WO2019207498A1 - Solid forms of 8-fluoro-2-{4-[(methylamino)methyl] phenyl}-1,3,4,5-tetrahydro-6h-azepino[5,4,3-cd] indol-6-one ((1s,4r)-7,7dimethyl-2-oxobicyclo [2.2.1] hept-1-yl) methanesulfonic acid salt (rucaparib camsylate) and the prerparation thereof - Google Patents

Abstract

The present invention relates to solid forms of Rucaparib camsylate (1). More particularly the invention relates to solid forms comprising of crystalline form R1, R2, R3, R4, R5 and R6 of Rucaparib camsylate (1) and solid dispersions of Rucaparib camsylate (1) with suitable pharmaceutically acceptable excipients. It further discloses the process for preparing the crystalline forms and solid dispersions of Rucaparib camsylate (1).

Description

“SOLID FORMS OF 8-FLUORO-2-{4-[(METHYLAMINO)METHYL] PHENYL}-l,3,4,5-TETRAHYDRO-6H-AZEPINO[5,4,3-CD] INDOL-6-ONE ((lS,4R)-7,7DIMETHYL-2-OXOBICYCLO [2.2.1] HEPT-l-YL) METHANESULFONIC ACID SALT (RUCAPARIB CAMSYLATE) AND

THE PRERPARATION THEREOF”

CROSS REFERENCE

This application claims the priority from Indian Patent Application No. 201841015635 filed Indian Patent Office on April 25, 2018.

FIELD OF THE INVENTION

The present invention relates to solid forms of Rucaparib camsylate (1) and process for preparation thereof. Specifically, the present invention relates to crystalline forms Rl, R2, R3, R4, R5 and R6 of Rucaparib camsylate (1) and solid dispersions of Rucaparib camsylate (1) using pharmaceutically acceptable excipient.

BACKGROUND OF THE INVENTION

Rucaparib camsylate is an anti-cancer agent which is a poly (ADP-ribose) polymerase (PARP) inhibitor used as monotherapy for the treatment of patients with advanced ovarian cancer in women with deleterious Breast Cancer gene (BRCA) mutation-positive. It was approved by the FDA in December 2016 as monotherapy treatment of patients who have been treated with more than two prior chemotherapies.

The following patents and applications describe the different polymorphs and salts of Rucaparib camsylate (1)

US8754072 discloses the crystalline polymorphic forms A, B, C and amorphous form of S-Rucaparib camsylate and form A of R-Rucaparib camsylate. Hence, the present inventors hereby disclose polymorphic forms Rucaparib camsylate and the process for the preparation of the same with better physiochemical parameters, which could be advantageous in preparation of better formulations and manufacture. OBJECTIVE OF THE INVENTION

The primary objective of the invention is to provide solid forms of Rucaparib camsylate (1), wherein the solid forms comprises of the crystalline forms Rl, R2, R3, R4, R5 and R6 of Rucaparib camsylate (1). In another objective of the present invention is to provide solid dispersions of Rucaparib camsylate (1).

Another objective of the invention is to provide process for the preparation of crystalline forms of Rl, R2, R3, R4, R5 and R6 of Rucaparib camsylate (1).

A further objective of the invention is to provide process for the preparation of solid dispersions of Rucaparib camsylate (1) using pharmaceutically acceptable excipient.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides solid forms of Rucaparib camsylate (1).

In another aspect, the present invention provides the crystalline forms Rl, R2, R3, R4, R5 and R6 of Rucaparib camsylate (1).

In another aspect, the present invention provides solid dispersions of Rucaparib camsylate (1).

In another aspect, the present invention provides crystalline form Rl of Rucaparib camsylate (1) characterized by its X-ray powder diffraction pattern having peaks at about 2(0) values of 5.95, 12.00, 12.65, 13.37, 14.19, 14.66, 15.06,

15.79,16.47,18.11,18.37, 18.96, 20.35, 20.90, 22.23, 22.97 ,23.97, 23.92, 24.26, 25.35, 26.43, 27.24, 27.51, 28.80, 29.79, 30.49, 31.05, 32.51, 32.80, 33.06 and 37.85 ± (0.2) degrees .

In another aspect, the present invention provides crystalline form R2 of Rucaparib camsylate (1), characterized by X-ray powder diffraction (XRPD) pattern having 2 theta values at 5.97, 8.99, 11.42, 12.05, 12.67, 13.39, 13.72, 14.21, 14.70, 15.10, 15.84, 16.46, 18.13, 18.41, 18.99, 19.60, 20.39, 20.95, 21.58, 22.34, 22.99, 23.36, 23.94, 24.92, 25.49, 26.44, 27.26, 27.80, 28.32, 28.81, 29.95, 30.54, 31.01, 32.55, 32.84 and 34.12 + 0.2 degrees.

In yet another aspect, the present invention provides crystalline form Rl and R2 of Rucaparib camsylate (1) which is characterized by X-ray powder diffraction pattern substantially as shown in figurel and figure 2.

In some aspect, the present invention provides a process for preparing crystalline forms Rl and R2 of Rucaparib camsylate (1), comprising:

i. Suspending Rucaparib camsylate (1) in a suitable first solvent; ii. adding a second solvent to the reaction mass of step i);

iii. heating the reaction mixture to 40°C -70°C;

iv. filtering the reaction mixture;

v. cooling the filtrate to a suitable temperature;

vi. isolating the crystalline forms of Rucaparib camsylate (1) from a third solvent; and

vii. optionally, drying crystalline Rucaparib camsylate (1) using a suitable technique at a suitable temperature.

In another aspect, the present invention provides crystalline form R3 of Rucaparib camsylate (1) characterized by X-ray powder diffraction pattern having peaks at about 2(q) values of 2.48, 5.92, 7.82, 8.86, 11.98, 12.58, 13.30, 14.12, 14.59, 15.00, 15.76, 16.37, 18.07, 18.79, 19.18, 20.26, 20.83, 22.23, 23.81, 25.32, 26.41, 28.74,

30.49, 30.87, 32.44, 35.69, 33.97, 34.56, 35.77, 36.27, 38.54, 39.49, 40.81 and 41.60 ± 0.2 degrees.

In yet another aspect, the present invention provides crystalline form R3 of Rucaparib camsylate (1), which is characterized by X-ray powder diffraction pattern substantially as shown in figure 3.

In some aspect, the present invention provides process for the preparation of crystalline form R3 of Rucaparib camsylate (1), comprising:

1. suspending Rucaparib camsylate (1) in a suitable first solvent;

2. heating the reaction mixture to 30 °C - 60 °C; 3. optionally, adding a second solvent to the reaction mass of step 2);

4. cooling the filtrate to a suitable temperature;

5. filtering the reaction mixture;

6. isolating the crystalline forms of Rucaparib camsylate (1) from a third solvent; and

7. optionally, drying crystalline Rucaparib camsylate (1) at a suitable temperature.

In another aspect, the present invention provides crystalline form R4 of Rucaparib camsylate (1) characterized by its X-ray powder diffraction pattern having peaks at about 2(q) values of 5.97, 8.97, 11.41, 12.01, 12.65, 13.37, 13.66, 14.18, 14.68, 15.07, 15.80, 16.47, 18.09, 18.39, 18.96, 20.35, 20.90, 21.50, 22.25, 22.91, 23.30,

23.89, 24.32, 25.39, 26.38, 27.31, 27.54, 28.77, 29.95, 30.53, 31.03, 32.54, 32.80,

34.09 and 41.58 ± 0.2 degrees.

In another aspect, the present invention provides crystalline form R5 of Rucaparib camsylate (1) characterized by its X-ray powder diffraction pattern having peaks at about 2(0) values of 6.11, 12.17, 12.81, 13.54, 13.86, 14.34, 14.84, 15.26, 15.96,

16.65, 18.26, 18.55, 19.12, 20.50, 21.02, 22.45, 23.47, 24.07, 25.03, 25.52, 27.38,

29.86, 32.79 and 33.04 ± 0.2 degrees.

In another aspect, the present invention provides crystalline form R6 of Rucaparib camsylate (1) characterized by its X-ray powder diffraction pattern having peaks at about 2(0) values of 3.23, 5.62 ,6.22, 11.11, 12.30, 12.89, 13.63, 14.44, 14.93, 15.35, 16.21, 16.76, 18.38, 19.24, 19.62, 20.58, 21.15, 22.53, 23.13, 24.14, 24.56, 25.18, 25.70, 27.73, 28.51, 30.84, 31.56 and 33.18 ± 0.2 degrees.

In yet another aspect, the present invention provides crystalline form R4, R5 and R6 of Rucaparib camsylate (1) which is characterized by X-ray powder diffraction pattern substantially as shown in figure 6.

In some aspect the, the present invention provides process for the preparation of crystalline forms R4, R5 and R6 of Rucaparib camsylate (1) comprising:

I. suspending Rucaparib camsylate (1) in a suitable first solvent; II. filtering the reaction mixture;

III. heating the reaction mixture to 40 °C - 70 °C;

IV. optionally, adding a second solvent to the reaction mass of step (III);

V. filtering the reaction mixture;

VI. isolating the crystalline forms R4, R5 and R6 of Rucaparib camsylate (1); and

VII. drying crystalline forms R4, R5 and R6 of Rucaparib camsylate (1) at a suitable temperature.

In some aspect, the present invention provides solid dispersion of Rucaparib camsylate (1) which is characterized by X-ray powder diffraction pattern substantially as shown in figure 7.

In another aspect, the present invention is to provides a process for the preparation of solid dispersion of Rucaparib camsylate (1) using a pharmaceutically acceptable excipient, comprising:

A. suspending Rucaparib camsylate (1) in a suitable first solvent;

B. heating the reaction mixture to 50 °C -70 °C;

C. adding the suitable second solvent and filtering;

D. cooling the filtrate to a suitable temperature;

E. adding a slurry of a suitable pharmaceutically acceptable excipient at 25-30 °C;

F. adding a suitable third solvent to the step E) reaction mixture; and

G. isolating solid dispersion form of Rucaparib camsylate (1).

In another aspect, the present invention provides solid dispersions of Rucaparib camsylate (1) which are characterized by X-ray powder diffraction pattern substantially as shown in figure 8 and figure 9.

A further aspect is to provide an alternative process for the preparation of solid dispersions of Rucaparib camsylate (1) using pharmaceutically acceptable excipient, comprising:

(i) suspending Rucaparib camsylate (1) in a suitable first solvent; (ii) adding the suitable pharmaceutically acceptable excipient at 25 °C -30 °C;

(iii) heating the reaction mixture to 50°C -70 °C;

(iv) optionally, adding a second solvent;

(v) filtering the reaction mixture;

(vi) removing the solvent from the filtrate under vacuum; and

(vii) isolating solid dispersion form of Rucaparib camsylate (1).

In another embodiment, the solid forms of Rucaparib camsylate (1) obtained by any of the above method was having purity more than equal to 99.5% by HPLC.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1: X-Ray powder diffraction (XPRD) pattern of crystalline form Rl of Rucaparib camsylate (1) prepared by example- 1.

Figure 2: X-Ray powder diffraction (XPRD) pattern of crystalline form R2 of Rucaparib camsylate (1) prepared by example-2.

Figure 3: X-Ray powder diffraction (XPRD) pattern of crystalline form R3 of Rucaparib camsylate (1) prepared by example-3.

Figure 4: X-Ray powder diffraction (XPRD) pattern of crystalline form R4 of Rucaparib camsylate (1) prepared by example-4.

Figure 5: X-Ray powder diffraction (XPRD) pattern of crystalline form R5 Rucaparib camsylate (1) prepared by example-5.

Figure 6: X-Ray powder diffraction (XPRD) pattern of crystalline form R6 Rucaparib camsylate (1) prepared by example-6.

Figure 7: X-Ray powder diffraction (XPRD) pattern of solid dispersions of Rucaparib camsylate (1) with g-cyclodextrin prepared by example-7.

Figure 8: X-Ray powder diffraction (XPRD) pattern of solid dispersions of Rucaparib camsylate (1) with sulfobutylether-P-cyclodextrin (SBECD) prepared by example- 8.

Figure 9: X-Ray powder diffraction (XPRD) pattern of solid dispersions of Rucaparib camsylate (1) with polyvinylpyrrolidone (PVP) prepared by example-9. DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the first embodiment of the present invention provides solid forms of Rucaparib camsylate (1).

In another embodiment, the present invention provides crystalline forms Rl, R2, R3, R4, R5 and R6 of Rucaparib camsylate (1).

Yet another embodiment, the present invention provides solid dispersions of Rucaparib camsylate (1) using a suitable pharmaceutically acceptable excipient.

In another embodiment, the present invention provides a process for the preparation of solid forms Rl, R2, R3, R4, R5 and R6 of Rucaparib camsylate (1) and solid dispersions of Rucaparib camsylate (1), using a suitable pharmaceutically acceptable excipient.

In another embodiment, the present invention provides crystalline form Rl of Rucaparib camsylate (1) characterized by its X-ray powder diffraction pattern having peaks at about 2(q) values of 5.95, 12.00, 12.65, 13.37, 14.19, 14.66, 15.06, 15.79,16.47,18.11,18.37, 18.96, 20.35, 20.90, 22.23, 22.97 ,23.97, 23.92, 24.26,

25.35, 26.43, 27.24, 27.51, 28.80, 29.79, 30.49, 31.05, 32.51, 32.80, 33.06 and 37.85 ± (0.2) degrees .

In another embodiment, the present invention provides crystalline form R2 of Rucaparib camsylate (1), characterized by X-ray powder diffraction (XRPD) pattern having 2 theta values at 5.97, 8.99, 11.42, 12.05, 12.67, 13.39, 13.72, 14.21, 14.70, 15.10, 15.84, 16.46, 18.13, 18.41, 18.99, 19.60, 20.39, 20.95, 21.58, 22.34, 22.99, 23.36, 23.94, 24.92, 25.49, 26.44, 27.26, 27.80, 28.32, 28.81, 29.95, 30.54, 31.01, 32.55, 32.84 and 34.12 + 0.2 degrees.

In some aspect, the present invention provides a process for preparing crystalline forms Rl and R2 of Rucaparib camsylate (1), comprising:

i. Suspending Rucaparib camsylate (1) in a suitable first solvent; ii. adding a second solvent to the reaction mass of step i);

iii. heating the reaction mixture to 40 °C -70 °C;

iv. filtering the reaction mixture; v. cooling the filtrate to a suitable temperature;

vi. isolating the crystalline forms of Rucaparib camsylate (1) from a third solvent; and

vii. optionally, drying crystalline Rucaparib camsylate (1) using a suitable technique at a suitable temperature.

In some embodiment, the present invention provides process for the preparation of crystalline forms Rl and R2 of Rucaparib camsylate (1) by suspending Rucaparib camsylate (1) in a suitable solvent and adding a second solvent at 25 °C -35 °C. The reaction mass was then heated to a temperature of 40 °C -70 °C; preferably 55°C - 60 °C and filtered. The filtrate was cooled to 0°C -40 °C, preferably to 25°C -35 °C and the solid formed was isolated from the third solvent. The obtained solid was dried using a suitable technique to yield crystalline form Rl or R2 of Rucaparib camsylate (1).

In some embodiment, the solvents used to suspend Rucaparib camsylate (1) may be selected from a group comprising of but not limited to water, methanol, ethanol, isopropyl alcohol, benzyl alcohol, 2-ethoxy ethanol or the like. Preferably, the crystalline form Rl of Rucaparib camsylate (1) can be obtained by suspending Rucaparib camsylate (1) in benzyl alcohol and cooling to 25°C -35 °C and crystalline form R2 of Rucaparib camsylate (1) can be obtained by suspending Rucaparib camsylate (1) in methanol and cooling to 0°C -5°C.

In yet another embodiment, the present invention provides crystalline form Rl and R2 of Rucaparib camsylate (1) which is characterized by X-ray powder diffraction pattern substantially as shown in figure 1 and figure 2.

In another embodiment,, the present invention provides crystalline form R3 of Rucaparib camsylate (1) characterized by its X-ray powder diffraction pattern having peaks at about 2(q) values of 2.48, 5.92, 7.82, 8.86, 11.98, 12.58, 13.30, 14.12, 14.59, 15.00, 15.76, 16.37, 18.07, 18.79, 19.18, 20.26, 20.83, 22.23, 23.81, 25.32, 26.41, 28.74, 30.49, 30.87, 32.44, 35.69, 33.97, 34.56, 35.77, 36.27, 38.54, 39.49, 40.81 and 41.60 ± 0.2 degrees. In some embodiment, the present invention provides process for the preparation of crystalline form R3 of Rucaparib camsylate (1) comprising:

1. Suspending Rucaparib camsylate (1) in a suitable first solvent;

2. heating the reaction mixture to 30°C-60 °C;

3. optionally, adding a second solvent to the reaction mass of step 2);

4. cooling the filtrate to a suitable temperature;

5. filtering the reaction mixture;

6. isolating the crystalline forms of Rucaparib camsylate (1) from a third solvent; and

7. optionally, drying crystalline Rucaparib camsylate (1) using a suitable technique at a suitable temperature.

In some embodiment, the present invention provides process for the preparation of crystalline form R3 of Rucaparib camsylate (1) by suspending Rucaparib camsylate (1) in a suitable first solvent at 25 °C -30 °C and heating the reaction mixture to a temperature of 30 °C -60 °C, preferably 35 °C -40 °C. A suitable second solvent was then added to the reaction mixture and filtered. The filtrate was cooled to 0 °C -30 °C, preferably 0 °C -5°C and a suitable third solvent, preferably aprotic solvent was then added to the filtrate. The solid formed was isolated and dried using a suitable technique to yield crystalline form R3 of Rucaparib camsylate (1). In yet another aspect, the present invention provides crystalline form R3 of Rucaparib camsylate (1), which is characterized by X-ray powder diffraction pattern substantially as shown in figure 3.

In another embodiment, the present invention provides crystalline form R4 of Rucaparib camsylate (1) characterized by its X-ray powder diffraction pattern having peaks at about 2(0) values of 5.97, 8.97, 11.41, 12.01, 12.65, 13.37, 13.66, 14.18, 14.68, 15.07, 15.80, 16.47, 18.09, 18.39, 18.96, 20.35, 20.90, 21.50, 22.25, 22.91, 23.30, 23.89, 24.32, 25.39, 26.38, 27.31, 27.54, 28.77, 29.95, 30.53, 31.03, 32.54, 32.80, 34.09 and 41.58 ± 0.2 degrees. In another embodiment , the present invention provides crystalline form R5 of Rucaparib camsylate (1) characterized by its X-ray powder diffraction pattern having peaks at about 2(0) values of 6.11, 12.17, 12.81, 13.54, 13.86, 14.34, 14.84, 15.26, 15.96, 16.65, 18.26, 18.55, 19.12, 20.50, 21.02, 22.45, 23.47, 24.07, 25.03, 25.52, 27.38, 29.86, 32.79 and 33.04 ± 0.2 degrees.

In another embodiment, the present invention provides crystalline form R6 of Rucaparib camsylate (1) characterized by its X-ray powder diffraction pattern having peaks at about 2(0) values of 3.23, 5.62 ,6.22, 11.11, 12.30, 12.89, 13.63, 14.44, 14.93, 15.35, 16.21, 16.76, 18.38, 19.24, 19.62, 20.58, 21.15, 22.53, 23.13, 24.14, 24.56, 25.18, 25.70, 27.73, 28.51, 30.84, 31.56 and 33.18 ± 0.2 degrees

In some aspect the, the present invention provides process for the preparation of crystalline forms R4, R5 and R6 of Rucaparib camsylate (1) comprising:

I. suspending Rucaparib camsylate (1) in a suitable first solvent;

II. filtering the reaction mixture;

III. heating the reaction mixture to 40 °C -70 °C;

IV. optionally, adding a second solvent to the reaction mass of step III);

V. filtering the reaction mixture;

VI. isolating the crystalline form R4 or R5 or R6 of Rucaparib camsylate (1); and

VII. drying crystalline form of Rucaparib camsylate (1); at a suitable temperature

In some embodiment, the present invention provides a process for the preparation of crystalline form R4, R5 and R6 of Rucaparib camsylate (1) by suspending Rucaparib camsylate (1) in a suitable first solvent at 25 °C -35 °C and filtering. The filtrate was heated at 40 °C -70 °C, preferably at 50 °C to about 55 °C. A suitable second solvent was then added to the filtrate and stirred. The solid formed was isolated and dried using a suitable technique to yield crystalline forms R4, or R5 or R6 of Rucaparib camsylate (1). In some embodiment, the solvents used to suspend Rucaparib camsylate (1) may be selected from a group comprising of aprotic solvents selected from but not limited to acetone, acetonitrile, nitromethane, l,4-dioxane, diethyl ether, dichloromethane, dimethyl sulfoxide ethyl acetate, N, N-dimethylformamide (DMF), N-Methyl-2- pyrrolidone (NMP), methyl tertiary butyl ether, hexane, butyl acetate cyclohexane, toluene, tetrahydrofuran or the like. Preferably the crystalline form R3 of Rucaparib camsylate (1) may be obtained by suspending Rucaparib camsylate (1) in dimethyl sulfoxide (DMSO), crystalline form R5 of Rucaparib camsylate (1) may be obtained by suspending Rucaparib camsylate (1) in N-Methyl-2-pyrrolidone (NMP) and crystalline form R6 of Rucaparib camsylate (1) may be obtained by suspending Rucaparib camsylate (1) in dimethylformamide.

In yet another embodiment the present invention provides crystalline form R4, R5 and R6 of Rucaparib camsylate (1) which is characterized by X-ray powder diffraction pattern substantially as shown in figure 4, figure 5 and figure 6.

In another embodiment, the present invention is to provides a process for the preparation of solid dispersion of Rucaparib camsylate (1) using a pharmaceutically acceptable excipient, comprising:

A. suspending Rucaparib camsylate (1) in a suitable first solvent;

B. heating the reaction mixture to 50 °C -70 °C;

C. adding the suitable second solvent and filtering;

D. cooling the filtrate to a suitable temperature;

E. adding a slurry of a suitable pharmaceutically acceptable excipient at 25 °C -30 °C;

F. adding a suitable third solvent to the step E) reaction mixture; and

G. isolating solid dispersion form of Rucaparib camsylate (1).

In some embodiment, the present invention provides a process for the preparation of solid dispersions of Rucaparib camsylate (1) using a suitable pharmaceutically acceptable excipient. Rucaparib camsylate (1) may be suspended in a suitable first solvent at 25 °C -30 °C and heated at 50 °C -70 °C, preferably at 60 °C to about 65 °C. The reaction mass was filtered, and the filtrate was cooled to 0 °C-40 °C. A slurry of pharmaceutically acceptable excipient in a suitable solvent was then added to the filtrate at 25 °C-30 °C, followed by addition of a third solvent. The solid formed was filtered and dried using a suitable technique to yield solid dispersion of Rucaparib camsylate (1).

In another embodiment, the present invention provides solid dispersion of Rucaparib camsylate (1) prepared by the above method which is characterized by X-ray powder diffraction pattern substantially as shown in figure 7.

In another embodiment, the present invention is to provides an alternative process for the preparation of amorphous solid dispersion of Rucaparib camsylate (1) using a pharmaceutically acceptable excipient, comprising:

(i) suspending Rucaparib camsylate (1) in a suitable first solvent;

(ii) adding the suitable pharmaceutically acceptable excipient at 25 °C -30 °C;

(iii) heating the reaction mixture to 50 °C -70 °C;

(iv) optionally, adding a second solvent;

(v) filtering the reaction mixture;

(vi) removing the solvent from the filtrate under vacuum; and

(vii) isolating amorphous solid dispersion form of Rucaparib camsylate (1).

In some embodiment the present invention provides an alternative process for the preparation of solid dispersions of Rucaparib camsylate (1) using pharmaceutically acceptable excipient. Rucaparib camsylate (1) may be suspended in a suitable solvent at 25 °C -30 °C and a slurry of a suitable pharmaceutically acceptable excipient in a suitable solvent added to the reaction mass. The reaction mixture was heated to 50 °C -70 °C, preferably from 55 °C to about 60 °C. A suitable second solvent was then added to the reaction mixture and filtered. The filtrate was removed and dried using a suitable technique to yield solid dispersions of Rucaparib camsylate (1). In another aspect, the present invention provides solid dispersions of Rucaparib camsylate (1) prepared by the above process which may be characterized by X-ray powder diffraction pattern substantially as shown in figure 8 and figure 9.

In some embodiment the suitable solvents used in the present invention were selected from a group comprising of organic or inorganic. Preferably organic solvents may be used from a group comprising or protic or aprotic solvents. The protic solvents may be selected from a group comprising of water, methanol, ethanol, isopropyl alcohol, benzyl alcohol, 2-ethoxy ethanol or the like, preferably methanol, 2-ethoxy ethanol and water were used in the present invention. The aprotic solvents may be selected from a group comprising of acetone, acetonitrile, nitromethane, l,4-dioxane, diethyl ether, dichloromethane, dimethyl sulfoxide ethyl acetate, N, N-dimethylformamide (DMF), N-Methyl-2-pyrrolidone (NMP), methyl tertiary butyl ether, hexane, butyl acetate cyclohexane, toluene, tetrahydrofuran or the like, preferably acetone, methyl tertiary butyl ether, dichloromethane, dimethyl sulfoxide , N-Methyl-2-pyrrolidone (NMP), N,N-dimethyl formamide (DMF) were used in the present invention.

The suitable pharmaceutically acceptable excipients used in the present invention may be selected from a group comprising of lactose, sorbitol, mannitol, saccharose, cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone K-30, (PVP K- 30), polyvinyl acetate hydroxyethyl cellulose (HEC), hydroxy propyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxy propyl methyl cellulose acetate succinate (HPMC-AS), g-cyclodextrin, hydroxypropyl beta cyclodextrin (HPBCD), sulfobutylether-P-cyclodextrin (SBCED) or the like, preferably g-cyclodextrin, sulfobutylether-P-cyclodextrin (SBCED) and polyvinylpyrrolidone K-30 (PVP-K-30) were used in the present invention.

In another embodiment, the weight to weight ratio of Rucaparib camsylate (1) and the pharmaceutically acceptable excipients may be selected from 1:1 to 1:20, preferably 1:1 to 1:10 and more preferably 1:1 to 1:5 may be used in the present invention.

In another embodiment the solid forms obtained in the present invention may be isolated and dried by a suitable technique comprising of but not limited to filtration, cooling, re-crystallization, concentrating the mass, flash evaporation, simple evaporation, fast solvent evaporation, rotational drying, spray drying, thin-film drying, agitated thin-film drying, freeze-drying or the like , preferably by filtration and precipitation were used in the present invention.

In another embodiment of the present application, drying of crystalline forms of Rucaparib camsylate (1) may be carried out using suitable drying technique comprising of but not limited to air tray dryer, vacuum tray dryer, fluidized bed dryer or the like. Preferably air tray dryer (ATD) is used for the drying in the present invention. The drying can be carried out at a suitable temperature ranging from 30 °C to about 80°C, preferably from 40 °C to about 45 °C. In another embodiment, the crystalline form Rl of Rucaparib camsylate (1) as obtained in example 1 was having X-Ray diffraction (XRD) pattern as shown in figure 1 and the 2 theta values provided in Table 1.

Table 1:

In another embodiment, the crystalline form R2 of Rucaparib camsylate (1) as obtained in example 2 was having X-Ray diffraction (XRD) pattern as shown in figure 2 and the 2 theta values provided in Table 2

Table 2:

In another embodiment, the crystalline form R3 of Rucaparib camsylate (1) as obtained in example 3 was having X-Ray diffraction (XRD) pattern as shown in figure 3 and the 2 theta values provided in Table 3 Table 3:

In another embodiment, the crystalline form R4 of Rucaparib camsylate (1) as obtained in example 4 was having X-Ray diffraction (XRD) pattern as shown in figure 4 and the 2 theta values provided in Table 4.

Table 4:

In another embodiment, the crystalline form R5 of Rucaparib camsylate (1) as obtained in example 5 was having X-Ray diffraction (XRD) pattern as shown in figure5 and the 2 theta values provided in Table 5. Table 5:

In another embodiment, the crystalline R6 of Rucaparib camsylate (1) as obtained in example 6 was having X-Ray diffraction (XRD) pattern as shown in figure 6 and the 2 theta values provided in Table 6.

Table 6:

In another embodiment, the solid dispersion of Rucaparib camsylate (1) as obtained in example 7 was having X-Ray diffraction (XRD) pattern as shown in figure 7 and the 2 theta values provided in Table 7.

Table 7:

The following examples further illustrate the present invention, but should not be construed in anyway, as to limit its scope.

EXAMPLES

EXAMPLE- 1: Preparation of crystalline form R1 of Rucaparib camsylate (1) lg of Rucaparib camsylate (1) was suspended in 20 mL benzyl alcohol at 25-30 °C. To this 2 mL of water was added. The reaction mixture was heated to 55 °C -60 °C and stirred for 15-20 mins to form a clear solution. The clear solution was filtered to remove any particulate matter and the filtrate cooled to 25 °C -35 °C. 40 mL of methyl tertiary butyl ether was then added to the filtrate and stirred for 2-3hrs at 25 °C -35 °C. The precipitated solid was filtered and dried under vacuum followed by drying in air tray dryer (ATD) below 45°C to obtain crystalline form Rl of Rucaparib camsylate (1). Yield: 84%; XRD: Figure 1.

EXAMPLE- 2: Preparation of crystalline form R2 of Rucaparib camsylate (1) lg of Rucaparib camsylate (1) was suspended in 20 mL methanol at 25 °C -30 °C. To this 2 mL of water was added. The reaction mixture was heated to 55 °C -60 °C and stirred for 15-20 mins to form a clear solution. The clear solution was filtered to remove any particulate matter. 40 mL of methyl tertiary butyl ether was added to the filtrate at 0°C -5 °C and stirred for l-2hrs at 0-5 °C with the precipitation of solid. The solid was filtered and dried under vacuum, followed by drying in air tray dryer (ATD) at 40 °C -45 °C for 2 to 3hrs to obtain crystalline form R2 of Rucaparib camsylate (1). Yield: 82%; XRD: Figure 2.

EXAMPLE- 3: Preparation of crystalline form R3 of Rucaparib camsylate (1) lg of Rucaparib camsylate (1) was suspended in 20 mL of dichloromethane at 25°C -30 °C. The reaction mixture was heated for 15-20 mins at 35 °C -40 °C. To the heated reaction mixture 20 mL of methanol was added to form a clear solution. The clear solution was filtered to remove any particulate matter and the filtrate cooled to 0 °C -5 °C. 40 mL of methyl tertiary butyl ether was added to the filtrate at 0 °C -5 °C with the precipitation of the solid. The reaction mass was stirred for l-2hrs at 0°C -5 °C and the solid formed was filtered, dried under vacuum, followed by drying in air tray dryer (ATD) below 45 °C to obtain crystalline form R3 of Rucaparib camsylate (1). Yield: 80%; XRD: Figure 3.

EXAMPLE- 4: Preparation of crystalline form R4 of Rucaparib camsylate (1) lg of Rucaparib camsylate (1) was suspended in 10 mL of dimethyl sulfoxide at 25 °C -30 °C and stirred for 10-15 mins to form a clear solution. The filtrate was heated at 50-55 °C and 40 mL of acetone was added. The reaction mass was stirred for 15- 20 mins and the solid formed was filtered and dried under vacuum. The dried solid was further dried in air tray dryer (ATD) below 45 °C to obtain crystalline form R4 of Rucaparib camsylate (1). Yield: 96%; XRD: Figure 4.

EXAMPLE- 5: Preparation of crystalline form R5 of Rucaparib camsylate (1) lg of Rucaparib camsylate (1) was suspended in 10 mL of N-methyl-2-pyrrolidone (NMP) at 25°C -30 °C and stirred for 10-15 mins to form a clear solution. The filtrate was heated at 50 °C -55 °C and 40mL of acetone was added. The reaction mass was stirred for 15-30 mins and the solid formed was filtered and dried under vacuum. The solid was further dried in air tray dryer (ATD) below 45 °C to obtain crystalline form R5 of Rucaparib camsylate (1). Yield: 98%; XRD: Figure 5.

EXAMPLE- 6: Preparation of crystalline form R6 of Rucaparib camsylate (1) lg of Rucaparib camsylate (1) was suspended in 30 mL of dimethylformamide at 25 °C -30 °C and stirred for 10-15 mins to form a clear solution. The filtrate was heated at 50 °C -55 °C and 40mL of acetone was added till precipitation of the solid. The reaction mass was stirred for 15-30 mins and the solid formed was filtered and dried under vacuum. The dried solid was further dried in air tray dryer (ATD) at 40 °C - 45 °C for 2 to 3hrs to obtain crystalline form R6 of Rucaparib camsylate (1). Yield: 96%; XRD: Figure 6.

EXAMPLE- 7: Preparation of solid dispersion of Rucaparib camsylate (1) with g-cyclodextrin

lg of Rucaparib camsylate (1) was suspended in 20 mL of 2-ethoxy ethanol and stirred for 15-30 mins at 25 °C -30 °C. The reaction mixture was then heated to 60- 65 °C and 4 mL of water was added to the reaction mass to form a clear solution and filtered. The filtrate was cooled to 25 °C -30 °C s and a slurry of 200mg of g- cyclodextrin in 60 mL dichloromethane was added to form a hazy solution. 60 mL of methyl tertiary butyl ether was further added to the hazy reaction solution resulting in the precipitation of solid. The solid so formed was dried under vacuum and further dried in air tray dryer (ATD) at 40 °C -45 °C for 2 -3hrs to obtain solid dispersion of Rucaparib camsylate (1) with g-cyclodextrin. Yield: 93%; XRD: figure 7.

EXAMPLE- 8: Preparation of solid dispersion of Rucaparib camsylate (1) with sulfobutylether-p-cyclodextrin (SBCED)

2g of Rucaparib camsylate (1) was suspended in 40 mL of methanol and lg of sulfobutylether-P-cyclodextrin (SBCED) was added at 25 °C -30 °C. The reaction mixture was then heated at 55 °C -60 °C and 4 mL of water was added to the reaction mass. The reaction mass was stirred for 15-30 mins at 55 °C -60 °C to form a clear solution and filtered. The filtrate was distilled under vacuum and the residue dried under vacuum below 60 °C to obtain amorphous solid dispersion of Rucaparib camsylate (1) with sulfobutylether-P-cyclodextrin (SBCED). Yield: 93%; Purity: 99.90%; XRD: figure 8.

EXAMPLE- 9: Preparation of solid dispersion of Rucaparib camsylate (1) with polyvinylpyrrolidone-K-30 (PVP-K-30)

2g of Rucaparib camsylate (1) was suspended in 40 mL of methanol and lg of polyvinylpyrrolidone-K-30 (PVP-K-30) was added at 25°C -30 °C. The reaction mixture was then heated at 55 °C -60 °C and stirred for 15-30 mins. 4 mL of water was added to the reaction mass, stirred for 15-30 mins at 55 °C -60 °C to form a clear solution and filtered. The filtrate was distilled under vacuum and the residue dried under vacuum below 60 °C to obtain amorphous solid dispersion of Rucaparib camsylate (1) with polyvinylpyrrolidone-K-30 (PVP-K-30). Yield: 86 %; XRD: figure 9.

Claims

We claim:

1. A crystalline Rucaparib camsylate ( 1 ) form R 1 , characterized by X-ray powder diffraction (XRPD) spectrum having peaks at 2 theta values at 5.95, 12.00, 12.65, 13.37, 14.19, 14.66, 15.06, 15.79,16.47,18.11,18.37, 18.96, 20.35, 20.90, 22.23, 22.97 ,23.97, 23.92, 24.26, 25.35, 26.43, 27.24, 27.51, 28.80, 29.79, 30.49, 31.05, 32.51, 32.80, 33.06 and 37.85 ± (0.2) degrees.

2. A crystalline Rucaparib camsylate ( 1 ) form R2, characterized by X-ray powder diffraction (XRPD) spectrum having 2 theta values at 5.97, 8.99, 11.42, 12.05, 12.67, 13.39, 13.72, 14.21, 14.70, 15.10, 15.84, 16.46, 18.13, 18.41, 18.99, 19.60, 20.39, 20.95, 21.58, 22.34, 22.99, 23.36, 23.94, 24.92, 25.49, 26.44, 27.26, 27.80, 28.32, 28.81, 29.95, 30.54, 31.01, 32.55, 32.84 and 34.12 ± 0.2 degrees.

3. A process for the preparation of crystalline form Rl and R2 as defined in claim 1 and claim 2, which comprises the steps of:

(i) Suspending Rucaparib camsylate (1) in a suitable first solvent;

(ii) adding a second solvent to the reaction mass of step i);

(iii) heating the reaction mixture to 40 - 70 °C;

(iv)filtering the reaction mixture;

(v) cooling the filtrate to a suitable temperature; and

(vi)isolating the crystalline forms of Rucaparib camsylate (1) from a third solvent at a suitable temperature; and

(vii) optionally, drying crystalline Rucaparib camsylate (1) using a suitable technique at a suitable temperature.

4. The process of claim 3, wherein the solvent is selected from a group comprising of water, methanol, ethanol, isopropyl alcohol, benzyl alcohol, butyl alcohol, isobutyl alcohol, acetone, acetonitrile, l,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N,N-dimethylformamide, methyl tertiary butyl ether, diethyl ether, n-hexane, cyclohexane, toulene, tetrahydrofuran or the like.

5. A crystalline Rucaparib camsylate ( 1 ) form R3, characterized by X-ray powder diffraction (XRPD) pattern having 2 theta values at 2.48, 5.92, 7.82, 8.86, 11.98, 12.58, 13.30, 14.12, 14.59, 15.00, 15.76, 16.37, 18.07, 18.79, 19.18, 20.26, 20.83, 22.23, 23.81, 25.32, 26.41, 28.74, 30.49, 30.87, 32.44, 35.69, 33.97, 34.56, 35.77, 36.27, 38.54, 39.49, 40.81 and 41.60 ± 0.2 degrees.

6. A process for the preparation of crystalline Rucaparib camsylate (1) form R3, comprising:

1. suspending Rucaparib camsylate ( 1 ) in a suitable first solvent;

2. heating the reaction mixture to 40 - 70 °C;

3. optionally, adding a second solvent to the reaction mass of step i);

4. cooling the filtrate to a suitable temperature;

5. filtering the reaction mixture;

6. isolating the crystalline forms of Rucaparib camsylate (1) from a third solvent; and

7. optionally, drying crystalline Rucaparib camsylate (1) using a suitable technique at a suitable temperature.

7. A crystalline Rucaparib camsylate ( 1 ) form R4, characterized by X-ray powder diffraction (XRPD) pattern having 2 theta values at 5.97, 8.97, 11.41, 12.01, 12.65, 13.37, 13.66, 14.18, 14.68, 15.07, 15.80, 16.47, 18.09, 18.39, 18.96, 20.35, 20.90, 21.50, 22.25, 22.91, 23.30, 23.89, 24.32, 25.39, 26.38, 27.31, 27.54, 28.77, 29.95, 30.53, 31.03, 32.54, 32.80, 34.09 and 41.58 ± 0.2 degrees.

8. A crystalline Rucaparib camsylate ( 1 ) form R5, characterized by X-ray powder diffraction (XRPD) pattern having 2 theta values at 6.11, 12.17, 12.81, 13.54, 13.86, 14.34, 14.84, 15.26, 15.96, 16.65, 18.26, 18.55, 19.12, 20.50, 21.02, 22.45, 23.47, 24.07, 25.03, 25.52, 27.38, 29.86, 32.79 and 33.04 ± 0.2 degrees and 34.12 + 0.2 degrees.

9. A crystalline Rucaparib camsylate (1) form R6, characterized by X-ray

powder diffraction (XRPD) pattern having 2 theta values at 3.23, 5.62 ,6.22, 11.11, 12.30, 12.89, 13.63, 14.44, 14.93, 15.35, 16.21, 16.76, 18.38, 19.24,

19.62, 20.58, 21.15, 22.53, 23.13, 24.14, 24.56, 25.18, 25.70, 27.73, 28.51, 30.84, 31.56 and 33.18 ± 0.2 degrees

10. A process for preparing crystalline form R4, R5 and R6 of Rucaparib camsylate (1), comprising:

I. suspending Rucaparib camsylate ( 1 ) in a suitable first solvent

II. filtering the reaction mixture

III. heating the reaction mixture to 40 °C -70 °C;

IV. optionally, adding a second solvent to the reaction mass of step III);

V. filtering the reaction mixture;

VI. isolating crystalline forms R4 or R5 or R6 of Rucaparib camsylate (1); and

VII. drying crystalline form of Rucaparib camsylate (1); at a suitable temperature.

11. A process for the preparation of solid dispersion of Rucaparib camsylate (1), which comprises:

A. suspending Rucaparib camsylate ( 1 ) in a suitable first solvent;

B. heating the reaction mixture to 50-70 °C;

C. adding the suitable second solvent and filtering;

D. cooling the filtrate to a suitable temperature;

E. adding a slurry of a suitable pharmaceutically acceptable excipient at 25-30 °C;

F. adding a suitable third solvent to the step E) reaction mixture; and

G. isolating solid dispersion form of Rucaparib camsylate (1).

12. A process for the preparation of solid dispersion of Rucaparib camsylate (1), with pharmaceutically acceptable excipient, which comprises:

a) suspending Rucaparib camsylate ( 1 ) in a suitable first solvent;

b) adding the suitable pharmaceutically acceptable excipient at 25-30 °C; c) heating the reaction mixture to 50-70 °C;

d) optionally, adding a second solvent; e) filtering the reaction mixture;

f) removing the solvent from the filtrate under vacuum; and

g) isolating solid dispersion form of Rucaparib camsylate (1).

13. The process of claim 11 and claim 12, wherein the suitable pharmaceutically acceptable excipients used is selected from a group comprising of lactose, sorbitol, mannitol, saccharose, cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone K-30, (PVP K-30), polyvinyl acetate hydroxyethyl cellulose (HEC), hydroxy propyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxy propyl methyl cellulose acetate succinate (HPMC-AS), g-cyclodextrin, hydroxypropyl beta cyclodextrin (HPBCD), sulfobutylether-P-cyclodextrin (SBCED) or the like.

14. The process of claim 11 and claim 12, wherein the suitable solvent is selected from a group comprising of water, methanol, ethanol, isopropyl alcohol, benzyl alcohol, 2-ethoxy ethanol or the like, preferably methanol, 2-ethoxy ethanol, acetone, acetonitrile, nitromethane, l,4-dioxane, diethyl ether, dichloromethane, , dimethyl sulfoxide ethyl acetate, , N, N-dimethylformamide (DMF), NMethyl-2-pyrrolidone (NMP), methyl tertiary butyl ether, hexane, butyl acetate cyclohexane, toluene, tetrahydrofuran or the like.