WO2018134190A1

WO2018134190A1 - Co-crystals of an antitumoral compound

Info

Publication number: WO2018134190A1
Application number: PCT/EP2018/050989
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: IT201700006157A1

Abstract

The present invention relates to co-crystals of Dasatinib with phenolic compounds selected among resorcinol, vanillyl alcohol, 4-ethoxyphenol, carvacrol and p-cresol, processes for their preparation, pharmaceutical compositions containing them and their use in treatment of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL).

Description

CO-CRYSTALS OF AN ANTITUMORAL COMPOUND

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TECHNICAL FIELD

The present invention relates to new co-crystals of Dasatinib with phenolic compounds having improved properties, processes for their preparation, their use in therapy and pharmaceutical compositions containing them.

BACKGROUND ART

Dasatinib, chemically known as N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2- hydroxyethyl)-1 -piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, has the following formula

It is marketed under the trade name Sprycel^® and it is administered in dosages of 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, and 140 mg.

Such compound is an oral dual BCR/ABL and SRC family tyrosine kinase inhibitor approved for use in treatment of chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL).

The marketed pharmaceutical formulations contain Dasatinib monohydrate as active ingredient.

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

As known, Dasatinib free base in monohydrate or in anhydrous form is a compound with a very low solubility, in particular Dasatinib free base monohydrate has been reported to have an aqueous solubility of 0.36 μg/mL and Dasatinib free base in anhydrous form of about 0.9 μg/mL at 25°C (see Table 1 at page 12 of WO 2013/186726). It is known that bioavailability of a drug is influenced by its solubility in water. For this reason a high aqueous solubility positively influences the bioavailability of the drug, whereas a low aqueous solubility negatively impacts on the bioavailability of the drug.

In order to address the problem of low solubility of Dasatinib free base, several co- crystals of Dasatinib with methyl-4-hydroxy-benzoate, nicotinamide, ethyl gallate, ethyl maltol, vanillin, methyl gallate, menthol, (1 R, 2S, 5R)-(-)-menthol have been provided (see WO 2013/186726).

Such co-crystals have been stated to have very high solubilities compared to Dasatinib free base in monohydrate and anhydrous forms, but no experimental data about the stability of these co-crystals have been reported in WO 2013/186726.

Moreover, all the co-crystals of WO 2013/186726 have been prepared through processes that are not suitable for a preparation on an industrial scale.

As far as the co-crystals of Dasatinib with fructose and lactose as disclosed in WO 2010/081443 is concerned, on the basis of the sole pieces of information given in said International 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

The present invention relates to co-crystals of Dasatinib with phenolic compounds selected among resorcinol, vanillyl alcohol, 4-ethoxyphenol, carvacrol and p-cresol. The invention also relates to processes for the preparation of said co-crystals, pharmaceutical compositions containing them and use of these co-crystals as medicaments and 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 phenolic compounds selected among resorcinol, vanillyl alcohol, 4-ethoxyphenol, carvacrol and p-cresol have been characterized through X-ray diffraction from crystalline powders (XRPD) (X-ray powder diffraction), and/or by nuclear magnetic resonance spectrometer (¹H-NMR), and/or by differential scanning calorimetry (DSC) and/or through Karl Fischer (KF). 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 appreciated from Figure 1.

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 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 plastic sheet used in the preparation of the samples to be analysed.

FIG 2: XRPD spectrum of co-crystal of Dasatinib with resorcinol herein defined as Form 1

FIG 3: DSC thermogram of Dasatinib with resorcinol herein defined as Form 1.

FIG. 4: XRPD spectrum of co-crystal of Dasatinib with resorcinol herein defined as Form 2.

FIG 5: ¹H-NMR spectrum of co-crystal of Dasatinib with resorcinol herein defined as Form 2. FIG 6: DSC thermogram of co-crystal of Dasatinib with resorcinol herein defined as Form 2.

FIG 7: XRPD spectrum of co-crystal of Dasatinib with vanillyl alcohol.

FIG 8: XRPD spectrum of co-crystal of Dasatinib with 4-ethoxyphenol.

Fig 9: ¹H-NMR spectrum of co-crystal of Dasatinib with 4-ethoxyphenol.

FIG 10: DSC thermogram of co-crystal of Dasatinib with 4-ethoxyphenol.

FIG 1 1 : XRPD spectrum of co-crystal of Dasatinib with carvacrol.

FIG 12: ¹H-NMR spectrum of co-crystal of Dasatinib with carvacrol.

FIG 13: DSC thermogram of co-crystal of Dasatinib with carvacrol.

FIG 14: XRPD of co-crystal of Dasatinib with p-cresol.

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 a phenolic compound selected among resorcinol, vanillyl alcohol, 4-ethoxyphenol, carvacrol and p-cresol.

Two co-crystals of Dasatinib with resorcinol are object of the present invention:

- A co-crystal of Dasatinib with resorcinol in a molar ratio Dasatinib:resorcinol of about 1 :2, herein defined as Form 1 , preferably characterized by a XRPD as reported in FIG 2 wherein the most relevant peaks fall at 5.0, 1 1 .0, 15.2, 16.3, 19.1 , 23.2, 24.1 , 25.1 , 25.8 ± 0.2° in 2Θ and having a DSC thermogram, as substantially reported in FIG 3, with a sole endothermic peak at about 175 - 178°C which represents the fusion of the co-crystal; and

- A co-crystal of Dasatinib with resorcinol in a molar ratio Dasatinib:resorcinol of about 1 :2, herein defined as Form 2, preferably characterized by a XRPD as reported in FIG 4 wherein the most relevant peaks fall at 5.2, 10.4, 15.6, 16.5, 18.1 ± 0.2° in 2Θ and having a DSC thermogram, as substantially reported in FIG. 6 having a sharp endothermic peak at 173 - 176°C which represents the fusion of the co-crystal.

In addition to the characteristic peaks of the co-crystal of Dasatinib with resorcinol, in FIG. 2 (Form 1 ) and in FIG. 4 (Form 2), also the amorphous pattern of the plastic sheet used in the preparation of the samples to be analysed is shown. However, given FIG. 1 , the latter is easily distinguishable.

The co-crystal of Dasatinib with vanillyl alcohol according to the present invention has a molar ratio Dasatinib:vanillyl alcohol comprised between 1 :1 and 1 :2. It is preferably characterized by a XRPD, as reported in FIG 7, wherein the most relevant peaks fall at 5.3, 8.1 , 13.2, 15.5, 17.4, 21.3, 25.3, 26.2, 26.6 ± 0.2° in 2Θ. In addition to the characteristic peaks of the co-crystal of Dasatinib with vanillyl alcohol, in said FIG. 7, also the amorphous pattern of the plastic sheet used in the preparation of the samples to be analysed is shown. However, given FIG. 1 , the latter is easily distinguishable.

The co-crystal of Dasatinib with 4-ethoxyphenol according to the present invention has a molar ratio Dasatinib:4-ethoxyphenol of about 1 :1. It is preferably characterized by a XRPD, as reported in FIG 8, wherein the most relevant peaks fall at 5.7, 9.0, 16.6, 17.3, 18.9, 19.8, 23.4, 25.3, 26.4, 27.2 ± 0.2° in 2Θ and it has preferably a DSC thermogram as substantially reported in FIG. 10 showing multiple endothermic peaks, wherein the endothermic peak representing the fusion of the co- crystal is at 200 - 207°C.

In addition to the characteristic peaks of the co-crystal of Dasatinib with 4- ethoxyphenol, in said FIG. 8, also the amorphous pattern of the plastic sheet used in the preparation of the samples to be analysed is shown. However, given FIG. 1 , the latter is easily distinguishable.

From a Karl Fischer analysis, it has been found that co-crystal of Dasatinib with 4- ethoxyphenol according to the present invention has a water content of about 3.4% w/w.

The co-crystal of Dasatinib with carvacrol according to the present invention has a molar ratio Dasatinib:carvacrol of about 2:1. It is preferably characterized by a XRPD as reported in FIG. 1 1 wherein the most relevant peaks fall at 5.9, 1 1 .8, 15.2, 16.6, 17.7, 18.3, 21.1 , 21 .5, 23.0, 24.0 ± 0.2° in 2Θ and it has preferably a DSC thermogram as substantially reported in FIG. 13 with two endothermic peaks wherein the endothermic peak representing the fusion of the co-crystal is at 215 - 223°C.

In addition to the characteristic peaks of the co-crystal of Dasatinib with carvacrol, in said FIG. 1 1 , also the amorphous pattern of the plastic sheet used in the preparation of the samples to be analysed is shown. However, given FIG. 1 , the latter is easily distinguishable.

The co-crystal of Dasatinib with p-cresol has a molar ratio Dasatinib:p-cresol of about 1 :1. It is preferably characterized by a XRPD as reported in FIG. 14 wherein the most relevant peaks fall at 5.5, 10.8, 15.7, 17.2, 23.7 ± 0.2° in 2Θ.

In addition to the characteristic peaks of the co-crystal of Dasatinib with p-cresol, in said FIG. 14, also the amorphous pattern of the plastic sheet used in the preparation of the samples to be analysed is shown. However, given FIG. 1 , the latter is easily distinguishable.

In a surprising and completely unexpected way, the present inventors have found that co-crystals of Dasatinib with phenolic compounds selected among resorcinol, vanillyl alcohol, 4-ethoxyphenol, carvacrol and p-cresol have improved properties compared to the crystalline and co-crystalline forms known in the art.

Therefore these new co-crystals of Dasatinib have improved characteristics making them very advantageous for the use in the pharmaceutical field.

A second object of the present invention are processes for the preparation of the co- crystals of Dasatinib with phenolic compounds as reported above.

A co-crystal of Dasatinib with resorcinol having a molar ratio Dasatinib:resorcinol 1 :2, herein defined as Form 1 , can be prepared through a process comprising:

1 ) Forming a mechanical mixture with a molar ratio 1 :2 of Dasatinib:resorcinol and heating it from 25 to 165°C at 10°C/min, cooling the formed solid at room temperature; or

2) Slow evaporation from a dioxane solution containing Dasatinib:resorcinol in a molar ratio 1 :2 or 1 :3 at room temperature for a range of time between 3 and 7 days, using an amount of Dasatinib to dioxane of 0.025 g/mL.

In a process for preparing a co-crystal of Dasatinib with resorcinol having a molar ratio Dasatinib:resorcinol 1 :2, herein defined as Form 1 , Dasatinib used as starting material can be, for example, crystalline anhydrous form N-6 known by US 7 491 725.

A co-crystal of Dasatinib with resorcinol having a molar ratio Dasatinib:resorcinol 1 :2, herein defined as Form 2, can be prepared through a process comprising the slow evaporation from a methanol solution containing Dasatinib:resorcinol in a molar ratio 1 :2 or 1 :3 at room temperature for a range of time between 2 and 6 days, using an amount of Dasatinib to methanol of 0.025 g/mL. ln a process for preparing a co-crystal of Dasatinib with resorcinol having a molar ratio Dasatinib:resorcinol 1 :2, herein defined as Form 2, Dasatinib used as starting material can be, for example, crystalline anhydrous form N-6 known by US 7 491 725.

A co-crystal of Dasatinib with vanillyl alcohol can be prepared through a process comprising the slow evaporation from a methanol solution containing Dasatinib:vanillyl alcohol in a molar ratio comprised between 1 :1 and 1 :3 at room temperature for a range of time between 2 and 6 days, using an amount of Dasatinib to methanol of 0.025 g/mL.

In a process for preparing a co-crystal of Dasatinib with vanillyl alcohol, Dasatinib used as starting material can be for example crystalline anhydrous form N-6 known by US 7 491 725.

A co-crystal of Dasatinib with 4-ethoxyphenol can be prepared through:

1 ) wet grinding in a solvent selected from water, dimethyl sulfoxide (DMSO) and methanol using a molar ratio Dasatinib:4-ethoxyphenol of 1 :1 ; or

2) suspending Dasatinib and 4-ethoxyphenol in water at 50°C using a molar ratio Dasatinib:4-ethoxyphenol of 1 :2 and an amount of Dasatinib to water of 0.05 g/mL.

In a preferred embodiment, a co-crystal of Dasatinib with 4-ethoxyphenol is prepared through suspension of Dasatinib and 4-ethoxyphenol in water at 50°C. Optionally, the formation of the co-crystal of Dasatinib with 4-ethoxyphenol can be triggered adding to the suspension seeds of the co-crystal of Dasatinib with 4- ethoxyphenol previously obtained according to the processes disclosed above. In a process for preparing a co-crystal of Dasatinib with 4-ethoxyphenol, Dasatinib used as starting material can be, for example, crystalline anhydrous form N-6 known by US 7 491 725.

A co-crystal of Dasatinib with carvacrol can be prepared through:

1 ) wet grinding in a solvent selected from water, dimethyl sulfoxide (DMSO), methanol, isopropanol, tetrahydrofuran and dimethylformamide (DMF) using a molar ratio Dasatinib:carvacrol of 1 :1 ; or

2) suspending Dasatinib and carvacrol in methanol at 50°C using a molar ratio Dasatinib:carvacrol of 1 :8 and an amount of Dasatinib to methanol of 0.4 g/mL. ln a process for preparing a co-crystal of Dasatinib with carvacrol, Dasatinib used as starting material can be, for example, crystalline anhydrous form N-6 known by US 7 491 725.

Preferably, the co-crystal of Dasatinib with carvacrol is obtained through suspension in methanol at 50°C. Optionally, the formation of the co-crystal of Dasatinib with carvacrol can be triggered adding to the slurry seeds of the co-crystal of Dasatinib with carvacrol previously obtained according to the processes disclosed above. A co-crystal of Dasatinib with p-cresol can be prepared through wet grinding in a solvent selected from water and tetrahydrofuran using a molar ratio Dasatinib:p- cresol of 1 :1.

In a process for preparing a co-crystal of Dasatinib with p-cresol, Dasatinib used as starting material can be, for example, crystalline anhydrous form N-6 known by US 7 491 725.

It has been surprisingly found that the co-crystals of Dasatinib with 4-ethoxyphenol and with carvacrol are very stable, also for long time and even under thermal stress conditions. In particular, the co-crystal of Dasatinib with 4-ethoxyphenol and carvacrol have been stored at 40°C (±2°C)/75±5% RH, according to the accelerated stability conditions of the ICH guidelines, in open vials and the results are the following:

Table 1 - Stability of the co-crystal of Dasatinib with 4-ethoxyphenol

Control XRPD Visual aspect

Initial As in Figure 8 White solid

1 ^st week As in Figure 8 White solid

1^st month As in Figure 8 White solid

2^nd month As in Figure 8 White solid

3^rd month As in Figure 8 White solid

4^th month As in Figure 8 White solid

Table 2 - Stability of the co-crystal of Dasatinib with carvacrol

Control XRPD Visual aspect

Initial As in Figure 1 1 White solid

1 ^st week As in Figure 1 1 White solid

1^st month As in Figure 1 1 White solid 2^nd month As in Figure 1 1 White solid

3^rd month As in Figure 1 1 White solid

4^th month As in Figure 1 1 White solid

Moreover the degradation of the co-crystals of Dasatinib with 4-ethoxyphenol and with carvacrol after 4 months at 40°C (±2°C)/75±5% RH has been calculated through HPLC and it is lower than 1 %.

Therefore, the co-crystals of Dasatinib with 4-ethoxyphenol and with carvacrol are very stable and maintain their crystalline lattice in accelerated stability conditions, also after four months.

These results are proof that the new co-crystals are stable both to thermal stress and to the presence of moisture, and besides they do not dissociate to form a polymorph of Dasatinib, such as anhydrous Dasatinib Form N-6 or Dasatinib monohydrate.

A further object of the present invention is a pharmaceutical composition comprising a co-crystal of Dasatinib with a phenolic compound, 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 a co-crystal of Dasatinib with the phenolic compounds, as defined above, also comprising imatinib as further active ingredient.

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

A further object of the invention is a co-crystal of Dasatinib with a phenolic compound, 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 a co-crystal of Dasatinib with a phenolic compound, 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

EXAMPLE 1 - Preparation of the co-crystal of Dasatinib and resorcinol (molar ratio 1 :2) Form 1 by heating.

A mixture of Dasatinib form N-6 (100 mg, 0.205 mmol) and resorcinol (45 mg, 0.409 mmol, 2 eq.) was milled in a mortar. An aliquot was heated at 10 °C/ min from 25 to 145°C (or 165°C) in a 40 μΙ_ aluminium crucible with a pinhole lid (DSC) affording the co-crystal of Dasatinib with resorcinol.

EXAMPLE 2 - Preparation of the co-crystal of Dasatinib and resorcinol (molar ratio 1 :2) Form 2 by slow evaporation in MeOH (methanol).

In a test tube equipped with a magnetic stirrer Dasatinib form N-6 (500 mg, 1.025 mmol), resorcinol (226 mg, 2.052 mmol, 2 eq.) and MeOH (20 ml_, 40 volumes) were added. The mixture was heated at reflux and the resulting solution was transferred to a glass crystallizing dish. The solvent was allowed to evaporate under ambient conditions and the solid obtained was dried under vacuum (approximately 1 mbar, RT) overnight affording the co-crystal of Dasatinib with resorcinol.

1H-NMR (DMSO-d6 - 400 MHz) δ (ppm): 1 1 .45 (s, 1 H), 9.87 (s, 1 H), 9.12 (s, 4.6H), 8.21 (s, 1 H), 7.40 (dd, J = 1 .6 Hz, J = 7.4 Hz, 1 H), 7.32-7.22 (m, 2H), 6.95-6.86 (m, 2.3H), 6.22-6.14 (m, 6.6H)), 6.05 (s, 1 H), 5.60 (s, 1 H), 4.45 (t, J = 5.5 Hz, 1 H), 3.58- 3.45 (m, 6H), 2.45-2.38 (m, 4H), 2.24 (s, CH₃).

EXAMPLE 3 - Preparation of the co-crystal of Dasatinib with vanillyl alcohol by slow evaporation in MeOH (methanol).

In a test tube equipped with a magnetic stirrer, Dasatinib form N-6 (100 mg, 0.205 mmol), vanillyl alcohol (63 mg, 0.409 mmol, 2 eq.) and MeOH (4 ml_, 40 volumes) were added. The mixture was heated at reflux and the resulting solution was transferred to a glass vials. The solvent was allowed to evaporate under ambient conditions and the solid obtained was dried under vacuum (approximately 1 mbar, RT) overnight affording the co-crystal of Dasatinib with vanillyl alcohol.

EXAMPLE 4 - Preparation of the co-crystal of Dasatinib with 4-ethoxyphenol by suspending in water. In a round-bottomed flask equipped with magnetic stirrer, Dasatinib form N-6 (5.02 g, 10.29 mmol) and 4-ethoxyphenol (2.84 g, 20.56 mmol, 2.0 equivalents) water (100 mL, 20 volumes) was added. The suspension was heated at 50°C overnight. The solid was filtered with a sintered funnel (porosity 3), washed with water at 50°C (3 x 10 mL, 3 x 2 volumes) and dried under vacuum (approximately 1 mbar, room temperature) to give the co-crystal of Dasatinib with 4-ethoxyphenol (6.26 g, 97% yield) as a white solid.

Ή-NMR (DMSO-d6 - 400 MHz) δ (ppm): 1 1.45 (s br, 1 H), 9.87 (s, 1 H), 8.22 (s, 1 H), 7.40 (dd, J = 1 .6 Hz, J = 7.4 Hz, 1 H), 7.32-7.22 (m, 2H), 6.75-6.69 (m, 2H), 6.68- 6.62 (m, 2H), 6.04 (s, 1 H), 5.60 (s, 1 H), 4.45 (t, J = 5.5 Hz, 1 H), 3.89 (q, J = 7.0 Hz, -O-CH2), 3.58-3.45 (m, 6H), 2.45-2.38 (m, 4H), 2.24 (s, CH₃), 1.26 (t, J = 7.0 Hz, C- CH₃).

The co-crystal of Dasatinib with 4-ethoxyphenol has a XRPD as reported in FIG. 8 wherein the most relevant peaks fall at 5.7, 9.0, 16.6, 17.3, 18.9, 19.8, 23.4, 25.3, 26.4, 27.2 ± 0.2° in 2Θ.

The co-crystal of Dasatinib with 4-ethoxyphenol has a DSC thermogram as substantially reported in FIG. 10 showing multiple endothermic peaks, wherein the endothermic peak representing the fusion of the co-crystal is at 200 - 207°C.

EXAMPLE 5 - Preparation of the co-crystal of Dasatinib and 4-ethoxyphenol by wet grinding in water.

To a 2 mL eppendorf containing Dasatinib form N-6 (26 mg, 0.053 mmol), 4- ethoxyphenol (7.8 mg, 0.056 mmol) and three 4 mm stainless steel grinding balls, one drop of water was added. The reactor was stirred 45 minutes at a rate of 30 Hz (3 x 15 minutes). The product was dried under vacuum (approximately 1 mbar, room temperature) overnight affording the co-crystal of Dasatinib with 4-ethoxyphenol. EXAMPLE 6 - Preparation of the co-crystal of Dasatinib with carvacrol.

In a round-bottomed flask equipped with magnetic stirrer and Dasatinib Form N-6 (5.00 g, 10.25 mmol), carvacrol (12.5 mL, 2.5 volumes, d=0.98 g/mL, 81.55 mmol, 8.0 eq) MeOH (12.5 mL, 2.5 volumes) were added. The suspension was heated at 50°C overnight. The solid was filtered with a sintered funnel (porosity 3), washed with a mixture heptane/methyl tert-butyl ether (8:2, 2 x 10 mL, 2 x 2 volumes) and dried under vacuum (approximately 1 mbar, room temperature) to give the co-crystal of Dasatinib with carvacrol (5.22 g, 90% yield) as a white solid. ¹H-NMR (DMSO-d6 - 400 MHz) δ (ppm): 1 1 .45 (s, 1 H), 9.87 (s, 1 H), 9.04 (s, 0.5H), 8.21 (s, 1 H), 7.40 (dd, J = 1 .6 Hz, J = 7.4 Hz, 1 H), 7.32-7.22 (m, 2H), 6.93 (d, J = 7.8 Hz, 1 H), 6.63 (d, J = 1.9 Hz, 0.5H), 6.55 (dd, J = 1 .9 Hz, J = 7.8 Hz, 0.5H), 6.05 (s, 1 H), 5.60 (s, 1 H), 4.45 (t, J = 5.5 Hz, 1 H), 3.58-3.45 (m, 6H), 2.73 (heptuplet, J = 7.0 Hz, 0.5H), 2.45-2.38 (m, 4H), 2.24 (s, CH₃), 2.05 (s, 1.5H), 1.13 (d, J = 7.0 Hz, 3H).

The co-crystal of Dasatinib with carvacrol has a XRPD as reported in FIG. 1 1 wherein the most relevant peaks fall at 5.9, 1 1.8, 15.2, 16.6, 17.7, 18.3, 21 .1 , 21.5, 23.0, 24.0 ± 0.2° in 2Θ.

The co-crystal of Dasatinib with carvacrol has a DSC thermogram as substantially reported in FIG. 13, with two endothermic peaks, wherein the endothermic peak representing the fusion of the co-crystal is at 215 - 223°C.

EXAMPLE 7 - Preparation of the co-crystal of Dasatinib with p-cresol by wet grinding in water.

To a 2 mL eppendorf containing Dasatinib form N-6 (50 mg, 0.102 mmol), p-cresol (1 1 μΙ_, 0.105 mmol, d = 1 .0347) and three 4 mm stainless steel grinding balls, one drop of water was added. The reactor was stirred 45 minutes at a rate of 30 Hz (3 x 15 minutes). The product was dried under vacuum (approximately 1 mbar, room temperature) overnight affording the co-crystal of Dasatinib with p-cresol.

Claims

1 ) A co-crystal of Dasatinib with a phenolic compound selected from resorcinol, vanillyl alcohol, 4-ethoxyphenol, carvacrol and p-cresol.

2) A co-crystal according to claim 1 selected from:

- co-crystals of Dasatinib with resorcinol having a molar ratio

Dasatinib:resorcinol of about 1 :2;

- a co-crystal of Dasatinib with vanillyl alcohol having a molar ratio Dasatinib:vanillyl alcohol comprised between 1 :1 and 1 :2;

- a co-crystal of Dasatinib with 4-ethoxyphenol having a molar ratio Dasatinib:4- ethoxyphenol of about 1 :1 ;

- a co-crystal of Dasatinib with carvacrol having a molar ratio Dasatinib:carvacrol of about 2:1 ;

- a co-crystal of Dasatinib with p-cresol having a molar ratio Dasatinib:p-cresol of about 1 :1 .

3) A co-crystal of Dasatinib with resorcinol according to claim 2 wherein:

- the co-crystal of Dasatinib, herein defined as Form 1 , is characterized by a XRPD wherein the peaks fall at 5.0, 1 1.0, 15.2, 16.3, 19.1 , 23.2, 24.1 , 25.1 , 25.8 ± 0.2° in 2Θ and has a DSC thermogram with a sole endothermic peak at about 175 - 178°C which represents the fusion of the co-crystal; or

- the co-crystal of Dasatinib, herein defined as Form 2, is characterized by

XRPD wherein the peaks fall at 5.2, 10.4, 15.6, 16.5, 18.1 ± 0.2° in 2Θ and has a DSC thermogram having a sharp endothermic peak at 173 - 176°C which represents the fusion of the co-crystal.

4) A co-crystal according to claim 2 wherein:

- the co-crystal of Dasatinib with vanillyl alcohol is characterized by a XRPD wherein the peaks fall at 5.3, 8.1 , 13.2, 15.5, 17.4, 21.3, 25.3, 26.2, 26.6 ± 0.2° in 2Θ;

- the co-crystal of Dasatinib with 4-ethoxyphenol is characterized by a XRPD wherein the peaks fall at 5.7, 9.0, 16.6, 17.3, 18.9, 19.8, 23.4, 25.3, 26.4, 27.2 ± 0.2° in 2Θ and has a DSC thermogram showing multiple endothermic peaks, wherein the endothermic peak representing the fusion of the co-crystal is at 200 - 207°C;

- the co-crystal of Dasatinib with carvacrol is characterized by a XRPD wherein the peaks fall at 5.9, 1 1.8, 15.2, 16.6, 17.7, 18.3, 21.1 , 21.5, 23.0, 24.0 ± 0.2° in 2Θ and has a DSC thermogram with two endothermic peaks wherein the endothermic peak representing the fusion of the co-crystal is at 215 - 223°C; - the co-crystal of Dasatinib with p-cresol is characterized by a XRPD wherein the peaks fall at 5.5, 10.8, 15.7, 17.2, 23.7 ± 0.2° in 2Θ.

5) A co-crystal of Dasatinib with 4-ethoxyphenol according to each of claims 1 , 2 or 4 having a water content of 3.4% w/w.

6) A pharmaceutical composition comprising a co-crystal according to each of claims 1 -5 and at least a pharmaceutically acceptable excipient and/or carrier.

7) A pharmaceutical composition according to claim 6 also comprising imatinib as further active ingredient.

8) A co-crystal of Dasatinib with a phenolic compound as defined in claims 1 -5 for use as a medicament.

9) A co-crystal of Dasatinib with a phenolic compound as defined in claims 1 -5 for use as an oral dual BCR/ABL and SRC family tyrosine kinase inhibitor.

10) A co-crystal of Dasatinib with a phenolic compound as defined in claims 1 -5 for use in a method of treatment of chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL).