WO2018134189A1

WO2018134189A1 - Co-crystal of an antitumoral compound

Info

Publication number: WO2018134189A1
Application number: PCT/EP2018/050983
Authority: WO
Inventors: Nicolas Tesson; Montserrat Trilla Castano
Original assignee: Cerbios Pharma SA
Current assignee: Cerbios Pharma SA
Priority date: 2017-01-20
Filing date: 2018-01-16
Publication date: 2018-07-26
Anticipated expiration: 2019-07-20
Also published as: IT201700006145A1

Abstract

he present invention relates to a co-crystal of Dasatinib with triethyl citrate, processes for its preparation, pharmaceutical compositions thereof and its use in the treatment of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

Description

CO-CRYSTAL OF AN ANTITUMORAL COMPOUND

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TECHNICAL FIELD

The present invention relates to a new co-crystal of Dasatinib having improved properties than other known crystalline or co-crystalline forms of Dasatinib, processes for its preparation, its use in therapy and pharmaceutical compositions containing it.

BACKGROUND ART

Dasatinib is the name of the chemical compound N-(2-chloro-6-methylphenyl)-2-[[6- [4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5- thiazolecarboxamide and has the followin formula

Such compound is an anti-cancer drug produced by Bristol-Myers Squibb and it is marketed under the trade name Sprycel^®.

Dasatinib is an oral dual BCR/ABL and SRC family tyrosine kinase inhibitor approved for use in the treatment of chronic myelogenous leukemia (CML) after treatment with imatinib and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). It is administered in dosages of 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, and 140 mg.

The marketed pharmaceutical formulation contains Dasatinib monohydrate as active ingredient.

Dasatinib is disclosed in the International patent application WO 00/62778 and in the patent US 6,596,746.

Several crystalline forms of Dasatinib are known in the art.

In WO 2005/077945 Dasatinib monohydrate (H1 -7) and butanol solvate (BU-2) along with their preparation processes are described.

US 2006/0004067 discloses two ethanol solvates forms (E2-1 ; T1 E2-1 ) and two anhydrous forms (N-6 and T1 H1 -7) of Dasatinib. As pointed out in WO2013/186726, Dasatinib in the monohydrate or anhydrous forms has a very low aqueous solubility at 25°C. In particular, Dasatinib monohydrate has a solubility of 0.36 μς/πΊ ΐ. at 25°C and Dasatinib in anhydrous form has a solubility of about 0.9 μς/πΊ ΐ. at 25°C.

In order to solve the solubility issues of Dasatinib in the anhydrous or monohydrate forms, co-crystals of Dasatinib have been envisaged.

As known, pharmaceutical compositions containing a co-crystal of an Active Pharmaceutical Ingredient (API) may have more advantageous properties compared with the ones that contain the only API.

However, it should be considered that the possibility of formation of a co-crystal of an API with a coformer cannot be foreseen, and the formation of the co-crystal is not always possible. Furthermore, it is not possible to foresee the physical, chemical and biologic properties of the co-crystal of an API, till this is actually obtained.

In a surprising and completely unexpected way, the present inventors have found a new co-crystal of Dasatinib with triethyl citrate having improved properties compared to the crystalline and co-crystalline forms of Dasatinib known in the art.

In WO 2013/186726 different co-crystals of Dasatinib have been disclosed, in particular co-crystalline forms of Dasatinib wherein the coformers are methyl 4- hydroxybenzoate, nicotinamide, ethyl gallate, ethyl maltol, vanillin, methyl gallate, menthol or (1 R,2S,5R)-(-)-menthol. Even if in WO2013/186726 the Dasatinib co- crystals with methyl 4-hydroxybenzoate, nicotinamide, ethyl gallate, ethyl maltol, vanillin, methyl gallate or (1 R,2S,5R)-(-)-menthol have been stated to have very high aqueous solubilities at 25°C (see Table 1 at page 12), the present inventors have found that these co-crystals have a much lower solubility in sole water.

It has been found that the aqueous solubilities reported in Table 1 at page 12 for the above mentioned co-crystals are actually consistent when the evaluation of aqueous solubility is made using aqueous solutions containing a buffer.

As the solubility of Dasatinib is strongly dependent on pH, a buffer solution with a pH little lower than 7 would afford solubility values much higher than the values obtained in sole water. In addition, all the processes disclosed in WO 2013/186726 for the co-crystal manufacturing can be carried out in laboratory, but they are not suitable for the preparation of these co-crystals on an industrial scale. As far as the co-crystals of Dasatinib with fructose and lactose as disclosed in WO 2010/081443 are concerned, on the basis of the sole pieces of information given in said International patent application they are very difficult to be reproduced.

Furthermore, they were not characterized from an instrumental point of view.

There is therefore the need of new forms of Dasatinib which overcome the disadvantages and drawbacks of the crystalline and co-crystalline forms of Dasatinib known in the art.

SUMMARY OF THE INVENTION

It has been found a co-crystal of Dasatinib with triethyl citrate, in particular a co- crystal of Dasatinib with triethyl citrate wherein the molar ratio Dasatinib:triethyl citrate is 1 :1. The invention also relates to processes for the preparation of said co- crystal, pharmaceutical compositions containing it and use of this co-crystal in a method of treatment of chronic myelogenous leukemia or Philadelphia chromosome- positive acute lymphoblastic leukemia.

DESCRIPTION OF THE FIGURES AND ANALYTICAL METHODS

The co-crystals of Dasatinib with triethyl citrate have been characterized through X- ray diffraction from crystalline powders (XRPD) (X-ray powder diffraction), by nuclear magnetic resonance spectrometer (¹H-NMR) and by differential scanning calorimetry (DSC).

The X-ray powder diffraction (XRPD) spectra were collected with a PANalytical X'Pert PRO Θ-Θ diffractometer of 240 mm of radius in reflection geometry, equipped with Cu Ka radiation (λ =1 .5406 A) and a PIXcel detector, operated at 45 kV and 40 mA. The samples were mounted on a zero-background silicon holder and allowed to spin during the data collection at 0.25 rev/s. Scanning: 2Θ angle, angular range measurement of 3.0° to 40°, with a step size of 0.013° and a scanning speed of 0.328 s (10.20 s/step). For safety reasons the samples were covered with a plastic sheet before making the XRPD analysis. Such plastic sheet exhibits an amorphous profile, as it can be appreciated from Figure 2.

It is to be understood that the co-crystals of the present invention are not limited to the ones that provide X-ray diffraction patterns completely identical to the X-ray diffraction patterns depicted in the accompanying figures. In fact, a diffraction angle measurement error of about 5% or less should always be taken into account. The ¹H-NMR spectra were recorded in deuterated dimethyl sulfoxide (DMSO-d6) with a Varian Mercury 400 MHz spectrometer, equipped with a broadband probe ATB 1 H/19F/X of 5 mm. Spectra are acquired dissolving 5-10 mg of sample in 0.7 mL of deuterated dimethyl sulfoxide (DMSO-d6).

The DSC thermograms were acquired with a Mettler-Toledo DSC2. The samples were weighted into a 40 μΙ_ aluminium crucible with a pinhole lid and heated from 25 to 300°C at a rate of 10°C/min under nitrogen (50 mL/min).

Karl Fischer (KF) analyses were recorded with a Metrohm 787 KF Trinito. The samples were analyzed in duplicate using the following reactants: Hydranal- Composite 5 (Riedel de Haen Ref. 34805), Hydranal Methanol Rapid (Riedel de Haen Ref. 37817) and Hydranal Water Standard 1 .0 (Riedel de Haen Ref. 34828 used to calculate the factor).

FIG. 1 : XRPD spectrum of the co-crystal of Dasatinib with triethyl citrate.

FIG. 2: XRPD spectrum of the plastic sheet used in the preparation of the samples to be analysed.

FIG 3: ¹H-NMR spectrum of the co-crystal of Dasatinib with triethyl citrate.

FIG. 4: DSC thermogram of the co-crystal of Dasatinib with triethyl citrate.

FIG. 5: DSC thermogram of Dasatinib anhydrous form N-6.

FIG. 6: DSC thermogram of Dasatinib monohydrate.

DEFINITIONS

For the purpose of the present invention, the term "about", when referred to a value, means the stated value plus or minus 5% while, when referred to a range, means the outmost values plus or minus 5%.

DETAILED DESCRIPTION OF THE INVENTION

The first object of the present invention is a co-crystal of Dasatinib with triethyl citrate, preferably a co-crystal of Dasatinib with triethyl citrate having a molar ratio of

1 :1 between Dasatinib and triethyl citrate.

Said co-crystal has a DSC thermogram as substantially shown in FIG. 4, having an endothermic peak at about 91 - 97°C and another endothermic peak at about 255 - 265°C.

The same co-crystal has a XRPD spectrum as substantially shown in FIG. 1 , wherein the most relevant peaks fall at 4.5, 8.2, 9.1 , 10.4, 10.6, 13.6, 17.7, 19.7, 22.0, 24.7 ± 0.2 ° in 2Θ. In addition to the characteristic peaks of the co-crystal of Dasatinib with triethyl citrate, in said FIG. 1 , also the amorphous pattern of the plastic sheet used in the preparation of the samples to be analysed is shown. However, given FIG. 2, this latter is easily distinguishable.

The co-crystal of Dasatinib and triethyl citrate is a substantially anhydrous product, having a KF of 0.3% w/w.

In a surprising and completely unexpected way, the present inventors have found a co-crystal of Dasatinib with triethyl citrate, as disclosed above, which has improved properties compared to the crystalline and co-crystalline forms of Dasatinib known in the art.

This new co-crystal has in particular an improved solubility, a good thermal stability, it is very stable during storage and does not decompose in accelerated stability tests.

Moreover, the co-crystal of Dasatinib with triethyl citrate has an optimal morphology and structure which positively impacts on the flowability and compressibility properties and therefore on the preparation of oral pharmaceutical formulations.

Therefore, this new co-crystal of Dasatinib with triethyl citrate has improved characteristics making it very advantageous for the use in the pharmaceutical field.

A second object of the present invention is a process for the preparation of a co- crystal of Dasatinib with triethyl citrate, as defined above, comprising:

a) forming a suspension of Dasatinib, triethyl citrate and methanol;

b) stirring the resultant suspension at a temperature ranging from room temperature till 50°C; and

c) recovering the co-crystal of Dasatinib with triethyl citrate.

Dasatinib used as starting material for forming the suspension at step a) can be any form of Dasatinib known in the art, which is scarcely soluble in methanol, for example crystalline form N-6, which is a substantially anhydrous form, known by US 7 491 725.

The amount of Dasatinib in the suspension can be comprised between about 0.05 g/mL and about 0.5 g/mL and it is preferably about 0.5 g/mL.

The molar ratio between Dasatinib and triethyl citrate in the suspension can be comprised for example between about 1 :5 and about 1 :40 and it is preferably about Preferably the suspension at step b) is stirred at room temperature for at least two hours, more preferably for a time range comprised between 2 and 10 hours, even more preferably for three or four hours.

The suspension can be stirred using a mechanical or magnetic stirring, the mechanical stirring is preferred on large scale production to avoid heterogeneity problems, while magnetic stirring is preferred for small scale production.

Besides, in order to promote the formation of the co-crystal, the cocrystallization can be triggered by seeding the suspension at step b) with a co-crystal previously obtained according to the above disclosed process.

The recovery of the co-crystal of Dasatinib with triethyl citrate can be carried out according to known techniques to a man skilled in the art, for example through a Buckner filter, a sintered funnel or by centrifugation.

Preferably, the co-crystal of Dasatinib with triethyl citrate is recovered by filtration with a sintered funnel washing the obtained co-crystal with a mixture of heptane/TBME (methyl ie/f-butyl ether).

Optionally, the resultant co-crystal of Dasatinib and triethyl citrate can be dried, preferably at reduced pressure, according to known methods.

In addition to the formation of a co-crystal of Dasatinib with triethyl citrate making a suspension in methanol, Dasatinib co-crystal with triethyl citrate can be prepared by:

- suspending Dasatinib and triethyl citrate in acetonitrile at room temperature; or

- suspending Dasatinib and triethyl citrate in heptane at 50°C; or

- suspending Dasatinib and triethyl citrate, using triethyl citrate as solvent; or

- crystallization in methanol.

Dasatinib used as starting material in the three suspension preparation methods and crystallization reported above can be for example Dasatinib in crystalline form N-6, known by US 7 491 725.

The suspension of Dasatinib and triethyl citrate in acetonitrile can be carried out using a large excess of triethyl citrate in respect of Dasatinib, in particular a molar ratio Dasatinib:triethyl citrate comprised between about 1 :20 and about 1 :40; preferably of about 1 :40 and the concentration of Dasatinib in acetonitrile is 0.025 - 0.05 g/mL. The suspension of Dasatinib and triethyl citrate in heptane can be carried out using a slight excess of triethyl citrate in respect of Dasatinib, in particular a molar ratio Dasatinib:triethyl citrate comprised between about 1 :2 and about 1 :10; preferably of about 1 :3 and the concentration of Dasatinib in heptane is about 0.1 g/mL.

The suspension of Dasatinib and triethyl citrate, using triethyl citrate as solvent, can be carried out using a large excess of triethyl citrate in respect of Dasatinib, in particular a molar ratio Dasatinib:triethyl citrate of about 1 :80.

The crystallization method in methanol can be carried out using a large excess of triethyl citrate in respect of Dasatinib, in particular a molar ratio Dasatinib:triethyl citrate of about 1 :40.

The co-crystal of Dasatinib with triethyl citrate can also be prepared through wet grinding in a solvent selected from water, dimethyl sulfoxide, methanol, isopropanol, tetrahydrofuran, dimethylformamide, and chloroform using a molar ratio Dasatinib:triethyl citrate of 1 :1.

The co-crystal of Dasatinib with triethyl citrate can also be prepared through dry grinding using a molar ratio Dasatinib:triethyl citrate from 3:1 to 1 :3, preferably from 1 :1 to 1 :3.

Moreover, said co-crystal can also be prepared through slow evaporation from methanol using a molar ratio Dasatinib:triethyl citrate from 3:1 to 1 :3, preferably from 1 :1 to 1 :3.

Dasatinib used in the processes disclosed above (wet-grinding, dry-grinding or slow evaporation) as starting material for the preparation of the co-crystal can be, for example, Dasatinib in crystalline anhydrous form N-6, known by US 7 491 725. The co-crystal of Dasatinib with triethyl citrate has been surprisingly found to be a stable solid from a crystallinity point of view, as proven for example by the results of the tests disclosed here below.

The co-crystal of Dasatinib with triethyl citrate has been stored at 40°C (±2 °C)/75±5% RH, according to the accelerated stability conditions of the ICH guidelines and the results are the following:

Table 1

Control XRPD Visual aspect

Initial As in Figure 1 White solid

1 ^st week As in Figure 1 White solid 1^st month As in Figure 1 White solid

2^nd month As in Figure 1 White solid

3^rd month As in Figure 1 White solid

4^th month As in Figure 1 White solid

Therefore, the co-crystal of Dasatinib with triethyl citrate is very stable and maintains its crystalline form, also after four months.

These results prove that the new co-crystal is stable both to thermal stress and to the presence of moisture, and besides it does not dissociate to form a polymorph of Dasatinib, such as anhydrous Dasatinib Form N-6 or Dasatinib monohydrate.

Moreover, the solubility of the co-crystal of Dasatinib with triethyl citrate in water after two hours of stirring at 25°C was evaluated and it has been found that the co- crystal of Dasatinib with triethyl citrate has a solubility of about 1.6 μg/mL.

As known, the solubility of Dasatinib monohydrate, which is the form present in the marketed formulation, is of 0.36 g/mL (as reported in WO 2013/186726, in Table 1 at page 12).

Therefore, the co-crystal of Dasatinib with triethyl citrate is 4 - 5 times more soluble than Dasatinib in monohydrate form.

Moreover, the co-crystal of Dasatinib with triethyl citrate is much more soluble than Dasatinib in anhydrous form.

It should also be noticed that the DSC thermogram of the co-crystal of Dasatinib with triethyl citrate shows a peak at 91 - 97°C and another endothermic peak at 255 - 265°C, as it can be appreciated from the DSC thermogram in FIG. 4.

The melting point of the co-crystal of Dasatinib with triethyl citrate is much lower than the melting point of Dasatinib in anhydrous form N-6 or Dasatinib in monohydrate form as it can be appreciated by making a comparison of the DSC thermograms at FIG. 4, 5 and 6.

In fact, the DSC thermogram in FIG. 5 shows that Dasatinib in anhydrous form N-6 has a melting point of about 285°C and FIG. 6 shows that Dasatinib monohydrate has two thermal events: the first is the dehydration event with an onset at about 1 14°C leading to Dasatinib in anhydrous form and then, the melting of this anhydrous form with an onset at about 286°C.

Therefore, the co-crystal of Dasatinib with triethyl citrate has a melting point much lower than Dasatinib in anhydrous or monohydrate forms. As known by the man skilled in the art, crystalline forms having a stronger crystal lattice have higher melting point and lower solubility in water.

On the contrary, crystalline forms having a less strong crystal lattice have lower melting points and higher solubility in water.

Surprisingly, it has been found that the co-crystal of Dasatinib with triethyl citrate is soluble in water but also very stable.

On the contrary, the anhydrous crystalline form N-6 is very stable, but scarcely soluble in water, the same for Dasatinib in monohydrate form.

The co-crystal of Dasatinib with triethyl citrate is proven to have improved properties compared to the crystalline and co-crystalline forms of Dasatinib known in the art.

A further object of the present invention is a pharmaceutical composition comprising the co-crystal of Dasatinib with triethyl citrate, as defined above, as active ingredient and at least a pharmaceutically acceptable excipient and/or carrier.

It is also an object of the present invention a pharmaceutical composition comprising the co-crystal of Dasatinib with triethyl citrate further comprising imatinib as further active ingredient.

Such pharmaceutical compositions can be prepared in a pharmaceutical dosage form according to known techniques. The dosages of active ingredient present in such composition can be the ones commercially used in therapy for Dasatinib.

A further object of the invention is a co-crystal of Dasatinib with triethyl citrate, as defined above, for use as a medicament, preferably as oral dual BCR/ABL and SRC family tyrosine kinase inhibitor; more preferably for the treatment of chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

Therefore, a further object of the invention is a method of treatment of a human being, in need of an oral dual BCR/ABL and SRC family tyrosine kinase inhibitor in a method of treatment of chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), comprising administering to said human being a therapeutically effective amount of the co- crystal of Dasatinib with triethyl citrate, as defined above.

Even if the invention has been disclosed in its characterizing features, changes and equivalents known to a man skilled in the art fall within the scope of the present invention.

The following examples illustrate the invention. EXAMPLES

Legenda:

Form N-6: anhydrous crystalline form known by US 7 491 725

IPA: Isopropyl alcohol;

MeOH: Methanol;

RT: Room Temperature;

TBME: Methyl ferf-butyl ether.

EXAMPLE 1 - Preparation of the co-crystal of Dasatinib and triethyl citrate from a suspension in methanol.

In a round-bottomed flask equipped with a magnetic stirrer Dasatinib form N-6 (5.00 g, 10.25 mmol), triethyl citrate (15 mL, 3 volumes, d = 1 .137 g/mL, 61.73 mmol, 6.0 equivalents) and MeOH (10 mL, 2 volumes) were added. The suspension was stirred at room temperature (RT) for 3 hours and the solid was filtered with a sintered funnel (porosity 3) and analysed by XRPD (revealing the formation of the co-crystal). The solid was suspended again in the mother liquors and it was stirred at RT for 20 min. The solid was filtered with a sintered funnel (porosity 3), analysed by XRPD, washed with a mixture heptane/TBME (8:2, 2 x 10 mL, 2 x 2 volumes) and dried under vacuum (approximately 1 mbar, RT) overnight. A co-crystal of Dasatinib with triethyl citrate was obtained as a white solid but an excess of triethyl citrate was still observed by ¹H-NMR (1 :1 .7, Dasatinib:triethyl citrate). The solid (8.59 g) was suspended in a mixture heptane/TBME (8:2, 60 mL, 12 volumes) and it was stirred at RT for 1 hour. The solid was filtered with a sintered funnel (porosity 3), washed with the mixture heptane/TBME (8:2, 2 x 10 mL, 2 x 2 volumes) and dried under vacuum (approximately 1 mbar, RT) overnight affording pure co-crystal of Dasatinib with triethyl citrate (6.76 g, 86% yield) with 1 :1 molar ratio (Dasatinib:triethyl citrate).

¹H-NMR (DMSO-d6 - 400 MHz) δ (ppm): 1 1.44 (s, 1 H), 9.86 (s, 1 H), 8.21 (s, 1 H), 7.40 (dd, J = 1 .9 Hz, J = 7.4 Hz, 1 H), 7.32-7.22 (m, 2 H), 6.04 (s, 1 H), 5.60 (s, 1 H), 4.43 (t, J = 5.5 Hz), 4.1 1 (q, J = 7.0 Hz, CO-0-CH₂), 4.02 (q, J = 7.0 Hz, 2xCO-0- CH₂), 3.58-3.45 (m, 6H), 2.85 (d, J = 15.2 Hz, CH₂-CO-0), 2.70 (d, J = 15.2 Hz, CH2-CO-O), 2.45-2.38 (m, 4H), 2.24 (s, CH₃), 1.19 (t, J = 7.0 Hz, C-CH₃), 1.16 (t, 7.0 Hz, 2xC-CH₃). The co-crystal of Dasatinib with triethyl citrate has a DSC thermogram as reported in FIG. 4, having an endothermic peak at about 91 - 97°C and another endothermic peak at about 255 - 265°C.

The co-crystal of Dasatinib with triethyl citrate has a XRPD, as reported in Figure 1 , wherein the most relevant peaks fall at 4.5, 8.2, 9.1 , 10.4, 10.6, 13.6, 17.7, 19.7, 22.0, 24.7 ± 0.2° in 2Θ.

EXAMPLE 2 - Preparation of the co-crystal of Dasatinib and triethyl citrate by wet grinding in IPA.

To a 2 mL eppendorf containing Dasatinib form N-6 (25 mg, 0.051 mmol), triethyl citrate (12 μΙ_, 0.049 mmol, d = 1.137 g/mL) and three 4 mm stainless steel grinding balls, one drop of IPA was added. The reactor was stirred for 45 minutes at a rate of 30 Hz (3 x 15 minutes). The product was dried under vacuum (approximately 1 mbar, RT) overnight affording the co-crystal of Dasatinib with triethyl citrate.

EXAMPLE 3 - Preparation of the co-crystal of Dasatinib and triethyl citrate by slow evaporation in MeOH.

In a test tube equipped with a magnetic stirrer Dasatinib form N-6 (25 mg, 0.051 mmol), triethyl citrate (12 μΙ_, 0.049 mmol, d = 1.137 g/mL) and MeOH (1 mL, 40 volumes) were added. The mixture was heated at reflux and the resulting solution was transferred to a glass vial. The solvent was allowed to evaporate at room temperature and the solid obtained was dried under vacuum (approximately 1 mbar, RT) overnight and milled in a mortar affording the co-crystal of Dasatinib with triethyl citrate.

EXAMPLE 4 - Preparation of the co-crystal of Dasatinib and triethyl citrate by crystallization in MeOH.

In a test tube equipped with a magnetic stirrer Dasatinib form N-6 (50 mg, 0.102 mmol), triethyl citrate (1 mL, 4.12 mmol, d = 1.137 g/mL) and MeOH (1 mL, 20 volumes) were added. The mixture was heated at reflux and the resulting solution was cooled to room temperature. A white solid precipitated and the mixture was stirred at RT overnight. The solid was filtered with a sintered funnel (porosity 4) and analysed by XRPD (revealing the formation of the co-crystal). The solid was suspended in heptane (0.5 mL) and it was stirred at RT for 1 hour. The solid was filtered with a sintered funnel (porosity 4), washed with heptane (0.1 mL) and dried under vacuum (approximately 1 mbar, RT) overnight affording the co-crystal of Dasatinib with triethyl citrate with a Dasatinib:triethyl citrate molar ratio of 1 :1.

Claims

1 ) A co-crystal of Dasatinib with triethyl citrate.

2) A co-crystal according to claim 1 wherein the molar ratio Dasatinib:triethyl citrate is 1 :1.

3) A co-crystal according to claims 1 or 2 having a DSC thermogram with an endothermic peak at about 91 - 97°C and another endothermic peak at about 255 - 265°C.

4) A co-crystal according to claims 1-3 having a XRPD wherein the peaks fall at 4.5, 8.2, 9.1 , 10.4, 10.6, 13.6, 17.7, 19.7, 22.0, 24.7 ± 0.2° in 2Θ.

5) A process for the preparation of a co-crystal of Dasatinib with triethyl citrate according to claims 1-4 comprising:

a) forming a suspension of Dasatinib, triethyl citrate and methanol;

c) recovering the co-crystal of Dasatinib with triethyl citrate.

6) A process according to claim 5 wherein the amount of Dasatinib in the suspension is comprised between about 0.05 g/ml to about 0.5 g/ml and it is preferably about 0.5 g/ml.

7) A process according to claim 5 wherein the molar ratio between Dasatinib and triethyl citrate in the suspension is comprised between about 1 :5 and about 1 :40 and it is preferably about 1 :6.

8) A process according to claims 5-7 wherein the suspension at step b) is stirred at room temperature for at least two hours, for a range of time comprised between 2 and 10 hours.

9) A process according to claims 5-8 further comprising seeding the suspension at step b) with a co-crystal of Dasatinib with triethyl citrate.

10) A process for the preparation of a co-crystal of Dasatinib with triethyl citrate according to claims 1-4 selected among:

- suspending Dasatinib and triethyl citrate in heptane at 50°C; or

- suspending Dasatinib in triethyl citrate, using triethyl citrate as solvent; or

- crystallization in methanol. 1 1 ) A co-crystal of Dasatinib with triethyl citrate according to claims 1-4 for use as a medicament.

12) A co-crystal of Dasatinib with triethyl citrate according to claim 1 1 for use as an oral dual BCR/ABL and SRC family tyrosine kinase inhibitor.

13) A co-crystal of Dasatinib with triethyl citrate according to claim 12 for use in a method of treatment of chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

14) A pharmaceutical composition comprising a co-crystal of Dasatinib with triethyl citrate according to claims 1-4, as active ingredient, and at least a pharmaceutically acceptable excipient and/or carrier.

15) A pharmaceutical composition according to claim 14 also comprising imatinib as further active ingredient.