Field of the invention

The present invention relates to processes for the preparation of crystalline N-(2-chloro-6- methylphenyl) -2- [[6- [4- (2-hydroxyethyl) - 1 -piperazinyl] -2-methyl-4-pyrimidinyl] amino] -5- thiazolecarboxamide (dasatinib) monohydrate. The invention further relates to pure polymorphs, to pharmaceutical compositions comprising said polymorphs and to uses thereof.

Background of the invention

Dasatinib is an active pharmaceutical ingredient approved for the treatment of cancer, in particular treatment of adults with chronic, accelerated or blast phase chronic myeloid leukaemia (CML) with resistance or intolerance to prior therapy including imatinib mesilate. Dasatinib is also indicated for the treatment of adults with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) and lymphoid blast CMT, with resistance or intolerance to prior therapy.

dasatinib

There is considerable interest in the development of novel polymorphs of dasatinib and processes for their preparation. The new polymorphs may be advantageous for dosage form development and enhancing bioavailability owing to the altered physicochemical properties. There is also interest in the development of novel processes for the preparation of known polymorphs of dasatinib. Such novel processes can result in polymorphs of increased and reproducible chemical and/or polymorphic purity. Further the novel processes should be robust and capable of preparing said compounds on an industrial scale.

US 2006/0004067 discloses four crystalline forms of dasatinib. A monohydrate, a 'neat' crystalline form, a butanol solvate and an ethanol solvate and processes for their preparation are described.

The processes disclosed in US 2006/0004067 are as follows:

1. Dasatinib was dissolved in ethanol : water (22:3 volumes w.r.t. dasatinib) by heating at approximately 75-80 ⁰ C. Water (8 volumes) was added at such a rate that the temperature was maintained between 75-80 ⁰ C. The mixture was slowly cooled to 70 ⁰ C and maintained at this temperature for 1 hour and then cooled to 5°C over 2 hours resulting in a slurry. Dasatinib monohydrate crystals may be added as seeding during the initial cooling. Filtration of the solid and drying the material at <50°C gave the monohydrate form of dasatinib. This form was characterized by XRPD and DSC. The moisture content by KF was in the range of 3.4-4.1%.

2. Alternatively, an aqueous suspension of dasatinib, seeded with the monohydrate form, was heated to 70 ⁰ C for 4 hours. The slurry gave the dasatinib monohydrate form on cooling. 3. In still another alternative, an aqueous solution of an acetate salt of dasatinib was heated to 80 ⁰ C to give the monohydrate form of dasatinib.

4. In another method, dasatinib was heated in a mixture of ethanol, butanol and water and seeded with monohydrate crystals before cooling to afford the monohydrate form of dasatinib. 5. In yet another approach, a solution of dasatinib in solvents such as NMP or DMA was treated with water until the solution turned cloudy. The reaction mixture was maintained at 75-80 ⁰ C for several hours to obtain the monohydrate form after cooling and filtration.

6. The butanol solvate of dasatinib was prepared by heating dasatinib in butanol at a concentration of 1 g in 25 ml of solvent at 116-118°C. On cooling, the butanol solvate crystallises out of the solution. The butanol solvate was characterised by XRPD.

7. The ethanol solvate of dasatinib was prepared by an elaborate process. As outlined in Figure 2 of US 2006/0004067 which is hereby incorporated herein by reference, intermediate 3 and N-(2-hydroxyethyl)piperazine (HEP) were heated together in butanol at 120 ⁰ C in the presence of the base diisopropylethylamine. On cooling the reaction mixture, a precipitate formed which was isolated by filtration and washings. This solid was then heated to 77°C in ethanol : water. On further cooling, a solid precipitated which when isolated was characterised as ethanol solvate.

8. To obtain a crystalline form of dasatinib, called neat form N-6, intermediate 3 and N-(2-hydroxyethyl)-piperazine (HEP) were heated together in NMP solvent at 110 ⁰ C in the presence of diisopropylethylamine as a base. Water (46 volumes w.r.t. intermediate 3) was added at 90 ⁰ C and the reaction mixture was maintained at this temperature for 15 minutes. On cooling, a solid precipitate was obtained which was isolated by filtration and dried under vacuum at 55-60 ⁰ C. This form was characterized by XRPD.

9. Another crystalline form, called neat form T1H1-7, was obtained by heating the monohydrate form above the dehydration temperature.

All the methods disclosed in US 2006/0004067 require initial preparation of dasatinib followed by a further recrystallisation process to obtain the desired polymorphic form. Of course if further purification is required this adds another step to the process. Indeed methods 5 to 9 described above relate to the preparation of dasatinib solvates which require further processing to prepare dasatinib that can be used in a pharmaceutical product. Such further processing may include multiple recrystallisations and washings. This of course means that additional solvents and equipment and time are required, so increasing the cost and complexity of the synthesis of dasatinib for use in pharmaceutical products. Further, studies by the inventors have shown that the dasatinib so prepared only has a purity of approximately 90%.

The discovery of new polymorphic forms is a continuing goal of formulators. Discovering novel processes to prepare known polymorphic forms is also a primary goal of the pharmaceutical development scientist. New processes can provide novel intermediates or synthetic pathways that result in product with increased chemical and polymorphic purity. There is thus a need to provide novel synthetic routes that can provide crystalline dasatinib of increased purity that adhere to ICH Guidelines on purity. The crystalline dasatinib should be able to be prepared in a simple and cost effective manner, for use in pharmaceutical products. - A -

Summary of the invention

Accordingly, in a first aspect of the invention there is provided a process for preparin crystalline dasatinib monohydrate, comprising reacting an intermediate having a formula 3

with N-(2-hydroxyethyl)piperazine (HEP), characterised in that the HEP is employed as a reactant, base and solvent.

Preferably the crystalline dasatinib monohydrate is prepared directly without first isolating any other forms of dasatinib.

The inventors found that when the amount of HEP was reduced the reaction mass increased in viscosity. In order to reduce the viscosity, solvents were added to the reaction mixture. Accordingly in particularly preferred embodiments when the molar ratio of intermediate 3 : HEP is 1:5 or less in the reaction mixture, one or more additional solvent(s) is/are added to the reaction mixture. Preferably the additional solvent(s) comprise one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2- pyrrolidone or dimethyl sulphoxide. The inventors surprisingly found that crystalline dasatinib monohydrate could be prepared without the need for first preparing dasatinib, isolating the dasatinib and then the subsequent processing steps required by the prior art. The crystalline dasatinib monohydrate of the invention is prepared in pure form in a simple process. Of course it may be desired that the crystalline dasatinib monohydrate prepared according to the invention is even further purified. However, even in those embodiments that comprise further purification, the process is still only a simple two step process.

A particularly preferred embodiment of the first aspect comprises a process wherein:

(i) intermediate 3, HEP and a solvent system are combined in a reaction mixture; and (ii) crystalline dasatinib monohydrate is isolated.

In one embodiment when the solvent system comprises one or more of N,N- dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidone, a base, preferably an alkyl amine, most preferably dϋsopropylethylamine, is further added to the reaction mixture. Of course it will be understood that any of a number of bases, in particular alkyl amine bases, may be utilised in the invention, for example triethylamine. However the inventors found that dϋsopropylethylamine was particularly advantageous. In particularly preferred embodiments 2 molar equivalents of dϋsopropylethylamine with respect to intermediate 3 are added to the reaction mixture.

In a preferred process according to the first aspect, the reaction mixture in step (i) is heated until a clear solution is formed, preferably the reaction mixture is heated to between about 50 ⁰ C and 70 ⁰ C, preferably to about 60 ⁰ C, however, in alternative embodiments when dϋsopropylethylamine is added to the reaction mixture, the mixture is preferably heated to between about 100 ⁰ C and 120 ⁰ C.

In one embodiment of a process according to the invention the crystalline dasatinib monohydrate is isolated by cooling the reaction mixture until a precipitate is formed. Preferably the reaction mixture is allowed to cool to about 20-30 ⁰ C. In alternative embodiments when diisopropylethylamine is added to the reaction mixture, the reaction mass is cooled to about 80-90 ⁰ C.

In alternative processes according to the invention the crystalline dasatinib monohydrate is isolated by adding an anti-solvent to the reaction mixture. Preferably the anti-solvent is water, most preferably between 10 to 50 molar equivalents of water with respect to intermediate 3 are added to the reaction mixture.

In a particularly preferred process the crystalline dasatinib monohydrate from step (ϋ) is: (a) isolated by filtration;

(b) washed with water; and

(c) dried. Preferably, the isolated crystalline dasatinib monohydrate in step (c) is dried in a vacuum tray drier at about 50 ⁰ C preferably until a constant weight is achieved, most preferably for between about 8-12 hours.

In certain embodiments the crystalline dasatinib monohydrate prepared according to the invention may be further purified by recrystallisation from a polar organic solvent system.

Preferred embodiments for further purification of crystalline dasatinib monohydrate comprise refluxing the crystalline dasatinib monohydrate in a solution comprising an alcohol and allowing the reaction mixture to cool. In a preferred embodiment the solution comprises an alcohol and water, most preferably the solution comprises ethanol and water, which in particularly preferred embodiments comprises ethanol : water in a ratio of about 22:3.

A second aspect according to the invention provides crystalline dasatinib monohydrate having a chemical purity of greater than 99% (as measured by HPLC).

A third aspect provides crystalline dasatinib monohydrate having a chemical purity of greater than 99.5% (as measured by HPLC).

A fourth aspect provides crystalline dasatinib monohydrate having a chemical purity of greater than 99.7% (as measured by HPLC).

Preferably the dasatinib monohydrate according to the invention or prepared by a process according to the invention has a chemical purity of greater than 99%, more preferably greater than 99.5%, more preferably greater than 99.7%, most preferably greater than

99.8% (as measured by HLPC). Preferably the dasatinib monohydrate according to the invention or prepared by a process according to the invention has a polymorphic purity of greater than 95%, more preferably greater than 98%, more preferably greater than 99%, more preferably greater than 99.5%, most preferably greater than 99.8% (as measured by

XRPD). A fifth aspect provides a pharmaceutical composition comprising crystalline dasatinib monohydrate prepared by a process according to the invention or crystalline dasatinib monohydrate according to the second, third or fourth aspects of the invention, and one or more pharmaceutically acceptable excipients.

In a sixth aspect of the invention use of a pharmaceutical composition according to the fifth aspect is provided for the treatment of cancer. In particularly preferred embodiments pharmaceutical compositions are provided for use in the treatment of adults with chronic, accelerated or blast phase chronic myeloid leukaemia (CML) with resistance or intolerance to prior therapy including imatinib mesilate or in the treatment of adults with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) or lymphoid blast CML with resistance or intolerance to prior therapy.

A seventh aspect provides crystalline dasatinib monohydrate prepared by a process according to the first aspect and accompanying embodiments or according to any of the second, third or fourth aspects of the invention for use in medicine, preferably for use in the treatment cancer, most preferably for use in the treatment of adults with chronic, accelerated or blast phase chronic myeloid leukaemia (CML) with resistance or intolerance to prior therapy including imatinib mesilate or in the treatment of adults with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) or lymphoid blast CML with resistance or intolerance to prior therapy.

An eighth aspect of the invention provides use of crystalline dasatinib monohydrate according to the invention in the manufacture of a medicament for treating cancer. Preferably the medicament is for treating adults with chronic, accelerated or blast phase chronic myeloid leukaemia (CML) with resistance or intolerance to prior therapy including imatinib mesilate or for treating adults with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) or lymphoid blast CMT, with resistance or intolerance to prior therapy.

A ninth aspect of the invention provides a method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of crystalline dasatinib monohydrate according to the invention or a therapeutically effective amount of the pharmaceutical composition according to the invention. Preferably the method is for treating adults with chronic, accelerated or blast phase chronic myeloid leukaemia (CML) with resistance or intolerance to prior therapy including imatinib mesilate or for treating adults with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) or lymphoid blast CML with resistance or intolerance to prior therapy. Preferably the patient is a mammal, preferably a human.

Brief description of the drawings

Figure 1 shows an XRP diffractogram of crystalline dasatinib monohydrate according to the invention.

Figure 2 shows a differential scanning calorimetry (DSC) trace of crystalline dasatinib monohydrate according to the invention.

Figure 3 shows a thermogravimetric analysis (TGA) trace of crystalline dasatinib monohydrate according to the invention.

Detailed description of the invention

As used herein, reference to chemical purity refers to a compound having a purity of greater than 95%, including greater than 96%, greater than 97%, greater than 98%, greater than 99% and 100% as determined by HPLC. In one embodiment crystalline dasatinib monohydrate according to the invention can be substantially pure in having a purity of greater than 99%, where the remaining less than 1% of material comprises reaction and/or processing impurities arising from its preparation. This level of consistent chemical purity has not been seen before in the prior art.

A first aspect of the invention provides a process for preparing crystalline dasatinib monohydrate, comprising reacting an intermediate having a formula 3 with N-(2-hydroxyethyl)piperazine (HEP), characterised in that the HEP is employed as a reactant, base and solvent.

The inventors found that when the amount of HEP was reduced the reaction mass increased in viscosity. In order to reduce the viscosity, solvents were added to the reaction mixture. In certain embodiments the solvent system comprises polar organic solvents. Accordingly in particularly preferred embodiments when the molar ratio of intermediate 3 : HEP is 1:5 or less in the reaction mixture, one or more additional solvent(s) is/are added to the reaction mixture. Preferably the additional solvent(s) comprise one or more of N ,N- dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulphoxide. The inventors found that highly polar organic solvents such as those described above were particularly advantageous in the preparation of the monohydrate form of dasatinib

A particularly preferred embodiment of the first aspect comprises a process wherein:

(i) intermediate 3, HEP and a solvent system are combined in a reaction mixture; and

(ii) crystalline dasatinib monohydrate is isolated.

The inventors found that dissolving intermediate 3 in the solvent system before adding the HEP resulted in a particularly pure product. Alternatively the HEP, intermediate 3 and solvent may all be added simultaneously. Of course the skilled person will realise that there are a number of techniques to facilitate dissolution of intermediate 3. In preferred embodiments the reaction mixture comprising the polar solvent and intermediate 3 are heated to effect dissolution. Preferably the mixture is heated to around 60 ⁰ C, but any temperature that effects dissolution could be employed. For example in those embodiments where the solvent system comprises one or more of N ₅ N- dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidone, and a base, preferably diisopropylethylamine, is added to the reaction mixture, the mixture is preferably heated to between about 100 ⁰ C and 120 ⁰ C. Other embodiments may comprise stirring or sonication to dissolve the intermediate 3. The skilled person would of course be aware of such techniques.

In order to obtain crystalline dasatinib monohydrate from solution, a number of techniques may be employed. In preferred embodiments the crystalline dasatinib monohydrate is isolated by cooling the reaction mixture until a precipitate is formed. Preferably the reaction mixture is allowed to cool to about 20-30 ⁰ C, which is approximately ambient temperature. In alternative embodiments when diisopropylethylamine is added to the reaction mixture, the reaction mass is cooled to about 80-90 ⁰ C. In these embodiments the initial reaction mixture has generally been heated to between about 100 ⁰ C to about 120 ⁰ C.

There are of course a number of techniques open to the skilled person to isolate a crystalline solid from solution. Accordingly the inventors found that adding an anti-solvent to the reaction mixture is particularly suitable. In preferred embodiments the anti-solvent is water. Most preferably between 10 to 50 molar equivalents of water with respect to intermediate 3 are added to the reaction mixture. The inventors found maintaining the reaction mixture including the water anti-solvent at the cooled temperature for a period of time to be particularly advantageous. Most preferably the resultant crystalline dasatinib monohydrate is filtered and may be further washed. Preferable the solid is washed in about 20 volumes of water, but any amount sufficient to remove traces of the initial solvent may be employed.

The isolated crystalline dasatinib monohydrate may be dried in any of a number ways. The inventors dried the dasatinib monohydrate obtained by the process of the invention under a number of conditions: (a) in a vacuum tray drier at 50 ⁰ C for 8-12 hours; (b) in a rotary evaporator at 25-30 ⁰ C for 8-12 hours; and (c) at ambient temperature for 2 days. The conditions above can all be varied within the scope of the invention. The important factors ate that the end point of drying occurs when a constant weight is achieved and to ensure that there is no degradation or conversion to another form. All the tested conditions resulted in chemically pure crystalline dasatinib monohydrate having a crystalline structure with the XRDP as shown in Figure 1. It can thus be seen that the processes of the invention provide a stable product.

Illustrative of the invention is a pharmaceutical composition made by mixing crystalline dasatinib monohydrate according to the invention and one or more pharmaceutically acceptable excipients.

Solid pharmaceutical compositions of the present invention include powders, granulates, aggregates and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages may be conveniently presented in unit dosage form and prepared by any of the methods well known in the pharmaceutical arts. Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and lozenges, as well as liquid syrups, suspensions and elixirs.

The dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or a soft shell. The shell may be made from gelatin and optionally contain a plasticizer such as glycerine and sorbitol, and an opacifying agent or colourant. The active ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art.

A composition for tabletting or capsule filling may be prepared by wet granulation. In wet granulation, some or all of the active ingredient and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate may then be tabletted or other excipients may be added prior to tabletting, such as a glidant and/or a lubricant.

A tabletting composition may be prepared conventionally by dry granulation. For example, the blended composition of the actives and excipients may be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.

As an alternative to dry granulation, a blended composition may be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a uniform tablet without granules. Excipients that are particularly well suited for direct compression tabletting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tabletting is known to those in the art with experience and skill in particular formulation challenges of direct compression tabletting.

A capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tabletting, however, they are not subjected to a final tabletting step.

In further embodiments the pharmaceutical compositions of the invention may further comprise one or more additional active ingredients.

The details of the invention, its objects and advantages are explained hereunder in greater detail in relation to non-limiting exemplary illustrations.

Examples

Methods for the preparation of crystalline dasatinib monohydrate

In the following examples the relative values relate to molar equivalents with respect to intermediate 3.

Example 1: Intermediate 3 (5 g, 1 equivalent) was added to dimethyl sulfoxide (DMSO) (13 volumes) and heated to 60 ⁰ C. When the reaction mixture became clear, HEP (3 molar equivalents) was added. The reaction mixture was maintained at 60-65 ⁰ C for 2 hours. The reaction mass was allowed to cool to 25-30 ⁰ C and water (20 volumes) was added and maintained at same temperature for 45 minutes. The resultant solid was filtered and washed with water and dried in a vacuum tray drier at 50 ⁰ C for 8-12 hours. The isolated solid weighed 4.4 g. XRPD characterisation showed the isolated product to be crystalline dasatinib monohydrate substantially matching the XRP diffractogram according to Figure 1. Chemical Purity > 97% as measured by HPLC.

Example 2:

Intermediate 3 (5 g, 1 equivalent) was added to dimethyl sulfoxide (DMSO) (13 volumes) followed by addition of HEP (3 molar equivalents). The reaction mixture was maintained between 25-30 ⁰ C for 15-24 hours. Water (20 volumes) was added and maintained at this temperature for 45 minutes. The resultant solid was filtered and washed with water and dried in a vacuum tray drier at 50 ⁰ C for 8-12 hours. The isolated solid weighed 4.5 g. XRPD characterisation showed the isolated product to be crystalline dasatinib monohydrate substantially matching the XRP diffractogram according to Figure 1. Chemical Purity > 97% as measured by HPLC.

Example 3:

Intermediate 3 (5 g, 1 equivalent) and HEP (5 molar equivalents) were added to N ₅ N- dimethylacetamide (6.7 volumes) or N-methyl-2-pyrrolidone (6.7 volumes) followed by the addition of diisopropylethylamine (2 molar equivalents), and the reaction mixture was heated at 110 ⁰ C for 0.5 hour. The reaction mixture was cooled to 90 ⁰ C and then added to water (45 volumes). The mixture was cooled to 80 ⁰ C until a solid precipitated out and maintained at this temperature for 15 minutes. The reaction mixture was cooled to 25- 30 ⁰ C. The resultant solid was filtered and washed with water (3 volumes) and dried in a vacuum tray drier at 50 ⁰ C for 8-10 hours. The isolated solid weighed 3.8 g.

XRPD characterisation showed the isolated product to be crystalline dasatinib monohydrate substantially matching the XRP diffractogram according to Figure 1. Chemical Purity > 97% as measured by HPLC.

All products obtained were characterised as follows. The XRPDs were recorded on a Bruker D8 Advance Instrument (BRUKER AXS), using copper radiation as the X-ray source and LynxEye as the detector. Samples were placed on a silica background holder.

The DSCs were recorded on a Perkin Elmer Pyris 1. The DSC sample chamber was purged with 40 ml/min of ultra high purity indium. The accuracy of the measured sample temperature with this method is within about + 1°C. The sample was placed into a closed aluminium DSC pan with pinhole. At least 2 mg of sample powder was placed in the pan and sealed. The instrument was programmed to heat at a rate of 10 ⁰ C per minute in the temperature range between 25°C and 350 ⁰ C.

The TGAs were recorded on a Perkin Elmer Pyris 1. Samples of at least 10 mg were analysed at a heating rate of 10 ⁰ C per minute in the temperature range between 25°C and about 350 ⁰ C.

It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined by the following claims only.