DESC:The following specification describes the invention and the manner in which it is to be performed:

PROCESS FOR THE PREPARATION OF AMORPHOUS DASATINIB

INTRODUCTION
The present application provides process for the preparation of amorphous form of dasatinib.
BACKGROUND OF THE INVENTION
The drug compound having the adopted name “dasatinib” has a chemical name N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyridiminyl]amino]-5-thiazolecarboxamide, and is structurally represented by Formula I.

Formula I
Dasatinib is sold under the trade name Sprycel®. Dasatinib is an oral dual BCR/ ABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatemant and Philadelphia chromosome-positive acute lymphoblasticjeukemia (Ph+ ALL).
The PCT application WO2005077945 discloses several crystalline forms of Dasatinib which are designated as monohydrate, butanol solvate, ethanol solvate, crystalline neat form (?-6) and crystalline neat form (T1H1-7).
US patent no. 7973045 discloses anhydrous form and various other solvates of dasatinib. US ‘045 also discloses process for the preparation of amorphous dasatinib by evaporating the solvent from the suspension. The solvents used in the process were selected from dimethylformamide, 1, 2-dichlorobenzene, propylene glycol, ethylene glycol and glycerole. The process suffers from major drawbacks such as high boiling point of solvent and the amount of residual solvents in the product. Such a process is not well suited for use in a large scale commercial preparation.
US20140343073A1 discloses process for the preparation of amorphous form of dasatinib by milling.
There remains a need for the process, which is amenable to scale up and devoid of residual solvents, for preparing the formulation of therapeutic benefits.
The inventors of the present invention have surprisingly found a process for the preparation of amorphous dasatinib that eliminates the problems encountered in the process of prior art.
SUMMARY OF THE INVENTION
In an aspect, the present application provides a process for the preparation of amorphous form of dasatinib, comprising the steps of:
a) mixing dasatinib in an organic solvent system;
b) adding either concentrated HCl or an organic solution of HCl to the mixture from step a) or adding the mixture from step a) to either concentrated HC1 or an organic solution of HCl; and
c) adjusting the pH to 7-8;
d) isolating amorphous form of dasatinib.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates the PXRD pattern of amorphous dasatinib, obtained by the process of Example 1.
Figure 2 illustrates the PXRD pattern of amorphous dasatinib, obtained by the process of Example 2.
DETAILED DESCRIPTION
In an aspect, the present application provides a process for the preparation of amorphous form of dasatinib, comprising the steps of:
a) mixing dasatinib in an organic solvent system;
b) adding either concentrated HCl or an organic solution of HCl to the mixture from step a) or adding the mixture from step a) to either concentrated HC1 or an organic solution of HCl; and
c) Adjusting the pH to 7-8;
d) isolating amorphous form of dasatinib.
Organic solvent used in step a) may be selected from but not limited to petroleum ether, diispropyl ether, methyl tert-butyl ether, diethyl ether or the like; N,N-dimethylacetamide, methanol, methanol-water, acetone, ethanol, acetonitrile, isopropyl alcohol, n-butanol, N-methyl-pyrrolidine, tetrahydrofuran, dimethyl sulfoxide or N, N-dimethylformamide or mixtures thereof.
In step b) of the process, preferably either concentrated HC1 or an organic solution of HCl is added to the mixture from step a).
Preferably the organic solution of HCl in step b) is prepared by passing HCl gas through the organic solvent. In preferred embodiments the organic solvent used in preparing the organic solution of HCl is selected from the group comprising a C1-4 alcohol, ethyl acetate and acetonitrile or mixtures thereof. Most preferably, the C1-4 alcohol is one or more of methanol, ethanol, isopropanol and n-butanol or mixtures thereof.
Isolation of the amorphous form may involve methods such as removal of solvent by filtration, distillation under vacuum, spray drying or freeze drying.
The isolated material may optionally be dried. Drying may be suitably carried out using any equipment such as a gravity oven, tray dryer, vacuum oven, Büchi® Rotavapor®, air tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. In an embodiment, the drying may be carried out at atmospheric pressure or under reduced pressures. In an embodiment, the drying may be carried out at a temperature of about 120°C, at a temperature of about 115°C, at a temperature of about 110°C or at a temperature of about 105°C. 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 application 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
Example 1: preparation of amorphous dasatinib
110 mL of diethyl ether and 10.0 g dasatinib were charged into the reactor at 25 oC. 100 mL of methanolic HCl was charged into the reactor and stirred for one hour at 25 oC. The contents were filtered, washed with 20 mL of methanol and dried. The dried material was taken in a reactor and 120 mL of demineralized water was added. 10% sodium bicarbonate solution was added and pH was adjusted to 7.5 – 8. The contents were stirred, filtered and washed with 12 mL of water. The material was suck dried to afford the title compound.
Result: Amorphous
Example 2: preparation of amorphous dasatinib
100 mL of diethyl ether and 10.0 g dasatinib were charged into the reactor at 25 oC. 100 mL of methanolic HCl (1.5 g of Con. HCl) was charged into the reactor and stirred for one hour at 25 oC. The contents were filtered, washed with 20 mL of methanol and dried in air tray dryer to afford the solid. This solid obtained was taken in a reactor and 200 mL of demineralized water was added. 10% sodium bicarbonate solution was added and pH was adjusted to 7.5 – 8. The contents were stirred, filtered and washed with 10 mL of water. The material was dried in air tray dryer at 75 oC to afford the title compound.
Result: Amorphous
Stability data:
Conditions Period Purity XRD
2-8oC 6 months 99.92% Amorphous
25oC±2oC; 60 ± 5% RH 6 months 99.93% Amorphous
40oC±2oC; 75 ± 5% RH 6 months 99.90% Amorphous
,CLAIMS:We Claim:
1. A process for the preparation of amorphous form of dasatinib, comprising the steps of:
a) mixing dasatinib in an organic solvent system;
b) adding concentrated HCl to the mixture from step a);
c) adjusting the pH to 7-8; and
d) isolating amorphous form of dasatinib.
2. The process of claim 1 wherein organic solvent is selected from diispropyl ether, methyl tert-butyl ether, diethyl ether, N,N-dimethylacetamide, methanol, methanol-water, acetone, ethanol, acetonitrile, isopropyl alcohol, n-butanol, N-methyl-pyrrolidine, tetrahydrofuran, dimethyl sulfoxide and N, N-dimethylformamide or mixtures thereof.
3. The process of claim 1 wherein step b) either concentrated HC1 or an organic solution of HCl is added to the mixture from step a).