WO2015107545A1 - Water soluble salts of dasatinib hydrate - Google Patents

Water soluble salts of dasatinib hydrate Download PDF

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Publication number
WO2015107545A1
WO2015107545A1 PCT/IN2014/000782 IN2014000782W WO2015107545A1 WO 2015107545 A1 WO2015107545 A1 WO 2015107545A1 IN 2014000782 W IN2014000782 W IN 2014000782W WO 2015107545 A1 WO2015107545 A1 WO 2015107545A1
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WO
WIPO (PCT)
Prior art keywords
dasatinib
monohydrate
methane sulphonate
methane
water soluble
Prior art date
Application number
PCT/IN2014/000782
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English (en)
French (fr)
Inventor
Dharmesh Mahendrabhai Shah
Guruprasad Ramchandra Wader
Original Assignee
Dharmesh Mahendrabhai Shah
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dharmesh Mahendrabhai Shah filed Critical Dharmesh Mahendrabhai Shah
Publication of WO2015107545A1 publication Critical patent/WO2015107545A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the present invention relates to stable water soluble salts of Dasatinib monohydrate and process for the preparation ther eof.
  • the invention also describes an improved, commercially adoptable process for preparing pure Dasatinib Monohydrate.
  • Dasatinib is a small molecule tyrosine kinase inhibitor which is used to treat disorders like chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL).
  • Dasatinib activity lies in inhibition of cellular signalling by targeting multiple receptor and cellular tyrosine kinases including Bcr-Abl, Src, cKit and platelet-derived growth factor receptor ⁇ (PDGFR).
  • Dasatinib is from a class of compounds of 5 - thiazole carboxamide series having anti - neoplastic activity. These products are disclosed in WO Patent Publication Number 00/62778 and US Pat No. 6,596,746. US Patent application No. 2005/0215795 Al described fine crystalline forms of Dasatinib. Dasatinib is chemically known as N - (2 - chloro - 6 - methylphenyl) - 2 - [ [6 - [4- (2 - hydroxymethyl) - 1 - piperazinyl] - 2 - methyl - 4 - pyrimidinyl] amino] - 5 - thiazole carboxamide and is represented by following structure (I). Dasatinib has a stable form of crystalline mono hydrate namely Dasatinib Monohydrate (II) which is first disclosed in WO 2005/077945.
  • II Dasatinib Monohydrate
  • patent application No 4309/DELNP/2006A describes Dasatinib monohydrate.
  • Dasatinib and its pharmaceutical effects on immunologic and oncologic disorders are known from WO 00/62778; WO 2006/135790 and WO 2007/047893.
  • WO 00/62778 and WO 2005/077945 disclose a process of preparing Dasatinib.
  • WO 2007/035874 and WO 2006/121742 describe pharmaceutical formulations comprising Dasatinib for oral administration.
  • Dasatinib is administered orally in a dose of 20 to 100 mg twice daily, which, if necessary, may be varied according to individual tolerance and safety.
  • Film coated tablets comprising the crystalline monohydrate of Dasatinib are sold under the brand name Sprycel® (by Bristol Myers Squibb), which is described in WO 2005/077945.
  • Dasatinib is a poorly water soluble drug and commercial Dasatinib is a monohydrate reported to have solubility of 8 ⁇ g/mL at 24 °C.
  • Dasatinib monohydrate has poor solubility in most of the solvents and therefore requires large amount of solvents or mixture of solvents during purification to obtain product of higher purity. Very often, repeated crystallizations are required to obtain Dasatinib Monohydrate (II) of desired purity for use in formulation as per ICH guidelines escalating the cost of production.
  • Dasatinib Monohydrate (II) is almost insoluble in' water and due to the poor solubility in other solvents; consequently, the bio-availability of Dasatinib monohydrate is very less.
  • the poor solubility is the cause of poor bio-availability of the drug and thereby affects the therapeutic efficacy upon administration.
  • Dasatinib is available as oral dosage forms only and preparation of no other dosage form such as inj ectable form is available due to the poor solubility of the drug.
  • the objective of the invention is to provide an efficient and robust process for preparation of Dasatinib monohydrate with higher purity by providing Stable Water Soluble salt of Dasatinib Monohydrate.
  • Stable Water Soluble salts of Dasatinib Monohydrate which can have more solubility & higher Bioavailability and can be suitable for preparing Injectable Formulations, are also being provided.
  • the present invention provides an efficient and robust process for preparation of Dasatinib monohydrate with higher purity by providing Stable Water Soluble forms of Dasatinib Monohydrate.
  • the process for preparation of Dasatinib monohydrate which comprises:
  • the above reaction is preferably carried out in presence of DMSO or N-methyl pyrolidone at a temperature ranging from 70-100°C.
  • the step of purification comprises dissolving Dasatinib Monohydrate in methanol and treated with methane sulfonic acid to obtain clear solution, which is further treated with suitable base to obtain Dasatinib Monohydrate (II) of purity above 99%.
  • the base is selected from sodium hydroxide, potassium hydroxide or ammonia.
  • the water soluble form of Dasatinib monohydrate according to the invention is dasatinib monohydrate methane sulphonate salt having water content of 3 to 8%; preferably 3 to 5%.
  • the invention provides Dasatinib Monohydrate methane sulphonate salt which is characterized by XRD pattern having characteristic peaks approximately at 15.21, 16.94, 21.44 , 25.04, 25.9 ,26.8 and 29.2 ⁇ 0.20 degrees 2 theta angle.
  • Dasatinib Monohydrate methane sulphonate salt which is characterized by DSC having endotherm at 180 to 192.48°C with melting range from 176 to 191°C.
  • the invention provides a process for purification of Dasatinib monohydrate which comprises,
  • the base according to this aspect may be selected from sodium hydroxide, potassium hydroxide or ammonia.
  • Dasatinib Monohydrate methane sulphonate salt prepared by the present process is highly soluble both in water and lower alcohol and hence provides higher Bioavailability. Accordingly, lgm of Dasatinib methane sulphonate Monohydrate/hydrate dissolves in 30 ml water (as defined in IP/ USP) and also in 30 ml Methanol.
  • Dasatinib monohydrate can also be advantageously used for preparing Injectable Formulations.
  • the invention provides pharmaceutical compositions comprising Dasatinib Monohydrate methane sulphonate salt in association with one or more pharmaceutical excipients.
  • the pharmaceutical composition of the invention can be conveniently administered to a patient in oral 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, sachets, troches and lozenges as well as liquid syrups, suspensions and elixirs. Liquid dosage forms also include injectable preparations.
  • the active ingredient (s) and excipients can be formulated into compositions and dosage forms according to methods known in the art. Selection of particular excipients and the amounts to use can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
  • the invention provides method of treatment for chronic myeloid leukemia and acute lymphoblastic leukemia in a subject which method comprises administering oral liquid and injectable compositions comprising soluble salts of Dasatinib methane sulphonate monohydrate to a subject in need thereof.
  • the invention provides use of water soluble Dasatinib methane sulphonate monohydrate for treating chronic myeloid leukemia and acute lymphoblastic leukemia in a subject.
  • the invention provides use of water soluble Dasatinib methane sulphonate monohydrate for preparation of oral liquid and injectable preparations for treating chronic myeloid leukemia and acute lymphoblastic leukemia in a subject.
  • Fig 1 depicts PXRD of Dasatinib Methane Sulphonate Hydrate
  • Fig 2 depict DSC of Dasatinib Methane Sulphonate Hydrate
  • Fig 3 depict IR of Dasatinib Methane Sulphonate Hydrate
  • the present invention provides an efficient process for the synthesis of Pure Dasatinib Monohydrate (II) free base and stable water soluble salts of Dasatinib monohydrate and process for its preparation.
  • the invention provides an efficient process for the synthesis of Dasatinib Monohydrate (II) by reacting 2 - (6 - chloro - 2 - methylpyrimidine - 4 - yl - amino) - N - (2 - chloro - 2 - methylphenyl) thiazole - 5 - carboxamide (III) with 2 - hydroxylmethyl piperazine (IV) in presence of Potassium Iodide and Di-isopropylethylamine. (Schenie-1) The reaction is conveniently carried out in presence of DMSO or N-methyl pyrolidone at a temperature ranging 70-100°C for approximately 3 to 4 hrs. The reaction mixture is quenched with water to obtain slurry, which is filtered and washed with chilled methanol to obtain Dasatinib Monohydrate (II) with HPLC purity of up to 95%.
  • the invention provides a process for the purification of Dasatinib Monohydrate (II) by formation of easily soluble Methane Sulphonate monohydrate salt of Dasatinib (V) (scheme 2).
  • Dasatinib Monohydrate is dissolved in methanol and treated with methane sulfonic acid to obtain clear solution, which is further treated with suitable base to obtain Dasatinib Monohydrate (II) of accepted purity.
  • the base may be selected from sodium hydroxide, potassium hydroxide or ammonia.
  • Dasatinib Monohydrate (II) thus obtained is further purified by crystallization from a mixture of methanol and water to obtain Dasatinib Monohydrate with a water content ranging from 3. '4 to 4.5 % and with purity of more than 99.5%.
  • the XRD of Dasatinib monohydrate obtained according to the process of the present invention is shown in figure 4.
  • the instant inventors have prepared different pharmaceutically acceptable salts of Dasatinib Monohydrate (II) such as Dasatinib Formate, Dasatinib Tartarate, Dasatinib Tosylate, Dasatinib Lactate, Dasatinib Palmoate, Dasatinib Methane sulfonate and Dasatinib Lactobionate, for studying the solubility behavior
  • Dasatinib Formate Dasatinib Tartarate, Dasatinib Tosylate, Dasatinib Lactate, Dasatinib Palmoate and Dasatinib Lactobionate failed at water solubility tests ; however, Methane sulfonate salt of Dasatinib hydrate (V) exhibits good water solubility.
  • Methane sulfonate salt of Dasatinib monohydrate (V) of the present invention is also soluble in other solvents. Accordingly, in yet another preferred embodiment, the invention provides stable Dasatinib Methane sulfonate monohydrate salt (V). Accordingly, Dasatinib Monohydrate obtained in the previous embodiment is treated with Methane Sulphonic acid in methanol to obtain clear solution, which is stirred; filtered; concentrated and cooled to obtain crystalline Dasatinib Methane Sulfonate Monohydrate (II), having water content in the range of 3 to 8 %, preferably, 3 to 5 %.
  • Dasatinib Methane Sulfonate can also be prepared as dihydrate, trihydrate or sesquihydrate by controlling the moisture content.
  • the Dasatinib Methane Sulphonate Monohydrate salt (V) thus obtained is isolated, purified and characterized as a stable novel salt of dasatinib monohydrate form.
  • the novel methane sulphonate monohydrate salt of Dasatinib is subjected to solubility tests and found that the same has high water and solvents solubility and is a stable storable product.
  • DSCs were recorded using Perkin Elmer Pyris 1 instrument. Sample (2.5mg) were weighed into DSC pans; the DSC profiles were recorded at heating rate of 10°C/min), range from 45 to 250°C. The DSC experiments were run using pans that were open, closed, or closed with a corner hole. b) FT-IR spectral analysis
  • FTIR spectra of the dasatinib methane sulphonate monohydrate was obtained using a dispersion (0.5%) in alkali Halide (KBr) disk and directly on untreated powder by means of spectrometer. Spectra was recorded at room temperature from 4000 cm “1 to 650 cm “1 , for each sample 32 scans were collected at a resolution of 4 cm “1 . c) X-ray powder diffraction studies
  • the PXRD pattern was measured on a Phillips, Holand, and Xpert MPD powder X-Ray Diffractometer.
  • the Dasatinib Methane Sulphonate monohydrate thus obtained is subjected to spectral evaluation such as XRD using XRD, Phillips, Holand, and Xpert MPD ( Figure 1); DSC using Perkin Elmer Pyris 1 (figure 2) and IR ( Figure 3).
  • the Dasatinib Methane Sulphonate monohydrate is characterized by an XRD pattern comprising characteristic peaks approximately at least at 15.21 , 16.94, 21.44, 25.04, 25.9, 26.8 and 29.2 ⁇ 0.02 degrees 2 theta angle ( Figure 1).
  • the Dasatinib Methane Sulphonate monohydrate is characterized by DSC (figure 2) having endotherm at 180 to 192.48°C with melting range from 176 to 191°C.
  • the inventors have further found that the process for preparation of Dasatinib monohydrate and its Methane Sulfonate salt according to the invention is easily adoptable for commercial production.
  • the Methane Sulfonate salt of Dasatinib hydrate (V) has higher solubility and bioavailability compared to Dasatinib or its monohydrate.
  • Methane Sulfonate Hydrate salt of Dasatinib (V) has been found to provide optimum solubility and bioavailability. Further, on preliminary evaluation, it has also been found that Methane Sulfonate salt of Dasatinib hydrate provides enhanced efficacy due to its good solubility and bioavailability.
  • Methane Sulfonate salt of Dasatinib hydrate of the instant invention is highly suitable not only for oral solid dosage forms but also for liquid dosage forms including parenteral dosage forms.
  • the invention provides pharmaceutical compositions comprising Dasatinib Monohydrate methane sulphonate salt in association with one or more pharmaceutical excipients.
  • the pharmaceutical composition of the invention can be conveniently administered to a patient in oral 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, sachets, troches and lozenges as well as liquid syrups, suspensions and elixirs. Liquid dosage forms also include injectable preparations.
  • the active ingredient (s) and excipients can be formulated into compositions and dosage forms according to methods known in the art. Selection of particular excipients and the amounts to use can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
  • the invention provides method of treatment for chronic myeloid leukemia and acute lymphoblastic leukemia in a subject .
  • which method comprises administering oral liquid and injectable compositions comprising soluble salts of Dasatinib methane sulphonate monohydrate to a subject in need thereof.
  • the invention discloses use of water soluble Dasatinib methane sulphonate monohydrate for treating chronic myeloid leukemia and acute lymphoblastic leukemia in a subject.
  • the invention provides use of water soluble Dasatinib methane sulphonate monohydrate for preparation of oral liquid and injectable preparations for treating chronic myeloid leukemia and acute lymphoblastic leukemia in a subject.
  • the yellow powder of Dasatinib Hydrate crude obtained in the example 1 was taken in 200 ml methanol and warmed to 50°C. To this slurry, 1 1 ml methane sulfonic acid was added and stirred for 10 minutes to obtain a clear solution. To this clear solution, 4 gm. of activated carbon was added and stirred for 1 hour. The solution was then filtered through filter-aid to obtain pale off-white solution.
  • Moisture content 3.4 to 4 % shows monohydrate nature.
  • Solubility 100 mg. in 3 ml of water, clear solution
  • the Dasatinib Methane Sulphonate Hydrate thus obtained is characterized by X-Ray Powder Diffraction Pattern having characteristic peaks at approximately 15.21, 16.94 , 21.44, 25.04, 25.9, 26.8 and 29.2 ⁇ 0.20 degrees 2 theta angle.

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  • Organic Chemistry (AREA)
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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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PCT/IN2014/000782 2013-12-18 2014-12-17 Water soluble salts of dasatinib hydrate WO2015107545A1 (en)

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IN3610/MUM/2013 2013-12-18
IN3610MU2013 IN2013MU03610A (enrdf_load_stackoverflow) 2013-12-18 2014-12-17

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019209908A1 (en) 2018-04-25 2019-10-31 Johnson Matthey Public Limited Company Crystalline forms of dasatinib

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000062778A1 (en) 1999-04-15 2000-10-26 Bristol-Myers Squibb Co. Cyclic protein tyrosine kinase inhibitors
WO2005077945A2 (en) 2004-02-06 2005-08-25 Bristol-Myers Squibb Company Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors
US20050215795A1 (en) 2004-02-06 2005-09-29 Bang-Chi Chen Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors
WO2006121742A2 (en) 2005-05-05 2006-11-16 Bristol-Myers Squibb Company Formulations of a src/abl inhibitor
WO2006135790A1 (en) 2005-06-09 2006-12-21 Bristol-Myers Squibb Company Methods of identifying and treating individuals exhibiting mutant kit protein
WO2007035874A1 (en) 2005-09-21 2007-03-29 Bristol-Myers Squibb Company Oral administration of n-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-1,3-thiazole-5-carboxamide and salts thereof
WO2007047893A2 (en) 2005-10-20 2007-04-26 Bristol-Myers Squibb Company Use of dasatinib for the treatment of bone metastasis
WO2010139979A2 (en) * 2009-06-03 2010-12-09 Generics [Uk] Limited Processes for preparing crystalline forms
WO2013157019A2 (en) * 2012-04-20 2013-10-24 Shilpa Medicare Ltd. Process for preparing dasatinib monohydrate

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000062778A1 (en) 1999-04-15 2000-10-26 Bristol-Myers Squibb Co. Cyclic protein tyrosine kinase inhibitors
US6596746B1 (en) 1999-04-15 2003-07-22 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
WO2005077945A2 (en) 2004-02-06 2005-08-25 Bristol-Myers Squibb Company Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors
US20050215795A1 (en) 2004-02-06 2005-09-29 Bang-Chi Chen Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors
WO2006121742A2 (en) 2005-05-05 2006-11-16 Bristol-Myers Squibb Company Formulations of a src/abl inhibitor
WO2006135790A1 (en) 2005-06-09 2006-12-21 Bristol-Myers Squibb Company Methods of identifying and treating individuals exhibiting mutant kit protein
WO2007035874A1 (en) 2005-09-21 2007-03-29 Bristol-Myers Squibb Company Oral administration of n-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-1,3-thiazole-5-carboxamide and salts thereof
WO2007047893A2 (en) 2005-10-20 2007-04-26 Bristol-Myers Squibb Company Use of dasatinib for the treatment of bone metastasis
WO2010139979A2 (en) * 2009-06-03 2010-12-09 Generics [Uk] Limited Processes for preparing crystalline forms
WO2013157019A2 (en) * 2012-04-20 2013-10-24 Shilpa Medicare Ltd. Process for preparing dasatinib monohydrate

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019209908A1 (en) 2018-04-25 2019-10-31 Johnson Matthey Public Limited Company Crystalline forms of dasatinib
US11440908B2 (en) 2018-04-25 2022-09-13 Johnson Matthey Public Limited Company Crystalline forms of dasatinib

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