DESC:FIELD OF INVENTION
The present invention provides amorphous form of dasatinib and process for its preparation.

BACKGROUND OF THE INVENTION
Dasatinib is chemically know as N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, and is structurally represented by Formula I.

Dasatinib is sold under the trade name Sprycel®. Dasatinib is a oral tyrosine kinase inhibitor and developed by BMS Company. It is used to cure adult chronic myelogenous leukemia (CML), and acute lymphatic leukemia (ALL) with positive Philadelphia chromosome, etc.

The U.S. Pat. No. 6,596,746 B1 discloses preparation of dasatinib.

The PCT publication WO 2005/077945 A1 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).

Das, Jagabandhu et. al., (Bristol-Myers Squibb) in Journal of Medicinal Chemistry (2004), 47 (27), 6658-61 discloses conversion of dasatinib to its corresponding hydrochloride salt with methanolic HCl in ether.

The PCT publication WO 2007/035874 A1 discloses several acid salt of dasatinib such as p-acetamidobenzoic acid, acetic acid, benzoic acid, benzenesulfonic acid, citric acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, methanesulfonic acid, phosphoric acid, salicylic acid, sulfuric acid, D-tartaric acid, L-tartaric acid, or p-toluenesulfonic acid. It also discloses that such salts may be amorphous, crystalline, and/or mixtures thereof and may be formed by various reactions including, for example, combining dasatinib and at least one acid, combining dasatinib with a different acid salt, combining an acid salt of dasatinib with a different acid; or combining an acid salt of dasatinib with a different acid salt.

The U.S. Pat. No. 7,973,045 B2 discloses anhydrous Form-B 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 are selected from dimethylformamide, 1, 2-dichlorobenzene, propylene glycol, ethylene glycol and glycerol. The process suffers from major drawbacks such as high boiling point of solvent and the amount of residual solvents in the product and hence not feasible in a large scale commercial preparation.

The U.S. Pat. Publication No. US 2014/0343073A1 discloses process for the preparation of amorphous dasatinib by milling.

The PCT publication WO 2015/049645 A2 discloses process for the preparation of amorphous dasatinib by treating hydrochloride salt of dasatinib with aqueous solution of base, removing the solvent from the solution obtained above, treating dasatinib with aqueous solution of base and isolating amorphous dasatinib from the reaction mixture. It also discloses that the acid salt may be formed by various reactions including, for example, combining dasatinib and at least one acid, combining dasatinib with a different acid salt, combining an acid salt of dasatinib with a different acid; or combining an acid salt of dasatinib with a different acid salt.

The published Indian Pat. Application 466/CHE/2015 discloses process for the preparation of amorphous dasatinib by providing a solution of dasatinib in a first solvent (in which dasatinib is highly soluble) and a second solvent (in which dasatinib is sparingly soluble).

Dasatinib is practically insoluble in water or organic solvents like methanol, ethanol, propanol, isopropanol, butanol and the like even in the condition of heating. Therefore, higher amount of solvents are required which is disadvantageous in industrial production.

It is known that the amorphous forms of a number of pharmaceutical substances exhibit different dissolution characteristics and in some cases bioavailability patterns compared to crystalline forms. For some therapeutic indications the bioavailability is one of the key parameters determining the form of the substance to be used in a pharmaceutical formulation. An amorphous form of Cefuroxime axetil is a good example for exhibiting higher bioavailability than the crystalline form. Therefore, there is a constant need for processes which enable the preparation of dasatinib in an amorphous form without simultaneous formation of crystalline forms, or which will enable the conversion of the crystalline forms into the amorphous form.

Thus the present invention provides an efficient, more economical, less hazardous and eco-friendly process for the preparation of amorphous dasatinib that eliminates the problems encountered in the process of prior art. The amorphous dasatinib provided herein is at least stable under ordinary stability conditions with respect to purity and storage.

Following are the advantages of the process of the present invention:
i) The process is simple and easy to handle.
ii) It does not require special handling care or critical temperature conditions.
iii) Provides industrially feasible process for preparing dasatinib in pure amorphous form to avoid the drawback associated with the prior art.
iv) Process is economical and industrially applicable.

SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of amorphous form of dasatinib, comprising:
a) reacting acid addition salt of dasatinib in water with base to adjust pH between 8.5 - 10.5; and
b) isolating amorphous dasatinib from reaction mixture thereof.

In the context of the present invention the following abbreviations have the indicated meaning, unless explicitly stated otherwise:
XRPD: X-ray powder diffraction pattern/diffractogram
DSC: Differential scanning calorimetry
IR: Infrared spectrum
RH: relative humidity

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: XRPD of amorphous form of dasatinib
Figure 2: DSC thermogram of amorphous form of dasatinib
Figure 3: IR spectrum of amorphous form of dasatinib
Figure 4: XRPD of amorphous form of dasatinib which is stable after exposure to a RH of 75% at 40°C for 2 months

DETAILED DESCRIPTION OF THE INVENTION
The amorphous dasatinib obtained by the process of the present invention is suitable for pharmaceutical use and having greater stability.

As used herein, the term "amorphous" refers to a solid without long-range crystalline order. The amorphous dasatinib obtained by the process of the present invention is essentially free of crystalline forms.

As used herein, the term "essentially free of crystalline forms" means that no crystalline polymorph forms can be detected within the limits of an X-ray Powder Diffractometer.

As used herein, the term “stable” includes either: amorphous dasatinib that after exposure to a relative humidity of 60% at 25°C or 75% at 40°C, for a period of at least two months does not convert to any other polymorphic forms.

In one aspect, the present invention provides a process for the preparation of amorphous form of dasatinib, comprising:
a) reacting acid addition salt of dasatinib in water with base to adjust pH between 8.5 - 10.5; and
b) isolating amorphous dasatinib from reaction mixture thereof.

The acid addition salt of dasatinib may be obtained by methods known in the literature. The addition salts such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, methanesulfonic acid, citric acid, fumaric acid, maleic acid, malic acid, D-tartaric acid, L-tartaric acid, benzoic acid, gentisic acid, benzenesulfonic acid, salicylic acid, p-acetamidobenzoic acid, or p-toluenesulfonic acid can be used. Preferably acid addition salt is hydrochloric acid salt.

Reacting acid addition salt of dasatinib in water with base may include adding, dissolving, slurrying, refluxing, stirring, or a combination thereof. The acid addition salt of dasatinib in water may be treated with base at a temperature of about 20°C to about 40°C, preferably at about 25°C to about 30°C.

Base is selected from ammonium hydroxide, potassium hydroxide, potassium tert-butoxide, potassium tert-pentoxide, sodium hydroxide, sodium tert-butoxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, sodium hydride, lithium hydride, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate. Preferably the base is ammonium hydroxide.

The isolation of amorphous dasatinib may be affected by removing the solvent. Suitable techniques which may be used for the removal of solvent includes one or more of distillation using a rotational distillation device for example Buchi Rotavapor, distillation under vacuum, spray drying, agitated thin film drying (ATFD), freeze drying (lyophilization), filtration, filtration under vacuum, decantation and centrifugation; or any other technique known in the art. Preferably amorphous dasatinib is isolated by filtration or filtration under vacuum and combination thereof.

The reaction of acid addition salt of dasatinib with base, and removing the solvent for isolation of amorphous dasatinib is preferably carried out at atmospheric pressure and room temperature.

Optionally, the solution, prior to any solids formation, can 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, prior to any solids formation, can be filtered to remove any undissolved solids or solid impurities prior to removal of the solvent. Any filtration system and filtration techniques known in the art can be used.

The X-ray Powder Diffraction Pattern of the amorphous form of dasatinib prepared by the process of the present invention is as depicted by Figure 1.

The DSC thermogram of the amorphous form of dasatinib prepared by the process of the present invention is as depicted by Figure 2.

The IR spectrum of the amorphous form of dasatinib prepared by the process of the present invention is as depicted by Figure 3.

The amorphous form of dasatinib prepared by the process of the present invention is stable. This amorphous form of dasatinib does not convert to any other polymorphic form after exposure to a relative humidity of 75% at 40°C for 2 months as depicted by X-ray Powder Diffraction Pattern in Figure 4.

An amorphous dasatinib obtained by the process of the present invention is having a purity of greater than about 95%, or greater than about 98%, or greater than about 99%, or greater than about 99.5%, or greater than about 99.8%, or greater than about 99.9%, as determined using high performance liquid chromatography (HPLC).

In another general aspect, there is provided a pharmaceutical composition comprising therapeutically effective amount of an amorphous dasatinib obtained by the process of the present invention together with one or more pharmaceutically acceptable carriers, excipients or diluents.

The amorphous dasatinib obtained by the process of the present invention may be micronized to achieve the better particle size distribution in order to make suitable Formulation. Micronization may be done using one or a combination of ball milling, jet milling, jet blending, high-pressure homogenation, or any other milling method.

The amorphous dasatinib of the present invention may be formulated as solid oral dosage forms such as powders, granules, pellets, tablets and capsules, pills, suppositories, sachets, troches or lozenges; liquid oral dosage forms such as syrups, suspensions, dispersions, emulsions; and injectables.

Pharmaceutical compositions containing the amorphous dasatinib of the present invention may be prepared by using one or more pharmaceutically acceptable carriers, diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants.

To understand the present invention following preparative and testing examples are set forth, which are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.
EXAMPLES:
Example 1: Preparation of dasatinib hydrochloride
In 3 liter round bottom flask equipped with mechanical stirrer, thermometer and an addition funnel, dasatinib (150 gm,), methanol (1500 ml, 10 times) and conc. HCl (75 ml, 0.5 times) were heated for 20-30 minutes at 55-65 °C to get thick white slurry. The reaction mixture was stirred for 1-1.5 hours, cooled to 22-27 °C, stirred again for 1.5-2 hours, filtered and washed with methanol (300 ml) and dried under vacuum for 24 hours at 50° C to obtain the dasatinib hydrochloride (152 gm).
Yield - 94 %.

Example 2: Preparation of dasatinib hydrochloride
In 3 liter round bottom flask equipped with mechanical stirrer, thermometer and an addition funnel, dasatinib (130 gm,), methanol (1300 ml, 10 times) and conc. HCl (65 ml, 0.5 times) were heated for 20-30 minutes at 55-65 °C to get thick white slurry. The reaction mixture was stirred for 1-1.5 hours, cooled to 22-27 °C, stirred again for 1.5-2 hours, filtered and washed with methanol (260 ml) and dried under vacuum for 24 hours at 50° C to obtain the dasatinib hydrochloride (131 gm).
Yield - 93 %.

Example 3: Preparation of amorphous dasatinib
In 3 liter round bottom flask equipped with mechanical stirrer, thermometer and an addition funnel, dasatinib hydrochloride (130 gm,), water (1300 ml, 10 times) and ammonium hydroxide (130 ml, 1 times, pH=9-10) were stirred for 3 hours at 23-27 °C to get thick white slurry. The solid obtained was filtered, washed with water (520 ml) and dried under vacuum for 24 hours at 40° C to obtain the amorphous dasatinib (117 gm).
Yield - 97 %. HPLC purity: 99.97

Example 4: Preparation of amorphous dasatinib
In 3 liter round bottom flask equipped with mechanical stirrer, thermometer and an addition funnel, dasatinib hydrochloride (150 gm,), water (1500 ml, 10 times) and ammonium hydroxide (150 ml, 1 times, pH=9-10) were stirred for 3 hours at 23-27 °C to get thick white slurry. The solid obtained was filtered, washed with water (600 ml) and dried under vacuum for 24 hours at 40° C to obtain the amorphous dasatinib (135 gm).
Yield - 97 %. HPLC purity: 99.87
,CLAIMS:1. A process for the preparation of a stable amorphous form of dasatinib, comprising:
a) reacting acid addition salt of dasatinib in water with base to adjust pH between 8.5 - 10.5; and
b) isolating amorphous dasatinib from reaction mixture thereof.
2. The process of claim 1, wherein the acid addition salt of dasatinib is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, methanesulfonic acid, citric acid, fumaric acid, maleic acid, D-tartaric acid, L-tartaric acid, benzoic acid.
3. The process of claim 2, wherein acid addition salt is hydrochloric acid salt.
4. The process of claim 1, wherein base is selected from ammonium hydroxide, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate.
5. The process of claim 4, wherein base is ammonium hydroxide.
6. The process of claim 1, wherein isolation of amorphous dasatinib is achieved by methods selected from distillation, spray drying, agitated thin film drying (ATFD), freeze drying (lyophilization), filtration, filtration under vacuum, decantation and centrifugation.
7. A stable amorphous form of dasatinib characterized by at least one of:
X-ray powder diffraction pattern as depicted by Figure 1.
DSC thermogram as depicted by Figure 2.
IR spectrum as depicted by Figure 3.
8. Amorphous dasatinib obtained by the process of claim 1 having HPLC purity greater than 98%.
9. Stable amorphous form of dasatinib.
10. A pharmaceutical composition comprising an amorphous form of dasatinib obtained by the process of claim 1 with one or more pharmaceutically acceptable carriers, excipients or diluents.