DESC:FIELD OF THE INVENTION
The present invention provides pharmaceutically acceptable salts of Rucaparib and polymorphic forms
thereof.

BACKGROUND OF THE INVENTION
Rucaparib is an inhibitor of the mammalian polyadenosine 5’-diphosphoribose polymerase (PARP) enzyme. The chemical name is 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 is represented by the following structural formula.

Rucaparib is marketed under the brand name RUBRACA by Clovis Oncology.
Rucaparib is first reported in US 6495541. This patent describes process for the preparation of Rucaparib comprising reacting 2-bromo-8-fluoro-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one with 4-formyl Phenyl boronic acid in presence of a base and solvent gives 4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzaldehyde, which on reaction with methyl amine gives Rucaparib.
Rucaparib Camsylate salt is known in US 9045487; phosphate salt is known in US 7268126 and US 20040248879.
OBJECT AND SUMMARY OF THE INVENTION
The principle object of the present invention is to provide pharmaceutically acceptable salts of Rucaparib selected from hydrochloride salt, succinate salt, fumarate salt, citrate salt and oxalate salt. Present invention also provides crystalline form M1 and M2 of Rucaparib hydrochloride salt.
In one aspect, present invention provides Rucaparib hydrochloride salt and process for the preparation of the same comprising:
a) dissolving Rucaparib in a solvent;
b) adding hydrochloric acid; and
c) isolating Rucaparib hydrochloride salt.
In another aspect, present invention provides crystalline Form M1 of Rucaparib hydrochloride and process for the preparation of the same comprising:
a) dissolving Rucaparib in alcohol solvent;
b) adding hydrochloric acid; and
c) isolating crystalline Form M1 of Rucaparib hydrochloride.
In one more aspect, present invention provides process for the preparation of crystalline Form M1 of Rucaparib hydrochloride comprising:
a) dissolving Rucaparib in alcohol solvent;
b) seeding with crystalline Form M1 of Rucaparib hydrochloride;
c) adding hydrochloric acid;
d) adding an ether solvent to isolate crystalline Form M1 of Rucaparib hydrochloride.
In one more aspect, present invention provides crystalline Form M2 of Rucaparib hydrochloride and process for the preparation of the same comprising:
a) suspending Rucaparib in water;
b) adding hydrochloric acid; and
c) isolating crystalline Form M2 of Rucaparib hydrochloride.
In one more aspect, present invention provides a process for the preparation of crystalline Form M2 of Rucaparib hydrochloride comprising:
a) dissolving Rucaparib in alcohol solvent;
b) adding hydrochloric acid;
c) adding above reaction mixture to the ether solvent seeded with Rucaparib hydrochloride Form M2; and
d) isolating crystalline Form M2 of Rucaparib hydrochloride.
In one aspect, present invention provides Rucaparib succinate salt and process for the preparation of the same comprising:
a) suspending Rucaparib in a solvent;
b) adding succinic acid; and
c) isolating Rucaparib succinate.
In another aspect, present invention provides Rucaparib fumarate salt and process for the preparation of the same comprising:
a) suspending Rucaparib in a solvent;
b) adding fumaric acid; and
c) isolating Rucaparib fumarate.
In one more aspect, present invention provides Rucaparib citrate salt and process for the preparation of the same comprising:
a) suspending Rucaparib in a solvent;
b) adding citric acid; and
c) isolating Rucaparib citrate.
In one more aspect, present invention provides Rucaparib oxalate salt and process for the preparation of the same comprising:
a) suspending Rucaparib in a solvent;
b) adding oxalic acid; and
c) isolating Rucaparib oxalate.

BRIEF DESCRIPTION OF THE DRAWINGS
Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing therefrom will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying figures wherein:
Figure 1: PXRD pattern of crystalline Form M1 of Rucaparib hydrochloride.
Figure 2: PXRD pattern of crystalline Form M2 of Rucaparib hydrochloride.
Figure 3: TGA thermogram of Rucaparib succinate.
Figure 4: DSC thermogram of Rucaparib succinate.
Figure 5: 1H NMR spectrum of Rucaparib succinate.
Figure 6: TGA thermogram of Rucaparib fumarate.
Figure 7: DSC thermogram of Rucaparib fumarate.
Figure 8: 1H NMR spectrum of Rucaparib fumarate.
Figure 9: TGA thermogram of Rucaparib citrate.
Figure 10: DSC thermogram of Rucaparib citrate.
Figure 11: 1H NMR spectrum of Rucaparib citrate.
Figure 12: TGA thermogram of Rucaparib oxalate
Figure 13: DSC thermogram of Rucaparib oxalate.
Figure 14: 1H NMR spectrum of Rucaparib oxalate.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides Rucaparib hydrochloride salt, Rucaparib Succinate salt, Rucaparib fumarate salt, Rucaparib citrate salt, Rucaparib oxalate salt and crystalline Form M1 and M2 of Rucaparib hydrochloride.
Instrumentation Details:
The PXRD measurements were carried out using BRUKER D8 Discover powder diffractometer equipped with goniometer of ?/2? configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2? range of 2.0°-50.0°, 0.030° step size and 0.4 seconds step time.
Differential Scanning Calorimetry (DSC):
Differential Scanning Calorimetry of novel forms were measured on TA Q1000 of TA instruments. The experiment was conducted from 30°C to 300°C at heating rate of 10.0°C/min and nitrogen purging at a flow rate of 50ml/min. Standard aluminum pans covered by lids with pin holes were used.
Differential Scanning Calorimetry of amorphous form was measured on TA Q1000 of TA instruments. The samples were heated from 30°C to 250°C at heating rate of 5.0°C/min with modulation amplitude ±1.0°C, modulation period 60sec and nitrogen purging at a flow rate of 50ml/min. Standard aluminum pans covered by lids with five pin holes were used. The glass transition temperature (Tg) of the amorphous form was measured using modulated DSC software.
Thermo Gravimetric Analysis (TGA):
TGA was recorded using on instrument TA Q5000 of TA instruments. The experiments were performed at a heating rate of 10.0°C/min over a temperature range of 25°C-300°C purging with nitrogen at a flow rate of 25m1/min.
Nuclear Magnetic Resonance (NMR) spectroscopy:
The 1HNMR experiments were performed on Bruker 300MHz Avance NMR spectrometer equipped with 5mm BBO probe in DMSO-d6. The data collected and processed by Top Spin-NMR software.
In one embodiment, present invention provides Rucaparib hydrochloride salt and process for the preparation of the same comprising:
a) dissolving Rucaparib in a solvent; and
b) adding hydrochloric acid; and
c) isolating Rucaparib hydrochloride salt.
In one embodiment, Rucaparib is dissolved in a solvent selected from polar solvent such as water, methanol, ethanol,1-propanol, isopropanol, 1-butanol, 2-butanol, isobutanol and 2-methyl-2-butanol to give clear solution.
Within the context, to the resulting clear solution is added hydrochloric acid; preferably aqueous hydrochloric acid, alcoholic hydrochloric acid such as methanolic hydrochloric acid and heated to 65-75°C and the resulting solid is fileted to isolate Rucaparib hydrochloride salt.
In another embodiment, present invention provides crystalline Form M1 of Rucaparib hydrochloride.
Within the context of the present invention, crystalline Form M1 of Rucaparib hydrochloride disclosed herein may be characterized by PXRD spectrum having peaks 15.44, 15.92, 16.23, 18.83, 23.15, 24.51, 25.91, 27.00, 27.44 and 28.39 ± 0.2° 2?.
In another embodiment, present invention provides crystalline Form M1 of Rucaparib hydrochloride and process for the preparation of the same comprising:
a) dissolving Rucaparib in alcohol solvent;
b) adding hydrochloric acid; and
c) isolating crystalline Form M1 of Rucaparib hydrochloride.
In one embodiment Rucaparib is dissolved in alcohol solvent such as water, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, isobutanol and 2-methyl-2-butanol preferably methanol to give clear solution.
Within the context, the resulting clear solution is added hydrochloric acid; preferably alcoholic hydrochloric acid such as methanolic hydrochloric acid and heated to 65-75°C followed by cooling the reaction mixture to 20-30°C. The resulting sloid is filtered to isolate crystalline Form M1 of Rucaparib hydrochloride.
In one more aspect, present invention provides process for the preparation of crystalline Form M1 of Rucaparib hydrochloride comprising:
a) dissolving Rucaparib in alcohol solvent;
b) seeding with crystalline Form M1 of Rucaparib hydrochloride;
c) adding hydrochloric acid;
d) adding an ether solvent to isolate crystalline Form M1 of Rucaparib hydrochloride.
In one embodiment, Rucaparib is dissolved in an alcohol solvent such methanol, ethanol, 1-propanol, isopropanol, 1-butanol,2-butanol, isobutanol and 2-methyl-2-butanol; preferably methanol, ethanol and seeded with Rucaparib hydrochloride crystalline Form M1. Further, to the reaction mixture added hydrochloric acid; preferably alcoholic hydrochloric acid such as methanolic hydrochloric acid and heated to 75-85°C.
Next, to the above resulting reaction mass is cooled to 20-30°C and added ether solvent such as cyclo pentyl methyl ether and methyl tertiary butyl ether and fileted; dried to isolate crystalline Form M1 of Rucaparib hydrochloride.
In one more embodiment, present invention provides crystalline Form M2 of Rucaparib hydrochloride.
Within the context of the present invention, crystalline Form M2 of Rucaparib hydrochloride disclosed herein may be characterized by PXRD spectrum having peaks 14.53, 15.42, 16.33, 22.42, 23.56, 24.06, 25.23, 25.62, 26.58, 27.24, 27.88, and 28.30 ± 0.2° 2?.
In one more embodiment, present invention provides crystalline Form M2 of Rucaparib hydrochloride and process for the preparation of the same comprising:
a) suspending Rucaparib in water;
b) adding hydrochloric acid; and
c) isolating crystalline Form M2 of Rucaparib hydrochloride.
Within the context, Rucaparib is suspended in water and added hydrochloric acid, preferably aqueous hydrochloric acid and heated to 75-85°C followed by cooling the reaction mixture to 20-30°C. The resulting solid is filtered and dried at 75-85°C isolate crystalline Form M2 of Rucaparib hydrochloride.
In another embodiment, the present invention provides a process for preparing crystalline Form M2 of Rucaparib hydrochloride comprising:
a) dissolving Rucaparib in alcohol solvent;
b) adding hydrochloric acid;
c) adding above reaction mixture to the ether solvent seeded with Rucaparib hydrochloride Form M2; and
d) isolating crystalline Form M2 of Rucaparib hydrochloride.
In one embodiment, Rucaparib is dissolved in alcohol solvent such as methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, isobutanol and 2-methyl-2-butanol; preferably methanol and ethanol and added hydrochloric acid; preferably methanolic HCl at 75-85°C.
Next, crystalline Rucaparib hydrochloride Form M2 seeds are added to an ether solvent such as methyl tertiary butyl ether, isopropyl ether and cyclopentyl methyl ether and to this was added Rucaparib reaction mixture at 25-35°C. The resulting reaction mass is cooled, filtered and dried to yield crystalline Form M2 of Rucaparib hydrochloride.
In another embodiment, present invention provides Rucaparib succinate salt and process for the preparation of the same comprising:
a) suspending Rucaparib in a solvent;
b) adding succinic acid; and
c) isolating Rucaparib succinate.
In one embodiment, Rucaparib is suspended in a solvent selected from polar solvent selected from alcohol solvents such as methanol, ethanol, propanol, isopropanol, butanol; preferably methanol.
To the resulting Rucaparib suspension is added succinic acid; preferably succinic acid solution, i.e succinic acid dissolved in a solvent selected from alcohol solvents such as methanol, ethanol, propanol, isopropanol, butanol; more preferably succinic acid dissolved in methanol and heated to room temperature. The resulting solid is filtered to isolate Rucaparib Succinate.
In one more embodiment, present invention provides Rucaparib fumarate salt and process for the preparation of the same comprising:
a) suspending Rucaparib in a solvent;
b) adding fumaric acid; and
c) isolating Rucaparib fumarate.
In one embodiment, Rucaparib is suspended in a solvent selected from polar solvent selected from alcohol solvents such as methanol, ethanol, propanol, isopropanol, butanol; preferably methanol.
To the resulting Rucaparib suspension is added fumaric acid; preferably fumaric acid solution, i.e fumaric acid dissolved in a solvent selected from alcohol solvent such as methanol, ethanol, propanol, isopropanol, butanol; more preferably fumaric acid dissolved in methanol and heated to room temperature. The resulting solid is filtered to isolate Rucaparib Fumarate.
In another embodiment, present invention provides Rucaparib citrate salt and process for the preparation of the same comprising:
a) suspending Rucaparib in a solvent;
b) adding citric acid; and
c) isolating Rucaparib citrate.
In one embodiment, Rucaparib is suspended in a solvent selected from polar solvent selected from alcohol solvents such as methanol, ethanol, propanol, isopropanol, butanol; preferably methanol.
To the resulting Rucaparib suspension is added citric acid; preferably citric acid solution, i.e citric acid dissolved in a solvent selected from alcohol solvent such as methanol, ethanol, propanol, isopropanol, butanol; more preferably citric acid dissolved in methanol and heated to room temperature. The resulting solid is filtered to isolate Rucaparib citrate.
In one more aspect, present invention provides Rucaparib oxalate salt and process for the preparation of the same comprising:
a) suspending Rucaparib in a solvent;
b) adding oxalic acid; and
c) isolating Rucaparib oxalate.
In one embodiment, Rucaparib is suspended in a solvent selected from polar solvent selected from alcohol solvent such as methanol, ethanol, propanol, isopropanol, butanol; preferably methanol.
To the resulting Rucaparib suspension is added oxalic acid; preferably oxalic acid solution, i.e oxalic acid dissolved in a solvent selected from alcohol solvent such as methanol, ethanol, propanol, isopropanol, butanol; more preferably oxalic acid dissolved in and heated to room temperature. The resulting solid is filtered to isolate Rucaparib oxalate.
In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.
Examples:
Example 1: Rucaparib HCl Form M1.
0.1 g of Rucaparib was dissolved in 2 ml of methanol at 70±5°C and cooled to 25±5°C. To the resulting clear solution was slowly added methanolic hydrochloride solution (1mL, 7.1% w/v) at 25±5°C and maintained under stirring for 15h. The solid obtained was filtered and identified as crystalline Form M1 of Rucaparib hydrochloride salt.
Yield: 60 mg
Example 2: Rucaparib HCl Form M1.
0.5 g of Rucaparib was dissolved in 5 ml of methanol at 80±5°C. To this clear solution seeded with 5 mg of Form M1 of Rucaparib hydrochloride at 80±5°C then slowly added methanolic hydrochloride solution (2mL, 7.1%w/v) and stirred at 80±5°C for 1h. The reaction mass was cooled to 25±5°C and maintained under stirring for 12h. To the reaction mass was added 10 ml of methyl tertiary butyl ether and stirred for 30 min at 25±5°C. The product obtained was filtered and dried at 50°C under vacuum for 12h. The solid obtained was identified as crystalline Form M1 of Rucaparib hydrochloride salt.
Yield: 0.4 g

Example 3: Rucaparib HCl Form M2.
0.5g of Rucaparib was suspended in 5 ml of water at 25±5°C and heated to 80±5°C. To the reaction mass slowly added 0.5 ml of aqueous hydrochloride solution at 80±5°C; cooled to 25±5°C and maintained under stirring for 15 h at 25±5°C. The product obtained was filtered and dried at 80°C under vacuum for 48h. The solid obtained was identified as crystalline Form M2 of Rucaparib hydrochloride salt.
Yield: 0.42 g
Example 4: Rucaparib HCl Form M2.
0.5 g of Rucaparib was dissolved in 5 ml of methanol at 80±5°C and then slowly added methanolic hydrochloride solution (2mL, 7.1%w/v) at 80±5°C. In another flask charged 10 ml of methyl tertiary butyl ether at 30±5°C and added 5 mg of Rucaparib hydrochloride Form M2 seeds. To the reaction mass slowly added to initially prepared hot Rucaparib methanolic hydrochloride solution at 30±5°C. The reaction mass was then cooled to 25±5°C and maintained under stirring for 3h. The product obtained was filtered and dried at 50°C under vacuum for 12h. The solid obtained was identified as crystalline Form M2 of Rucaparib hydrochloride salt.
Yield: 0.43 g
Example 5: Rucaparib Succinate
To a suspension of 1.0 mmol of Rucaparib in 5 ml of Methanol, a solution of 1.2 mmol of Succinic acid in 5 mL of methanol was added and contents were stirred at room temperature. The precipitated solid was filtered, washed with Methanol and dried under vacuum to get the successive Rucaparib Succinate.
Example 6: Rucaparib Fumarate
To a suspension of 1.0 mmol of Rucaparib base in 5 mL of methanol, a solution of 1.2 mmol of Fumaric acid in 5 mL of methanol was added and contents were stirred at room temperature. The precipitated solid was filtered, washed with methanol and dried under vacuum to get the successive Rucaparib Fumarate.

Example 7: Rucaparib Citrate
To a suspension of 1.0 mmol of Rucaparib base in 5 mL of methanol, a solution of 1.2 mmol of citric acid in 5 mL of methanol was added and contents were stirred at room temperature. The precipitated solid was filtered, washed with methanol and dried under vacuum to get the successive Rucaparib Citrate.
Example 8: Rucaparib Oxalate
To a suspension of 1.0 mmol of Rucaparib base in 5 mL of methanol, a solution of 1.2 mmol of oxalic acid in 5 mL of methanol was added and contents were stirred at room temperature. The precipitated solid was filtered, washed with methanol and dried under vacuum to get the successive Rucaparib Oxalate.

,CLAIMS:1. Rucaparib Succinate.

2. A process for the preparation of Rucaparib succinate comprising the steps of:
a) suspending Rucaparib in a solvent;
b) adding succinic acid; and
c) isolating Rucaparib succinate.

3. Rucaparib fumarate.

4. A process for the preparation of Rucaparib fumarate comprising the steps of:
a) suspending Rucaparib in a solvent;
b) adding fumaric acid; and
c) isolating Rucaparib fumarate.

5. Rucaparib oxalate.

6. A process for the preparation of Rucaparib oxalate comprising the steps of:
a) suspending Rucaparib in a solvent;
b) adding oxalic acid; and
c) isolating Rucaparib oxalate.

7. The process as claimed in the above claims, wherein the solvent is selected from alcohol solvent such as methanol, ethanol, propanol, isopropanol and butanol.

8. A process for the preparation of crystalline Form M1 of Rucaparib hydrochloride comprising:
a) dissolving Rucaparib in alcohol solvent;
b) seeding with crystalline Form M1 of Rucaparib hydrochloride;
c) adding hydrochloric acid;
d) adding an ether solvent to isolate crystalline Form M1 of Rucaparib hydrochloride

9. A process for the preparation of crystalline Rucaparib hydrochloride Form M2 comprising the steps of:
a) suspending Rucaparib in water;
b) adding hydrochloric acid; and
c) isolating crystalline Form M2 of Rucaparib hydrochloride.

10. A process for preparing crystalline Form M2 of Rucaparib hydrochloride comprising:
a) dissolving Rucaparib in alcohol solvent;
b) adding hydrochloric acid;
c) adding above reaction mixture to the ether solvent seeded with Rucaparib hydrochloride Form M2; and
d) isolating crystalline Form M2 of Rucaparib hydrochloride.