DESC:FIELD OF THE INVENTION
The present invention relates to novel stable crystalline form of Nilotinib Sulfate salt and methods of preparing the same

The process disclosed for the preparation of crystalline forms of Nilotinib Sulfate salt is commercially viable and lead to consistently produce as the stable material.

BACKGROUND OF THE INVENTION
Nilotinib is chemically known as 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide.

Nilotinib is an orally bioavailable aminopyrimidine-derivative Bcr-Abl tyrosine kinase inhibitor with antineoplastic activity. Designed to overcome imatinib resistance, nilotinib binds to and stabilizes the inactive conformation of the kinase domain of the Abl protein of the Bcr-Abl fusion protein, resulting in the inhibition of the Bcr-Abl-mediated proliferation of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) cells. This agent also inhibits the receptor tyrosine kinases platelet-derived growth factor receptor (PDGF-R) and c-kit, a receptor tyrosine kinase mutated and constitutively activated in most gastrointestinal stromal tumors (GISTs). With a binding mode that is energetically more favorable than that of imatinib, nilotinib has been shown to have an approximately 20-fold increased potency in kinase and proliferation assays compared to imatinib.

Nilotinib monohydrate monohydrochloride was approved by USFDA on Oct 29, 2007 and is marketed under the brand name TASIGNA which is indicated 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.

Nilotinib monohydrate monohydrochloride is marketed in a crystalline form. It appears as a white to slightly yellowish or slightly greenish yellowish powder, formulated into a capsule (150 mg/200 mg). The solubility of nilotinib hydrochloride monohydrate in aqueous solutions at 25°C strongly decreases with increasing pH, and it is practically insoluble in buffer solutions of pH 4.5 and higher pH values. Nilotinib is sparingly soluble in ethanol and methanol. The pKa1 for nilotinib hydrochloride monohydrate is 2.1, and pKa2 is around 5.4. The chemical formula of Nilotinib monohydrate monohydrochloride is C28H22F3N7O.HCl.H2O and the relative molecular mass 565.98 Daltons.

Werner Breitenstein et al in US patent No. 7169791 B2 provided the first disclosures of the compound Nilotinib along with the process for preparation thereof.

Paul W Manley in US8163904B2 disclosed the mono hydrochloride salt of Nilotinib and its process for preparing the same. This patent also disclosed various salts such as Nilotinib Mono and Di phosphate salts, crystalline Form A, Form B and amorphous of Sulfate salt, Mesylate Salt, Ethane sulfonate, Benzene sulfonate, para toluene sulfonate salt. Additionally disclosed Nilotinib crystalline Form A and From A' of dihydrate hydrochloride, Form B and Form C of the mono hydrate monohydrochloride, crystalline Form A'', Form B', Form C' of anhydrous monohydrochloride. This patent further disclosed Nilotinib solvates such as Form SB HCl (Dimethanol solvate), Form SB'HCl (Monomethyl Solvate), Form SE HCl(DMF Solvate) and Amorphous forms of HCl.

Greta Sterimbaum et al in US 8227477 B2 disclosed various crystalline forms of Nilotinib HCl (T17-anhydrous, T18, T19), Form T1 (DMSO Solvate), Forms T2-T17 of nilotinib HCl and its process for preparation were also disclosed respectively.

Maytal Piran et al in US 8937082B2 disclosed various crystalline forms of Nilotinib-L-tartarate, Nilotinib HBr Form-I to till Form XI, Nilotinib Succinate Form-I, Form II, Form III, Niloinib Glutamate, Nilotinib Acetate Form-I to till Form VI, Nilotinib maleate Form-1 to till Form -V respectively.

US 9090598 disclosed crystalline forms of T20, T27,T28 and T29 of Nilotinib HCl, Nilotinib Fumarate (Form-1 & Form II), Nilotinib 2 chloro mandelate Form -1, Nilotinib adipate, Nilotinib glutarate(Form I to Form III), Nilotinib p-toluenesulfonate (Form I & Form II), Nilotinib camphorsulfonate, Nilotinib palmitate, Nilotinib quinate, Nilotinib citrate, Nilotinib L- Aspartate (Form I to Form III), Nilotinib malonate, Nilotinib oxalate etc.

Probal Kanti Datta et al of US 9376419 discloses crystalline forms of Nilotinib HCl in different solvates such as benzyl alcohol solvate(APO-I), Propylene glycol solvate (APO-II), Acetic acid salt 2: 1(APO-III), isopropanol solvate (APO-IV), acetic acid salt 1:1 (APO-V).

WO2016024289 discloses Nilotinib crystalline forms of benzenesulfonic acid, butanedisulfonic acid, 1-5-naphthalenedisulfonic acid, naphthalene- 1- sulfonic acid and 1-hydroxynaphthoic acid and hydrates, anhydrates thereof.

Vishweshwar Reddy et al of US9580408B2 discloses Nilotinib hydrochloride crystalline forms of R5, Form R5a, R5b, R6 and process for their preparation.

The conversion of one polymorphic form into another polymorphic form can be unfavorable in pharmaceutical dosage forms such as tablets, often resulting in different hygroscopicity, dissolution and pharmacokinetic properties. As a result thereof, the bioavailability of the active agent might be undesirably unpredictable. Consequently, active agents having different interchangeable polymorphs may lead to regulatory and commercial disadvantages since they very often do not fulfill the requirements of the corresponding regulation authorities such as the FDA and EMEA.

In view of the above it is pertinent to note that there exists an inherent need to develop stable crystalline form of Nilotinib Sulfate having further improved physical and/or chemical properties besides high purity levels. Hence it was thought worthwhile by the inventors of the present application to explore novel process/crystallization process for the preparation of Nilotinib Sulfate, which may further improve the characteristics of drug Nilotinib Sulfate and in developing the substantially pure stable crystalline form of Nilotinib Sulfate consistently obtainable and amenable to scale-up.

As polymorphism has been given importance in the recent literatures owing to its relevance to the drugs having oral dosage forms due to its apparent relation to dose preparation/suitability in composition steps/bioavailability and other pharmaceutical profiles, stable polymorphic form of a drug has often remained the clear choice in composition due to various reason of handling, mixing and further processing including bioavailability and stability.

Exploring new polymorphic form for developing a stable and pure form of Nilotinib Sulfate which is amenable to scale up for pharmaceutically active useful compounds in the preparation of Nilotinib Sulfate may thus provide an opportunity to improve the drug performance characteristics of products such as purity and solubility. Hence, inventors of the present application report a new polymorphic form, which is a stable and substantially pure form of Nilotinib Sulfate, which may be industrially amenable and usable for preparing the corresponding pharmaceutical compositions.

In view of above and overcome the prior art problems the present inventors had now developed a new polymorphic form of Nilotinib Sulfate. It was apparent to develop a process/or crystallization process resulting in the product, which is complying with the ICH requirements of quality parameters. Nilotinib Sulfate crystalline material was obtained by the process of the present invention is chemically stable and has been found with good dissolution properties.

OBJECTIVE OF THE INVENTION
The main objective of the invention relates to new stable polymorphic form of Nilotinib Sulfate.
Yet another objective of the invention relates to crystalline form of Nilotinib Sulfate, which is a stable and substantially pure form of Nilotinib Sulfate, which may be industrially amenable and usable for preparing the corresponding pharmaceutical compositions.

Yet another objective of the invention relates a process for the preparation of crystalline form of Nilotinib Sulfate, which is free of process related impurities

SUMMARY OF THE INVENTION
The main aspect of the present invention relates to Crystalline Nilotinib Sulfate

In another aspect of the present invention relates to Crystalline Nilotinib Sulfate designated as Form-SNS characterized by
a) X-ray powder diffraction pattern comprising 2?° peaks selected from 11.3, 12.3, 13.5, 18.3, 20.3, 21.3, 24.5 ±0.2 2?°, and
b) DSC isotherm comprising endothermic peak ranging between 130-140°C

In another aspect of the present invention relates Crystalline Nilotinib Sulfate characterized by X-ray powder diffraction pattern comprising 2?° peaks selected from 11.3, 12.3, 13.5, 18.3, 20.3, 21.3, 24.5 ±0.2 2?°, wherein process comprises of:
a) treating Nilotinib free base with Sulphuric acid in presence of a solvent;
b) followed by treating with an anti-solvent to obtain pure crystals.

In another aspect of the present invention relates to Crystalline Nilotinib Sulfate, wherein Nilotinib sulfate obtained according to the process having purity of greater than 99.59% by HPLC.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is an example of X-ray powder diffraction (“XRPD”) pattern of Crystalline Nilotinib Sulfate Form-SNS obtained according the present invention.
Fig. 2 is an example of DSC thermogram of Crystalline Nilotinib Sulfate Form-SNS obtained according the present invention.

DETAILED DESCRIPTION OF THE INVENTION
Although several polymorphs of Nilotinib Sulfate have been identified and well known in the literature, each polymorphic form can be distinguished using several different analytical parameters, alone or in combination, such as, but not limited to, powder X-ray diffraction pattern peaks or combinations of two or more peaks. However, the present inventors now developed a new stable crystalline polymorphic form, which are different from the prior-art polymorphic forms disclosed in the literature.

In one embodiment of the present invention relates to a Crystalline Nilotinib Sulfate characterized by X-ray powder diffraction pattern comprising 2?° peaks selected from 11.3, 12.3, 13.5, 18.3, 20.3, 21.3, 24.5 ±0.2 2?°

Crystalline Nilotinib Sulfate is further characterized by X-ray powder diffraction pattern comprising at 2?° peaks selected from 11.8, 15.2, 16.5, 16.9, 23.5 and 25.8 ±0.2 2?°.
Crystalline Nilotinib Sulfate is further characterized by DSC thermogram comprising endothermic peak ranging between 130-140°C.

Crystalline Nilotinib Sulfate characterized by X-ray powder diffraction pattern comprising 2?° peaks selected from 11.3, 12.3, 13.5, 18.3, 20.3, 21.3, 24.5 ±0.2 2?°, wherein process comprises of:
a) treating Nilotinib free base with Sulphuric acid in presence of a solvent;
b) followed by treating with an anti-solvent to obtain pure crystals.
Solvent used is selected from N,N-dimethyl acetamide (DMAc), N,N Dimethylformamide (DMF), Dimethyl sulfoxide (DMSO), N-Methyl 2-pyrrolidone (NMP), Acetonitrile and Tetrahydrofuran (THF).
Anti-solvent selected from methyl tertiary butyl ether (MTBE), Di ethyl ether, Di isopropyl ether (DIPE), n-Hexane, n-Heptane, Cyclohexane, Toluene and Ethyl acetate.

In one embodiment of the present invention the crystalline Nilotinib Sulfate disclosed is designated as Form-SNS. Crystalline Nilotinib Sulfate Form-SNS obtained by the above process is anhydrous and having a moisture content in between 2.00 to 4.00%. The crystalline Nilotinib Sulfate Form-SNS obtained by this process is stable and free of process related impurities

Further embodiment of the present invention provides crystalline Nilotinib Sulfate Form-SNS obtained by the present invention is free of other polymorphic impurities, wherein said crystalline form is present in a solid form greater than 99.59%by weight

Crystalline Nilotinib Sulfate Form-SNS is found to be a very stable crystal lattice which is adequately stable to handle and store for longer time without any significant or measurable change in its morphology and physicochemical characteristics. Crystalline Nilotinib Sulfate Form-SNS retains its nature even on exposure to uncontrolled environmental conditions. This stable form thus, offers various advantages in terms of storage, shelf life and favorable impurity profile.

The obtained crystalline Nilotinib Sulfate Form-SNS obtained by the present invention appears more soluble compare to the marketed form. The comparative details are as below:

Solubility Data at pH 1.2 buffer
Nilotinib Mono hydrochloride monohydrate – Form B (In house) (mg/ml) Nilotinib Sulfate Form-SNS obtained as per present invention(mg/ml)
2.07 3.7

No accountable solubility was observed at pH 3.0, 4.5, 5.0, 6.8 and 7.4 buffers.

Any form of Crude or Pure Nilotinib Sulfate obtained by any process may be used for preparing Nilotinib Sulfate crystalline Form-SNS. Nilotinib Sulfate Form-SNS of the present invention may have one or more advantageous and desirable properties compared to the known Crystalline Nilotinib Sulfate forms, which are not limited to better stability, high solubility and high purity leading to improved storage and distribution.

The process related impurities, including degradation products and other medium dependent impurities like residual solvent, that appear in the impurity profile of the Crystalline Nilotinib Sulfate can be substantially removed by the process of the present invention resulting in the formation pure Crystalline Nilotinib Sulfate Form-SNS. A substantially pure product i.e. Crystalline Nilotinib Sulfate Form-SNS having purity more than 99.9% (by HPLC) can be obtained in high yield by the process of the present invention.

The Crystalline Nilotinib Sulfate Form-SNS described herein may be characterized by X-ray powder diffraction pattern (XRPD) and Thermal techniques such as differential scanning calorimetric (DSC) Analysis and TGA. The samples of Crystalline Nilotinib Sulfate Form-SNS were analyzed by XRPD on a Bruker AXS D8 Advance Diffractometer using X-ray source - Cu Ka radiation using the wavelength 1.5418 Å. DSC was done on a TA DSC Q2000 instrument measured at a heating rate of 10°C/min. Illustrative example of analytical data for the Crystalline Nilotinib Sulfate Form-SNS obtained in the Examples is set forth in the Figures 1-2.

The Nilotinib used in the present invention may be selected from any of the prior art processes or the process disclosed in this present invnetion

The process comprises the steps of charging 3-[(Aminoiminomethyl) amino]-4-methylbenzoic acid ethyl ester mono nitrate in the reaction flask containing a solvent selected from amide solvents such as formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-Methyl pyrrolidone, N-methyl formamide, N-vinyl acetamide, N-vinyl pyrrolidone, 2- pyrrolidone at a temperature ranging from 25-35 °C. To the above reaction mixture 1-(3-Pyridyl)-3-(dimethyl amino)-2-propen-1-one and sodium hydroxide was added at 25-350C. The contents heated to 120-1300C and maintained for about 20 hours and cooled to 50-550C, to it DM water and sodium hydroxide was added and maintained for 2 hours at 50-550C and are cooled to 10-15 °C. pH was adjusted to ~ 6.5-5.5 using 50% aqueous hydrochloric acid. The obtained reaction mass was filtered and washed a solvent selected from alcohols selected from methanol, ethanol, propanol, isopropanol, butanol was added, stirred for about 20 hours at room temperature. The precipitated solid was filtered and washed with methanol and followed by toluene. The product was dried at 85-90 °C under vacuum for 12 hours to obtain 3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylbenzoic acid.

The process for preparation of 3-(trifluoromethyl)-5-(4-methyl-1H-imidazol-1-yl) benzoic acid comprising the steps of charging 3-Fluoro-5-(trifluoromethyl) benzonitrile in the reaction flask containing a solvent selected from amide solvents such as N,N Dimethyl acetamide, formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-Methyl pyrrolidone, N-methyl formamide, N-vinyl acetamide, N-vinyl pyrrolidone, 2- pyrrolidone at a temperature ranging from 25-35 °C. To the above reaction 4(5)-Methyl imidazole was added and the reaction mass was heated to 140-1500C maintained for about 24 hours and cooled to 0-5°C. DM was added at 0-30°C and maintained the reaction for 2h at 0-5°C. The obtained solid was filtered and wet cake washed with DM water. In another reaction flask carboxylate esters which is selected from methyl acetate, ethyl acetate, propyl acetate, butyl acetate was added and the wet compound obtained above was added at 25-35°C. The reaction mass was heated to 45-500C and maintained for about 30 minutes. The reaction was filtered through hyflo bed and washed with Ethyl acetate and distilled the filtrate at below 50°C under vacuum up to 2.0 volumes and co distilled with water. The reaction mixture obtained was treated with solvent selected from alcohols selected from methanol, ethanol, propanol, isopropanol, butanol, NaOH, DM water at below 85°C. The reaction mixture was maintained till 8 hours at 80-85°C. pH was adjusted to 1.0 using Conc.HCl at room temperature. The reaction mass was cooled to 10-15°C and maintain the reaction mass for 2h. The precipitated solid was filtered and washed with aqueous HCl solution followed by acetone. The product was dried at 90-95 °C under vacuum for 12 hours to obtain 3-(trifluoromethyl)-5-(4-methyl-1H-imidazol-1-yl) benzoic acid

The process for preparation of 3-(trifluoromethyl)-5-(4-methyl-1H-imidazol-1-yl) benzoic acid Hydrochloride comprising the steps of reacting 3-(Trifluoromethyl)-5-(4-methyl-1H-imidazol-1-yl)benzoic acid compound obtained above and dissolved in solvent selected from alcohols methanol, ethanol, propanol, isopropanol, butanol t-butanol using reaction flask. Charge Diphenyl phosphorylazide and amines selected from Dimethylamine, Trimethylamine, N-Nitrosodimethylamine, Diethylamine, Diisopropylamine, Dimethylaminopropylamine, Diethylenetriamine, N,N-Diisopropylethylamine, Triisopropylamine, Tris(2-aminoethyl)amine at 25-35°C. The reaction mass obtained was heated to 80-85°C and maintained for 5h and cool to 25-35°C. DM water and carboxylate esters which is selected from methyl acetate, ethyl acetate, propyl acetate, butyl acetate was added at 25-35°C to the reaction mass and stirred for 10 minutes and the layers were separated at 25-35°C. The organic layer obtained was washed with weak bases selected from sodium bicarbonate, ammonium bicarbonate, potassium bicarbonate solution and stirred for about 10 minutes and the layers were separated respectively. The organic layer obtained was washed with tri carboxylic acid group selected from Citric acid, isocitric acid, aconitic acid, Propane-1,2,3-tricarboxylic acid, Trimesic acid solution and Stirred for about 10 minutes and layers were seperated at 25-35°C. The Organic layer obtained was filtered through hyflo and washed with carboxylate esters which is selected from methyl acetate, ethyl acetate, propyl acetate, butyl acetate which is further distilled the organic layer at below 50°C under vacuum up to 2.0 volumes. The reaction mass treated with ketone group selected from propanone, acetone, butanone, pentanone and Conc.HCl at 25-35°C, heated the reaction mass to 55-60°C and maintain the reaction mass for 10h. The reaction mass again Cooled to 0-5°C and maintained the reaction for 2h. The precipitated solid was filtered and washed with aqueous HCl solution followed by acetone. The product was dried at 90-95 °C under vacuum for 16 hours to obtain (Nilotinib Intermediate-II) 3-(Trifluoromethyl)-5-(4-methyl-1H-imidazol-1-yl)benzenamine compound.

The above obtained (Nilotinib Intermediate-1) 3-(4-(Pyridin-3-yl)pyrimidin-2-ylamino)-4-methylbenzoic acid was dissolved in amide solvents selected from formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-methyl formamide, N-vinyl acetamide, N-vinyl pyrrolidone, 2- pyrrolidone N-Methyl pyrrolidone (NMP) in a reaction flask at 25-35°C. The above reaction mass obtained was treated with (Nilotinib Intermediate –II) 3-(Trifluoromethyl)-5-(4-methyl-1H-imidazol-1-yl)benzenamine and Thionyl halides selected from thionyl chloride, thionyl fluoride, thionyl bromide, thionyl iodide was added at 25-30°C. The reaction mass was heated to 90-95°C, maintained for 5h and cooled to 25-35°C. The reaction mass was treated with carboxylate esters which is selected from methyl acetate, ethyl acetate, propyl acetate, butyl acetate at 25-35°C and Stirred for 30 minutes at 25-35°C. The solid obtained was filtered and wet cake washed with Ethyl acetate. In an another reaction flask charge DM water and wet compound obtained was transferred into it at 25-35°C and Stirred the reaction mass 20-30 minutes . The solid obtained was again filtered through hyflo and washed with DM water. pH was adjusted to 10-11 with 20% Sodium hydroxide solution at 25-35°C and the reaction mass was stirred for about 20h at 25-35°C. The obtained solid was filtered and washed with DM water and followed by Methanol. The reaction mass obtained was heated for about 60-65°C and cooled to room temperature for 1 hour. The precipitated solid was filtered and washed with methanol. The product was dried at 70-75 °C under vacuum for 12 hours to obtain Nilotinib free base.

The above obtained Nilotinib free base was dissolved in polar aprotic solvent which is selected from N, N dimethyl acetamide, dimethyl sulfide, hexamethylphosphoramide, diethyl ether, dimethyl sulfoxide, acetonitrile, dimethylformamide, acetone, N- methyl pyrrolidone N, N-dimethyl acetamide into a reaction flask at 25-35°C. The reaction mass was cooled to 0-5°C. Slowly add Con.H2SO4 and dimethyl acetamide mixture at 0-5°C. The reaction mass temperature was raised to 25-35°C and stirred for about 12h at 25-35°C. The reaction mass obtained was further treated with ethers which is selected from Methyl tert butyl ether, dibutylether, diethylether, diisopropylether, dimethoxyethane, 1-4 dioxane, methoxyethane, ethyl tert-butyl ether, polyethylene glycol, tetrahydrofuran, 2-methyltetrahydrofuran at 25-35°C and stirred for about 4h at 25-35°C. The precipitated solid was filtered and washed with MTBE. The product was dried at 90-100 °C under vacuum for 12 hours to obtain Nilotinib Sulfate.

The obtained pure Nilotinib sulfate was analyzed, if it is not matching with the desired purity; again repeat the process by treating Nilotinib sulfate with a solvent, followed by distillation to obtain substantially pure Nilotinib sulfate having a purity of greater than 99.5% and meeting the ICH guidelines. The process schematic representation is as shown below:

Another embodiment of the present invention relates to substantially pure crystalline Nilotinib sulfate having a purity of greater than 99.5 %, wherein substantially pure Nilotinib sulfate contains the process related impurities collectively below 0.3% area percentage by HPLC and meeting the ICH guidelines.

The process related impurities that appear in the impurity profile of the Nilotinib sulfate may be substantially removed by the process of the present invention resulting in the formation of substantially Nilotinib sulfate, which meets the ICH guidelines.

The merit of the process according to the present invention resides in that product isolated after drying is stable and having a purity of greater than 99.5% purity by HPLC, which was not disclosed in any of the prior-art. The product obtained as per the present invention is highly pure than any of the prior-art products obtained. No prior publication discloses a purity of greater than 99.5%.

Solubility is one of the important parameters to achieve desired concentration of drug in systemic circulation for achieving required pharmacological response. Poorly water soluble drugs often require high doses in order to reach therapeutic plasma concentrations after oral administration. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as generic formulation development. Most of the drugs are either weakly acidic or weakly basic having poor aqueous solubility. The improvement of drug solubility thereby its oral bio-availability remains one of the most challenging aspects of drug development process especially for oral-drug delivery system. The poor solubility and low dissolution rate of poorly water soluble drugs in the aqueous gastrointestinal fluids often cause insufficient bioavailability. The enhancement in the purity of Nilotinib sulfate and crystalline arrangement of novel polymorphic form (Nilotinib sulfate Form-SNS) which is free of process related impurities inherently increases the solubility of Nilotinib sulfate, which plays a major role for enhancement of drug dissolution rate in solid oral dosage forms.

The present invention also relates to a process for the preparation of Nilotinib sulfate, which is substantially pure having a purity of greater 99.5 % and meeting the ICH guidelines, by limiting the content of each impurity less than 0.3%. Further, the Nilotinib sulfate obtained as per the present process is found devoid of any other process related impurities and is adequately stable to handle and store for longer time (at least up to more than 6 months) without any significant or measurable change in its morphology and physicochemical characteristics.

Drying may also be performed by any conventional process not limited to spray drying or distillation to remove the solvent. Drying may be performed under reduced pressure conditions also. Reduced pressure conditions may be suitably utilized by person skilled in the art in order to obtain the dried material. The drying may be performed at a temperature ranging from 50-75°C for a time ranging from 5 to 10 hours depending upon the physical attributes of the end product obtained i.e. Pure Nilotinib sulfate, which is obtained according to the present invention is having purity greater than 99.5%.

In another embodiment of the present invention the substantially pure Nilotinib sulfate obtained by the processes of the present application may be taken as such in crystalline form for manufacture of solid dosage forms like tablets, capsules and/or for manufacture of oral liquids.
In another embodiment, the substantially pure crystalline form of Nilotinib sulfate (Nilotinib sulfate Form-SNS) obtained by the processes of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin.

In one embodiment of the present invention, it also includes premix comprising one or more pharmaceutically acceptable excipients in the range of 1 to 50% w/w with the substantially pure Nilotinib sulfate or its acid addition salt, while retaining the crystalline nature of the premix.

The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

Pharmaceutically acceptable excipients used in the compositions comprising substantially pure Nilotinib sulfate or its acid addition salt obtained as per the present application process- include, but are not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, di-calcium phosphate, tri-calcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

Pharmaceutically acceptable excipients used in the compositions derived from substantially pure Nilotinib sulfate or its acid addition salt of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES
Example-1
Preparation of 3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylbenzoic acid (Nilotinib Intermediate-I)
Charge N-Methyl pyrrolidone (NMP) (300.0 mL) and 3-[(Aminoiminomethyl) amino]-4-methylbenzoic acid ethyl ester mono nitrate (100 g) into the RBF at 25-35°C. Charge 1-(3-Pyridyl)-3-(dimethyl amino)-2-propen-1-one (80.5 g) and NaOH (21.1 g) at 25-35°C. Heat to 120-130°C and maintain for 20h and cool to 50-55°C. Charge DM water (1000.0 mL) and NaOH (28.1 g) at 50-55°C. Maintained for 2h at 50-55°C and cool to 10-15°C. Reaction mass pH adjusting to 6.5 to 5.5 by using 50% aqueous HCl solution. Raise the reaction mass temperature to 25-35°C and charge Methanol (500.0 mL). Maintain the reaction for 20h at 25-30°C. Filter the solid and wet cake wash with Methanol (100.0 mL) and followed by Toluene (100.0 mL) and dry the compound at 85-90°C for 12h under vacuum.
Chromatographic Purity (By HPLC): 98.94%
Yield: 93.0 g; Theoretical weight: 107.74 g

Example-2
Preparation of 3-(trifluoromethyl)-5-(4-methyl-1H-imidazol-1-yl) benzoic acid (Stage-1 of Nilotinib Intermediate-II)
Charge N,N Dimethyl acetamide (DMAc) (500.0 mL) and 3-Fluoro-5-(trifluoromethyl) benzonitrile (100 g) into the RBF at 25-35°C.Charge 4(5)-Methyl imidazole (130.2 g) at 25-35°C.Heat to 140-150°C and maintain for 24h and cool to 0-5°C.Charge DM water (2.5 L) at 0-30°C. Maintain the reaction for 2h at 0-5°C.Filter the solid and wet cake wash with DM water (100.0 mL).Take another RBF and charge Ethyl acetate (1000.0 mL) and wet compound into the RBF at 25-35°C. Heat the reaction mass to 45-50°C and maintain for 30 minutes at 45-50°C. Filter the reaction mass through hyflo bed and wash with Ethyl acetate (100.0 mL). Distil the filtrate at below 50°C under vacuum up to 2.0 volumes. Co-distil with DM water (200.0 mL) up to 2.0 volumes. Charge Methanol (500.0 mL), DM water (1500.0 mL) and NaOH (42.3 g) into the RBF at below 85°C. Heat the reaction mass to 80-85°C and maintain the reaction for 8h at 80-85°C. Cool the reaction mass to 25-30°C.Reaction mass pH adjusting to 1-0 by using Con. HCl at 25-30°C. Reaction mass cool to 10-15°C and maintain the reaction mass for 2h.Filter the solid and wash with wet cake 50% aqueous HCl solution (200.0 mL) followed by Acetone (200.0 mL). Wet compound drying at 90-95°C for 12h under vacuum.
Chromatographic Purity (By HPLC): 98.69%.
Yield: 92.0 g

Example-3
Preparation of 3-(trifluoromethyl)-5-(4-methyl-1H-imidazol-1-yl) benzoic acid Hydrochloride (Nilotinib Intermediate-II)
Charge t-Butanol (375.0 mL) and Stage-I (3-(Trifluoromethyl)-5-(4-methyl-1H-imidazol-1-yl)benzoic acid) (75.0 g) into the RBF, under nitrogen atmosphere at 25-35°C. Charge Tri ethyl amine (41.10 g) and Diphenyl phosphorylazide (84.02 g) at 25-35°C.Heat to 80-85°C and maintain for 5h and cool to 25-35°C. Charge DM water (750.0 mL) and Ethyl acetate (750.0 mL) at 25-35°C. Stir for 10 minutes and settle and separate the layers at 25-35°C. Take organic layer and wash with 5% sodium bi carbonate solution (375.0 mL). Stir for 10 minutes and settle and separate the layers at 25-35°C. Take organic layer and wash with DM water (375.0 mL). Stir for 10 minutes and settle and separate the layers at 25-35°C. Take organic layer and wash with 2.5% Citric acid solution (375.0 mL). Stir for 10 minutes and settle and separate the layers at 25-35°C. Take organic layer and wash with 2.5% Citric acid solution (375.0 mL). Stir for 10 minutes and settle and separate the layers at 25-35°C. Take organic layer and wash with 2.5% Citric acid solution (375.0 mL). Stir for 10 minutes and settle and separate the layers at 25-35°C. Organic layer filter the through hyflo and wash with Ethyl acetate (75.0 mL).Settle the filtrate and separate the layers. Distil the organic layer at below 50°C under vacuum up to 2.0 volumes. Charge Acetone (1125.0 mL) and Conc.HCl (150.0 mL) at 25-35°C. Heat the reaction mass to 55-60°C and maintain the reaction for 10h. Cool the reaction mass to 0-5°C and maintain the reaction for 2h.Filter the solid and wet cake wash with Acetone (75.0 mL) and dry the compound at 90-95°C for 16h under vacuum.
Chromatographic Purity (By HPLC): 99.50%
Yield: 46.25 g
Example-4
Preparation of Nilotinib Free base
Charge N-Methyl pyrrolidone (NMP) (300.0 mL) and Stage-I (30.0 g) into the RBF at 25-35°C. Charge SM2Stagte-II (32.59 g) and Thionyl chloride (30.0 mL) at 25-30°C.Heat to 90-95°C and maintain for 5h and cool to 25-35°C. Charge Ethyl acetate (600.0 mL) at 25-35°C. Stir for 30 minutes at 25-35°C and filter the solid and wet cake wash with Ethyl acetate (60.0 mL). Take another RBF and charge DM water (300.0 mL) and wet compound into the RBF at 25-35°C. Stir the reaction mass 20-30 minutes and filter through hyflo and wash with DM water (30.0 mL). Take filtrate and reaction mass pH adjusting to 10-11 with 20% Sodium hydroxide solution at 25-35°C. Stir the reaction mass for 20h at 25-35°C. Filter the solid and wash with DM water (30.0 mL) and followed by Methanol. Take another RBF and charge Methanol (450.0 mL) at 25-35°C.Heat the reaction mass to 60-65°C and maintained for 1h. Cool the reaction mass to 25-35°C and stir for 1h at 25-35°C. Filter the solid and wet cake wash with Methanol (60.0 mL) and dry the compound at 70-75°C for 12h under vacuum.
Chromatographic Purity (By HPLC): 99.41%
Yield: 34.2 g

Example-5
Preparation of Nilotinib Sulfate salt
Charge DMAc (100.0 mL) and Stage-II (25.0 g) into the RBF at 25-35°C. Cool the reaction mass to 0-5°C. Slowly add Con.H2SO4 (5.09 g) and DMAc (25.0 mL) mixture into the RBF at 0-5°C. Raise the reaction mass temperature to 25-35°C and stir for 12h at 25-35°C. Charge MTBE (375.0 mL) into the RBF at 25-35°C and stir for 4h at 25-35°C. Filter the solid and wash wet cake with MTBE (25.0 mL).Dry the compound at 90-100°C for 12h under vacuum.
Chromatographic Purity (By HPLC): 99.59%.
Yield:28.15 g

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are for illustrative purpose only of the core of the invention and non-limiting in their scope. Furthermore, as many changes may be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.
,CLAIMS:We Claim:

1) Crystalline Nilotinib Sulfate designated as Form-SNS characterized by
a) X-ray powder diffraction pattern comprising 2?° peaks selected from 11.3, 12.3, 13.5, 18.3, 20.3, 21.3, 24.5 ±0.2 2?°, and
b) DSC isotherm comprising endothermic peak ranging between 130-140°C
2) Crystalline Nilotinib Sulfate according to claim 1, which is further characterized by X-ray powder diffraction pattern comprising 2?° peaks selected from 11.8, 15.2, 16.5, 16.9, 23.5 and 25.8 ±0.2 2?°.
3) Crystalline Nilotinib Sulfate according to claim 1, further characterized by DSC isotherm comprising endothermic peak ranging between 130-140°C
4) Crystalline Nilotinib Sulfate characterized by X-ray powder diffraction pattern comprising 2?° peaks selected from 11.3, 12.3, 13.5, 18.3, 20.3, 21.3, 24.5 ±0.2 2?°, wherein process comprises of:
a) treating Nilotinib free base with Sulphuric acid in presence of a solvent;
b) followed by treating with an anti-solvent to obtain pure crystals.
5) Crystalline Nilotinib Sulfate according to claim-4, wherein solvent selected from N,N-dimethyl acetamide (DMAc) , N,N Dimethylformamide (DMF), Dimethyl sulfoxide (DMSO), N-Methyl 2-pyrrolidone (NMP) Acetonitrile and Tetrahydrofuran (THF).
6) Crystalline Nilotinib Sulfate according to claim-4, wherein anti solvent selected from methyl tertiary butyl ether (MTBE), Di ethyl ether, Di isopropyl ether (DIPE), n-Hexane, n-Heptane, Cyclohexane, Toluene and Ethyl acetate.
7) Crystalline Nilotinib Sulfate according to claim-4, wherein Nilotinib sulfate obtained according to the process claimed in claim-5 is having purity of greater than 99.59% by HPLC.
8) Crystalline Nilotinib sulfate Form-SNS according to claim 1, utilized in the preparation of pharmaceutical composition with at least one or more pharmaceutically acceptable excipients