WO2019207596A1 - Novel crystalline forms of rucaparib (s)-camsylate salt and rucaparib free base - Google Patents

Novel crystalline forms of rucaparib (s)-camsylate salt and rucaparib free base Download PDF

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WO2019207596A1
WO2019207596A1 PCT/IN2019/050324 IN2019050324W WO2019207596A1 WO 2019207596 A1 WO2019207596 A1 WO 2019207596A1 IN 2019050324 W IN2019050324 W IN 2019050324W WO 2019207596 A1 WO2019207596 A1 WO 2019207596A1
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rucaparib
camsylate
crystalline
butanol
solvent
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PCT/IN2019/050324
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French (fr)
Inventor
Ramakoteswara Rao Jetti
Subramanyam Dandala
Aggi Ramireddy Bommareddy
Daveedu BHATRAJU
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Mylan Laboratories Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems

Definitions

  • the present invention provides polymorphic forms of Rucaparib (S)-camsylate and Rucaparib free base.
  • Rucaparib is an inhibitor of the mammalian polyadenosine 5’-diphosphoribose polymerase (PARP) enzyme.
  • PARP polyadenosine 5’-diphosphoribose polymerase
  • the chemical name is 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.l]hept- l-yl)methanesulfonic acid salt, which 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. Rucaparib Camsylate salt and polymorphs are reported in US 9045487 and US 8754072. OBJECT AND SUMMARY OF THE INVENTION
  • the principal aspect of the present invention is to provide crystalline forms of Rucaparib (S)- Camsylate, Rucaparib free base and processes for the preparation of the same.
  • present invention provides crystalline Form Ml of Rucaparib (S)-camsylate and process for the preparation of the same comprising: a) dissolving Rucaparib in 18-22 volumes of solvent;
  • present invention provides crystalline Form Ml of Rucaparib (S)-camsylate and process for the preparation of the same comprising: a) dissolving Rucaparib in a solvent;
  • present invention provides crystalline Form M2 of Rucaparib (S)- camsylate and process for the preparation of the same comprising: a) suspending Rucaparib in a solvent or mixtures thereof;
  • present invention provides crystalline Form M3 of Rucaparib (S)-camsylate and process for the preparation of the same comprising: a) dissolving Rucaparib in 13-17 volumes of solvent;
  • present invention provides crystalline Form M3 of Rucaparib (S)-camsylate and process for the preparation of the same comprising: a) dissolving Rucaparib in a solvent;
  • present invention provides crystalline Form Ml of Rucaparib and process for the preparation of the same. a) suspending Rucaparib (S)-camsylate in an aqueous base and alcohol solvent; and b) drying at 45-55 °C to isolate crystalline Rucaparib Form Ml.
  • present invention provides Crystalline Form M2 of Rucaparib.
  • present invention provides crystalline Form M3 of Rucaparib and process for the preparation of the same. a) suspending Rucaparib (S)-camsylate in an aqueous base and alcohol solvent; and b) drying at 60-70 °C to isolate crystalline Rucaparib Form M3;
  • present invention provides crystalline Form M4 of Rucaparib and process for the preparation of the same. a) suspending Rucaparib Form M3 in a ketone solvent; and
  • present invention provides crystalline Form M5 of Rucaparib and process for the preparation of the same. a) drying Rucaparib Form M2; and
  • Figure 5 PXRD pattern of crystalline Form M2 of Rucaparib.
  • Figure 6 PXRD pattern of crystalline Form M3 of Rucaparib.
  • Figure 7 PXRD pattern of crystalline Form M4 of Rucaparib.
  • Figure 8 PXRD pattern of crystalline Form M5 of Rucaparib.
  • the present invention provides crystalline forms of Rucaparib (S)-Camsylate; Rucaparib free base and processes for the preparation of the same.
  • the PXRD measurements were carried out using BRUKER D8 Discover powder diffractometer equipped with goniometer of Q/2Q configuration and Lynx Eye detector.
  • the Cu-anode X-ray tube was operated at 40kV and 40mA.
  • the experiments were conducted over the 2Q range of 2.0°-50.0°, 0.030° step size and 0.2 seconds step time.
  • crystalline Form Ml of Rucaparib (S)- camsylate provides crystalline Form Ml of Rucaparib (S)- camsylate.
  • crystalline Form Ml of Rucaparib (S)-camsylate disclosed herein may be characterized by PXRD pattern having peaks 11.89, 12.90, 15.34, 16.33, 17.87, 20.0, 21.95, 24.94 and 30.0 ⁇ 0.2° 2Q.
  • present invention provides crystalline Form Ml of Rucaparib (S)- camsylate characterized by PXRD pattern substantially as depicted in FIG. 1
  • present invention provides crystalline Form Ml of Rucaparib (S)-camsylate and process for the preparation of the same comprising: a) dissolving Rucaparib in 18-22 volumes of solvent;
  • Rucaparib is dissolved in 18-22 volumes of a solvent to give clear solution of Rucaparib.
  • the solvent is selected from polar solvents; preferably alcoholic solvent such as methanol, ethanol, n-propanol, n-butanol, 2-butanol, 2-methyl-2-butanol, isopropyl alcohol; more preferably ethanol.
  • camphor sulphonic acid solution To the resulting Rucaparib solution is added camphor sulphonic acid solution.
  • the solution of camphor sulfonic acid may prepare by dissolving camphor sulfonic acid in a solvent.
  • the solvent is selected from polar solvents; preferably alcoholic solvent such as methanol, ethanol, n-propanol, n-butanol, 2-butanol, 2-methyl-2-butanol, isopropyl alcohol; more preferably ethanol.
  • the above obtained crystalline Rucaparib (S)-Camsylate is dried at 40- 60 °C, preferably 45-55 °C for 2-5 h to isolate crystalline Rucaparib (S)-Camsylate Form Ml.
  • in another embodiment of the present invention provides a process for the preparation of Form Ml of Rucaparib (S)-camsylate comprising: a) dissolving Rucaparib in a solvent; b) seeding with Rucaparib (S)-camsylate Form Ml;
  • Rucaparib is dissolved in solvent to give clear solution.
  • the solvent is selected from polar solvents; preferably alcoholic solvent such as methanol, ethanol, n-propanol, n-butanol, 2-butanol, 2-methyl-2-butanol, isopropyl alcohol; more preferably ethanol.
  • camphor sulphonic acid solution To the resulting Rucaparib solution is added camphor sulphonic acid solution.
  • the solution of Camphor sulfonic acid may prepare by dissolving camphor sulfonic acid in a solvent.
  • the solvent is selected from polar solvents; preferably alcoholic solvent such as methanol, ethanol, n-propanol, n-butanol, 2-butanol, 2-methyl-2-butanol, isopropyl alcohol; more preferably ethanol.
  • the above obtained crystalline Rucaparib (S)-Camsylate is dried at 40-60 °C, preferably 45-55°C for 2-5 h to isolate crystalline Rucaparib (S)-Camsylate Form
  • One more embodiment of the present invention provides crystalline Form M2 of Rucaparib (S)-camsylate.
  • crystalline Form M2 of Rucaparib (S)-camsylate disclosed herein may be characterized by PXRD pattern having peaks 13.49, 17.99, 20.47, 22.09, 23.46, 24.06 and 27.79 ⁇ 0.2° 2Q.
  • present invention provides crystalline Form M2 of Rucaparib Camsylate characterized by PXRD pattern substantially as depicted in FIG. 2
  • Another embodiment of the present invention provides a process for the preparation of Form M2 of Rucaparib (S)-camsylate comprising: a) suspending Rucaparib in suitable solvent or mixture thereof;
  • Rucaparib is suspended in a suitable solvent or mixtures thereof and heated to give clear solution of Rucaparib.
  • the suitable solvent or mixtures thereof are selected from tetralin, 2-methyl-2-butanol, methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, 2-butanol; preferably mixture of tetralin and 2-methyl-2-butanol.
  • Rucaparib may be suspended in tetralin.
  • Rucaparib may be suspended in 2-methyl-2-butanol.
  • Rucaparib suspension may be optionally seeded with crystalline Rucaparib (S)-camsylate Form M2.
  • the resulting Rucaparib suspension is heated to 60-80 °C; preferably 65-75 °C.
  • camphor sulphonic acid solution To the resulting Rucaparib solution is added camphor sulphonic acid solution.
  • the solution of Camphor sulfonic acid may prepare by dissolving camphor sulfonic acid in a solvent.
  • the solvent is selected from polar solvents; preferably alcoholic solvent such as methanol, ethanol, n-propanol, n-butanol, 2-butanol, 2-methyl-2-butanol, isopropyl alcohol; more preferably 2- methyl-2-butanol.
  • the above obtained crystalline Rucaparib (S)-Camsylate may be dried at 40-60 °C, preferably 45-55 °C for 2-5 h to isolate crystalline Rucaparib (S)-Camsylate Form M2.
  • isolated crystalline Rucaparib (S)-Camsylate may be dried for 10-15 h, preferably 10-12 h to isolate crystalline Rucaparib (S)-Camsylate Form M2.
  • Another embodiment of the present invention provides crystalline Form M3 of Rucaparib (S)- camsylate.
  • crystalline Form M3 of Rucaparib (S)-camsylate disclosed herein may be characterized by PXRD pattern having peaks 13.31, 15.70, 20.29, 20.80, 23.36, 23.82, 24.74, and 26.24+0.2° 2Q.
  • present invention provides crystalline Form M3 of Rucaparib (S)- camsylate is characterized by PXRD pattern substantially as depicted in FIG. 3
  • present invention provides crystalline Form M3 of Rucaparib (S)-camsylate and process for the preparation of the same comprising: a) dissolving Rucaparib in 13-17 volumes of solvent;
  • Rucaparib is dissolved in 13-17 volumes of solvent to give clear solution.
  • the solvent is selected from polar solvents; preferably alcoholic solvent such as methanol, ethanol, n- propanol, n-butanol, 2-butanol, isopropyl alcohol, 2-methyl-2-butanol; more preferably ethanol.
  • the solution of Camphor sulfonic acid may prepare by dissolving camphor sulfonic acid in a solvent.
  • the solvent is selected from polar solvents; preferably alcoholic solvent such as methanol, ethanol, n-propanol, n-butanol, 2-butanol, 2-methyl-2-butanol and isopropyl alcohol.
  • the isolated crystalline Rucaparib (S)-Camsylate is dried at 40-55 °C for 10-14 h to give crystalline Rucaparib (S)-Camsylate Form M3.
  • present invention provides crystalline Form M3 of Rucaparib (S)- camsylate and process for the preparation of the same comprising: a) dissolving Rucaparib in a solvent;
  • Rucaparib is dissolved in solvent to give clear solution.
  • the solvent is selected from polar solvents; preferably alcoholic solvent such as methanol, ethanol, n- propanol, n-butanol, 2-butanol, isopropyl alcohol, 2-methyl-2-butanol; more preferably ethanol.
  • Rucaparib solution may be optionally seeded with crystalline Rucaparib (S)-camsylate Form M3.
  • the solution of Camphor sulfonic acid may prepare by dissolving camphor sulfonic acid in a solvent.
  • the solvent is selected from polar solvents; preferably alcoholic solvent such as methanol, ethanol, n- propanol, n-butanol, 2-butanol, 2-methyl-2-butanol, isopropyl alcohol; more preferably ethanol.
  • the isolated crystalline Rucaparib (S)-Camsylate is dried at 40-55°C for 10-14 h to give crystalline Rucaparib (S)-Camsylate Form M3.
  • Another embodiment of the present invention provides crystalline Form Ml of Rucaparib.
  • crystalline Form Ml of Rucaparib disclosed herein may be characterized by PXRD pattern having peaks 9.09, 15.19, 22.69, 23.20, 27.72 ⁇ 0.2° 2Q.
  • present invention provides crystalline Form Ml of Rucaparib characterized by XRPD pattern substantially as depicted in FIG. 4
  • Another embodiment of the present invention provides a process for the preparation of Form Ml of Rucaparib comprising: a) suspending Rucaparib (S)-camsylate in an aqueous base and alcohol solvent; and b) drying at 45-55 °C to isolate crystalline Rucaparib Form Ml.
  • Rucaparib (S)-camsylate is suspended in aqueous base and alcohol solvent.
  • the base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like;
  • alcohol solvent is selected from methanol, ethanol, n-propanol, n-butanol, 2-butanol, 2- methyl-2-butanol, isopropyl alcohol; preferably methanol.
  • One more embodiment of the present invention provides crystalline Form M2 of Rucaparib.
  • crystalline Rucaparib Form Ml is stored at 20-40 °C; preferably at 20-30 °C for about 8-14 days, preferably 9-11 days gives crystalline Rucaparib Form M2.
  • crystalline Form M2 of Rucaparib disclosed herein may be characterized by PXRD pattern having peaks 8.48, 18.67, 19.34, 21.80 and 24.24+0.2° 2Q.
  • present invention provides crystalline Form M2 of Rucaparib characterized by XRPD pattern substantially as depicted in FIG. 5.
  • crystalline Form M3 of Rucaparib disclosed herein may be characterized by PXRD pattern having peaks 14.69, 22.10, 22.56, and 27.80 ⁇ 0.2° 2Q.
  • present invention provides crystalline Form M3 of Rucaparib characterized by PXRD pattern substantially as depicted in FIG. 6.
  • Another embodiment of the present invention provides a process for the preparation of Form M3 of Rucaparib comprising: a) suspending Rucaparib (S)-camsylate in aqueous base and alcohol solvent; and b) drying at 60-70 °C to isolate crystalline Rucaparib Form M3.
  • Rucaparib (S)-camsylate is suspended in aqueous base and alcohol solvent.
  • the base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like;
  • alcohol solvent is selected from methanol, ethanol, n-propanol, n-butanol, 2-butanol, 2- methyl-2-butanol, isopropyl alcohol; preferably methanol.
  • crystalline Form M4 of Rucaparib disclosed herein may be characterized by PXRD pattern having peaks 7.79, 13.53, 13.86,14.82, 15.64, 17.017.70,19.87, 20.59, 21.34, 22.50 and 23.35 ⁇ 0.2° 2Q.
  • present invention provides crystalline Form M4 of Rucaparib characterized by PXRD pattern substantially as depicted in FIG. 7.
  • Another embodiment of the present invention provides a process for the preparation of Form M4 of Rucaparib comprising. a) suspending Rucaparib Form M3 in a ketone solvent; and
  • Rucaparib Form M3 of present invention is dissolved in a ketone solvent such as methyl isobutyl ketone and heated to 35-50°: preferably 40-45°C to and cooled. The resulting reaction mixture is filtered and dried at 40-60°C; preferably 45-50°C to isolate Rucaparib Form M4.
  • a ketone solvent such as methyl isobutyl ketone
  • crystalline Form M5 of Rucaparib disclosed herein may be characterized by PXRD pattern having peaks 8.27, 11.66, 14.11, 18.41, 19.06, 21.55, 23.90 and 24.73 ⁇ 0.2° 2Q.
  • present invention provides crystalline Form M5 of Rucaparib characterized by PXRD pattern substantially as depicted in FIG. 8.
  • Another embodiment of the present invention provides a process for the preparation of Form M5 of Rucaparib comprising. a) drying Rucaparib Form M2; and
  • Rucaparib Form M2 of present invention may be dried at l20-l43°C; preferably 125-135 °C to isolate Rucaparib Form M5.
  • the Rucaparib S-Camsylate Form M2 shows no change in PXRD pattern when stored for 3 months at 40°C and 75% relative humidity (RH) and at 25 °C and 60% relative humidity (RH) conditions as mentioned in below Table 1.
  • the Rucaparib S-Camsylate Form M3 shows no change in PXRD pattern when stored for 3 months at 40°C and 75% relative humidity (RH) and at 25 °C and 60% relative humidity (RH) conditions as mentioned in below Table 1.
  • Rucaparib Form M2 0.2 g was dissolved in 4 mL of ethanol at 80 ⁇ 5°C. To the clear solution was added (S)-Camphor sulfonic acid solution [dissolved (S)-camphor sulfonic acid (0.l4g) in ethanol (lmL)] slowly at 80 ⁇ 5°C for 5-10 min and maintained under stirring for 3h. The reaction mass was cooled to 25 ⁇ 5°C and further stirred for 12 h. The reaction mass was filtered and dried under vacuum at 50°C for 3h. The product obtained was identified as Rucaparib S- Camsylate Form Ml.
  • Rucaparib Form M2 0.5 g was dissolved in 5 mL of ethanol at 80+5 °C. To the clear solution was seeded with 10 mg of Rucaparib S-Camsylate Form Ml at 80 ⁇ 5°C and stirred for 15 min. To the solution was added slowly (S)-Camphor sulfonic acid solution [dissolved (S)-Camphor sulfonic acid (0.36g) in ethanol (lmL)] at 80 ⁇ 5°C for 5-10 min and maintained under stirring for 3 h at 80 ⁇ 5°C. The reaction mass was cooled to 25 ⁇ 5°C and further stirred for 12 h. The reaction mass was filtered and dried under vacuum at 50 °C for 3h. The solid obtained was identified as Rucaparib S-Camsylate form ML
  • Rucaparib Form M3 was suspended in 8 mL of tetralin at 25+5 °C and heated to 70+5°C.
  • S-Camphor sulfonic acid solution [dissolved (S)- camphor sulfonic acid (0.29g) in 2-methyl 2-butanol (4mL)] at 70+5°C for 10-15 min and maintained under stirring for 30 min.
  • reaction mass was cooled to 25+5°C and further maintained under stirring for 12 h.
  • the reaction mass was filtered and dried under vacuum at 50°C for 3h.
  • the solid obtained was identified as Rucaparib S-Camsylate Form M2.
  • Rucaparib Form M3 0.2 g was suspended in a mixture of 4 mL of 2-methyl 2-butanol and 4 mL of tetralin at 25 ⁇ 5°C and heated to 70 ⁇ 5°C to obtain clear solution.
  • To the reaction solution was slowly added (S)-Camphor sulfonic acid solution [dissolved (S)-camphor sulfonic acid (0.l4g) in 2-methyl 2-butanol (2mL)] at 70 ⁇ 5°C for 10-15 min and maintained under stirring for 30 min at 70+5 °C.
  • the reaction mass was further cooled to 25+5 °C, stirred for l2h, filtered and dried under vacuum at 50 °C for 3 h.
  • the solid obtained was identified as Rucaparib S- Camsylate form M2.
  • Rucaparib Form M3 0.5 g was suspended in 5 mL of 2-methyl 2-butanol at 25+5°C and heated to 80+5°C. To this suspension was seeded with 5 mg of Rucaparib S-Camsylate Form M2. To the reaction mass slowly added S-Camphor sulfonic acid solution [dissolved (S)- camphor sulfonic acid (0.36g) in 2-methyl 2-butanol (5mL)] at 80+5°C for 5-l0min and maintained under stirring for lh. The reaction mass was cooled to 25+5°C and further maintained under stirring for l2h. The reaction mass was filtered and dried under vacuum at 50 °C for l2h. The solid obtained was identified as Rucaparib S-Camsylate Form M2.
  • Rucaparib Form Ml 4 g was suspended in 100 mL of 2-Methyl-2-Butanol at 25+5°C and heated to 80+5°C.
  • Slowly added (S)-camphor sulfonic acid solution [dissolved (S)-camphor sulfonic acid (2.88g) in 2-methyl 2-butanol (40mL)] at 80+5°C for l0-l5min.
  • the reaction mass was filtered, washed with 2-Methyl-2-Butanol and dried under vacuum at 50 °C for lOh.
  • the solid obtained was identified as Rucaparib S-Camsylate Form M2.
  • Example 7 Rucaparib S-Camsylate Form M3 0.5 g of Rucaparib Form M2 was dissolved in 7.5 mL of ethanol at 80 ⁇ 5°C to obtain clear solution. To the clear solution was slowly added (S)-Camphor sulfonic acid solution [dissolved (S)-camphor sulfonic acid (0.36g) in ethanol (3mL)] for 5-l0min and maintained under stirring for 4h at 80 ⁇ 5°C. The reaction mass was further cooled to 25 ⁇ 5°C, stirred for l2h, filtered and dried under vacuum at 50°C for l2h. The solid obtained was identified as Rucaparib S- Camsylate form M3.
  • Rucaparib Form M2 0.5 g was dissolved in 7.5 mL of ethanol at 80+5 °C to obtain clear solution. The clear solution was seeded with 5 mg of Rucaparib S-Camsylate Form M3 seeds. Further, to the reaction mixture was slowly added (S)-Camphor sulfonic acid solution [dissolved (S)-camphor sulfonic acid (0.36g) in ethanol (3mL)] for 5-10 min and maintained under stirring for 4 h at 80 ⁇ 5°C. The reaction mass was further cooled to 25 ⁇ 5°C, stirred for 12 h, filtered and dried under vacuum at 50°C for l2h. The solid obtained was identified as Rucaparib S-Camsylate form M3.
  • Rucaparib THF solvate 5 g was suspended in 100 mL of 2-methyl-2-butanol at 25 ⁇ 5°C and heated to 80 ⁇ 5°C.
  • the reaction mixture was seeded with 50 mg of Rucaparib S-Camsylate Form M3.
  • Slowly added (S)-camphor sulfonic acid solution dissolved (S)-camphor sulfonic acid (3.59 g) in 2-methyl 2-butanol (50 mL)
  • the reaction mass was stirred for 60 min at 80+5 °C, cooled to 25+5° C and further stirred for 15 h at 25+5 °C.
  • the reaction mass was filtered, washed with 2-Methyl-2-Butanol and dried under vacuum at 50 °C for lh.
  • the solid obtained was identified as Rucaparib S-Camsylate Form M3.
  • Rucaparib Form Ml was stored at 25 ⁇ 5°C in a closed condition for several days and the resulting solid was identified as Rucaparib form M2.
  • Rucaparib Form M3 1 g was suspended in 20 mL of methyl isobutyl ketone at 25+5 °C and heated to 40 ⁇ 5°C and maintained under stirring for 30 min. The reaction mass was cooled to 25+5 °C and stirred for 12 h. The reaction mass was filtered and dried under vacuum at 50 °C for 12 h. The product obtained was identified as Rucaparib form M4.
  • Rucaparib Form M2 was dried at 130 °C under vacuum for 1-2 h. The resulting solid was identified as Rucaparib crystalline Form-M5.

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Abstract

The present invention provides, crystalline Form M1, Form M2 and Form M3 of Rucaparib (S)-camsylate salt. It also provides crystalline Form M1, Form M2, Form M3, Form M4 and Form M5 of Rucaparib and processes for the preparation of the same.

Description

NOVEL CRYSTALLINE FORMS OF RUCAPARIB (S)-CAMSYLATE SALT AND RUCAPARIB FREE BASE
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of earlier Indian provisional patent application No. Provisional Patent Application Nos. 201841015613 filed on April 25, 2018 which is incorporated by reference herein in its entirety. All literature and patent references cited in this specification are likewise incorporated herein by reference in their entirety.
FIELD OF THE INVENTION The present invention provides polymorphic forms of Rucaparib (S)-camsylate and Rucaparib free base.
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}-l, 3,4,5- tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((lS,4R)-7,7dimethyl-2-oxobicyclo[2.2.l]hept- l-yl)methanesulfonic acid salt, which is represented by the following structural formula.
Figure imgf000002_0001
Rucaparib Camsylate
Rucaparib is marketed under the brand name RUBRACA by Clovis Oncology.
Rucaparib is first reported in US 6495541. Rucaparib Camsylate salt and polymorphs are reported in US 9045487 and US 8754072. OBJECT AND SUMMARY OF THE INVENTION
The principal aspect of the present invention is to provide crystalline forms of Rucaparib (S)- Camsylate, Rucaparib free base and processes for the preparation of the same.
In one aspect, present invention provides crystalline Form Ml of Rucaparib (S)-camsylate and process for the preparation of the same comprising: a) dissolving Rucaparib in 18-22 volumes of solvent;
b) adding (S)-camphor sulfonic acid solution; and
c) isolating crystalline Rucaparib (S)-Camsylate Form Ml.
In another aspect, present invention provides crystalline Form Ml of Rucaparib (S)-camsylate and process for the preparation of the same comprising: a) dissolving Rucaparib in a solvent;
b) seeding with Rucaparib (S)-camsylate Form Ml;
c) adding (S)-camphor sulfonic acid solution; and
d) isolating crystalline Rucaparib (S)-Camsylate Form Ml.
In one more aspect, present invention provides crystalline Form M2 of Rucaparib (S)- camsylate and process for the preparation of the same comprising: a) suspending Rucaparib in a solvent or mixtures thereof;
b) optionally seeding with Rucaparib (S)-Camsylate Form M2;
c) adding (S)-camphor sulfonic acid solution; and
e) isolating crystalline Rucaparib (S)-Camsylate Form M2.
In another aspect, present invention provides crystalline Form M3 of Rucaparib (S)-camsylate and process for the preparation of the same comprising: a) dissolving Rucaparib in 13-17 volumes of solvent;
b) adding (S)-camphor sulfonic acid solution; and
c) isolating crystalline Rucaparib (S)-Camsylate Form M3. In another aspect, present invention provides crystalline Form M3 of Rucaparib (S)-camsylate and process for the preparation of the same comprising: a) dissolving Rucaparib in a solvent;
b) seeding with Rucaparib (S)-camsylate Form M3;
c) adding (S)-camphor sulfonic acid solution; and
d) isolating crystalline Rucaparib (S)-Camsylate Form M3.
In one aspect, present invention provides crystalline Form Ml of Rucaparib and process for the preparation of the same. a) suspending Rucaparib (S)-camsylate in an aqueous base and alcohol solvent; and b) drying at 45-55 °C to isolate crystalline Rucaparib Form Ml.
In one aspect, present invention provides Crystalline Form M2 of Rucaparib.
In one more aspect, present invention provides crystalline Form M3 of Rucaparib and process for the preparation of the same. a) suspending Rucaparib (S)-camsylate in an aqueous base and alcohol solvent; and b) drying at 60-70 °C to isolate crystalline Rucaparib Form M3;
In one aspect, present invention provides crystalline Form M4 of Rucaparib and process for the preparation of the same. a) suspending Rucaparib Form M3 in a ketone solvent; and
b) isolating crystalline Rucaparib Form M4.
In one aspect, present invention provides crystalline Form M5 of Rucaparib and process for the preparation of the same. a) drying Rucaparib Form M2; and
b) isolating crystalline Rucaparib Form M5. 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 Ml of Rucaparib (S)-camsylate;
Figure 2: PXRD pattern of crystalline Form M2 of Rucaparib (S)-camsylate
Figure 3: PXRD pattern of crystalline Form M3 of Rucaparib (S)-camsylate
Figure 4: PXRD pattern of crystalline Form Ml of Rucaparib.
Figure 5: PXRD pattern of crystalline Form M2 of Rucaparib. Figure 6: PXRD pattern of crystalline Form M3 of Rucaparib.
Figure 7: PXRD pattern of crystalline Form M4 of Rucaparib.
Figure 8: PXRD pattern of crystalline Form M5 of Rucaparib.
DETAILED DESCRIPTION OF THE INVENTION The present invention provides crystalline forms of Rucaparib (S)-Camsylate; Rucaparib free base and processes for the preparation of the same.
Instrumentation Details:
The PXRD measurements were carried out using BRUKER D8 Discover powder diffractometer equipped with goniometer of Q/2Q configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40kV and 40mA. The experiments were conducted over the 2Q range of 2.0°-50.0°, 0.030° step size and 0.2 seconds step time.
One embodiment of the present invention provides crystalline Form Ml of Rucaparib (S)- camsylate. Within the context of the present invention, crystalline Form Ml of Rucaparib (S)-camsylate disclosed herein may be characterized by PXRD pattern having peaks 11.89, 12.90, 15.34, 16.33, 17.87, 20.0, 21.95, 24.94 and 30.0±0.2° 2Q.
In another embodiment, present invention provides crystalline Form Ml of Rucaparib (S)- camsylate characterized by PXRD pattern substantially as depicted in FIG. 1
In one aspect, present invention provides crystalline Form Ml of Rucaparib (S)-camsylate and process for the preparation of the same comprising: a) dissolving Rucaparib in 18-22 volumes of solvent;
b) adding (S)-camphor sulfonic acid solution; and
c) isolating crystalline Rucaparib (S)-Camsylate Form Ml.
As per the above embodiment, Rucaparib is dissolved in 18-22 volumes of a solvent to give clear solution of Rucaparib. The solvent is selected from polar solvents; preferably alcoholic solvent such as methanol, ethanol, n-propanol, n-butanol, 2-butanol, 2-methyl-2-butanol, isopropyl alcohol; more preferably ethanol.
To the resulting Rucaparib solution is added camphor sulphonic acid solution. The solution of camphor sulfonic acid may prepare by dissolving camphor sulfonic acid in a solvent. The solvent is selected from polar solvents; preferably alcoholic solvent such as methanol, ethanol, n-propanol, n-butanol, 2-butanol, 2-methyl-2-butanol, isopropyl alcohol; more preferably ethanol.
Next, the solution of Rucaparib and Camphor sulphonic acid is heated to 70-90 °C; preferably at 75-85 °C. The reaction mixture further cooled and filtered to isolate crystalline Rucaparib (S)-Camsylate.
In another embodiment, the above obtained crystalline Rucaparib (S)-Camsylate is dried at 40- 60 °C, preferably 45-55 °C for 2-5 h to isolate crystalline Rucaparib (S)-Camsylate Form Ml.
In another embodiment of the present invention provides a process for the preparation of Form Ml of Rucaparib (S)-camsylate comprising: a) dissolving Rucaparib in a solvent; b) seeding with Rucaparib (S)-camsylate Form Ml;
c) adding (S)-camphor sulfonic acid solution; and
d) isolating crystalline Rucaparib (S)-Camsylate Form Ml.
As per the above embodiment, Rucaparib is dissolved in solvent to give clear solution. The solvent is selected from polar solvents; preferably alcoholic solvent such as methanol, ethanol, n-propanol, n-butanol, 2-butanol, 2-methyl-2-butanol, isopropyl alcohol; more preferably ethanol.
To the resulting Rucaparib solution is added camphor sulphonic acid solution. The solution of Camphor sulfonic acid may prepare by dissolving camphor sulfonic acid in a solvent. The solvent is selected from polar solvents; preferably alcoholic solvent such as methanol, ethanol, n-propanol, n-butanol, 2-butanol, 2-methyl-2-butanol, isopropyl alcohol; more preferably ethanol.
Next, the solution of Rucaparib and Camphor sulphonic acid is heated to 70-90°C; preferably at 75-85°C. The reaction mixture further cooled and filtered to isolate crystalline Rucaparib (S)-Camsylate.
In another embodiment, the above obtained crystalline Rucaparib (S)-Camsylate is dried at 40-60 °C, preferably 45-55°C for 2-5 h to isolate crystalline Rucaparib (S)-Camsylate Form
Ml.
One more embodiment of the present invention provides crystalline Form M2 of Rucaparib (S)-camsylate.
Within the context of the present invention, crystalline Form M2 of Rucaparib (S)-camsylate disclosed herein may be characterized by PXRD pattern having peaks 13.49, 17.99, 20.47, 22.09, 23.46, 24.06 and 27.79±0.2° 2Q.
In another embodiment, present invention provides crystalline Form M2 of Rucaparib Camsylate characterized by PXRD pattern substantially as depicted in FIG. 2
Another embodiment of the present invention provides a process for the preparation of Form M2 of Rucaparib (S)-camsylate comprising: a) suspending Rucaparib in suitable solvent or mixture thereof;
b) optionally seeding with Rucaparib (S)-camsylate Form M2;
c) adding (S)-camphor sulfonic acid solution; and
d) isolating crystalline Rucaparib (S)-Camsylate Form M2.
As per the above embodiment, Rucaparib is suspended in a suitable solvent or mixtures thereof and heated to give clear solution of Rucaparib. The suitable solvent or mixtures thereof are selected from tetralin, 2-methyl-2-butanol, methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, 2-butanol; preferably mixture of tetralin and 2-methyl-2-butanol.
In one embodiment, Rucaparib may be suspended in tetralin.
In another embodiment Rucaparib may be suspended in 2-methyl-2-butanol.
Within the context, Rucaparib suspension may be optionally seeded with crystalline Rucaparib (S)-camsylate Form M2.
The resulting Rucaparib suspension is heated to 60-80 °C; preferably 65-75 °C. To the resulting Rucaparib solution is added camphor sulphonic acid solution. The solution of Camphor sulfonic acid may prepare by dissolving camphor sulfonic acid in a solvent. The solvent is selected from polar solvents; preferably alcoholic solvent such as methanol, ethanol, n-propanol, n-butanol, 2-butanol, 2-methyl-2-butanol, isopropyl alcohol; more preferably 2- methyl-2-butanol.
Next, the solution of Rucaparib and Camphor sulphonic acid is heated to 60-80 °C; preferably 65-75 °C. The reaction mixture further cooled and filtered to isolate crystalline Rucaparib (S)- Camsylate.
In another embodiment, the above obtained crystalline Rucaparib (S)-Camsylate may be dried at 40-60 °C, preferably 45-55 °C for 2-5 h to isolate crystalline Rucaparib (S)-Camsylate Form M2.
In an additional embodiment, isolated crystalline Rucaparib (S)-Camsylate may be dried for 10-15 h, preferably 10-12 h to isolate crystalline Rucaparib (S)-Camsylate Form M2. Another embodiment of the present invention provides crystalline Form M3 of Rucaparib (S)- camsylate.
Within the context of the present invention, crystalline Form M3 of Rucaparib (S)-camsylate disclosed herein may be characterized by PXRD pattern having peaks 13.31, 15.70, 20.29, 20.80, 23.36, 23.82, 24.74, and 26.24+0.2° 2Q.
In another embodiment, present invention provides crystalline Form M3 of Rucaparib (S)- camsylate is characterized by PXRD pattern substantially as depicted in FIG. 3
In another aspect, present invention provides crystalline Form M3 of Rucaparib (S)-camsylate and process for the preparation of the same comprising: a) dissolving Rucaparib in 13-17 volumes of solvent;
b) adding (S)-camphor sulfonic acid solution; and
c) isolating crystalline Rucaparib (S)-Camsylate Form M3.
As per the above embodiment, Rucaparib is dissolved in 13-17 volumes of solvent to give clear solution. The solvent is selected from polar solvents; preferably alcoholic solvent such as methanol, ethanol, n- propanol, n-butanol, 2-butanol, isopropyl alcohol, 2-methyl-2-butanol; more preferably ethanol.
To the resulting Rucaparib solution added camphor sulphonic acid solution. The solution of Camphor sulfonic acid may prepare by dissolving camphor sulfonic acid in a solvent. The solvent is selected from polar solvents; preferably alcoholic solvent such as methanol, ethanol, n-propanol, n-butanol, 2-butanol, 2-methyl-2-butanol and isopropyl alcohol.
Next, the solution of Rucaparib and Camphor sulphonic acid is heated to 70-90 °C; preferably at 75-85°C. The reaction mixture further cooled and filtered to isolate crystalline Rucaparib (S)-Camsylate.
In another embodiment, the isolated crystalline Rucaparib (S)-Camsylate is dried at 40-55 °C for 10-14 h to give crystalline Rucaparib (S)-Camsylate Form M3.
In another embodiment, present invention provides crystalline Form M3 of Rucaparib (S)- camsylate and process for the preparation of the same comprising: a) dissolving Rucaparib in a solvent;
b) seeding with Rucaparib (S)-camsylate Form M3;
c) adding (S)-camphor sulfonic acid solution; and
d) isolating crystalline Rucaparib (S)-Camsylate Form M3.
As per the above embodiment, Rucaparib is dissolved in solvent to give clear solution. The solvent is selected from polar solvents; preferably alcoholic solvent such as methanol, ethanol, n- propanol, n-butanol, 2-butanol, isopropyl alcohol, 2-methyl-2-butanol; more preferably ethanol.
Within the context, Rucaparib solution may be optionally seeded with crystalline Rucaparib (S)-camsylate Form M3.
To the resulting clear Rucaparib solution is seeded with crystalline Rucaparib (S)-camsylate Form M3 and further added camphor sulphonic acid solution. The solution of Camphor sulfonic acid may prepare by dissolving camphor sulfonic acid in a solvent. The solvent is selected from polar solvents; preferably alcoholic solvent such as methanol, ethanol, n- propanol, n-butanol, 2-butanol, 2-methyl-2-butanol, isopropyl alcohol; more preferably ethanol.
Next, the solution of Rucaparib and Camphor sulphonic acid is heated to 70-90°C; preferably at 75-85°C. The reaction mixture further cooled and filtered to isolate crystalline Rucaparib (S)-Camsylate.
In another embodiment, the isolated crystalline Rucaparib (S)-Camsylate is dried at 40-55°C for 10-14 h to give crystalline Rucaparib (S)-Camsylate Form M3.
Another embodiment of the present invention provides crystalline Form Ml of Rucaparib.
Within the context of the present invention, crystalline Form Ml of Rucaparib disclosed herein may be characterized by PXRD pattern having peaks 9.09, 15.19, 22.69, 23.20, 27.72±0.2° 2Q.
In another embodiment, present invention provides crystalline Form Ml of Rucaparib characterized by XRPD pattern substantially as depicted in FIG. 4 Another embodiment of the present invention provides a process for the preparation of Form Ml of Rucaparib comprising: a) suspending Rucaparib (S)-camsylate in an aqueous base and alcohol solvent; and b) drying at 45-55 °C to isolate crystalline Rucaparib Form Ml.
Rucaparib (S)-camsylate is suspended in aqueous base and alcohol solvent. The base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like; alcohol solvent is selected from methanol, ethanol, n-propanol, n-butanol, 2-butanol, 2- methyl-2-butanol, isopropyl alcohol; preferably methanol.
Further, the above suspension is cooled to l0-20°C. The resulting reaction mass is filtered and dried at 45-55°C preferably at 50 °C to isolate Rucaparib Form Ml.
One more embodiment of the present invention provides crystalline Form M2 of Rucaparib.
In one embodiment, crystalline Rucaparib Form Ml is stored at 20-40 °C; preferably at 20-30 °C for about 8-14 days, preferably 9-11 days gives crystalline Rucaparib Form M2.
Within the context of the present invention, crystalline Form M2 of Rucaparib disclosed herein may be characterized by PXRD pattern having peaks 8.48, 18.67, 19.34, 21.80 and 24.24+0.2° 2Q.
In another embodiment, present invention provides crystalline Form M2 of Rucaparib characterized by XRPD pattern substantially as depicted in FIG. 5.
In one more embodiment of the present invention provides crystalline Form M3 of Rucaparib.
Within the context of the present invention, crystalline Form M3 of Rucaparib disclosed herein may be characterized by PXRD pattern having peaks 14.69, 22.10, 22.56, and 27.80 ±0.2° 2Q.
In another embodiment, present invention provides crystalline Form M3 of Rucaparib characterized by PXRD pattern substantially as depicted in FIG. 6.
Another embodiment of the present invention provides a process for the preparation of Form M3 of Rucaparib comprising: a) suspending Rucaparib (S)-camsylate in aqueous base and alcohol solvent; and b) drying at 60-70 °C to isolate crystalline Rucaparib Form M3.
Rucaparib (S)-camsylate is suspended in aqueous base and alcohol solvent. The base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like; alcohol solvent is selected from methanol, ethanol, n-propanol, n-butanol, 2-butanol, 2- methyl-2-butanol, isopropyl alcohol; preferably methanol.
Further, the above suspension is cooled to lO-25°C. The resulting reaction mass is filtered and dried at 60-70°C preferably at 60 °C to isolate Rucaparib Form M3.
In one more embodiment of the present invention provides crystalline Form M4 of Rucaparib.
Within the context of the present invention, crystalline Form M4 of Rucaparib disclosed herein may be characterized by PXRD pattern having peaks 7.79, 13.53, 13.86,14.82, 15.64, 17.017.70,19.87, 20.59, 21.34, 22.50 and 23.35 ±0.2° 2Q.
In another embodiment, present invention provides crystalline Form M4 of Rucaparib characterized by PXRD pattern substantially as depicted in FIG. 7.
Another embodiment of the present invention provides a process for the preparation of Form M4 of Rucaparib comprising. a) suspending Rucaparib Form M3 in a ketone solvent; and
b) isolating crystalline Rucaparib Form M4.
In one embodiment, Rucaparib Form M3 of present invention is dissolved in a ketone solvent such as methyl isobutyl ketone and heated to 35-50°: preferably 40-45°C to and cooled. The resulting reaction mixture is filtered and dried at 40-60°C; preferably 45-50°C to isolate Rucaparib Form M4.
In one more embodiment of the present invention provides crystalline Form M5 of Rucaparib.
Within the context of the present invention, crystalline Form M5 of Rucaparib disclosed herein may be characterized by PXRD pattern having peaks 8.27, 11.66, 14.11, 18.41, 19.06, 21.55, 23.90 and 24.73 ±0.2° 2Q. In another embodiment, present invention provides crystalline Form M5 of Rucaparib characterized by PXRD pattern substantially as depicted in FIG. 8.
Another embodiment of the present invention provides a process for the preparation of Form M5 of Rucaparib comprising. a) drying Rucaparib Form M2; and
b) isolating crystalline Rucaparib Form M5.
In one embodiment, Rucaparib Form M2 of present invention may be dried at l20-l43°C; preferably 125-135 °C to isolate Rucaparib Form M5.
In another embodiment, physical and chemical stability of Rucaparib S-Camsylate crystalline Form M2 and Form M3 samples were determined by storing the samples at 40 °C and 75% relative humidity (RH) and at 25°C and 60% relative humidity (RH) for 3 months. The samples were analyzed by PXRD.
The Rucaparib S-Camsylate Form M2 shows no change in PXRD pattern when stored for 3 months at 40°C and 75% relative humidity (RH) and at 25 °C and 60% relative humidity (RH) conditions as mentioned in below Table 1.
The Rucaparib S-Camsylate Form M3 shows no change in PXRD pattern when stored for 3 months at 40°C and 75% relative humidity (RH) and at 25 °C and 60% relative humidity (RH) conditions as mentioned in below Table 1.
Table 1
Figure imgf000013_0001
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 S-Camsylate Form Ml
0.2 g of Rucaparib Form M2 was dissolved in 4 mL of ethanol at 80±5°C. To the clear solution was added (S)-Camphor sulfonic acid solution [dissolved (S)-camphor sulfonic acid (0.l4g) in ethanol (lmL)] slowly at 80±5°C for 5-10 min and maintained under stirring for 3h. The reaction mass was cooled to 25±5°C and further stirred for 12 h. The reaction mass was filtered and dried under vacuum at 50°C for 3h. The product obtained was identified as Rucaparib S- Camsylate Form Ml.
Yield: 0.25 g
Example 2: Rucaparib S-Camsylate Form Ml
0.5 g of Rucaparib Form M2 was dissolved in 5 mL of ethanol at 80+5 °C. To the clear solution was seeded with 10 mg of Rucaparib S-Camsylate Form Ml at 80±5°C and stirred for 15 min. To the solution was added slowly (S)-Camphor sulfonic acid solution [dissolved (S)-Camphor sulfonic acid (0.36g) in ethanol (lmL)] at 80±5°C for 5-10 min and maintained under stirring for 3 h at 80±5°C. The reaction mass was cooled to 25±5°C and further stirred for 12 h. The reaction mass was filtered and dried under vacuum at 50 °C for 3h. The solid obtained was identified as Rucaparib S-Camsylate form ML
Yield: 0.6 g
Example 3: Rucaparib S-Camsylate Form M2
0.4 g of Rucaparib Form M3 was suspended in 8 mL of tetralin at 25+5 °C and heated to 70+5°C. To the reaction mass slowly added S-Camphor sulfonic acid solution [dissolved (S)- camphor sulfonic acid (0.29g) in 2-methyl 2-butanol (4mL)] at 70+5°C for 10-15 min and maintained under stirring for 30 min. Then reaction mass was cooled to 25+5°C and further maintained under stirring for 12 h. The reaction mass was filtered and dried under vacuum at 50°C for 3h. The solid obtained was identified as Rucaparib S-Camsylate Form M2.
Yield: 0.4 g
Example 4: Rucaparib S-Camsylate Form M2
0.2 g of Rucaparib Form M3 was suspended in a mixture of 4 mL of 2-methyl 2-butanol and 4 mL of tetralin at 25±5°C and heated to 70±5°C to obtain clear solution. To the reaction solution was slowly added (S)-Camphor sulfonic acid solution [dissolved (S)-camphor sulfonic acid (0.l4g) in 2-methyl 2-butanol (2mL)] at 70±5°C for 10-15 min and maintained under stirring for 30 min at 70+5 °C. The reaction mass was further cooled to 25+5 °C, stirred for l2h, filtered and dried under vacuum at 50 °C for 3 h. The solid obtained was identified as Rucaparib S- Camsylate form M2.
Yield: 0.2 g.
Example 5: Rucaparib S-Camsylate Form M2
0.5 g of Rucaparib Form M3 was suspended in 5 mL of 2-methyl 2-butanol at 25+5°C and heated to 80+5°C. To this suspension was seeded with 5 mg of Rucaparib S-Camsylate Form M2. To the reaction mass slowly added S-Camphor sulfonic acid solution [dissolved (S)- camphor sulfonic acid (0.36g) in 2-methyl 2-butanol (5mL)] at 80+5°C for 5-l0min and maintained under stirring for lh. The reaction mass was cooled to 25+5°C and further maintained under stirring for l2h. The reaction mass was filtered and dried under vacuum at 50 °C for l2h. The solid obtained was identified as Rucaparib S-Camsylate Form M2.
Yield: 0.7g
Example 6: Rucaparib S-Camsylate Form M2
4 g of Rucaparib Form Ml was suspended in 100 mL of 2-Methyl-2-Butanol at 25+5°C and heated to 80+5°C. Slowly added (S)-camphor sulfonic acid solution [dissolved (S)-camphor sulfonic acid (2.88g) in 2-methyl 2-butanol (40mL)] at 80+5°C for l0-l5min. Stirred the reaction mass for 60 min at 80+5°C, cooled to 25+5°C and further stirred for 15 h at 25+5°C. The reaction mass was filtered, washed with 2-Methyl-2-Butanol and dried under vacuum at 50 °C for lOh. The solid obtained was identified as Rucaparib S-Camsylate Form M2.
Yield: 6.3g
Example 7: Rucaparib S-Camsylate Form M3 0.5 g of Rucaparib Form M2 was dissolved in 7.5 mL of ethanol at 80±5°C to obtain clear solution. To the clear solution was slowly added (S)-Camphor sulfonic acid solution [dissolved (S)-camphor sulfonic acid (0.36g) in ethanol (3mL)] for 5-l0min and maintained under stirring for 4h at 80±5°C. The reaction mass was further cooled to 25±5°C, stirred for l2h, filtered and dried under vacuum at 50°C for l2h. The solid obtained was identified as Rucaparib S- Camsylate form M3.
Yield: 0.7g
Example 8: Rucaparib S-Camsylate Form M3
0.5 g of Rucaparib Form M2 was dissolved in 7.5 mL of ethanol at 80+5 °C to obtain clear solution. The clear solution was seeded with 5 mg of Rucaparib S-Camsylate Form M3 seeds. Further, to the reaction mixture was slowly added (S)-Camphor sulfonic acid solution [dissolved (S)-camphor sulfonic acid (0.36g) in ethanol (3mL)] for 5-10 min and maintained under stirring for 4 h at 80±5°C. The reaction mass was further cooled to 25±5°C, stirred for 12 h, filtered and dried under vacuum at 50°C for l2h. The solid obtained was identified as Rucaparib S-Camsylate form M3.
Yield: 0.7g
Example 9: Rucaparib S-Camsylate Form M3
5 g of Rucaparib THF solvate was suspended in 100 mL of 2-methyl-2-butanol at 25±5°C and heated to 80±5°C. The reaction mixture was seeded with 50 mg of Rucaparib S-Camsylate Form M3. Slowly added (S)-camphor sulfonic acid solution (dissolved (S)-camphor sulfonic acid (3.59 g) in 2-methyl 2-butanol (50 mL)) at 80±5°C for l0-l5min. The reaction mass was stirred for 60 min at 80+5 °C, cooled to 25+5° C and further stirred for 15 h at 25+5 °C. The reaction mass was filtered, washed with 2-Methyl-2-Butanol and dried under vacuum at 50 °C for lh. The solid obtained was identified as Rucaparib S-Camsylate Form M3.
Yield: 6.5g; HPLC Purity: 99.56%
Example 10: Rucaparib Form Ml
0.43 g of sodium hydroxide dissolved in a mixture of 42 mL of water and 16.5 mL of methanol at 25+5°C and then cooled to l5+5°C, to this was added 3 g of Rucaparib S-Camsylate salt for 10 min. Further, 42 mL of water was added to the reaction suspension and stirred for lh at 20+5°C. The reaction mass was filtered and dried under vacuum at 50 °C for 2 h. The product obtained was identified as Rucaparib form ML Yield: 2.2 g
Example 11: Rucaparib Form Ml
1.43 g of sodium hydroxide dissolved in a mixture of 140 mL of water and 55 mL of methanol at 25±5°C and then cooled to l5±5°C, to this was added 10 g of Rucaparib S-Camsylate lot- wise for lOmin and maintained under stirring for 90 min at same temperature. 120 mL of water was added to the reaction mixture and stirred for 16 h at 20±5°C. The reaction mass was filtered and dried under vacuum at 50 °C for 16 h. The product obtained was identified as Rucaparib form Ml.
Yield: 5.6 g
Example 12: Rucaparib Form M2
Rucaparib Form Ml was stored at 25±5°C in a closed condition for several days and the resulting solid was identified as Rucaparib form M2.
Example 13: Rucaparib Form M3
0.72 g of sodium hydroxide was dissolved in a mixture of 70 mL of water and 27.5 L of methanol at 25±5°C and then cooled to l5±5°C. To this was added 5 g of Rucaparib S- Camsylate lot-wise at l5±5°C for 10 min and maintained under stirring for 2 h at same temperature. 70 mL of water was added and stirred for 15 h at 20±5°C. The reaction mass was filtered and dried under vacuum at 65°C for l2h. The product obtained was identified as Rucaparib form M3.
Yield: 2.7 g
Example 14: Rucaparib Form M4
1 g of Rucaparib Form M3 was suspended in 20 mL of methyl isobutyl ketone at 25+5 °C and heated to 40±5°C and maintained under stirring for 30 min. The reaction mass was cooled to 25+5 °C and stirred for 12 h. The reaction mass was filtered and dried under vacuum at 50 °C for 12 h. The product obtained was identified as Rucaparib form M4.
Yield: 0.7g
Example 15: Rucaparib Form M5
0.2 g of Rucaparib Form M2 was dried at 130 °C under vacuum for 1-2 h. The resulting solid was identified as Rucaparib crystalline Form-M5.

Claims

We claim:
1. A crystalline Form M3 of Rucaparib (S)-camsylate characterized by PXRD pattern having peaks 13.31, 15.70, 20.29, 20.80, 23.36, 23.82, 24.74, and 26.24±0.2° 2Q.
2. The crystalline Form M3 as claimed in claim 1, wherein the crystalline Form M3 of Rucaparib (S)-camsylate characterized by PXRD pattern substantially as depicted in FIG. 3.
3. A process for the preparation of crystalline Form M3 of Rucaparib (S)-camsylate comprising:
a) dissolving Rucaparib in 13-17 volumes of solvent;
b) adding (S)-camphor sulfonic acid solution; and
c) isolating crystalline Rucaparib (S)-Camsylate Form M3.
4. A process for the preparation of crystalline Form M3 of Rucaparib (S)-camsylate comprising:
a) dissolving Rucaparib in a solvent;
b) seeding with Rucaparib (S)-camsylate Form M3;
c) adding (S)-camphor sulfonic acid solution; and
d) isolating crystalline Rucaparib (S)-Camsylate Form M3.
5. The process as claimed in claim 3 and 4, wherein the solvent is selected from alcoholic solvent such as methanol, ethanol, n-propanol, n-butanol, 2-butanol, 2-methyl-2- butanol and isopropyl alcohol.
6. A crystalline Form M2 of Rucaparib (S)-camsylate characterized by PXRD pattern having peaks 13.49, 17.99, 20.47, 22.09, 23.46, 24.06 and 27.79±0.2° 20.
7. The crystalline Form M2, as claimed in claim 6, wherein the crystalline Form M2 of Rucaparib (S)-camsylate characterized by PXRD pattern substantially as depicted in FIG. 2.
8. A process for the preparation of Form M2 of Rucaparib (S)-camsylate comprising: a) suspending Rucaparib in suitable solvent or mixture thereof;
b) optionally seeding with Rucaparib (S)-camsylate Form M2;
c) adding (S)-camphor sulfonic acid solution; and
d) isolating crystalline Rucaparib (S)-Camsylate Form M2.
9. The process as claimed in claim 8, wherein the solvent is selected from alcoholic solvent such as methanol, ethanol, n-propanol, n-butanol, 2-butanol, 2-methyl-2- butanol and isopropyl alcohol.
10. Crystalline Form Ml of Rucaparib (S)-camsylate characterized by PXRD pattern having peaks 11.89, 12.90, 15.34, 16.33, 17.87, 20.0, 21.95, 24.94 and 30.0±0.2° 2Q.
11. The crystalline Form Ml as claimed in claim 10, wherein the crystalline Form Ml of Rucaparib (S)-camsylate characterized by PXRD pattern substantially as depicted in FIG. 1.
12. A process for the preparation of crystalline Form Ml of Rucaparib (S)-camsylate comprising:
a) dissolving Rucaparib in 18-22 volumes of solvent;
b) adding (S)-camphor sulfonic acid solution; and
c) isolating crystalline Rucaparib (S)-Camsylate Form Ml.
13. A process for the preparation of crystalline Form Ml of Rucaparib (S)-camsylate comprising:
a) dissolving Rucaparib in a solvent;
b) seeding with Rucaparib (S)-camsylate Form Ml;
c) adding (S)-camphor sulfonic acid solution; and
d) isolating crystalline Rucaparib (S)-Camsylate Form Ml.
14. The process as claimed in claim 12 and 13, wherein the solvent is selected from alcoholic solvent such as methanol, ethanol, n-propanol, n-butanol, 2-butanol, 2- methyl-2-butanol and isopropyl alcohol.
15. A crystalline Form Ml of Rucaparib characterized by PXRD pattern having peaks 9.09, 15.19, 22.69, 23.20, 27.72±0.2° 2Q.
16. The crystalline Form Ml as claimed in claim 15, wherein the crystalline Form Ml of Rucaparib is characterized by XRPD pattern substantially as depicted in FIG. 4
17. A process for the preparation of Form Ml of Rucaparib comprising:
a) suspending Rucaparib (S)-camsylate in an aqueous base and alcohol solvent; and
b) drying at 45-55 °C to isolate crystalline Rucaparib Form Ml.
18. The process as claimed in claim 17, wherein the alcoholic solvent is selected from methanol, ethanol, n-propanol, n-butanol, 2-butanol, 2-methyl-2-butanol and isopropyl alcohol.
19. The process as claimed in claim 17, wherein the base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
20. A crystalline Form M2 of Rucaparib characterized by PXRD pattern having peaks 8.48, 18.67, 19.34, 21.80 and 24.24±0.2° 2Q.
21. The crystalline Form M2 as claimed in claim 20, wherein the crystalline Form M2 of Rucaparib characterized by XRPD pattern substantially as depicted in FIG. 5.
22. A crystalline Form M3 of Rucaparib characterized by PXRD pattern having peaks 14.69, 22.10, 22.56, and 27.80 ±0.2° 2Q.
23. The crystalline Form M3 as claimed in claim 22, wherein the crystalline Form M3 of Rucaparib characterized by PXRD pattern substantially as depicted in FIG. 6.
24. A process for the preparation of Form M3 of Rucaparib comprising:
a) suspending Rucaparib (S)-camsylate in aqueous base and alcohol solvent; and b) drying at 60-70 °C to isolate crystalline Rucaparib Form M3.
25. The process as claimed in claim 24, wherein the solvent is selected from alcoholic solvent such as methanol, ethanol, n-propanol, n-butanol, 2-butanol, 2-methyl-2- butanol and isopropyl alcohol.
26. The process as claimed in claim 24, wherein the base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
27. A crystalline Form M4 of Rucaparib characterized by PXRD pattern having peaks 7.79, 13.53, 13.86,14.82, 15.64, 17.017.70,19.87, 20.59, 21.34, 22.50 and 23.35 ±0.2° 20.
28. The crystalline Form M4 as claimed in claim 27, wherein the crystalline Form M4 of Rucaparib characterized by PXRD pattern substantially as depicted in FIG. 7
29. A process for the preparation of Form M4 of Rucaparib comprising.
a) suspending Rucaparib Form 3 in a ketone solvent; and
b) isolating crystalline Rucaparib Form M4.
30. The process as claimed in claim 29, wherein the solvent is methyl isobutyl ketone.
31. A crystalline Form M5 of Rucaparib characterized by PXRD pattern having peaks 8.27, 11.66, 14.11, 18.41, 19.06, 21.55, 23.90 and 24.73 ±0.2° 20.
32. The crystalline Form M5 as claimed in claim 26, wherein the crystalline Form M5 of Rucaparib characterized by PXRD pattern substantially as depicted in FIG. 8.
33. A process for the preparation of Form M5 of Rucaparib comprising.
a) drying Rucaparib Form 2; and
b) isolating crystalline Rucaparib Form M5.
34. The process as claimed in claim 33, wherein the Form M2 of Rucaparib is dried at 125- 135 °C.
PCT/IN2019/050324 2018-04-25 2019-04-22 Novel crystalline forms of rucaparib (s)-camsylate salt and rucaparib free base WO2019207596A1 (en)

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