DESC:The following specification particularly 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:
a) providing a solution of dasatinib in a solvent or mixture of solvents; and
b) 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.
Figure 3 illustrates the PXRD pattern of amorphous dasatinib, obtained by the process of Example 3.

DETAILED DESCRIPTION
In an aspect, the present application provides a process for the preparation of amorphous form of dasatinib, comprising:
a) providing a solution of dasatinib in a solvent or mixture of solvents; and
b) isolating amorphous form of dasatinib.
The solution of dasatinib may be obtained by dissolving any crystalline form in solvent or solvent mixtures.
Preferably, a solution of dasatinib in a mixture of solvents is used, which include a first solvent in which dasatinib is highly soluble and a second solvent in which dasatinib is sparingly soluble is used. Suitable solvents in which dasatinib is highly soluble include, polar solvents such as dimethylformamide, dimethylsulfoxide, N, N-dimethylacetamide, and acetic acid. The solvent in which dasatinib is sparingly soluble include, solvents such as water; alcohols such as methanol, propanol, isopropyl alcohol, butanol, pentanol, propylene glycol; ketones such as acetone, methyl isopropyl ketone, methyl isobutyl ketone or the like; esters such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, or the like; nitriles such as acetonitrile; aliphatic or alicyclic hydrocarbons such as hexane, heptane, pentane, cyclohexane, methyl cyclohexane, or the like; halogenated hydrocarbons such as dichloromethane, or the like; aromatic hydrocarbons such as toluene or the like;
The dissolution temperatures may range from about 20 °C to about the reflux temperature of the solvent or mixture of solvents to provide a clear solution of dasatinib without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow.
The ratio of first solvent to second solvent in the mixture of solvents may vary from about 1:1 to 1:10 by volume. Preferably the ratio is about 1:4 to 1:10 by volume.
In a preferred embodiment, the solvent mixture is a mixture of acetic acid and methanol in a ratio of 1:9 by volume.
Isolation of the amorphous form may involve methods such as removal of solvent by distillation under vacuum, spray drying and freeze drying.
The temperature at which the solvent is removed depends on the solvent employed and generally can be from about 20° C to about 200° C.
In a preferred embodiment, amorphous dasatinib may be obtained by using a spray drying technique. The drying gas used may be air or inert gases such as Nitrogen, Argon or the like. The air inlet temperature of the spray drier may vary from about 40 °C to about 100 °C.
After the spraying drying process, the compound may be dried in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, roto cone vacuum dryer or the like to remove the residual solvents if any. The drying may be carried out at temperatures less than about 150°C, less than about 130°C, less than about 110°C, less than about 80°C, less than about 60°C or any other suitable temperatures as long as the compound is not degraded in quality, at atmospheric pressure or under a reduced pressure. The drying time may vary from about 1 hour to about 10 hours, or longer, if required.
EXAMPLES
Example 1: Preparation of amorphous dasatinib
45.9 mL of methanol and 5.1 mL of acetic acid were charged into a round bottom flask at 27 oC. 5.0 g of dasatinib was charged to the round bottom flask and stirred for 15 minutes. The solution was spray dried for 20 minutes at 65 oC. The solid was dried under vacuum at 60-70 oC for 5-6 hours.
Result: Amorphous
Example 2: Preparation of amorphous dasatinib
32.4 mL of demineralized water and 3.6 mL of acetic acid were charged into a round bottom flask at 26 oC. 3.0 g of dasatinib was charged to the round bottom flask and stirred for 15 minutes. The solution was spray dried for 5 minutes at 80 oC. The solid was dried under vacuum at 60-70 oC for 5-6 hours.
Result: Amorphous
Example 3: Preparation of amorphous dasatinib
10 g of dasatinib and 1600 mL of methanol were charged into a round bottom flask at 25-30 oC and stirred. The contents were heated and 400 mL of demineralized water was added at 45-50 oC. The contents were further heated to 60-65 oC and maintained at same temperature for 20-30 minutes. The contents were filtered for particle free solution. The filtered solution was spray dried at 120 oC to obtain the title compound.
Result: Amorphous
,CLAIMS:We Claim:
1. A process for the preparation of amorphous dasatinib comprising:
a) providing a solution of dasatinib in a solvent or mixture of solvents; and
b) isolating amorphous form of dasatinib.
2. The process of claim 1 wherein, the solvent or mixture of solvents are selected from first solvent and second solvents.
3. The process of claim 2 wherein, the first solvent is one in which dasatinib is highly soluble.
4. The process of claim 2 wherein, the second solvent is one in which dasatinib is sparingly soluble.
5. The process of claim 3 wherein, the first solvent is selected from dimethylformamide, dimethylsulfoxide, N, N-dimethylacetamide, and acetic acid.
6. The process of claim 4 wherein, the second solvent is selected from water, methanol, propanol, isopropyl alcohol and acetonitrile.