DESC:The following specification describes the nature of the invention and the manner in which it is to be performed:
NILOTINIB SALTS AND SOLID STATE FORMS THEREOF
INTRODUCTION
The present invention is directed to Nilotinib Edisylate, Nilotinib isethionate and their solid state forms thereof.

BACKGROUND OF THE INVENTION
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 under the trade name 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 publication number WO2007/015870 describes hydrochloride and sulfate salts of Nilotinib, including crystalline and amorphous forms of Nilotinib free base, Nilotinib hydrochloride and Nilotinib Sulfate. The crystalline forms exist in either solvate, anhydrous or hydrate forms. International publication number WO2007/015871 describes various other salts of nilotinib such as diphosphate, monophosphate, methane sulfonate, ethane sulfonate, benzene sulfonate, p-toluene sulphonate. WO ‘871 also discloses crystalline forms of these salts.
International publication number WO2011163222 discloses nilotinib salts of fumarate, 2-chloromandelate, succinate, adipate, L-tartrate, glutarate, camphorsulfonate, glutamate, palmitate, quinate, citrate, maleate, acetate, L-malate, L-aspartate, formate, hydrobromide, oxalate, Malonate and PTSA.
The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety.
The present invention relates to new salt of Nilotinib that is useful for the manufacture of pharmaceutical dosage forms and possesses one or more properties that provides advantages when used as a pharmaceutical active ingredient.
SUMMARY OF THE INVENTION
In an aspect, the present invention provides Ethanedisulfonic acid salt of Nilotinib.

In an aspect, the present invention provides process for preparing Ethanedisulfonic acid salt of Nilotinib, comprising the steps of:
a) suspending Nilotinib free base in an organic solvent;
b) adding Ethane-1,2-disulfonic acid;
c) stirring the reaction mixture at a temperature of about 0°C to about reflux temperature;
d) isolating the ethane-1,2-disulfonic acid salt of Nilotinib; and
e) drying the product.

In an aspect, the present invention provides Isethionic acid salt of Nilotinib.

In an aspect, the present invention provides a process for preparing Isethionic acid salt of Nilotinib, comprising the steps of:
a) adding Nilotinib free base to Isethionic acid or its salt;
b) stirring the reaction mixture at a temperature of about 0°C to about reflux temperature;
c) isolating the Isethionic acid salt of Nilotinib; and
d) drying the product.
In an aspect, the present invention provides Napthalene-2-sulfonic acid salt of Nilotinib.
e)

In an aspect, the present invention provides process for preparing Napthalene-2-sulfonic acid salt of Nilotinib,

comprising the steps of:
f) suspending Nilotinib free base in an organic solvent;
g) adding Napthalene-2-sulfonic acid;
h) stirring the reaction mixture at a temperature of about 0°C to about reflux temperature;
i) isolating the Napthalene-2-sulfonic acid salt of Nilotinib; and
j) drying the product.
In an aspect, the present invention provides a process for preparing Napthalene-2-sulfonic acid salt of Nilotinib, comprising the steps of:
a) suspending Nilotinib free base in water;
b) adding Napthalene-2-sulfonic acid;
c) stirring the reaction mixture at a temperature of about 0°C to about reflux temperature;
d) isolating the Napthalene-2-sulfonic acid salt of Nilotinib; and
e) drying the product.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows a PXRD pattern of amorphous form of Napthalene-2-sulfonic acid salt of Nilotinib.
Figure 2 shows a PXRD pattern of crystalline form of Napthalene-2-sulfonic acid salt of Nilotinib.
Figure 3 shows a PXRD pattern of Ethanedisulfonic acid salt of Nilotinib.
Figure 4 shows a PXRD pattern of Isethionic acid salt of Nilotinib.
DETAILED DESCRIPTION
In an aspect, the present invention provides Ethanedisulfonic acid salt of Nilotinib, Isethionic acid salt of Nilotinib and Napthalene-2-sulfonic acid salt of Nilotinib.
In an aspect, the present invention provides process for preparing Edisylate salt of Nilotinib, comprising the steps of:
a) suspending Nilotinib free base in an organic solvent;
b) adding ethane-1,2-disulfonic acid;
c) stirring the reaction mixture at a temperature of about 0°C to about reflux temperature;
d) isolating the ethane-1,2-disulfonic acid salt of Nilotinib; and
e) drying the product.
In an aspect, the present invention provides a process for preparing Isethionic acid salt of Nilotinib, comprising the steps of:
a) adding Nilotinib free base to isethionic acid or salt;
b) stirring the reaction mixture at a temperature of about 0°C to about reflux temperature;
c) isolating the Isethionic acid salt of Nilotinib; and
d) drying the product.
In an aspect, the present invention provides process for preparing Napthalene-2-sulfonic acid salt of Nilotinib, comprising the steps of:
a) suspending Nilotinib free base in an organic solvent;
b) adding Napthalene-2-sulfonic acid;
c) stirring the reaction mixture at a temperature of about 0°C to about reflux temperature;
d) isolating the Napthalene-2-sulfonic acid salt of Nilotinib; and
e) drying the product.
In an aspect, the present invention provides a process for preparing Napthalene-2-sulfonic acid salt of Nilotinib, comprising the steps of:
a) suspending Nilotinib free base in water;
b) adding Napthalene-2-sulfonic acid;
c) stirring the reaction mixture at a temperature of about 0°C to about reflux temperature;
d) isolating the Napthalene-2-sulfonic acid salt of Nilotinib; and
drying the product.
The suitable solvents that may be used in the step a) of the above processes may be selected from a group consisting of polar aprotic solvents such as dimethyl sulfoxide, dimethylacetamide, N,N-dimethyl formamide, N-methylpyrollidine, nitromethane, pyridine and the like; nitrile solvents such as acetonitrile, propionitrile and the like; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane and the like; alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol, 2-methyl-2-butanol, 1-pentanol, 2-methyl-1-propanol, 1-butanol, 2-butanol, 3-methyl-1-butanol, 2-ethoxy ethanol, glycerol, propylene glycol, ethylene glycol, 2,2,2-trifloro ethanol and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, dimethyl carbonate and the like; acids such formic acid, acetic acid and the like.
Steps c) in the above processes involve stirring the reaction mixture at a temperature of about 0°C to about reflux temperature.
The reaction mixture of Nilotinib free base and the corresponding acid in the organic solvent is stirred and maintained at a temperature of about 0°C to about reflux temperature of the solvent selected, to facilitate the formation of corresponding salt of Nilotinib.
Step d) involves isolating the corresponding salt of Nilotinib. The Nilotinib salt is isolated in a manner known per se, and depending on the solvent used, which include, but not limited to filtration by gravity or by suction, distillation, centrifugation, or slow evaporation or the like. Optionally, an anti-solvent may be added to the reaction mass to obtain the corresponding salt of Nilotinib. The anti-solvent used for step d) may be selected from a group consisting of ethers such as tetrahydrofuran, methyl tetrahydrofuran, dioxane, diglyme, 1,2-dimethoxyethane, methyl tert-butyl ether and the like; aliphatic or alicyclic hydrocarbons such as hexane, heptane, pentane, cyclohexane, methyl cyclohexane and the like.
Drying may be carried out in a gravity oven, tray dryer, vacuum oven, Büchi® Rotavapor®, air tray dryer, vacuum tray dryer, Roto Cone Vacuum Dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. In an embodiment, the drying may be carried out at atmospheric pressure, under reduced pressures or by applying nitrogen/hot nitrogen. 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.
Certain specific aspects and embodiments of the present invention will be explained in more 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 present application in any manner.
Examples
Preparation of Napthalene-2-sulfonic acid salt of Nilotinib
Example 1:
Nilotinib free base (5 g) and 2, 2, 2-trifluoro ethanol (30 mL) were taken in a clean and dry round bottom flask. Napthalene-2-sulfonic acid (2.8 g) was charged to the above flask. The contents were heated to 50-60 oC and maintained for 4-5 hours. Methyl tert-butyl ether (130 mL) was added to the above reaction mass at 25-35 oC and stirred for 10-15 minutes. The reaction mass was filtered and washed with methyl tert-butyl ether (30 mL). The filtered material was dried at 60-70 oC under reduced pressure to obtain the title compound.
HPLC purity: 99.77 %
Characterized by PXRD given in figure 1.
1H NMR (400 MHz, DMSO-d6): d ppm 10.8 (s, 1H), 9.6 (s, 1H), 9.3 (m, 1H), 9.2 (s, 1H), 8.2 (m, 1H), 8.1(m, 2H), 8.5 (m, 1H), 8.35 (s, 1H), 8.25 (s, 1H), 8.15 (s, 1H), 8.05 (m, 1H), 7.9 (m, 1H), 7.85 (m, 3H), 7.75 (m, 1H), 7.70 (m, 1H), 7.4-7.6 (m, 5H), 2.37 (s, 6H).

Example 2:
Nilotinib free base (3 g) and methanol (30 mL) were taken in a clean and dry round bottom flask. Napthalene-2-sulfonic acid (1.68 g) was charged to the above flask. The contents were heated to 50-60 oC and maintained for 3-4 hours. The reaction mass was filtered and washed with methanol (30 mL). The filtered material was suck dried and then dried at 60-70 oC under reduced pressure to obtain the title compound.
HPLC purity: 99.73 %
Characterized by PXRD given in figure 2.
1H NMR (400 MHz, DMSO-d6): d ppm 10.8 (s, 1H), 9.6 (s, 1H), 9.3 (m, 1H), 9.2 (s, 1H), 8.2 (m, 1H), 8.1(m, 2H), 8.5 (m, 1H), 8.35 (s, 1H), 8.25 (s, 1H), 8.15 (s, 1H), 8.05 (m, 1H), 7.9 (m, 1H), 7.85 (m, 3H), 7.75 (m, 1H), 7.70 (m, 1H), 7.4-7.6 (m, 5H), 2.37 (s, 6H).

Example 3: Preparation of Napthalene-2-sulfonic acid salt of Nilotinib
Nilotinib free base (3 g) and de-mineralized water (30 mL) were taken in a clean and dry round bottom flask. Napthyl-2-sulfonic acid (1.68 g) was charged to the above flask. The contents were heated to 50-60 oC and maintained for 5-6 hours. The reaction mass was filtered and washed with de-mineralized water (30 mL) followed by hexane (30 mL). The filtered material was suck dried and then dried at 60-70 oC under reduced pressure to obtain the title compound.

Example 4: Preparation of Ethanedisulfonic acid salt of Nilotinib
Nilotinib free base (5 g) and 2, 2, 2-trifluoro ethanol (30 mL) were taken in a clean and dry round bottom flask. Ethane-1,2-disulfonic acid (1.8 g) was charged to the above flask. The contents were heated to 50-60 oC and maintained for 4-5 hours. Methyl tert-butyl ether (120 mL) was added to the above reaction mass at 25-35 oC and stirred for 10-15 minutes. The reaction mass was filtered and washed with methyl tert-butyl ether (30 mL). The filtered material was dried at 60-70 oC under reduced pressure to obtain the title compound.
Characterized by PXRD given in figure 3.
1H NMR (400 MHz, DMSO-d6): d ppm 10.85 (s, 1H), 9.6 (s, 1H), 9.32 (s, 1H), 9.25 (s, 1H), 8.78 (m, 1H), 8.7(m, 1H), 8.6 (m, 1H), 8.55 (m, 1H), 8.3 (s, 2H), 8.05 (s, 1H), 7.9 (s, 1H), 7.75 (m, 2H), 7.5 (m, 2H), 2.78 (m, 4H), 2.4 (s, 6H).

Example 5: Preparation of Isethionic acid salt of Nilotinib
Sodium salt of Isethionic acid (2.0 g) and demineralized water (5.0 mL) was taken in an RBF. 1N HCl (1.4 mL) was added to the above flask at 25-35 oC and stirred for 30-40 minutes. Nilotinib free base (7.13 g) taken in 2, 2, 2-Trifloroethanol (30 mL) was added to the above flask. The contents were heated to 50-60 oC and maintained for 5-6 hours. Methyl tert-butyl ether (120 mL) was added to the above reaction mass at 25-35 oC and stirred for 30-45 minutes. The reaction mass was filtered and washed with methyl tert-butyl ether (30 mL). The filtered material was dried at 60-70 oC under reduced pressure to obtain the title compound.
Characterized by PXRD given in figure 4.
1H NMR (400 MHz, DMSO-d6): d ppm 10.85 (s, 1H), 9.65 (s, 1H), 9.3 (m, 1H), 9.2 (s, 1H), 8.75 (m, 1H), 8.62(m, 2H), 8.55 (m, 2H), 8.35 (s, 1H), 8.3 (s, 1H), 7.95 (s, 1H), 7.85 (m, 1H), 7.65 (m, 1H), 7.55 (m, 1H), 7.45 (m, 1H), 2.55 (m, 4H), 2.38 (s, 6H).
,CLAIMS:1. Acid addition salt of Nilotinib, wherein the acid is Ethanedisulfonic acid, Isethionic acid, Napthalene-2-sulfonic acid.
2. A method for producing acid addition salt of Nilotinib, the method comprising:
a) suspending Nilotinib free base in an organic solvent;
b) adding the acid;
c) stirring the reaction mixture at a temperature of about 0°C to about reflux temperature;
d) isolating the acid addition salt of Nilotinib; and
e) optionally drying the product.
3. The method of claim 2, wherein the acid is selected from Ethanedisulfonic acid, Isethionic acid, Napthalene-2-sulfonic acid.