WO2010062715A2

WO2010062715A2 - Polymorphs of dasatinib and process for preparation thereof

Info

Publication number: WO2010062715A2
Application number: PCT/US2009/062966
Authority: WO
Inventors: Pavel Vraspir; Ales Gavenda; Roman Gabriel; Alexandr Jegorov
Original assignee: Teva Pharmaceutical Industries Ltd.; Teva Pharmaceutical Usa, Inc
Priority date: 2008-11-03
Filing date: 2009-11-02
Publication date: 2010-06-03
Also published as: WO2010062715A3

Abstract

The present invention provides solvates of Dasatinib, crystalline forms of Dasatinib solvates and methods of their preparation.

Description

POLYMORPHS OF DASATINIB AND PROCESS FOR PREPARATION THEREOF

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present invention claims the benefit of the following United States Provisional Patent Application No.: 61/110,735, filed November 3, 2008. The contents of this application is incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to polymorphs of dasatinib and process for preparation therof.

BACKGROUND OF THE INVENTION

[0003] Dasatinib, N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l- piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide a compound having the following chemical structure of formula (2):

also known as BMS-354825, is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel®. Dasatinib is an oral dual BCR/ ABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatemant and Philadelphia chromosome-positive acute lymphoblasticjeukemia (Ph+ ALL).

[0004] The Preparation of dasatinib is described in US 6,596,746 B 1 ; where the process is carried out by reacting compound 1 of the following formula (1):

i with N-(2-hydroxyethyl)piperazine at 80⁰C.

[0005] Several crystalline forms are described in the literature, these were designated forms H 1-7, BU-2, E2-1, N-6, T IHl -7, and T1E2-1. Crystalline dasatinib monohydrate (H 1-7) and butanol solvate (BU-2) along with the processes for their preparation are described in WO2005/077945A2. In addition US2006/0004067A1, which is continuation of WO 2005/077945 A2 also describes two ethanol solvates (E2-1; T1E2-1) and two anhydrous forms (N-6; T IHl -7)

[0006] The present invention describes the preparation of new forms of dasatinib.

[0007] Polymorphism, the occurrence of different crystal forms, is a property of some compounds and compound complexes. A single compound, like dasatinib, may give rise to a variety of crystalline forms having distinct crystal structures and physical characteristics like melting point, x-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC") as well as content of solvent in the crystalline form, which have been used to distinguish polymorphic forms.

[0008] The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.

[0009] One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubilities.

[0010] The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. Therefore, there is a need for additional solid state forms of dasatinib.

SUMMARY OF THE INVENTION

[0011] In one embodiment the present invention encompasses a solvate of dasatinib selected from the group consisting of: an isosorbide dimethyl ether solvate of dasatinib, an N,N'-dimethylethylene urea solvate of dasatinib, and an N₅N'- dimethyl-N,N'-propylene urea solvate of dasatinib.

[0012] In one embodiment, the present invention encompasses an isosorbide dimethyl ether solvate of dasatinib characterized by data selected from the group consisting of: a PXRD pattern having peaks at about 6.1 and 23.7 ± 0.2 degrees 2- theta and any 3 peaks at positions selected from the group consisting of: 12.1, 15.0, 16.5, 18.2, 21.5, and 24.2; a powder XRD pattern as depicted in Figure I₅ and a combination thereof.

[0013] In one embodiment, the present invention encompasses an N₅N'- dimethylethylene urea solvate of dasatinib characterized by data selected from the group consisting of: a PXRD pattern having peaks at about 5.0 and 10.0 ± 0.2 degrees 2-theta and any 3 peaks at positions selected from the group consisting of: 8.7, 13.7, 15.0, 17.5, 21.5, 22.4, 24.2 and 25.9 ± 0.2 degrees 2-theta ; a powder XRD pattern as depicted in Figure 3, and a combination thereof.

[0014] In one embodiment, the present invention encompasses an N,N'-dimethyl- N,N'-propylene urea solvate of dasatinib characterized by data selected from the group consisting of: a PXRD pattern having peaks at about 5.7 and 11.4 ± 0.2 degrees 2-theta and any 3 peaks at positions selected from the group consisting of: 12.6, 13.0, 17.4, 17.8, 19.5, 19.9, 22.0 and 22.6± 0.2 degrees 2-theta; a powder XRD pattern as depicted in Figure 5, and combination thereof.

[0015] In yet another embodiment the present invention encompasses pharmaceutical compositions comprising any one, or combination, of the above described solvates of Dasatinib and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE FIGURES

[0016] Figure 1 shows a powder XRD pattern of crystalline dasatinib form BN

[0017] Figure 2 shows a TGA record of crystalline dasatinib form BN.

[0018] Figure 3 shows a powder XRD pattern of crystalline dasatinib form BR.

[0019] Figure 4 shows a TGA record of crystalline dasatinib form BR.

[0020] Figure 5 shows a powder XRD pattern of crystalline dasatinib form BS.

[0021] Figure 6 shows a TGA record of crystalline dasatinib form BS.

DETAILED DESCRIPTION OF THE INVENTION

[0022] The present invention relates to polymorphs of dasatinib, process for preparing said polymorphs, and pharmaceutical compositions thereof.

[0023] As used herein in connection with a measured quantity, the term "about" refers to that variation in the measured quantity as would be expected by the skilled artisan performing the measurement and exercising a level of care commensurate with the objective of the measurement and the precision of the measuring apparatus being used.

[0024] As used herein, the term "isosorbide dimethyl ether" refers to a bicyclic ether derivative of glucitol having the following formula;

[0025] In one embodiment, the present invention encompasses an isosorbide dimethyl ether solvate of dasatinib. [0026] In certain embodiments the present invention encompasses isosorbide dimethyl ether solvate of dasatinib characterized by data selected from the group consisting of: a PXRD pattern having peaks at about 6.1 and 23.7 ± 0.2 degrees 2- theta and any 3 peaks at positions selected from the group consisting of: 12.1, 15.0,

16.5, 18.2, 21.5, and 24.2; a powder XRD pattern as depicted in Figure 1, and a combination thereof. This form can be designated dasatinib solvate form BN.

[0027] The above isosorbide dimethyl ether solvate of dasatinib designated Form

BN can be further characterized by data selected from the group consisting of: a powder XRD pattern with peaks at about 6.1, 12.1, 15.0, 18.2 and 21.5 ± 0.2 degrees

2-theta; a powder XRD pattern with peaks at about 12.1, 15.0, 16.5, 23.7 and 24.2 ±

0.2 degrees 2-theta; and a weight loss of less than about 4.0%, at temperatures of about 35⁰C to about 115⁰C, and less than about 15.5%, at temperatures of about 125⁰C to about 135⁰C as measured by TGA; a TGA thermogram as depicted in figure 2; and combinations thereof.

[0028] Dasatinib solvate Form BN can be prepared by a process comprising crystallizing dasatinib from isosorbide dimethyl ether.

[0029] The crystallization comprises dissolving dasatinib in isosorbide dimethyl ether to obtain a solution comprising dasatinib, and cooling the solution to obtain a suspension comprising the crystalline form.

[0030] Preferably, the dissolution in isosorbide dimethyl ether is carried out by heating. Preferably, heating is to a temperature of about 120⁰C to about 150⁰C, preferably about 140⁰C. Preferably, heating is done for a period of about 1-20 minutes, preferably about 5-10 minutes, more preferably about 5 minutes.

[0031] The solution is then cooled and a suspension is formed. Preferably, the solution is cooled to a temperature of about 10°C-30°C, preferably about 2O⁰C, preferably, over a period of about 10-20 minutes, preferably about 15 minutes.

[0032] After the suspension is formed, it is preferably maintained at the mentioned temperature for about 30 minutes to about 4 hours, preferably for about 1 hour.

[0033] The process for preparing form BN of dasatinib can further comprise recovering the said crystalline form. The recovery can be done, for example, by filtering the suspension, washing, and drying.

[0034] Preferably, washing is done with tert-butyl methyl ether (t-BME). [0035] Preferably, drying is done on air, preferably for a period of about 30 minutes to about 4 hours, preferably for about 1 hour.

[0036] In one embodiment, the present invention encompasses a N₅N'- dimethylethylene urea solvate of dasatinib.

[0037] In certain embodiments the present invention encompasses a N₅N'- dimethylethylene urea solvate of dasatinib characterized by data selected from the group consisting of: a PXRD pattern having peaks at about 5.0 and 10.0 ± 0.2 degrees

2-theta and any 3 peaks at positions selected from the group consisting of: 8.7, 13.7,

15.0, 17.5, 21.5, 22.4, 24.2 and 25.9 ± 0.2 degrees 2-theta; a powder XRD pattern as depicted in Figure 3, and a combination thereof. This form can be designated dasatinib solvate form BR.

[0038] The above N,N'-dimethylethylene urea solvate of dasatinib designated

Form BR can be further characterized by data selected from the group consisting of: a powder XRD pattern with peaks at about 5.0, 8.7, 15.0, 17.5 and 21.5 ± 0.2 degrees 2- theta; a powder XRD pattern with peaks at about 10.0, 13.7, 17.5, 22.4 and 25.9 ± 0.2 degrees 2-theta; and a weight loss of less than about 14.1%, at temperatures of about

25⁰C to about 148⁰C, and less than about 6.2%, at temperatures of about 148⁰C to about 224⁰C, and less than about 7.9%, at temperatures of about 224⁰C to about 281⁰C as measured by TGA; a TGA thermogram as depicted in figure 4; and combinations thereof.

[0039] Dasatinib Form BR can be prepared by a process comprising crystallizing dasatinib from N,N'-dimethylethylene urea.

[0040] The crystallization comprises dissolving dasatinib in N₅N'- dimethylethylene urea (DMI) to obtain a solution comprising dasatinib, and cooling the solution to obtain a suspension comprising said crystalline form.

[0041] Preferably, the dissolution in N,N'-dimethylethylene urea is carried out by heating. Preferably, heating is to a temperature of about 50°C-70°C, preferably about

55°C to about 60⁰C.

[0042] Preferably, cooling is carried out upon stirring in an ice bath. Preferably, stirring is done for about 1-4 hours, preferably about 2 hours.

[0043] The obtained solution is preferably maintained to allow precipitation of the said crystalline form, preferably for about 7-14 days, preferably about 11 days. [0044] The process for preparing form BR of dasatinib can further comprise recovering said crystalline form. The recovery can be carried out, for example, by filtering the suspension, and drying.

[0045] Preferably, drying is carried out under nitrogen. Preferably, drying is carried out for a period of about 30 minutes.

[0046] In one embodiment, the present invention encompasses a N,N'-dimethyl-

N,N'-propylene urea solvate of dasatinib.

[0047] In certain embodiments the present invention encompasses a N₅N'- dimethyl-N,N'-propylene urea solvate of dasatinib characterized by data selected from the group consisting of: a PXRD pattern having peaks at about 5.7 and 11.4 ± 0.2 degrees 2-theta and any 3 peaks at positions selected from the group consisting of:

12.6, 13.0, 17.4, 17.8, 19.5, 19.9, 22.0 and 22.6± 0.2 degrees 2-theta; a powder XRD pattern as depicted in Figure 5, and a combination thereof. This form can be designated dasatinib solvate form BS.

[0048] The above N,N'-dimethyl-N,N'-propylene urea solvate of dasatinib designated Form BS can be further characterized by data selected from the group consisting of: a powder XRD pattern with peaks at about 11.4, 12.6, 13.0, 17.4 and

17.8 ± 0.2 degrees 2-theta; a powder XRD pattern with peaks at about 5.7, 17.4, 19.5,

19.9 and 22.6 ± 0.2 degrees 2-theta; and a weight loss of less than about 15.0%, at temperatures of about 7O⁰C to about 22O⁰C, and less than about 13.4%, at temperatures of about 22O⁰C to about 28O⁰C as measured by TGA; a TGA thermogram as depicted in figure 6; and combinations thereof.

[0049] Dasatinib Form BS can be prepared by a process comprising crystallizing dasatinib from a mixture of N,N'-dimethyl-N,N'-propylene urea and water.

[0050] The crystallization comprises dissolving dasatinib in N,N'-dimethyl-N,N'- propylene urea to obtain a solution comprising dasatinib, cooling and adding water to the solution to obtain a suspension comprising said crystalline form.

[0051] Preferably, the dissolution in N,N'-dimethyl-N,N'-propylene urea is carried out by heating. Preferably, heating is to a temperature of about 50°C-70°C, preferably of about 55°C to about 60⁰C.

[0052] After the solution is formed it is preferably cooled prior to the addition of water. Preferably, cooling is to a temperature of about 15°C-30°C, preferably about

25⁰C. [0053] Preferably, water is added at a temperature of about 15°C-30°C, preferably about 25⁰C, providing a suspension.

[0054] After the suspension is formed it is preferably maintained, preferably upon stirring, preferably at the mentioned temperature for about 30 minutes to about 4 hours, preferably about 1 hour.

[0055] The process for preparing form BS of dasatinib can further comprise recovering said crystalline form. The recovery can be carried out, for example, by filtering the suspension, washing, and drying.

[0056] Preferably, drying is carried out under nitrogen, preferably, at a temperature of about 60⁰C. Preferably, drying is done for a period of about 30 minutes to about 4 hours, preferably about 1 hour.

[0057] The above described solvates of Dasatinib can be used to prepare pharmaceutical compositions comprising any one, or combination, of the above described solvates of Dasatinib and at least one pharmaceutically acceptable excipient, by any method known in the art.

[0058] Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The disclosures of the references referred to in this patent application are incorporated herein by reference. The invention is further defined by reference to the following examples describing in detail the process and compositions of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. EXAMPLES

PXRD

[0059] XRD diffraction was performed on X-Ray powder diffractometer: Philips X'pert Pro powder diffractometer, CuKa radiation, λ = 1.5418 A. X'Celerator detector active length (2 theta) = 2.122°, laboratory temperature 22-25 °C. Zero background sample holders were used. Prior to analysis the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass. Measurement parameters:

Scan range: at least 4 - 40° 2-theta;

Scan mode: continuous;

Step size: 0.0167 °;

Time per step: 21 s;

Sample spin: 16 rpm;

Sample holder: quartz plate.

DSC

[0060] DSC measurements were performed on Differential Scanning Calorimeter DSC823^e (Mettler Toledo). Aluminum crucibles 40 μl with PIN were used for sample preparation. Usual weight of sample was 1.5 - 3.5 mg.

[0061] Program: temperature range at least 30 - 350⁰C, heating rate 10°C/min, nitrogen flow 50 ml/min.

TGA

[0062] TGA measurements were performed on Thermo gravimetric analyzer TGA851^e (Mettler Toledo). Alumina crucibles 70 μl were used for sample preparation. Usual weight of sample was 7 - 13 mg.

[0063] Program: temperature range at least 30⁰C - 350⁰C, heating rate 10°C/min; nitrogen flow 50°C/min.

Example 1 : Preparation of dasatinib form BN

[0064] Dasatinib (Form A21, an isopropanol-DMSO solvate, 300 mg) was dissolved in isosorbide dimethyl ether (1.75 ml) by heating 5 min at 140 ⁰C. The solution was allowed to cool spontaneously to 20 ⁰C within about 15 minuted and then allowed to stand for 1 hr at 20 ⁰C. Crystals were recovered by filtration, washed with t-BME (10 ml) and dried on air for 1 h.

Example 2: Preparation of dasatinib form BR

[0065] Dasatinib (form C, a DMSO solvate, 0.5 g ) was dissolved in 1.0 ml of N,N'-dimethylethylene urea at 55-60 ⁰C. The solution was stirred at RT for 10 minutes, then 2 it was stirred at ice bath for 2 hours. The clear solution was given to the fume hood and left to crystallize 11 days. The product was filtered and dried under N2 for 30 minutes.

Example 3: Preparation of dasatinib form BS

[0066] Dastinib (form Hl-7, monohydrate, 0.5g) was dissolved in 1.0 ml of N₅N'- dimethyl-N,N'-propylene urea at 55-60⁰C. The solution was cooled during 30 min. cooling to 25°C over 30 minutes and 2ml of water were added. Then, the was stirred at RT for 60 minuted. The product was filtered, washed with water, and dried under N2 for 60 minutes at ambient temperature and then at 60 ⁰C for 60 minutes.

Claims

What is claimed is:

1. A solvate of Dasatinib selected from the group consisting of: an isosorbide dimethyl ether solvate of Dasatinib, a N,N'-dimethylethylene urea solvate of Dasatinib, and a N,N'-dimethyl-N,N'-propylene urea solvate of Dasatinib

2. An isosorbide dimethyl ether solvate of Dasatinib characterized by data selected from the group consisting of: a PXRD pattern having peaks at about 6.1 and 23.7 ± 0.2 degrees 2-theta and any 3 peaks at positions selected from the group consisting of: 12.1, 15.0, 16.5, 18.2, 21.5, and 24.2; a powder XRD pattern as depicted in Figure 1 , and a combination thereof.

3. The isosorbide dimethyl ether solvate of Dasatinib of claim 2, further characterized by data selected from the group consisting of: a powder XRD pattern with peaks at about 6.1, 12.1, 15.0, 18.2 and 21.5 ± 0.2 degrees 2-theta; a powder XRD pattern with peaks at about 12.1, 15.0, 16.5, 23.7 and 24.2 ± 0.2 degrees 2-theta; a weight loss of of less than about 4.0%, at temperatures of about 35⁰C to about 115⁰C, and less than about 15.5%, at temperatures of about 125⁰C to about 135⁰C, as measured by TGA; a TGA thermogram as depicted in Figure 2; and combinations thereof.

4. A N,N'-dimethylethylene urea solvate of Dasatinib characterized by data selected from the group consisting of: a PXRD pattern having peaks at about 5.0 and 10.0 ± 0.2 degrees 2-theta and any 3 peaks at positions selected from the group consisting of: 8.7, 13.7, 15.0, 17.5, 21.5, 22.4, 24.2 and 25.9 ± 0.2 degrees 2-theta; a powder XRD pattern as depicted in Figure 3.

5. The N,N'-dimethylethylene urea solvate of Dasatinib of claim 4, further characterized by data selected from the group consisting of: a powder XRD pattern with peaks at about 5.0, 8.7, 15.0, 17.5 and 21.5 ± 0.2 ± 0.2 degrees 2- theta; a powder XRD pattern with peaks at about 10.0, 13.7, 17.5, 22.4 and 25.9 ± 0.2 ± 0.2 degrees 2-theta; a weight loss of less than about 14.1%, at temperatures of about 25⁰C to about 148⁰C, and less than about 6.2%, at temperatures of about 148⁰C to about 224⁰C, and less than about 7.9%, at temperatures of about 224⁰C to about 281⁰C, as measured by TGA; a TGA thermogram as depicted in Figure 4; and combinations thereof.

6. A N,N'-dimethyl-N,N'-propylene urea solvate of Dasatinib characterized by data selected from the group consisting of: a PXRD pattern having peaks at about 5.7 and 11.4 ± 0.2 degrees 2-theta and any 3 peaks at positions selected from the group consisting of: 12.6, 13.0, 17.4, 17.8, 19.5, 19.9, 22.0 and 22.6± 0.2 degrees 2-theta; a powder XRD pattern as depicted in Figure 5.

7. The N,N'-dimethyl-N,N'-propylene urea solvate of Dasatinib of claim 6, further characterized by data selected from the group consisting of: a powder XRD pattern with peaks at about 11.4, 12.6, 13.0, 17.4 and 17.8 ± 0.2 degrees 2-theta; a powder XRD pattern with peaks at about 5.7, 17.4, 19.5, 19.9 and 22.6 ± 0.2 degrees 2-theta; a weight loss of less than about 15.0%, at temperatures of about 7O⁰C to about 22O⁰C, and less than about 13.4%, at temperatures of about 22O⁰C to about 28O⁰C, as measured by TGA; a TGA thermogram as depicted in Figure 6; and combinations thereof.

8. A Dasatinib solvate as defined in any of claims 1-7 for use as a medicament.

9. Use of a Dasatinib solvate as defined in any of claims 1-7 for the manufacture of a medicament for treating chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

10. A pharmaceutical composition comprising a Dasatinib solvate as defined in any of claims 1-7.