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WO2017093789A1 - Formes polymorphes de dimaléate d'afatinib - Google Patents

Formes polymorphes de dimaléate d'afatinib Download PDF

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Publication number
WO2017093789A1
WO2017093789A1 PCT/IB2015/059319 IB2015059319W WO2017093789A1 WO 2017093789 A1 WO2017093789 A1 WO 2017093789A1 IB 2015059319 W IB2015059319 W IB 2015059319W WO 2017093789 A1 WO2017093789 A1 WO 2017093789A1
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Prior art keywords
afatinib dimaleate
afatinib
crystalline
preparation
solution
Prior art date
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PCT/IB2015/059319
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English (en)
Inventor
Ramakoteswara Rao Jetti
Anjaneyaraju Indukuri
Satish BEERAVELLY
Asharani GORANTLA
B. A. Ramireddy
Ruchira M. SARBAJNA
Sivalakshmidevi ARIKATLA
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Mylan Laboratories Ltd
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Mylan Laboratories Ltd
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Priority to PCT/IB2015/059319 priority Critical patent/WO2017093789A1/fr
Publication of WO2017093789A1 publication Critical patent/WO2017093789A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates generally to amorphous and crystalline forms of afatinib dimaleate and afatinib free base and processes for the preparation thereof.
  • Afatinib dimaleate chemically known as 2-butenamide, N-[4-[(3-chloro-4- fluorophenyl)amino] 7- [ [(3 S )-tetrahydro-3 -furanyl] oxy] -6-quinazolinyl] -4-(dimethyl amino)-, (2E)-, (2Z)-2-butenedioate (1:2), is an orally administered irreversible inhibitor of the epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) tyrosine kinases.
  • EGFR epidermal growth factor receptor
  • HER2 human epidermal receptor 2
  • Afatinib dimaleate is marketed under the brand name GILOTRIF®, which is indicated for treatment of patients with several solid tumors including non-small cell lung cancer (NSCLC), breast, head and neck cancer, and a variety of other cancers.
  • NSCLC non-small cell lung cancer
  • the structural formula of afatinib dimaleate is:
  • the present invention provides novel crystalline and amorphous forms and process for the preparation of afatinib dimaleate.
  • the present invention also provides a crystalline form of afatinib.
  • the present invention further provides a solid dispersion preparation of afatinib dimaleate.
  • a first aspect of the present disclosure is to provide a novel crystalline afatinib dimaleate form-Ml, which is characterized by powdered X-ray diffraction pattern as shown in Fig. 1.
  • Another aspect of the present disclosure is to provide a process for the preparation of crystalline afatinib dimaleate form-Ml comprising the steps of:
  • Yet another aspect of the present disclosure is to provide a process for the preparation of crystalline afatinib dimaleate form-Mlcomprising the steps of:
  • a further aspect of the present disclosure is to provide a novel crystalline afatinib dimaleate form-M2.
  • One aspect of the present disclosure is to provide a novel crystalline afatinib dimaleate form-M2, which is characterized by powdered X-ray diffraction pattern as shown in Fig. 2.
  • Another aspect of the present disclosure is to provide a process for the preparation of crystalline afatinib dimaleate form-M2 comprising drying the crystalline afatinib dimaleate form-Mi at 35-55 °C for 15-24 hours.
  • a further aspect of the present disclosure is to provide a novel crystalline afatinib dimaleate form-M3, which is characterized by powdered X-ray diffraction pattern as shown in Fig. 3.
  • Another aspect of the present disclosure is to provide a process for the preparation of crystalline afatinib dimaleate form-M3 comprising the steps of:
  • An additional aspect of the present disclosure is to provide a novel crystalline afatinib dimaleate form-M4, which is characterized by the powdered X-ray diffraction pattern as shown in Fig. 4.
  • Another aspect of the present disclosure is to provide a process for the preparation of crystalline afatinib dimaleate form-M4 comprising the steps of:
  • step (a) adding maleic acid solution to the solution obtained in step (a);
  • a further aspect of the present disclosure is to provide a novel crystalline afatinib dimaleate form-M5, which is characterized by the powdered X-ray diffraction pattern as shown in Fig. 5.
  • Another aspect of the present disclosure is to provide a process for the preparation of crystalline afatinib dimaleate form-M5 comprising the steps of:
  • step (a) adding maleic acid solution to the solution obtained in step (a);
  • An additional aspect of the present disclosure is to provide a novel crystalline afatinib dimaleate form-M6, which is characterized by powdered X-ray diffraction pattern as shown in Fig. 6.
  • Another aspect of the present disclosure is to provide a process for the preparation of crystalline afatinib dimaleate form-M6 comprising the steps of:
  • Another aspect of the present disclosure is to provide a novel crystalline afatinib dimaleate form-M7.
  • One aspect of the present disclosure is to provide a novel crystalline afatinib dimaleate form-M7, which is characterized by powdered X-ray diffraction pattern as shown in Fig. 7.
  • Another aspect of the present disclosure is to provide a process for the preparation of crystalline afatinib dimaleate form-M7 comprises heating the crystalline afatinib dimaleate form-M6 at 80-90 °C for 1-2 hours.
  • the present disclosure provides a process for the preparation of crystalline afatinib dimaleate form-M7 comprises grinding the crystalline afatinib dimaleate form-M6.
  • An additional aspect of the present disclosure is to provide a novel crystalline afatinib dimaleate form-M8, which is characterized by powdered X-ray diffraction pattern as shown in Fig. 8.
  • Another aspect of the present disclosure is to provide a process for the preparation of crystalline afatinib dimaleate form-M8 comprising the steps of:
  • the present disclosure provides a process for the preparation of crystalline afatinib dimaleate form-M8 comprises heating the crystalline afatinib dimaleate form-M6 at approximately 40-50°C for about 30-60 minutes.
  • a further aspect of the present disclosure is to provide a novel crystalline afatinib dimaleate form-M9, which is characterized by powdered X-ray diffraction pattern as shown in Fig. 9.
  • Another aspect of the present disclosure is to provide a process for the preparation of crystalline afatinib dimaleate form-M9 comprising the steps of:
  • a further aspect of the present disclosure is to provide an amorphous afatinib dimaleate, which is characterized by powdered X-ray diffraction pattern as shown in Fig. 10.
  • Another aspect of the present disclosure is to provide a process for the preparation of amorphous afatinib dimaleate comprising the steps of:
  • Yet another aspect of the present disclosure is to provide a process for the preparation of amorphous afatinib dimaleate comprising the steps of:
  • An additional aspect of the present disclosure is to provide a solid dispersion of amorphous afatinib dimaleate together with one or more pharmaceutically acceptable carriers.
  • One aspect of the present disclosure is to provide a process for the preparation of solid dispersion of amorphous afatinib dimaleate comprising the steps of:
  • a further aspect of the present disclosure is to provide a novel crystalline afatinib form-M, which is characterized by powdered X-ray diffraction pattern as shown in Fig. 11.
  • Another aspect of the present disclosure is to provide a process for the preparation of crystalline afatinib form-M comprising the steps of:
  • FIGURE 1 is an X-ray powder diffractogram of crystalline form-M 1 of afatinib dimaleate
  • FIGURE 2 is an X-ray powder diffractogram of crystalline form-M2 of afatinib dimaleate
  • FIGURE 3 is an X-ray powder diffractogram of crystalline form-M3 of afatinib dimaleate
  • FIGURE 4 is an X-ray powder diffractogram of crystalline form-M4 of afatinib dimaleate
  • FIGURE 5 is an X-ray powder diffractogram of crystalline form-M5 of afatinib dimaleate
  • FIGURE 6 is an X-ray powder diffractogram of crystalline form-M6 of afatinib dimaleate
  • FIGURE 7 is an X-ray powder diffractogram of crystalline form-M7 of afatinib dimaleate
  • FIGURE 8 is an X-ray powder diffractogram of crystalline form-M8 of afatinib dimaleate
  • FIGURE 9 is an X-ray powder diffractogram of crystalline form-M9 of afatinib dimaleate
  • FIGURE 10 is an X-ray powder diffractogram of amorphous afatinib dimaleate; and FIGURE 11 is an X-ray powder diffractogram of crystalline form-M of afatinib.
  • the present disclosure provides amorphous and crystalline forms, and solid dispersion, of afatinib dimaleate.
  • the present disclosure also relates to crystalline form of afatinib and a process for the preparation of amorphous and crystalline forms of afatinib dimaleate.
  • the polymorph of the present disclosure may be characterized by their X-ray powder diffraction ("PXRD") patterns.
  • PXRD X-ray powder diffraction
  • the PXRD patterns of the polymorphs of the disclosure were measured on BRUKER D-8 DISCOVER powder diffractometer equipped with goniometer of ⁇ /2 ⁇ configuration and LYNX EYE detector.
  • the Cu-anode X-ray tube was operated at 40 kV and 30 mA. The experiments were conducted over the 2 ⁇ range of 2.0°-50.0°, 0.030° step size and 0.4 seconds step time.
  • crystalline afatinib dimaleate form-M 1 may be characterized by a PXRD pattern having significant peaks at 2 ⁇ angle positions of about 5.07, 20.43, 21.22, 22.73, and 27.78 + 0.2°.
  • crystalline afatinib dimaleate form-M 1 may be further characterized by a PXRD pattern having significant peaks at 2 ⁇ angle positions of about 5.07, 8.98, 9.34, 10.30, 11.79, 13.73, 14.43, 15.26, 16.30, 16.60, 17.05, 17.62, 18.40, 18.64, 19.40, 19.95, 20.43, 20.74, 21.22, 22.02, 22.73, 23.85, 24.41, 24.90, 25.64, 26.32, 26.86, 27.33, and 27.77 + 0.2°.
  • One embodiment of the present invention provides a process for the preparation of crystalline afatinib dimaleate form-Mi which includes the following steps:
  • afatinib and maleic acid are dissolved in an organic solvent.
  • this step may be carried out at a temperature of about 60 °C to about 75 °C.
  • suitable organic solvents include dimethyl formamide.
  • dimethyl formamide was found to be a particularly useful organic solvent.
  • the solution may then be cooled to a temperature of about 20 °C to about 35 °C.
  • an anti-solvent may be added and the solution may be stirred, forming a solid.
  • the anti- solvent employed may be, for example, an ether solvent, a hydrocarbon solvent, or mixtures thereof.
  • suitable ether solvents include diethyl ether, di-isopropyl ether, and methyl tert-butyl ether.
  • suitable hydrocarbon solvents include n-hexane and n-heptane.
  • methyl tert-butyl ether has been found to be a particularly useful anti-solvent.
  • the crystalline afatinib dimaleate form-Mi may be isolated using methods well known in the art, including, for example, by filtering the solution and drying the solid at a temperature of about 35 °C to about 45 °C under vacuum for 5-6 hours.
  • afatinib dimaleate is dissolved in an organic solvent at a temperature of about 60 °C to about 75 °C and then cooled the solution to a temperature of about 20 °C to about 35 °C.
  • suitable organic solvents include dimethyl formamide. In some embodiments of the present invention, dimethyl formamide was found to be a particularly useful organic solvent.
  • anti-solvent is added and then stirred.
  • the anti-solvent employed may be, for example, an ether solvent, a hydrocarbon solvent, or mixtures thereof.
  • suitable ether solvents include diethyl ether, di-isopropyl ether, and methyl tert-butyl ether.
  • hydrocarbon solvents examples include n-hexane and n-heptane.
  • ether solvents and hydrocarbon solvents that may be employed.
  • methyl tert-butyl ether has been found to be a particularly useful anti- solvent.
  • the crystalline afatinib dimaleate form-Mi may be isolated using methods well known in the art, including, for example, by filtering the solution and drying the solid at a temperature of about 35 °C to about 45 °C under vacuum for 1-2 hours.
  • crystalline afatinib dimaleate form-M2 may be characterized by a PXRD pattern having significant peaks at 2 ⁇ angle positions of about 5.12, 9.83, 18.51, 19.38, 20.32, 21.74, and 25.76 +0.2°.
  • crystalline afatinib dimaleate form-M2 may be further characterized by a PXRD pattern having significant peaks at 2 ⁇ angle positions of about 5.12, 5.44, 9.83, 10.23, 10.79, 14.54, 15.18, 16.08, 16.51, 16.91, 17.81, 18.51, 18.91, 19.38, 19.66, 20.32, 21.02, 21.43, 21.74, 23.0, 23.31, 24.04, 24.54, 24.95, 25.16, 25.76, 26.07, 26.52, 26.98, 28.81, 29.06, 30.95, 33.02, 34.11, and 36.69 +0.2°.
  • Another embodiment of the present invention provides a process for the preparation of crystalline afatinib dimaleate form-M2 which may be achieved by drying the crystalline afatinib dimaleate form-Mi at about 35 °C to about 55 °C for about 15 to about 24 hours.
  • drying crystalline afatinib dimaleate form-Mi under vacuum at about 40 °C for about 15 to about 24 hours was particularly useful in obtaining crystalline afatinib dimaleate form-M2.
  • crystalline afatinib dimaleate form-M3 may be characterized by a PXRD pattern having significant peaks at 2 ⁇ angle positions of about 9.61, 15.98, 18.20, 20.19, 20.85, 22.79, and 23.68 + 0.2°.
  • crystalline afatinib dimaleate form-M2 may be further characterized by a PXRD pattern having significant peaks at 2 ⁇ angle positions of about 4.98, 8.91, 9.61, 10.11, 10.59, 11.15, 12.02, 14.91, 15.98, 16.64, 17.53, 18.20, 18.43, 19.17, 20.19, 21.41, 22.0, 22.79, 23.68, 24.56, 24.85, 25.40, 25.72, 26.15, 26.75, 28.46, 28.69, 32.43, 33.27, 33.73, 34.73, 35.76, 36.60, 37.55, 38.04, 38.99, 40.31, 41.25, 42.48, 42.92, 46.24, and 46.62 + 0.2°.
  • Another embodiment of the present invention provides a process for the preparation of crystalline afatinib dimaleate form-M3, which includes the following steps:
  • afatinib and maleic acid are dissolved in an organic solvent.
  • this may be carried out at a temperature of about 25 °C to about 30 °C.
  • suitable organic solvents include, for example, 1 -methyl 2-pyrrolidinone.
  • 1 -methyl 2-pyrrolidinone was found to be a particularly useful organic solvent.
  • the anti- solvent may be a ketone, for example, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isopropyl ketone, or mixtures thereof.
  • acetone was found to be a particularly useful anti-solvent.
  • One of skill in the art will recognize other ketone solvents that may be employed.
  • Crystalline afatinib dimaleate form-M3 may then be isolated using methods well known in the art, including, for example, by filtering the solution and drying the obtained solid at a temperature of about 40 °C to about 50 °C under vacuum for about 2 to about 3 hours.
  • crystalline afatinib dimaleate form-M4 may be characterized by a PXRD pattern having significant peaks at 2 ⁇ angle positions of about 5.01, 17.66, 18.53, 20.49 and 25.58 + 0.2 °.
  • crystalline afatinib dimaleate form-M4 may be further characterized by a PXRD pattern having significant peaks at 2 ⁇ angle positions of about 4.24, 5.01, 5.35, 6.01, 7.12, 8.22, 9.90, 10.44, 11.08, 11.62, 14.06, 14.88, 15.26, 17.01, 17.66, 18.05, 18.53, 19.71, 20.49, 21.73, 22.17, 22.60, 24.95, 25.58, 26.28, 27.53, 28.1, 28.63, 29.37, 30.09, 30.69, 31.52, and 32.59 + 0.2°.
  • Another embodiment of the present invention provides a process for the preparation of crystalline afatinib dimaleate form-M4 which includes the following steps:
  • afatinib is dissolved in an organic solvent.
  • a solution of maleic acid is added.
  • the solution may be then stirred at a temperature of about 25°C to about 30 °C for about 17 to about 18 hours.
  • Crystalline afatinib dimaleate form-M4 may then be isolated using methods well known in the art, including, for example, by filtering the solution and drying the solid at a temperature of about 40 °C to about 50 °C under vacuum for about 3 to about 4 hours.
  • the organic solvent used to dissolve afatinib may be a ketone, for example, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isopropyl ketone, or mixtures thereof.
  • a ketone for example, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isopropyl ketone, or mixtures thereof.
  • methyl ethyl ketone was found to be a particularly useful organic solvent.
  • One of skill in the art will recognize other ketone solvents that may be employed.
  • the maleic acid solution may be prepared by dissolving maleic acid in the same organic solvent as used to dissolve afatinib in the first step for the process for the preparation of afatinib dimaleate form-M4.
  • crystalline afatinib dimaleate form-M5 may be characterized by a PXRD pattern having significant peaks at 2 ⁇ angle positions of about 4.95, 17.53, 18.29, 18.55, 19.69, 20.37, 21.15, and 27.74 + 0.2°.
  • crystalline afatinib dimaleate form-M5 may be further characterized by a PXRD pattern having significant peaks at 2 ⁇ angle positions of about 4.95, 5.32, 5.98, 6.38, 7.25, 7.95, 8.87, 10.25, 11.17, 11.65, 12.97, 13.61, 14.57, 16.40, 17.53, 18.29, 18.55, 19.69, 20.37, 21.15, 21.83, 22.68, 23.81, 24.39, 25.42, 27.74, and 29.19 + 0.2°.
  • One embodiment of the present invention provides a process for the preparation of crystalline afatinib dimaleate form-M5, which includes the following steps:
  • afatinib is dissolved in an organic solvent.
  • the organic solvent may be a ketone.
  • suitable ketones include acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isopropyl ketone, and mixtures thereof.
  • acetone was found to be a particularly useful organic solvent.
  • ketone solvents that may be employed.
  • a solution of maleic acid is added. The reaction may then be stirred for about 17 to about 18 hours at 25-35 °C.
  • Crystalline afatinib dimaleate form-M5 may then be isolated using methods well known in the art, including, for example, by filtering the solution and drying the obtained solid at a temperature of about 40 °C to about 50 °C under vacuum for about 3 to about 4 hours.
  • crystalline afatinib dimaleate form-M6 may be characterized by a PXRD pattern having significant peaks at 2 ⁇ angle positions of about 5.59, 18.94, 19.41, 21.23, 21.48, 22.19, 26.13, 27.95 + 0.2°.
  • crystalline afatinib dimaleate form-M6 may be further characterized by a PXRD pattern having significant peaks at 2 ⁇ angle positions of about 5.59, 7.21, 9.02, 9.43, 10.57, 11.14, 12.27, 13.78, 14.63, 15.87, 16.44, 17.04, 17.51, 18.00, 18.94, 19.41, 19.90, 20.89, 21.23, 21.48, 22.19, 22.69, 23.78, 24.06, 24.55, 25.10, 25.63, 26.13, 27.15, 27.95, 28.68, 29.28, 31.96, 34.84, and 37.93 + 0.2°.
  • One embodiment of the present invention provides a process for the preparation of crystalline afatinib dimaleate form-M6 which includes the following steps:
  • afatinib may be dissolved in an organic solvent at a temperature of about 25 °C to about 30 °C, and then cooled to about 0 °C to about 5 °C.
  • Maleic acid (which may be in the form, for example, of maleic acid dissolved in the same organic solvent) may then be added at the same temperature, and the solution may then be stirred.
  • the solution may optionally be seeded with afatinib dimaleate form-M6.
  • the organic solvent used to dissolve afatinib (and for making the maleic acid solution) may be, for example, acetone.
  • Crystalline afatinib dimaleate form-M6 may then be isolated using methods well known in the art, including, for example, by filtering the solution and drying the obtained solid at about 35 °C to about 45 °C under vacuum for about 3 to about 4 hours.
  • Another aspect of the present invention provides crystalline afatinib dimaleate form- M7.
  • crystalline afatinib dimaleate form-M7 may be characterized by a PXRD pattern having significant peaks at 2 ⁇ angle positions of about 5.63, 17.19, 18.96, 21.47, 22.53, and 25.39 + 0.2°.
  • crystalline afatinib dimaleate form-M7 may be further characterized by a PXRD pattern having significant peaks at 2 ⁇ angle positions of about 5.63, 5.86, 6.25, 8.29, 9.19, 9.60, 10.38, 10.72, 11.09, 11.50, 12.43, 13.94, 15.36, 16.03, 17.19, 17.61, 18.96, 19.25, 19.42, 20.09, 21.47, 22.53, 23.01, 25.39, 26.48, 27.59, 28.27, 29.08, 32.34, 34.66, 36.21, 37.78, and 38.35 + 0.2°.
  • One embodiment of the present invention provides a process for the preparation of crystalline afatinib dimaleate form-M7 which may be achieved by heating the crystalline afatinib dimaleate form-M6 at about 80 °C to about 90 °C for about 1 to about 2 hours.
  • Another embodiment of the present disclosure provides a process for the preparation of crystalline afatinib dimaleate form-M7 which can be achieved by grinding the crystalline afatinib dimaleate form-M6.
  • crystalline afatinib dimaleate form- M8 may be characterized by a PXRD pattern having significant peaks at 2 ⁇ angle positions of about 5.54, 17.17, 17.50, 18.91, 19.34, 21.43, and 22.60 + 0.2°.
  • crystalline afatinib dimaleate form-M8 may be further characterized by a PXRD pattern having significant peaks at 2 ⁇ angle positions of about 5.54, 8.28, 9.04, 9.42, 10.57, 11.02, 12.25, 14.64, 15.86, 17.17, 17.50, 18.91, 19.34, 20.04, 21.43, 22.60, 24.73, 26.48, 28.17, and 28.97 + 0.2°.
  • One embodiment of the present invention provides a process for the preparation of crystalline afatinib dimaleate form-M8 which includes the following steps:
  • afatinib is dissolved in an organic solvent a temperature of about 25 °C to about 30 °C.
  • maleic acid solution may be added, which may be prepared, for example, by dissolving maleic acid in the same organic solvent.
  • seeds of afatinib dimaleate form-M8 may be optionally added to the solution before adding the remaining maleic acid solution.
  • Crystalline afatinib dimaleate form-M8 may then be isolated using methods well known in the art, including, for example, by filtering the solution and drying the solid at about 50 °C to about 60 °C under vacuum for about 17 to about 18 hours.
  • the organic solvent used to dissolve afatinib may be, for example, acetone.
  • the process for the preparation of crystalline afatinib dimaleate form-M8 may be carried out by dissolving afatinib in an organic solvent at about 25 °C to about 30 °C, cooling the solution to a temperature of about 0 °C to about 5 °C, and then seeding the solution with afatinib dimaleate form-M8.
  • a maleic acid solution (which may be prepared, for example, by dissolving maleic acid in the same organic solvent) is then added maintaining the temperature of about 0 °C to about 5 °C and the reaction may then be stirred for 5-6 hours.
  • (and preparing the maleic acid solution) may be acetone.
  • Crystalline afatinib dimaleate form-M8 may then be isolated using methods well known in the art, including, for example, by filtering the solution and drying the resulting solid at about 35 °C to about 45 °C under vacuum for about 17 to about 18 hours.
  • Another embodiment of the present invention provides a process for the preparation of crystalline afatinib dimaleate form-M8 which may be achieved by heating the crystalline afatinib dimaleate form-M6 at about 40 °C to about 50 °C for about 30 to about 60 minutes.
  • crystalline afatinib dimaleate form-M9 may be characterized by a PXRD pattern having significant peaks at 2 ⁇ angle positions of about 15.87, 17.41, 19.26, 21.58, 22.57, 24.34, 25.56, and 28.06 + 0.2°.
  • crystalline afatinib dimaleate form-M9 may be further characterized by a PXRD pattern having significant peaks at 2 ⁇ angle positions of about 5.38. 6.12, 8.98, 9.92, 10.31, 10.56, 12.07, 13.55, 15.50, 15.87, 17.41, 18.03, 18.54, 18.79, 19.26, 19.68, 20.44, 21.01, 21.58, 22.11, 22.57, 22.88, 24.06, 24.34, 24.87, 25.26, 25.73, 26.37, 26.74, 27.52, 28.06, 28.94, 29.29, 29.53, 31.23, 31.53, 32.30, 33.73, 34.49, 35.34, 35.77, 36.99, 38.27, 39.41, 39.76, 41.46, 43.00, 44.81, 45.92, 47.24, and 48.42 + 0.2°.
  • Another embodiment of the present invention provides a process for the preparation of crystalline a
  • afatinib is dissolved in an organic solvent at a temperature of about 25 °C to about 30 °C.
  • maleic acid solution which may be prepared by dissolving maleic acid in the same organic solvent, is added to the solution and the solution may be stirred.
  • this step may be carried out and the organic solvent may be, for example, tetrahydrofuran.
  • Crystalline afatinib dimaleate form-M9 may then be isolated using methods well known in the art, including, for example, by filtering the solution and drying the solid at about 35°C to about 45 °C under vacuum for about 5 hours.
  • the process for the preparation of crystalline afatinib dimaleate form- M9 may be carried out by dissolving afatinib in an organic solvent at about 25 °C to about 30 °C.
  • a maleic acid solution which may be prepared by dissolving maleic acid in the same organic solvent, may be added at the same temperature of about 25 °C to about 30 °C.
  • the solution may then be seeded with afatinib dimaleate form-M9.
  • the organic solvent used to dissolve afatinib (and preparing the maleic acid solution) may be, for example, tetrahydrofuran.
  • Crystalline afatinib dimaleate form-M9 may then be isolated using methods well known in the art, including, for example, by filtering the solution and drying the solid at about 45 °C to about 55 °C under vacuum for about 17 to about 18 hours to yield crystalline afatinib dimaleate form-M9.
  • amorphous afatinib dimaleate may characterized by PXRD pattern as shown in FIG. 10.
  • One embodiment of the present invention provides a process for the preparation of amorphous afatinib dimaleate, which includes the following steps:
  • afatinib dimaleate is dissolved in an organic solvent.
  • this step may occur at a temperature of about 50 °C to about 70 °C.
  • the organic solvent may be an alcohol, for example, methanol, ethanol, isopropanol, 1-butanol, 2-butanol, isoamyl alcohol, isobutyl alcohol, 1-pentanol, 1-propanol, 2-propanol, or mixtures thereof.
  • alcohol for example, methanol, ethanol, isopropanol, 1-butanol, 2-butanol, isoamyl alcohol, isobutyl alcohol, 1-pentanol, 1-propanol, 2-propanol, or mixtures thereof.
  • alcoholic solvents that may be employed.
  • the solution may then be filtered, for example, through a Hyflo bed.
  • the solution may then be cooled to a temperature of about 20 °C to about 35 °C.
  • the organic solvent may be removed, for example, by distillation, spray drying, or agitated thin film drying (ATFD) to yield the amorphous form of afatinib dimaleate.
  • ATFD agitated thin film drying
  • afatinib and maleic acid are dissolved in an organic solvent.
  • this step may be carried out at a temperature of about 50 °C to about 70 °C.
  • the organic solvent may be an alcohol, for example, methanol, ethanol, isopropanol, 1-butanol, 2-butanol, isoamyl alcohol, isobutyl alcohol, 1-pentanol, 1-propanol, 2-propanol, or mixtures thereof.
  • alcohol for example, methanol, ethanol, isopropanol, 1-butanol, 2-butanol, isoamyl alcohol, isobutyl alcohol, 1-pentanol, 1-propanol, 2-propanol, or mixtures thereof.
  • the solution may then be filtered, for example, through a Hyflo bed.
  • the solution may then be cooled to a temperature of about 20 °C to about 35 °C.
  • the solvent is removed for example, by distillation, spray drying, or agitated thin film drying (ATFD) to yield the amorphous form of afatinib dimaleate.
  • Another aspect of the present invention provides a premix solid dispersion of the amorphous form of afatinib dimaleate.
  • One embodiment of the present invention provides a process for the preparation of the premix solid dispersion of amorphous afatinib dimaleate which includes the following steps: a) dissolving afatinib, maleic acid, and one or more pharmaceutically acceptable carriers in an organic solvent,
  • afatinib, maleic acid, and one or more pharmaceutical acceptable carriers are dissolved in an organic solvent.
  • this step may be carried out at a temperature of about 50 to about 70 °C.
  • the organic solvent may be alcoholic, for example, methanol, ethanol, isopropanol, 1-butanol, 2-butanol, isoamyl alcohol, isobutyl alcohol, 1-pentanol, 1-propanol, 2-propanol and mixtures thereof.
  • the solution may then be filtered, for example, through a Hyflo bed.
  • the solution may then be cooled to a temperature of about 20 °C to about 35 °C.
  • the solvent is removed, which may be achieved for example, by distillation, spray drying, or agitated thin film dryer (ATFD), to yield a solid dispersion of amorphous afatinib dimaleate.
  • the one or more pharmaceutically acceptable carriers may be, for example, plasdone S-630 or polyvinylpyrrolidineK-30.
  • crystalline afatinib dimaleate form-M may be characterized by a PXRD pattern having significant peaks at 2 ⁇ angle positions of about 6.64, 14.95, 17.71, and 18.98 + 0.2°.
  • crystalline afatinib dimaleate form-M may be further characterized by a PXRD pattern having significant peaks at 2 ⁇ angle positions of about 4.68, 6.64, 9.29, 10.55, 11.94, 13.38, 14.20, 14.95, 17.71, 18.11, 18.98, 20.38, 20.79, 21.25, 22.64, 23.31, 24.54, 25.67, 26.40, 27.86, 29.12, 30.35, 32.19, 33.31, 33.96, 36.65, 42.74, 44.84, and 46.30 + 0.2°.
  • afatinib is dissolved in an organic solvent.
  • the organic solvent may be, for example, a ketone, an alcohol, or mixtures thereof.
  • suitable ketones include acetone, methyl ethyl ketone, methyl isobutyl ketone, and ethyl isopropyl ketone.
  • suitable alcohols include methanol, ethanol, isopropanol, 1-butanol, 2-butanol, isoamyl alcohol, isobutyl alcohol, 1-pentanol, 1-propanol, and 2-propanol.
  • One of skill will recognize other ketone or alcoholic solvents that may be employed.
  • the solution may then be cooled to about 25 °C to about 30 °C.
  • an anti- solvent is added and the solution may be stirred.
  • the anti-solvent may be an ether solvent, a hydrocarbon solvent, water, or mixtures thereof.
  • Suitable ether solvents include diethyl ether, di-isopropyl ether, and methyl tert-butyl ether.
  • Suitable hydrocarbon solvents include n-hexane and n-heptane.
  • One of skill in the art will recognize other ether solvents or hydrocarbon solvents that may be employed.
  • Crystalline afatinib form-M may then be isolated using methods well known in the art, including, for example, by filtering the solution and drying the solid at about 40 °C to about 50 °C under vacuum.
  • reaction conditions e.g., reaction time or temperature
  • afatinib dimaleate may be adjusted to achieve appropriate yield without undertaking undue experimentation and without departing from the scope of the present disclosure.
  • afatinib dimaleate in the pharmaceutical composition may be crystalline or amorphous.
  • the afatinib dimaleate polymorphs and amorphous afatinib dimaleate of the present invention may be included in tablets for oral administration.
  • pharmaceutically acceptable excipients including lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate.
  • the tablets may be coated with a film that may contain additional pharmaceutically acceptable excipients, for example, hypromellose, polyethylene glycol, titanium dioxide, talc, polysorbate 80, and artificial colorings.
  • the afatinib dimaleate polymorphs and amorphous forms and formulations disclosed herein may be included in formulations prescribed for the treatment of first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.
  • NSCLC metastatic non-small cell lung cancer
  • EGFR epidermal growth factor receptor
  • L858R exon 21
  • the afatinib dimaleate polymorphs and amorphous forms and formulations disclosed herein may be formulated as a solid dosage form, such as a tablet, containing about 20 mg to about 40 mg per capsule for administration to patients.
  • Afatinib dimaleate (10 g) was dissolved in methanol (300 mL) at 60-65 °C. The clear solution was filtered through Hyflo to remove any undissolved particulate, cooled to 25-30 °C and subjected to spray-drying in a laboratory spray dryer (Model Buchi-290) with a feed rate of the solution 5-10 mL/min and an inlet temperature at 65 °C to yield amorphous form of afatinib dimaleate (6 g).
  • Afatinib (25 g) base and maleic acid (12.5 g) were dissolved in methanol (1125 mL) at 60-65 °C.
  • the clear solution was filtered through Hyflo to remove any undissolved particulate, cooled to 25-30 °C and subjected to spray drying in a laboratory spray dryer (Model Buchi-290) with a feed rate of the solution 5-10mL/min and an inlet temperature at 65 °C to yield amorphous form of afatinib dimaleate (30 g).
  • Afatinib (12 g) was dissolved in ⁇ , ⁇ -dimethyl formamide (2 mL) at 65-70 °C.
  • maleic acid solution 0.5 g dissolved in 1 mL of ⁇ , ⁇ -dimethyl formamide at 65-70 °C
  • Methyl tert- butyl ether (20 mL) was added to the clear solution and stirred for 16 hours.
  • the solid obtained was filtered and washed with methyl tert- butyl ether (2 mL) and dried at 40 °C under vacuum for 5-6 hours.
  • the resulting product was identified as form-Mi of afatinib dimaleate (1.1 g).
  • Afatinib (5 g) was dissolved in ⁇ , ⁇ -dimethyl formamide (10 mL) at 65-70 °C.
  • maleic acid solution 2.5 g dissolved in 5 mL of ⁇ , ⁇ -dimethyl formamide at 65-70 °C
  • Methyl tert-butyl ether 100 mL was then added to the clear solution and stirred for 6 hours.
  • the solid obtained was filtered and washed with methyl tert-butyl ether (10 mL) and dried at 40 °C under vacuum for 5-6 hours.
  • the resulting product was identified as form-Mi of afatinib dimaleate (6 g).
  • Afatinib (5 g), maleic acid (2.5 g) and Plasdone S-630 (3.75 g) was dissolved in methanol (250 mL) at 60 °C.
  • the clear solution was filtered through Hyflo to remove any undissolved particulate, cooled to 25-30 °C and subjected to spray drying in a laboratory spray dryer (Model Buchi-290) with feed rate of the solution 5 niL/min and inlet temperature at 70 °C to yield amorphous solid dispersion of afatinib dimaleate (6.5 g).
  • Afatinib (5 g), maleic acid (2.5 g), and Plasdone S-630 (7.5 g) was dissolved in methanol (250 mL) at 60 °C.
  • the clear solution was filtered through Hyflo to remove any undissolved particulate, cooled to 25-30 °C and subjected to spray drying in a laboratory spray dryer (Model Buchi-290) with feed rate of the solution 5 mL/min and inlet temperature at 70 °C to yield amorphous solid dispersion of afatinib dimaleate (7.1 g) .
  • Afatinib (5 g), maleic acid (2.5 g) and Plasdone S-630 (15 g) was dissolved in methanol (250 mL) at 60 °C.
  • the clear solution was filtered through Hyflo to remove any undissolved particulate, cooled to 25-30 °C and subjected to spray drying in a laboratory spray dryer (Model Buchi-290) with feed rate of the solution 5 mL/min and inlet temperature at 70 °C to yield amorphous solid dispersion of afatinib dimaleate (8 g).
  • Example 8 Preparation of crystalline afatinib dimaleate form-Mi Afatinib (6 g) and maleic acid (3 g) were dissolved in ⁇ , ⁇ -dimethyl formamide (18 mL) at 65-70 °C, the clear solution was then cooled to 25-30 °C. Slowly the material started precipitating and a thick mass was obtained after 5-10 minutes agitation at 25-30 °C. To the resulting reaction mass, methyl-tert-butyl ether (120 mL) was added and stirred for 6 hours at 25-30 °C. The free solid obtained was filtered and washed with methyl tert- butyl ether (12 mL) and dried at 40°C under vacuum for 1-2 hours. The resulting product was identified as crystalline afatinib dimaleate form-Mi.
  • Crystalline afatinib dimaleate form-Mi (as prepared in Example 8) was dried under vacuum at 40 °C for 15-24 hours. The resulting product was identified as crystalline afatinib dimaleate form-M2.
  • Crystalline afatinib dimaleate form-Mi (as prepared in Example 8) was dried under vacuum at 50 °C for 15 hours. The resulting product was identified as crystalline afatinib dimaleate form-M2.
  • Afatinib (1 g) and maleic acid (0.5 g) were dissolved in 1 -methyl 2-pyrrolidinone (3 mL) at 25-30 °C.
  • Acetone (20 mL) was added to the clear solution and stirred at 25-30 °C. Slowly the material started to precipitate out after 15-20 minutes.
  • the resulting suspension was further maintained under stirring at 25-30 °C for 18 hours.
  • the obtained solid was filtered, washed with acetone (2 mL), and dried at 50 °C under vacuum for 3 hours.
  • the resulting product was identified as crystalline afatinib dimaleate form-M3.
  • Afatinib (5 g) was dissolved in methyl ethyl ketone (75 mL) at 25-30 °C.
  • Maleic acid solution (2.5 g of maleic acid dissolved in 25 mL of methyl ethyl ketone) was added to the clear solution at 25-30 °C and stirred. Initially a gummy residue was obtained which, upon ageing at 25-30 °C for 18 hours, resulted in a free solid.
  • the solid obtained was filtered, washed with methyl ethyl ketone (10 mL), and dried at 40 °C under vacuum for 4 hours.
  • the resulting product was identified as crystalline afatinib dimaleate form-M4.
  • Example 13 Preparation of crystalline afatinib dimaleate form-M5
  • Afatinib (1 g) was dissolved in acetone (10 mL) at 25-30 °C.
  • Maleic acid solution 0.5 g of maleic acid was dissolved in (5 mL) of acetone
  • the obtained solid was filtered, washed with acetone (3 mL), and dried at 50 °C under vacuum for 4 hours.
  • the resulting product was identified as crystalline afatinib dimaleate form-M5.
  • Afatinib (1 g) was dissolved in acetone (20 mL) at 25-30 °C and cooled to 0-5 °C.
  • Maleic acid solution (0.5 g dissolved in 5 mL of acetone) was added to the clear solution at 0-5 °C and stirred for 4 hours.
  • the obtained solid was filtered, washed with acetone (3 mL), and dried at 40 °C under vacuum for 3 hours.
  • the resulting product was identified as form- M6 of afatinib dimaleate.
  • Example 15 Preparation of crystalline afatinib dimaleate form-M6
  • Afatinib (3 g) was dissolved in acetone (90 mL) at 25-30 °C. The clear solution was cooled to 0-5 °C and seeded with afatinib dimaleate form-M6 (30 mg). Maleic acid solution (1.5 g dissolved in 15 mL of acetone) was added to the reaction mass slowly at 0-5 °C and stirred for 6 hours. The obtained solid was filtered, washed with acetone (15 mL), and dried at 45 °C under vacuum for 16 hours. The resulting product was identified as form-M6 of afatinib dimaleate.
  • Afatinib (2 g) was dissolved in acetone (60 mL) at 25-30 °C. Seeds of afatinib dimaleate form-M6 (20 mg) was added to the clear solution. Maleic acid solution (1 g dissolved in 10 mL of acetone) was added slowly to the reaction mass at 25-30 °C and stirred for 18 hours. The obtained solid was filtered, washed with acetone (6 mL), and dried at 40 °C under vacuum for 3 hours. The resulting product was identified as form-M6 of afatinib dimaleate.
  • Afatinib (2 g) was dissolved in acetone (80 mL) at 25-30 °C. Seeds of afatinib dimaleate form-M6 (20 mg) was added to the clear solution. Maleic acid solution (1 g dissolved in 10 mL of acetone) was added to the reaction mass at 25-30 °C and stirred for 18 hours. The obtained solid was filtered, washed with acetone (6 niL), and dried at 40 °C under vacuum for 3 hours. The resulting product was identified as form-M6 of afatinib dimaleate.
  • Example 18 Preparation of crystalline afatinib dimaleate form-M6
  • Afatinib (10 g) was dissolved in acetone (300 mL) at 25-30 °C. The clear solution was cooled to 0-5 °C and seeded with afatinib dimaleate form-M6 (50 mg). Maleic acid solution (5 g dissolved in 50 mL of acetone) was added to the reaction mass slowly at 0-5°C and stirred for 6 hours. The obtained solid was filtered, washed with acetone (50 mL), and dried at 45 °C under vacuum for 16 hours. The product obtained is milled and the resulting product was identified as form-M6 of afatinib dimaleate.
  • Afatinib dimaleate crystalline form-M6 was heated to about at 80-90 °C for 1-2 hours using Bruker D8 variable temperature stage. The obtained product was identified as form-M7 of afatinib dimaleate.
  • Afatinib dimaleate crystalline form-M6 was ground in a laboratory ball mill (Model: Retsch M-400) at a frequency (10 Hz) for 10-20 minutes. The obtained solid was identified as form-M7 of afatinib dimaleate.
  • Afatinib (10 g) was dissolved in acetone (250 mL) at 25-30 °C, filtered the solution through Hyflo and washed with acetone (50 mL).
  • Maleic acid solution (5 g dissolved in 50 mL of acetone) was added to the clear solution slowly at 25-30 °C.
  • maleic acid solution seeds of afatinib dimaleate form-M8 100 mg were added and the rest of the maleic acid solution was added.
  • the obtained reaction mass was stirred for 24 hours at 25-30 °C.
  • the solid obtained was filtered, washed with acetone (50 mL), and dried at 50 °C under vacuum for 18 hours.
  • the resulting product was identified as crystalline afatinib dimaleate form-M8.
  • Example 22 Preparation of crystalline afatinib dimaleate form-M8
  • Afatinib (5 g) was dissolved in acetone (150 mL) at 25-30 °C. The clear solution was cooled to 0-5 °C and seeded with afatinib dimaleate form-M8 (50 mg). Maleic acid solution (2.5 g dissolved in 25 mL of acetone) was added to the reaction mass slowly at 0-5 °C and stirred for 6 hours. The obtained solid was filtered, washed with acetone (15 mL), and dried at 40 °C under vacuum for 17 hours. The resulting product was identified as crystalline afatinib dimaleate form-M8.
  • Afatinib dimaleate crystalline form-M6 was heated to about 40-50 °C for 30-60 minutes under nitrogen atmosphere using Bruker D8 variable temperature stage. The obtained product was identified as crystalline afatinib dimaleate form-M8.
  • Afatinib (2 g) was dissolved in tetrahydrofuran (10 mL) at 25-30 °C.
  • Maleic acid solution 1.0 g dissolved in 5 mL of tetrahydrofuran
  • a gummy residue was obtained.
  • Tetrahydrofuran 35 mL was added to this residue and stirred for 3 hours at 25-30 °C.
  • the obtained solid was filtered, washed with tetrahydrofuran (10 mL), and dried at 40 °C under vacuum for 5 hours.
  • the resulting product was identified as crystalline afatinib dimaleate form-M9.
  • Afatinib (6 g) was dissolved in tetrahydrofuran (120 mL) at 25-30 °C and the solution was filtered to remove un-dissolved particles.
  • Maleic acid solution (3.0 g dissolved in 60 mL of tetrahydrofuran) was added to the clear solution at 25-30 °C, stirred for 1 hour, then cooled to 0-5 °C, and stirred for 1 hour more.
  • the obtained solid was filtered, washed with tetrahydrofuran (30 mL), and dried at 50 °C under vacuum for 18 hours.
  • the resulting product was identified as crystalline afatinib dimaleate form-M9.
  • Example 26 Preparation of crystalline afatinib dimaleate form-M9
  • Afatinib (6 g) was dissolved in tetrahydrofuran (120 mL) at 25-30 °C and the solution was filtered to remove un-dissolved particles. The clear solution was seeded with afatinib dimaleate form-M9 (50 mg) then added maleic acid solution (3.0g dissolved in 60 mL of tetrahydrofuran) at 25-30 °C for 60 minutes, and stirred for 20 hours. The solid obtained was filtered, washed with tetrahydrofuran (30 mL) and dried at 50 °C under vacuum for 18 hours. The resulting product was identified as crystalline afatinib dimaleate form-M9.
  • Example 27 Preparation of crystalline afatinib dimaleate form-M9
  • Afatinib (3 g) was dissolved in tetrahydrofuran (60 mL) at 25-30 °C and filtered the solution to remove un-dis solved particles. Taken clear filtrate into round bottom flask under nitrogen atmosphere and seeded with afatinib dimaleate form-M9 (100 mg), then added maleic acid solution (1.5 g dissolved in 30mL of tetrahydrofuran) at 25-30 °C for 40 minutes, and stirred for 20 hours under nitrogen atmosphere. The solid obtained was filtered, washed with tetrahydrofuran (15 mL), and dried at 50 °C under vacuum for 18 hours. The resulting product was identified as crystalline afatinib dimaleate form-M9.
  • Afatinib (1 g) was dissolved in methyl isobutyl ketone (6 mL) at 50 °C, filtered the solution to remove un-dissolved particles. Taken clear filtrate, cool to 25-30 °C added methyl tert-butyl ether (30 mL) at same temperature and stirred for 16 hours. The solid obtained was filtered, washed with methyl tert- butyl ether (2 mL) and dried at 45 °C under vacuum for 6 hours. The resulting product was identified as form-M of afatinib.
  • Afatinib (1 g) was dissolved in methyl isobutyl ketone (6 mL) at 50 °C, filtered the solution to remove un-dissolved particles. Taken clear filtrate, cool to 25-30 °C added n- heptane (30 mL) at same temperature and stirred for 16 hours. The solid obtained was filtered, washed with butyl n-heptane (3 mL), and dried at 45 °C under vacuum for 6 hours. The resulting product was identified as form-M of afatinib.
  • Afatinib (1 g) was dissolved in acetone (5 mL) at 40 °C, filtered the solution to remove un-dissolved particles. Taken filtrate heated to 40 °C to get clear solution, then cool to 25-30 °C added water (15 mL) at same temperature and stirred for 16 hours. The solid obtained was filtered, washed with water (2 mL) and dried at 45 °C under vacuum for 6 hours. The resulting product was identified as form-M of afatinib Example 31: Preparation of crystalline afatinib form-M
  • Afatinib (1 g) was dissolved in acetone (5 niL) at 40 °C, filtered the solution to remove un-dissolved particles. Taken filtrate heated to 40 °C to get clear solution, then cool to 25-30 °C added methyl tert- butyl ether (30 mL) at same temperature and stirred for 16 hours. The solid obtained was filtered, washed with methyl tart- butyl ether (5 mL) and dried at 45 °C under vacuum for 6 hours. The resulting product was identified as form-M of afatinib.
  • Afatinib (1 g) was dissolved in acetone (5 mL) at 40 °C, filtered the solution to remove un-dissolved particles. Taken filtrate heated to 40 °C to get clear solution, then cool to 25-30 °C added n-heptane (30 mL) at same temperature and stirred for 16 hours. The solid obtained was filtered, washed with n-heptane (5 mL) and dried at 45 °C under vacuum for 6 hours. The resulting product was identified as form-M of afatinib.
  • Afatinib (70 g) was dissolved in methanol (250 mL) at 25-30 °C, filtered the solution through high-flow bed to remove un-dissolved particles, and washed bed with methanol (30 mL). The clear filtrate was placed into round bottomed flask, cooled to 25-30 °C, added water (1120 mL), and stirred at same temperature for 6 hours. The solid obtained was filtered, washed with water (100 mL) and dried at 50 °C under vacuum for 16 hours. The resulting product was identified as form-M of afatinib.

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Abstract

La présente invention concerne des formes amorphes et cristallines de 2-buténamide, N-[4-[(3-chloro-4-fluorophényl)amino]7-[[(3S)-tétrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-5 (diméthyl amino)-,(2E)-, (2Z)-2-butènedioate (1:2) (dimaléate d'afatinib). La présente invention concerne également un procédé de préparation des formes cristallines et amorphes de dimaléate d'afatinib. En outre, la présente invention concerne une dispersion solide de dimaléate d'afatinib amorphe et la forme cristalline d'afatinib.
PCT/IB2015/059319 2015-12-03 2015-12-03 Formes polymorphes de dimaléate d'afatinib Ceased WO2017093789A1 (fr)

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