WO2014167436A2 - Sel glucuronate de sunitinib et procédé pour sa préparation - Google Patents

Sel glucuronate de sunitinib et procédé pour sa préparation Download PDF

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Publication number
WO2014167436A2
WO2014167436A2 PCT/IB2014/060023 IB2014060023W WO2014167436A2 WO 2014167436 A2 WO2014167436 A2 WO 2014167436A2 IB 2014060023 W IB2014060023 W IB 2014060023W WO 2014167436 A2 WO2014167436 A2 WO 2014167436A2
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WO
WIPO (PCT)
Prior art keywords
sunitinib
glucuronic acid
acid addition
addition salt
glucuronate
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PCT/IB2014/060023
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English (en)
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WO2014167436A3 (fr
Inventor
Rampalli SRIRAM
Upalla LAVKUMAR
Seshagiri VIJAYA MURALI MOHANRAO
Pradeep SHIVAKUMAR
Akshaykant CHATURVEDI
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Shilpa Medicare Limited
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Application filed by Shilpa Medicare Limited filed Critical Shilpa Medicare Limited
Publication of WO2014167436A2 publication Critical patent/WO2014167436A2/fr
Publication of WO2014167436A3 publication Critical patent/WO2014167436A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to novel pharmaceutically acceptable glucuronic acid addition salt of Sunitinib (I) or its solvate thereof.
  • the present invention further relates to the processes for preparation of the glucuronic acid addition salt of Sunitinib.
  • Glucuronic acid addition salt of Sunitinib (I) prepared according to the process of the present invention is obtained as a solid material.
  • the pharmaceutical compositions comprising glucuronic acid addition salt of Sunitinib or its solvate thereof may be useful as anti-cancer agent.
  • Sunitinib is chemically described as N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro- 1,2- dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-lH-pyrrole-3-carboxamide and is represented by Formula (la).
  • the malic acid salt of Sunitinib is a kinase inhibitor and has been approved by US FDA as SUTENTTM for the treatment of Gastrointestinal Stromal Tumor (GIST) after disease progression on or intolerance to imatinib mesylate, advanced Renal Cell Carcinoma (RCC) and progressive, well-differentiated pancreatic NeuroEndocrine Tumors (pNET) in patients with unresectable locally advanced or metastatic disease.
  • GIST Gastrointestinal Stromal Tumor
  • RRCC Renal Cell Carcinoma
  • pNET pancreatic NeuroEndocrine Tumors
  • This patent application discloses general salts of Sunitinib such as acid addition salts and salts formed when acidic proton present in the parent compound is either replaced by a metal ion or coordinates with an organic base. However, this patent does not describe about the preparation of any salts of Sunitinib and their polymorphic forms.
  • compositions comprising of glucuronic acid addition salt of Sunitinib (I) or solvate thereof, which may be useful in the treatment of various cancerous disorders.
  • the present invention provides glucuronic acid addition salt of Sunitinib represented by Formula (I)
  • glucuronic acid addition salt of Sunitinib contains Sunitinib base and glucuronic acid in about 1:1 proportion.
  • glucuronic acid addition salt of Sunitinib or solvate thereof exists in a crystalline form or as an amorphous solid.
  • step d) optionally adding another solvent selected from water, C2-C5 ether, C2-C5 ester or a C3-C6 ketonic solvent, to the reaction mixture of step d) during the stirring process;
  • glucuronic acid addition salt of Sunitinib obtained by the process of the present invention is crystalline in nature and is characterized by X-ray powder diffraction pattern comprising of at least three 20° peaks selected from the XRPD peak set of 3.9, 14.6, 18.4, 25.6 and 27.6 + 0.2 20° and DSC isotherm comprising of at least one endothermic peak ranging between 115 to 130 °C.
  • This crystalline form of Sunitinib Glucuronate is designated as Form-SG2.
  • crystalline glucuronic acid addition salt of Sunitinib obtained from the process of the present invention, is characterized by X-ray powder diffraction pattern comprising of at least 4 characteristic 20° peaks selected from the XRPD peak set of 10.1, 11.3, 13.7, 15.1, 18.6, 19.7 and 24.9 + 0.2 20° and DSC isotherm comprising of at least one endothermic peak ranging between 160 to 185 °C or between 210 to 230 °C.
  • This crystalline form of Sunitinib Glucuronate is designated as Form-SGl.
  • the present invention also relates to a composition
  • a composition comprising glucuronic acid addition salt of Sunitinib or a hydrate or solvate thereof together with one or more pharmaceutically acceptable excipients, which may be useful in the treatment of various cancerous disorders. Further particular aspects of the present invention are detailed in the description of the invention, wherever appropriate.
  • Fig. 1 is illustration of X-ray powder diffraction ("XRPD") pattern of Sunitinib Glucuronate (I) obtained as per Example- 1.
  • XRPD X-ray powder diffraction
  • Fig. 2 is illustration of Differential Scanning Calorimetry ("DSC") curve of Sunitinib Glucuronate (I) as per Example- 1.
  • DSC Differential Scanning Calorimetry
  • Fig. 3 is illustration of X-ray powder diffraction ("XRPD") pattern of Sunitinib Glucuronate (I) obtained as per Example-3.
  • Fig. 4 is illustration of Differential Scanning Calorimetry ("DSC”) curve of Sunitinib Glucuronate (I) as per Example-3.
  • XRPD X-ray powder diffraction
  • DSC Differential Scanning Calorimetry
  • embodiments of the present invention relate to novel glucuronic acid addition salt of Sunitinib (I) or solvate thereof and processes for its preparation.
  • it provides glucuronic acid addition salt of Sunitinib represented by Formula (I),
  • Sunitinib contains Sunitinib base and glucuronic acid in a ratio of about 1: 1.
  • Ratio of about 1: 1 means that the glucuronic acid addition salt of the present application has Sunitinib base and glucuronic acid in stoichiometric ratio of 1: 1.
  • This composition may vary up to range of + 5% (mole ratios) i.e. stoichiometric ratio may range from 1: 0.95 to 1: 1.05, without deviating from the spirit of the invention.
  • Said compositions of about 1: 1 stoichiometric ratio are found to retain the characteristic XRPD diffraction pattern along with other solid state parameters.
  • Glucuronic acid content in glucuronic acid addition salt of Sunitinib ranges from 31.5-33.5 % w/w as determined by titrimetry (on dried basis).
  • glucuronic acid addition salt of Sunitinib represented by Formula (I) or solvate thereof may be obtained as a crystalline solid or as an amorphous material.
  • glucuronic acid addition salt of Sunitinib prepared according to the process of this invention, is obtained in a crystalline form and is characterized by:
  • crystalline glucuronic acid addition salt of Sunitinib characterized by X-ray powder diffraction pattern comprising of at least three 20° peaks selected from the XRPD peak set of 3.9, 14.6, 18.4, 25.6 and 27.6 + 0.2 20°, and/or, DSC isotherm comprising of at least one endothermic peak ranging between 115 to 130 °C.
  • This crystalline form of Sunitinib Glucuronate (I) is designated as Form-SG2.
  • DSC isotherm of crystalline Form-SG2 of Sunitinib Glucuronate may also show presence of other endothermic peaks.
  • Crystalline Form-SG2 of Sunitinib Glucuronate is further characterized by X-ray powder diffraction pattern comprising of diffraction angle peaks at about 7.9, 11.8, 20.9, 23.7, 26.7 + 0.2 20°.
  • the diffraction angle peaks at about 3.9, 11.8 and 18.4 + 0.2 20° are characterized by relative intensities of at least 20%.
  • Diffraction angle peak at about 18.4 ⁇ 0.2 20° is preferably a single un-split peak.
  • Table- 1 Characteristic XRPD Peaks of Crystalline Sunitinib Glucuronate (Form-SG2)
  • D-spacing values are calculated with observed 2 theta angles and copper K a wavelength using the Bragg equation well known to those of having skill in the art of XRPD diffractometry science.
  • the preferred method of comparing X-ray powder diffraction patterns in order to identify a particular crystalline form is to overlay the X-ray powder diffraction pattern of the unknown form over the X-ray powder diffraction pattern of a known form.
  • Glucuronic acid addition salt of Sunitinib can be converted into its amorphous form or its solid dispersion with suitable pharmaceutically acceptable excipients which are preferably selected from polyvinylpyrrolidones (povidones for e.g. Plasdone-K), copolymers of N- vinylpyrrolidone, gums, cellulose derivatives (for e.g. hydroxypropyl methylcelluloses- HPMC), mannitol, cyclodextrins, gelatins, sugars, polyhydroxy alcohols, polyethylene glycols, polyethylene oxides, polyoxyethylene derivatives, polyvinylalcohols, propylene glycol derivatives, or a mixture thereof.
  • suitable pharmaceutically acceptable excipients which are preferably selected from polyvinylpyrrolidones (povidones for e.g. Plasdone-K), copolymers of N- vinylpyrrolidone, gums, cellulose derivatives (for e.g.
  • Amorphous form of Sunitinib Glucuronate may be prepared by techniques known to the person skilled in art, such techniques comprising but not limited to dissolving in an organic solvent and suitably utilizing spray drying or film drying methods.
  • amorphous form of Sunitinib Glucuronate was prepared by using rotavapor technique in presence or absence of reduced pressure conditions.
  • the novel salt form of Sunitinib i.e. Sunitinib glucuronate as described by the present application has been found to be quite stable and easy to handle and store for longer time without any measurable changes in its morphology and physicochemical characteristics, while retaining its properties within the defined limits. This may offer advantages for large scale manufacturing in terms of handling, storage, shelf life and favorable impurity profile. Besides the physical/chemical properties, the novel salt form of the current application further provides advantage in terms of solubility of the drug and hence provides possibility of better bioavailability and pharmacological profile.
  • step d) optionally adding another solvent selected from water, C 2 -C5 ether, C 2 -C5 ester or a C3-C6 ketonic solvent, to the reaction mixture of step d) during the stirring process;
  • Step a) comprises providing a solution of Sunitinib base in a water-miscible organic solvent
  • Sunitinib base from any source is added to the water-miscible organic solvent, selected from Q-C 4 alcohol, DMSO (dimetylsulfoxide), DMF (dimethylformamide), NMP (N-methylpyrrolidone) and THF (tetrahydrofuran).
  • Ci-C 4 alcohol is used 15-50 times v/w (mL/g) w.r.t. weight of Sunitinib base. The reaction mass is stirred for 5 to 60 mins depending upon the dissolution of Sunitinib base.
  • Ci-C 4 alcohol used in this step may be selected from methanol, ethanol, n-propanol or iso-propanol.
  • a solution of Sunitinib base is provided in ethanol at an ambient temperature of 20-35 °C.
  • Amount of ethanol used to provide the said solution ranges from 20 times v/w (mL/g) w.r.t. the weight of Sunitinib base.
  • the reaction mixture is stirred for time duration of 10 mins to achieve dissolution.
  • Step b) comprises optionally heating the reaction mixture to a temperature of 50-55 °C, wherein the raising of temperature is carried out in a gradual manner. Temperature higher than 55 °C shall also be within the scope of the present invention, as per the requirements of the reaction.
  • Step c) comprises addition of glucuronic acid of Formula (A) to the reaction mixture;
  • glucuronic acid of Formula (A) is added in the mole ratio of 1.0 to 1.5 w.r.t. amount of Sunitinib base. Addition of glucuronic acid to the reaction mixture is done at a temperature ranging between 20-80 °C. Glucuronic acid may optionally be added to the reaction mixture in the form of a solution in water or a suitable organic solvent (concentration of 15-25 % w/w). When glucuronic acid is added to the reaction mixture in solution form, addition is performed slowly over time duration of 10-30 mins.
  • Step d) comprises stirring the reaction mass for time duration ranging from 30 mins-20 hrs;
  • the reaction mass obtained in step c) is stirred for time duration ranging between 30 mins-20 hrs.
  • Stirring may be performed in a single continuous time period or intermittently with certain time gaps for some reaction processing procedures.
  • solid material slowly starts emitting from the earlier obtained clear reaction mixture. After emission of the solid material, the reaction mass is further subjected to stirring for time duration of 2-20 hrs.
  • an anti-solvent like water or other organic solvents like C 2 -C5 ether (Eg. Diethylether, THF etc.), C 2 -C5 ester (Eg. ethylacetate) or a C 3 - C 6 ketonic solvent (Eg. acetone, methylisobutyl ketone etc.) may be added to the reaction mixture (Step e).
  • the amount of C 3 -C 6 ketonic solvent (preferably acetone) added to the reaction mixture may range from 40-70 times in volume (mL) w.r.t. the amount of Sunitinib base (in g) initially taken for the reaction.
  • Step f) comprises isolating Sunitinib Glucuronate (I) as a solid material.
  • the reaction mixture is cooled to a temperature of 20-30 °C, in case it was initially raised to a temperature of 50-55 °C. Rate of cooling shall not exceed 1 °C/ minute. Controlled rate of cooling is essential for obtaining the end product complying with the purity parameters and the pre-defined characteristic solid state features. Additional stirring may be carried out after lowering the temperature of the reaction mixture.
  • the reaction mass obtained is filtered to get a solid material. Filtration may be performed by any conventional method known to the person having skill in the art.
  • the solid material obtained from filtration is optionally given washing with an organic solvent selected from a Ci-C 4 alcohol like methanol and ethanol or a C3-C6 ketonic solvent like acetone.
  • the organic solvents used for washing the said solid material may be utilized in a low temperature state and in amount 2-5 times in volume (mL) w.r.t. the amount of Sunitinib base (in g) initially taken for the reaction.
  • the wet solid material is then dried at a temperature above 45 °C for a time duration ranging between 36-84 hrs, thus providing the pure solid glucuronic acid addition salt of Sunitinib as end product.
  • Reduced pressure conditions may be suitably utilized by person skilled in the art in order to isolate the glucuronic acid addition salt of Sunitinib.
  • the present process for preparation of Sunitinib Glucuronate solid forms is easily achievable, commercially viable and amenable for up scaling.
  • Process of isolating solid Sunitinib Glucuronate may also comprise other processes but not limited to conventional processes including scrapping, if required filtering from slurry and drying, which may be carried out at room temperature or a bit raised temperature for the suitable durations.
  • the process related impurities, including unreacted intermediates, side products, degradation products, residual solvents and other medium dependent impurities, that appear in the impurity profile of the Sunitinib Glucuronate may be substantially removed by the process of the present invention resulting in the formation of pure crystalline form of Sunitinib Glucuronate.
  • the process may require in-process quality checks to avoid unnecessary repetitions of the same process steps.
  • Substantially pure solid Sunitinib Glucuronate obtained according to the process of the present invention results in the final API purity by HPLC of more than 99.5 % w/w.
  • the moisture content of the final API obtained by the process of the present invention is about 1%; however it may be more or less than 1% without deviating from the scope of the invention.
  • moisture content may be higher.
  • the end product may be obtained as an anhydrous, hydrate or solvate form, which may be a crystalline solid or an amorphous material.
  • polymorphism is known to be a unique phenomenon in solid materials, wherein existence of different physical forms including shape, size, and arrangement of molecules in the physical state or polymorphs of same compound are known in the nature.
  • a single compound, or a salt complex may give rise to a variety of solids having distinct physical properties, which often results in substantial differences in bioavailability, stability, and other differences between production lots of formulated pharmaceutical products. Due to this reason, since polymorphic forms can vary in their chemical and physical properties, regulatory authorities often require that efforts be made to identify all polymorphic forms, e.g., hydrate or anhydrate, crystalline or amorphous, solvated or un-solvated forms, etc. of the drug substances.
  • Solid glucuronic acid addition salt of Sunitinib obtained by the process of the present invention is obtained as stable crystalline forms designated as Form-SG2 or Form-SGl.
  • Crystalline Sunitinib Glucuronate Form-SG2 and Form-SGl are very stable and have been found to retain their characteristic features in stability studies even up to 6 months, wherein the physicochemical properties remain substantially the same, without any inter-conversion to other polymorphic forms.
  • the crystalline form of glucuronic acid addition salt of Sunitinib (I) described herein may be characterized and analyzed by X-ray powder diffraction pattern (XRPD) on a Bruker AXS D8 Advance Diffractometer using X-ray source - Cu Ka radiation using the wavelength 1.5418 A and lynx Eye detector. IR study was performed on Perkin Elmer Spectrum ES Version 10.03.03 instrument. DSC was done on a Perkin Elmer Pyris 7.0 instrument. Illustrative examples of analytical data for the Sunitib glucuronate obtained in the examples are set forth in the Figs. 1-4.
  • glucuronic acid used in the present invention is found to occur naturally and may be obtainable by synthetic processes as well.
  • Glucuronic acid is a naturally occurring carboxylic acid and is reported to be present in food articles like Kombucha, which is an effervescent fermentation of sweetened tea that is used as a functional food. Otherwise, glucuronic acid is commonly found in carbohydrate chains of proteoglycans and is part of mucous animal secretions (such as saliva), cell glycocalyx and intercellular matrix.
  • glucuronic acid is involved in the xenobiotic metabolism of substances such as bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids.
  • glucuronic acid takes place in the liver of animals, including humans and other primates, and is derived from glucose. In most of the plants and mammals glucuronic acid is also a precursor of ascorbic acid, which is also known as Vitamin C. Moreover, glucuronic acid is part of the natural detoxification process in the body. Hence it has also been looked at as a treatment for certain diseases, most notably prostate cancer. In addition to removing harmful toxins in the body it also appears to regulate testosterone levels, which can help with this type of cancer.
  • the invention also relates to a composition containing glucuronic acid addition salt of Sunitinib (I) or solvate thereof.
  • the glucuronic acid addition salt of Sunitinib (I) or solvate thereof obtained by the process of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules.
  • the active product is mixed with one or more pharmaceutically acceptable excipients.
  • the drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin.
  • compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions.
  • a solvent or vehicle propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed.
  • These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents.
  • the sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
  • compositions comprising glucuronic acid addition salt of Sunitinib (I) or a hydrate or solvate thereof, of the present application include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxe
  • compositions of glucuronic acid addition salt of Sunitinib or solvate thereof of the present application may also comprise to include the pharmaceutically acceptable carriers used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.
  • Example-01 PROCESS FOR PREPARATION OF SUNITINIB GLUCURONATE 20 mL ethanol was charged into a 100 mL round bottomed flask at ⁇ 30°C and 1 g
  • Example-02 PROCESS FOR PREPARATION OF SUNITINIB GLUCURONATE 500 mL ethanol was charged into a 1 L 4-neck round bottomed flask at -25 °C and 25 g Sunitinib base was added to it. The reaction mass was stirred for -10 mins and then its temperature was increased to - 50 °C. After this, 13.4 g of D (-)-Glucuronic acid (dissolved in 62.5 mL DM water) was slowly added to the reaction mixture over a time duration of - 15 mins, wherein the reaction mass initially turned into a clear solution and then slowly a solid material started emitting. The reaction mass was further stirred for 50 mins followed by cooling to a temperature of - 20 °C.
  • Example-03 PROCESS FOR PREPARATION OF SUNITINIB GLUCURONATE 35 mL methanol was charged into a 250 mL round bottomed flask at 25-30°C and 1.0 g Sunitinib base was added to it. The reaction mass was stirred for 15 mins followed by addition of 0.534 g D (-)-Glucuronic acid to the reaction mixture, wherein the reaction mass turned into a clear solution. The reaction mass was further stirred for 30 mins till the solid material slowly started emitting from the solution. Then 60.0 mL acetone was added to the reaction mass and stirring was further continued for 17 hrs. The solid material obtained was filtered and washed with 2.0 mL acetone.
  • Example-04 PROCESS FOR PREPARATION OF SUNITINIB GLUCURONATE 35 niL methanol was charged into a 250 mL round bottomed flask at 25-30°C and 1.0 g Sunitinib base was added to it. The reaction mass was stirred for 15 mins followed by addition of 0.534 g D (-)-Glucuronic acid to the reaction mixture, wherein the reaction mass turned into a clear solution. The reaction mass was further stirred for 30 mins till the solid material slowly started emitting from the solution. After the emission of solid material, the reaction mass was further stirred for 5 hrs. Then the solid material was filtered and washed with 2.0 mL chilled methanol. The wet solid material obtained was suck dried and unloaded.

Abstract

La présente invention porte sur un nouveau sel d'addition d'acide glucuronique pharmaceutiquement acceptable du sunitinib de formule (I) ou son solvate. La présente invention porte en outre sur des procédés pour la préparation du sel d'addition d'acide glucuronique du sunitinib. Le sel d'addition d'acide glucuronique du sunitinib (I) préparé selon le procédé selon la présente invention est obtenu sous forme d'une matière solide. Les compositions pharmaceutiques comprenant du sel d'addition d'acide glucuronique du sunitinib ou son solvate peuvent être utiles comme agent anticancéreux.
PCT/IB2014/060023 2013-04-10 2014-03-21 Sel glucuronate de sunitinib et procédé pour sa préparation WO2014167436A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN1629CH2013 2013-04-10
IN1629/CHE/2013 2013-04-10
IN5614/CHE/2013 2013-12-06
IN5614CH2013 2013-12-06

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WO2014167436A2 true WO2014167436A2 (fr) 2014-10-16
WO2014167436A3 WO2014167436A3 (fr) 2015-02-19

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KR20110036588A (ko) * 2008-07-24 2011-04-07 테바 파마슈티컬 인더스트리즈 리미티드 수니티닙 아세테이트 및 이의 다형을 통한 수니티닙 말레이트의 제조 방법
EP2350056A1 (fr) * 2008-10-10 2011-08-03 Medichem, S.A. Procédé pour la préparation d'un sel de malate de 2-indolinone substituée par pyrrole en position 3
EP2477978A1 (fr) * 2009-09-16 2012-07-25 Ranbaxy Laboratories Limited Sels de sunitinib

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