DESC:LYMORPHIC FORMS OF NILOTINIB HYDROCHLORIDE

INTRODUCTION

The present invention provides a crystalline form of Nilotinib hydrochloride designated as Form R7 and process for its preparation thereof.

BACKGROUND

The drug compound having the adopted name “Nilotinib hydrochloride” has a chemical name 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl) phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide monohydrochloride, and is structurally represented by Formula I.

Formula I.
Nilotinib hydrochloride is a kinase inhibitor, approved as Nilotinib hydrochloride monohydrate, sold using the tradename Tasigna® , in the form of capsule for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (CML) in adult patients resistant to or intolerant to prior therapy that included Imatinib.
International application publication No. WO2007/015871 A1 describes salts of 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino]-benzamide, wherein the salt is a hydrochloride salt, hydrochloride monohydrate, monophosphate salt, diphosphate salt, sulfate salt, methanesulfate salt, ethanesulfonate salt, benzene sulfonate salt, p-toluene sulfonate salt, citrate salt, furmarate salt, malonate salt, malate salt, tartrate salt, etc., their polymorphic forms and process for the preparation thereof Further, it also discloses the crystalline forms of Nilotinib hydrochloride designated as Form A and Form B, process for their preparation and process for the preparation of Nilotinib hydrochloride monohydrate.
International application publication No. WO2007/015870 A2 describes substantially pure crystalline forms of Nilotinib hydrochloride designated as Form A, Form A’, Form A’’, Form B, Form B’, Form SB, Form SB’, Form C, Form C’, Form SC, Form D, Form SE, mixture of Form B and Form D, and amorphous form of Nilotinib hydrochloride. Further, it also discloses substantially pure crystalline forms A and B of Nilotinib free base and substantially pure crystalline forms A and B of Nilotinib sulfate salt.
International application publication No. WO2010/054056 A2 describes polymorphic forms of Nilotinib hydrochloride designated as forms T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12, T13, T14, T15 T16, T17, T18, and T19. Further, it also describes solid dispersion of Nilotinib hydrochloride in combination with a pharmaceutically suitable excipient.
International application publication No. WO2011/163222 describes polymorphic forms of Nilotinib hydrochloride designated as forms T20, T27, T28 and T29.
International application publication No. WO2011/086541 A1 describes a crystalline form of Nilotinib hydrochloride monohydrate having an X-ray diffraction pattern comprising peaks at 5.70, 7.56, 9.82, 15.01, 17.31 and 27.68 ± 0.2 degrees 2- theta and process for its preparation.
International application publication No. WO2012/055351 A1 describes a crystalline form of Nilotinib hydrochloride monohydrate having an X-ray diffraction pattern comprising peaks at 4.987, 8.430, 11.309, 14.403, 17.219, 19.225 and 25.544 degrees 2-theta and process for its preparation
International application publication No. WO2012/070062 A2 describes Nilotinib hydrochloride crystalline form H1, characterized by peaks in the powder X-ray diffraction spectrum having 2-theta angle positions at about 8.6, 11.4, 13.2, 14.3, 15.5, 17.3, 19.2 and 25.3 ± 0.2 degrees and process for its preparation.
US application publication No. 2013/0210847 A1 describes Nilotinib hydrochloride dihydrate, characterized by peaks in the powder X-ray diffraction pattern at 4.3, 8.7, 9.5, 11.3, 13.2, 14.4, 17.3, 18.6, 19.3, 20.8, 22.2 and 25.3 degrees 2- theta (± 0.1 degrees 2-theta).
International application publication No. WO2014/174456 describes Nilotinib hydrochloride crystalline forms designated as Form R5, Form R5a, Form R5b and Form R6 and their processes for preparation.
International application publication No. WO2020/095187 describes Nilotinib hydrochloride crystalline Form L and its preparation.
IP.com Journal (2010), 10(3B), 11 describes the crystalline forms T24, T25, and T26 of Nilotinib hydrochloride and process for their preparation.
IP com Journal (2010), 10(12A), 18 describes the crystalline forms of Nilotinib hydrochloride designated as Forms T19 and T20 and process for their preparation.
IP.com Journal (2009), 9(12B), 14 describes the Nilotinib hydrochloride crystalline forms T2-T6, T9 and T11-T13 and process for their preparation.
IP.com Journal (2010), 10(5A), 25 describes the Nilotinib hydrochloride crystalline form T5 and process for its preparation.
IP.com Journal (2010), 10(7B), 3 describes a method for the preparation of the 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3- pyridinyl)-2-pyrimidinyl]amino]benzamide salts in amorphous form.
The discovery of new polymorphic forms and/or solvates of a drug or a pharmaceutically useful compound provide opportunity to improve the characteristics of a pharmaceutically acceptable dosage form of the drug with a targeted release profile or other desired characteristics.
Despite the aforementioned disclosures mentioning various polymorphic forms, there is a need for new polymorphic forms of Nilotinib hydrochloride and processes for their preparation.
SUMMARY OF THE INVENTION
In the first aspect, the present invention provides a crystalline Nilotinib hydrochloride Form R7 characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 5.2, 7.1, 10.2, 16.9, 20.5 and 21.4 degrees 2theta. In the second aspect, the present invention provides a process for preparation of
crystalline Nilotinib hydrochloride Form R7, comprising the steps of:
a) providing a solution of Nilotinib free base in acetic acid;
b) adding hydrochloric acid taken in an organic solvent to the solution obtained in step a);
c) optionally, seeding Nilotinib hydrochloride Form R6;
d) isolating the crystalline Nilotinib Form R7.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrative a characteristic X-ray powder diffraction pattern of Nilotinib hydrochloride Form R7.
DETAILED DESCRIPTION
In the first aspect, the present invention provides a crystalline Nilotinib hydrochloride Form R7 characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 5.2, 7.1, 10.2, 16.9, 20.5 and 21.4 degrees 2-theta. In another aspect, the present invention provides crystalline Nilotinib hydrochloride Form R7, characterized by a PXRD substantially as shown in Figure 1.
In the second aspect, the present invention provides a process for preparation of crystalline Nilotinib hydrochloride Form R7, comprising the steps of:
a) providing a solution of Nilotinib free base in acetic acid;
b) adding hydrochloric acid taken in an organic solvent to the solution obtained in step a);
c) optionally, seeding Nilotinib hydrochloride Form R6;
d) isolating the crystalline Nilotinib Form R7.

The process comprises mixing Nilotinib free base in acetic acid at a suitable temperature until Nilotinib free base is dissolved completely; optionally, making the solution particle free; adding hydrochloric acid to the solution by dissolving in an suitable organic solvent; optionally adding an organic solvent to the above mixture to assist precipitation; optionally adding the seed crystals of Nilotinib hydrochloride Form R6.
Suitable organic solvent used in step b) may be selected from esters of alkanoic acid such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate or the like.
The isolation of step d) can be effected, if desired, by any suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping, or by shaking the container conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.
The temperature at which the above steps may be carried out in between about 8 °C and about 100 °C, preferably at about 10°C and about 80°C, most preferably at about 20°C and about 50°C.
Drying can be carried out at reduced pressures. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer, atmospheric drying and the like. The drying may be carried out for any time periods required for obtaining a desired quality, such as from about 15 minutes to several hours, or longer. Drying may be carried out at atmospheric pressure, under reduced pressures or by applying nitrogen/hot nitrogen.
Starting material may be either in a crystalline or amorphous state or an alternate crystalline form of Nilotinib hydrochloride known in the art.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
EXAMPLES
Example-1: Preparation of Nilotinib hydrochloride Form R7.
Acetic acid (960 mL) was charged into a clean and dry reactor at 25-35°C. Nilotinib free base (120 g) was added slowly into the reactor at 25-35°C under stirring. The reaction mass was stirred at 25-35 °C for 2-3 hrs. The reaction mass was passed through hyflow at 25-35 °C and washed with acetic acid (240 mL). The filtrate was charged into the reactor and ethyl acetate-HCl (91.37 g) was added slowly at 25-35 °C for 45-75 minutes. The reaction mass was maintained for 15-20 minutes at 25-35 °C and seed material (1.2 g, Form R6) was added and maintained at 27°C for 2-3 hours. Ethyl acetate (300 mL) was slowly added at 25-35°C to the reaction mass was maintained at 25-35 °C for 4 hours. The obtained solid was filtered and kept for vacuum tray drying in vacuum at 27°C to obtain the title compound.
Yield: 153.8 g
Example-2: Preparation of Nilotinib hydrochloride Form R7.
Acetic acid (80 mL) was charged into a clean and dry reactor at 25-35°C. Nilotinib free base (10 g) was added slowly into the reactor at 25-35°C under stirring. The reaction mass was stirred at 25-35 °C for 2-3 hrs. The reaction mass was passed through hyflow at 25-35 °C and washed with acetic acid (20 mL). The filtrate was charged into the reactor and ethyl acetate-HCl (18.9 g) was added slowly at 25-35 °C for 45-75 minutes. The reaction mass was maintained for 15-20 minutes at 25-35 °C and seed material (0.1 g, Form R6) was added and maintained at 27°C for 2-3 hours. Ethyl acetate (200 mL) was slowly added at 25-35°C to the reaction mass was maintained at 25-35 °C for 4 hours.
The obtained solid was filtered and kept for vacuum tray drying in vacuum at 27°C to obtain the title compound. The obtained solid is further slurried in acetic acid (20 mL) to obtain the title compound.
Yield: 12 g
,CLAIMS:CLAIMS

1. Crystalline Nilotinib hydrochloride Form R7 characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 5.2, 7.1, 10.2, 16.9, 20.5 and 21.4 degrees 2-theta.

2. Crystalline Nilotinib hydrochloride Form R7 according to claim 1, characterized by a PXRD substantially as shown in Figure 1.

3. Process for preparation of crystalline Nilotinib hydrochloride Form R7, comprising the steps of:
e) providing a solution of Nilotinib free base in acetic acid;
f) adding hydrochloric acid taken in an organic solvent to the solution obtained in step a);
g) optionally, seeding Nilotinib hydrochloride Form R6;
h) isolating the crystalline Nilotinib Form R7.

4. The process according to claim 3, wherein the organic solvent is selected from methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate.

5. The process according to claim 3, wherein the organic solvent is ethyl acetate.