0.2o. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2?±0.2º) of 19.6º" means "having a diffraction peak at a diffraction angle (2?) of 19.4º to 19.8º. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peaks and the peak locations are characteristic for a specific polymorphic form. The relative intensities of the XRD peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-theta values. Also, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings, for example, whether a Ni filter is used or not.
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 disclosure in any manner.

EXAMPLES
Example 1: Preparation of crystalline form RC1 of ceritinib
Crystalline form A of Ceritinib (3 g) was dissolved in acetic acid (15 mL) at 25 °C. Aqueous solution of sodium hydroxide (1 M, 500 mL) was added to the above reaction mass. The pH of the solution became 12.4. The resulting reaction mass was stirred at 25 °C for a period of about 24 hours and the precipitated solid was filtered and washed with water. The solid was dried at 25 °C under nitrogen atmosphere for about 4 hours to afford the title compound.
Example 2: Preparation of crystalline form RC2 of ceritinib
Crystalline form RC1 of ceritinib was dried in a vacuum tray drier for about 90 minutes at 50 °C to afford the desired compound.
Example 3: Preparation of crystalline form RC2 of ceritinib
Crystalline form RC1 of ceritinib was dried in an air tray drier for about 56 hours at 30 °C to afford the title compound.
Example 4: Preparation of crystalline form RC3 of ceritinib
Crystalline form RC1 (500 mg) was dried in an air tray drier for about 10 minutes at 120 °C to afford the desired compound.
Example 5: Preparation of crystalline form RC4 of ceritinib
Crystalline form RC1 of ceritinib was dissolved in toluene (10 mL) at 25 °C and cyclohexane (10 mL) was added to the solution. The solution was stirred for 5-10 minutes and then slowly evaporated at room temperature to afford the desired compound.
Example 6: Preparation of crystalline form RC4 of ceritinib
Ceritinib (2 g) was dissolved in toluene (80 mL) at 80 °C and filtered to remove any particulate matter. The solution was cooled to 25 °C and hexane (50 mL) was added to the above solution. Seed material from example 5 was added to the solution at this temperature. The reaction mass was stirred for 10-15 hours at 25 °C and filtered. The solid was dried in an air tray drier at 50 °C for about 1 hour to afford the title compound.
Example 7: Preparation of crystalline form RC5 of ceritinib
Ceritinib (250 mg) was dissolved in xylene (25 mL) at 25 °C stirred for 5-10 minutes and then slowly evaporated at room temperature to afford the desired compound.
Example 8: Preparation of crystalline form RC4 of ceritinib
Ceritinib (250 mg) was dissolved in anisole (25 mL) at 25 °C stirred for 5-10 minutes and then slowly evaporated at room temperature to afford the desired compound.
Example 9: Preparation of crystalline form RC7 of ceritinib
To a solution of amorphous ceritinib (0.5 g) in benzyl alcohol (5 mL) at 25 °C, water (60 mL) was added slowly and the reaction mass was stirred for about 16 hours. The solvent was decanted and nitrogen was flushed through the reaction vessel. Methyl tert-butyl ether (25 mL) and n-hexane (25 mL) was added to the reaction mass and stirred for about 30 minutes. The precipitated solid was filtered to provide the title compound.
Example 10: Preparation of crystalline form RC7 of ceritinib
To a mixture of amorphous ceritinib (1 g) in benzyl alcohol (5 mL) at 25 °C, water (50 mL) was added slowly and the reaction mass was stirred for about 29 hours. The solvent was decanted. Methyl tert-butyl ether (25 mL) and n-hexane (25 mL) was added to the reaction mass and stirred for about 30 minutes. The precipitated solid was filtered to afford the title compound.
,CLAIMS:WE CLAIM:
1. A crystalline form RC7 of ceritinib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 4.42, 10.04, 11.78, 12.97, 25.78 and 30.11 ± 0.2° 2?.
2. The crystalline form RC7 of ceritinib of claim 1, characterized by its powder X-ray diffraction (PXRD) pattern having additional peaks at about 14.73, 15.52, 17.15, 18.28, 18.86, 22.66 and 24.68 ± 0.2° 2?.
3. The crystalline form RC7 of ceritinib of claim 1, characterized by a PXRD pattern substantially as illustrated in Figure 7.
4. A process for preparing crystalline form RC7 of ceritinib comprising
a) providing a mixture of ceritinib in a mixture of benzyl alcohol and water; and
b) isolating crystalline form RC7 of ceritinib.
5. The process of claim 4, wherein ceritinib in step a) is amorphous ceritinib.
6. The process of claim 4, wherein a mixture of an ether solvent and an aliphatic hydrocarbon solvent is added in step b).
7. The process of claim 6, wherein the ether solvent is methyl tert-butyl ether.
8. The process of claim 6, wherein the aliphatic hydrocarbon solvent n-hexane.
9. A pharmaceutical composition comprising crystalline form RC7 of ceritinib and one or more pharmaceutically acceptable excipient.