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WO2017009784A1 - Formes à l'état solide de sel de trisodium du complexe valsartan/sacubitril et de sacubitril - Google Patents

Formes à l'état solide de sel de trisodium du complexe valsartan/sacubitril et de sacubitril Download PDF

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Publication number
WO2017009784A1
WO2017009784A1 PCT/IB2016/054173 IB2016054173W WO2017009784A1 WO 2017009784 A1 WO2017009784 A1 WO 2017009784A1 IB 2016054173 W IB2016054173 W IB 2016054173W WO 2017009784 A1 WO2017009784 A1 WO 2017009784A1
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Prior art keywords
valsartan
sacubitril
trisodium salt
complex
sodium
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English (en)
Inventor
Kumar Kamlesh SINGH
Santosh Devidas Diwakar
Shankar Dada JADHAV
Kishorkumar Maneklal Vinchhi
Tirth Harikrishna THAKER
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Zydus Lifesciences Ltd
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Cadila Healthcare Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the field of the invention relates to polymorphic forms and processes for the preparation of compounds containing S-N-valeiyl-N- ⁇ [2'-(lH-tetrazole-5-yl)- biphenyl-4-yl]-methyl ⁇ -valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxypropion- ylamino)-2-methylpentanoic acid ethyl ester moieties and cations.
  • the invention relates to crystalline and amorphous form of compounds and processes for their preparation.
  • Valsartan/sacubitril brand name Entresto, previously known as LCZ696
  • LCZ696 a combination drug consisting of two antihypertensives (blood pressure lowering drugs), valsartan and sacubitril, in a 1 : 1 mixture by molecule count developed by Novartis.
  • the combination is often described as a dual-acting angiotensin receptor-neprilysin inhibitor (ARNi) although the two effects are achieved by two different molecules. It was approved under the FDA's priority review process for use in heart failure on July 7, 2015.
  • Entresto contains a complex comprised of anionic forms of sacubitril and valsartan, sodium cations, and water molecules in the molar ratio of 1 : 1 :3 :2.5, respectively.
  • the complex is chemically described as Octadecasodiumhexakis(4- ⁇ [(l S,3R)-l-([l, -biphenyl]- 4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino ⁇ -4oxobutanoate)hexakis(N- pentanoyl-N- ⁇ [2'-(lH-tetrazol-l-id-5-yl)[l,l '-biphenyl]-4-yl]methyl ⁇ -L- valinate)-water (1/15).
  • Its empirical formula (hemipentahydrate) is C 48 H 55 N608Na3 2.5H 2 0.
  • Its molecular mass is 957.99 and its schematic structural formula is
  • LCZ696 is co-crystallized valsartan and sacubitril, in a one-to-one molar ratio.
  • One LCZ696 complex consists of six valsartan anions, six sacubitril anions, 18 sodium cations, and 15 molecules of water, resulting in the molecular formula C 288 H 3 3 0 N36Nai8O 4 8' 15H 2 0 and a molecular mass of 5748.03 g/mol.
  • the substance is a white powder consisting of thin hexagonal plates. It is stable in solid form as well as in aqueous (watery) solution with a pH of 5 to 7, and has a melting point of about 138°C.
  • U.S. 5,217,996 A discloses biaryl substituted 4-amino-butryic acid amides which includes sacubitril.
  • U.S. 8,877,938 B2 discloses trisodium [3-((l S,3R)-l- biphenyl-4ylmethyl-3-ethoxycarbonyl-l-butylcarbamoyl)propionate-(S)-3'- methyl-2'-(pentanoyl ⁇ 2"-(tetrazol-5-ylate)biphenyl-4'-ylmethyl ⁇ amino)butyrate] hemipentahydrate which is crystalline form and process for its preparation.
  • the '938 patent also discloses the pharmaceutical composition of trisodium salt of valsartan sacubitril complex.
  • WO 2016/051393 A2 discloses various crystalline forms of trisodium salt of valsartan sacubitril complex.
  • WO 2016/037098 Al discloses deuterated sacubitril.
  • the known prior art is described herein to present the invention in a proper technical context. Unless otherwise stated contrary, such disclosure should be construed as such art forms part of a common general knowledge in the field.
  • the present prior art provides trisodium salt of valsartan sacubitril complex as trisodium hemipentahydrate in crystalline form characterized by unit cell parameters and solid states MR data alongwith the x-ray powder diffraction pattern. It has been found that trisodium salt of valsartan sacubitril complex exhibits polymorphism. According to the disclosures in the prior art document, the known solid form of trisodium salt of valsartan sacubitril complex is crystalline form including hemipentahydrate. Therefore, there is a need to provide a solid form, an amorphous form, which is a suitable alternative for the preparation of trisodium salt of valsartan sacubitril complex drug product.
  • an amorphous form of trisodium salt of valsartan sacubitril complex in one general aspect, there is provided an amorphous form of trisodium salt of valsartan sacubitril complex.
  • a crystalline Form-IV of trisodium salt of valsartan sacubitril complex In another general aspect, there is provided a crystalline form of sacubitril sodium.
  • a process for the preparation of a trisodium salt of valsartan sacubitril complex comprising reacting a sacubitril sodium and a valsartan disodium or sacubitril and valsartan in the presence of sodium ion source in one or more of solvents to obtain a solution and obtaining the trisodium salt of valsartan sacubitril complex by the removal of the solvent from the solution or by adding an anti-solvent to the solution.
  • reaction mixture (a) reacting sacubitril and valsartan in the presence of sodium ion source in one or more solvents to obtain a reaction mixture;
  • reaction mixture (a) reacting sacubitril and valsartan in presence of sodium ion source in one or more first solvents to obtain a reaction mixture;
  • HX is an acid addition salt
  • HX is an acid addition salt
  • a pharmaceutical composition comprising amorphous trisodium salt of valsartan sacubitril complex having one or more of pharmaceutically acceptable carrier, diluents and excipients.
  • a pharmaceutical composition comprising crystalline Form-II of trisodium salt of valsartan sacubitril complex having one or more of pharmaceutically acceptable carrier, diluents and excipients.
  • a pharmaceutical composition comprising crystalline Form-Ill of trisodium salt of valsartan sacubitril complex having one or more of pharmaceutically acceptable carrier, diluents and excipients.
  • a pharmaceutical composition comprising crystalline Form-IV of trisodium salt of valsartan sacubitnl complex and one or more of pharmaceutically acceptable carrier, diluents and excipients.
  • the amorphous trisodium salt of valsartan sacubitril complex of present invention has a purity of more than 98% measured as area percentage by HPLC.
  • the crystalline Form-II of trisodium salt of valsartan sacubitril complex of present invention has a purity of more than 98%> measured as area percentage by HPLC.
  • the crystalline Form-Ill of trisodium salt of valsartan sacubitril complex of present invention has a purity of more than 98%> measured as area percentage by HPLC.
  • the crystalline Form-IV of trisodium salt of valsartan sacubitril complex of present invention has a purity of more than 98%> measured as area percentage by HPLC.
  • Fig. 1 Discloses x-ray powder diffractogram of crystalline Form-I of trisodium salt of valsartan sacubitril complex.
  • Fig. 2 Discloses differential scanning calorimetry (DSC) of crystalline Form-I of trisodium salt of valsartan sacubitril complex.
  • Fig. 3 Discloses thermogravimetric analysis (TGA) of crystalline Form-I of trisodium salt of valsartan sacubitril complex.
  • Fig. 4 Discloses x-ray powder diffractogram of sacubitril sodium.
  • Fig. 5 Discloses differential scanning calorimetry (DSC) of sacubitril sodium.
  • Fig. 6 Discloses thermogravimetric analysis (TGA) of sacubitril sodium.
  • Fig. 7 Discloses x-ray powder diffractogram of amorphous valsartan disodium.
  • Fig. 8 Discloses differential scanning calorimetry (DSC) of amorphous valsartan disodium.
  • Fig. 9 Discloses thermogravimetric analysis (TGA) of amorphous valsartan disodium.
  • Fig. 10 Discloses x-ray powder diffractogram of crystalline Form-II of trisodium salt of valsartan sacubitril complex.
  • Fig. 11 Discloses differential scanning calorimetry (DSC) of crystalline Form-II of trisodium salt of valsartan sacubitril complex.
  • Fig. 12 Discloses thermogravimetric analysis (TGA) of crystalline Form-II of trisodium salt of valsartan sacubitril complex.
  • Fig. 13 Discloses x-ray powder diffractogram of crystalline Form-III of trisodium salt of valsartan sacubitril complex.
  • Fig. 14 Discloses differential scanning calorimetry (DSC) of crystalline Form-III of trisodium salt of valsartan sacubitril complex.
  • Fig. 15 Discloses thermogravimetric analysis (TGA) of crystalline Form-III of trisodium salt of valsartan sacubitril complex.
  • Fig. 16 Discloses x-ray powder diffractogram of crystalline Form-IV of trisodium salt of valsartan sacubitril complex.
  • Fig. 17 Discloses x-ray powder diffraction pattern of amorphous trisodium salt of valsartan sacubitril complex as per example-14.
  • Fig. 18 Discloses x-ray powder diffraction pattern of amorphous trisodium salt of valsartan sacubitril complex as per example-15. DETAILED DESCRIPTION OF THE INVENTION
  • suspension may be interchangeable with “slurry” and refers to a heterogeneous mixture where complete dissolution does not occur. Also, heating the suspension or slurry can result in a homogenous mixture where complete or partial dissolution occurs at an elevated temperature or ambient temperature. All ranges recited herein include the endpoints, including those that recite a range "between” two values. Terms such as “about”, “general”, and “substantially,” are to be construed as modifying a term or value such that it is not an absolute. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
  • the product obtained by the process of the present invention may be further dried to achieve the desired moisture values.
  • the product may be dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
  • Particle Size Distribution means the cumulative volume size distribution of equivalent spherical diameters as determined by laser diffraction in Malvern Master Sizer 2000 equipment or its equivalent.
  • the PSD is measured as the (D 90 ), which is the size, in microns, below which 90% of the particles by volume are found, and the (D 50 ), which is the size, in microns, below which 50% of the particles by volume are found.
  • a D 90 or d(0.9) of less than 450 microns means that 90 volume-percent of the particles in a composition have a diameter less than 450 microns.
  • pharmaceutically acceptable means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable, and includes that which is acceptable for veterinary use and/or human pharmaceutical use.
  • composition is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.
  • trisodium salt of valsartan sacubitril complex herein means trisodium [3-((l S,3R)-l-biphenyl-4ylmethyl-3-ethoxycarbonyl-l-butylcarbamoyl) propionate-(S)-3'-methyl-2'-(pentanoyl ⁇ 2"-(tetrazol-5-ylate)biphi
  • solutions prior to any solid formation may, optionally, be filtered to remove any undissolved solids and/or impurities prior to removal of solvent.
  • an amorphous form of trisodium salt of valsartan sacubitril complex is provided.
  • the amorphous form of trisodium salt of valsartan sacubitril complex is also characterized by x-ray powder diffraction pattern substantially as shown in Fig.18.
  • a process for the preparation of a trisodium salt of valsartan sacubitril complex comprising reacting a sacubitril sodium and a valsartan disodium or sacubitril and valsartan in the presence of sodium ion source in one or more of solvents to obtain a solution and obtaining the trisodium salt of valsartan sacubitril complex by the removal of the solvent from the solution or by adding an anti-solvent to the solution.
  • the amorphous trisodium salt of valsartan sacubitril complex may be prepared by reacting sacubitril sodium and valsartan disodium in one or more solvents to obtain a solution and the removal of the solvent from the solution or by reacting valsartan and sacubitril in the presence of a sodium ion source.
  • the solution of valsartan disodium is prepared by reacting valsartan with 2 moles of sodium ion source.
  • the solution of sacubitril sodium may be added to the solution of valsartan disodium.
  • the solution of sacubitril sodium is prepared by reacting sacubitril with 1 mole of sodium ion source.
  • the solution of valsartan disodium may be added to the solution of sacubitril sodium.
  • the solution of sacubitril and valsartan may be prepared by dissolving sacubitril and valsartan in one or more solvents in the presence of sodium ion source.
  • the sodium ion source may be added to the solution to obtain a solution of trisodium salt of valsartan sacubitril complex.
  • the sodium ion source may be added to the solution in solid form or in form of its aqueous solution.
  • the trisodium salt of valsartan sacubitril complex obtained may be further isolated and redissolved in one or more solvents.
  • the solvents for preparation of the solution comprises one or more of alcohols selected from methanol, ethanol, 1-propanol, 2-propanol, 1- butanol, 2-butanol, 1-octanol and isopentanol; ketones selected from acetone, methyl ethyl ketone and methyl isobutyl ketone; esters selected from methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate; other solvents selected from toluene, methyl enedi chloride, acetonitrile, dimethylformamide, dimethyl sulfoxide; N-methylpyrrolidone, water, or mixture thereof.
  • methanol, ethanol, acetone, methylene dichloride or mixture thereof may be used.
  • the solvent is removed by one or more techniques selected from rotational distillation device (e.g. Buchi Rotavapor), spray drying, agitated thin film drying (“ATFD”), and freeze drying (lyophilization) to obtain the amorphous form of trisodium salt of valsartan sacubitril complex.
  • rotational distillation device e.g. Buchi Rotavapor
  • spray drying agitated thin film drying
  • freeze drying lyophilization
  • the solution, suspension or slurry comprising trisodium salt of valsartan sacubitril complex may be spray-dried to get the amorphous form.
  • the solution of trisodium salt of valsartan sacubitril complex may be evaporated using a rotational distillation device such as a Buchi rotavapor to obtain the amorphous form.
  • a rotational distillation device such as a Buchi rotavapor
  • the obtained amorphous trisodium salt of valsartan sacubitril after removal of the solvent may be isolated by adding one or more anti-solvent.
  • the anti-solvent comprises one or more of hydrocarbons selected from n-hexane, n-heptane, and cyclohexane; ethers selected from diethyl ether, diisopropyl ether, methyltertbutyl ether, and 1,4-dioxane.
  • the sacubitril sodium used for the preparation of trisodium salt of valsartan sacubitril complex may be crystalline.
  • the crystalline form of sacubitril sodium is characterized by x- ray powder diffraction pattern having characteristic peaks expressed in terms of 2- theta at about 6.3°, 12.0°, 13.8°, 16.5°, 18.3°, 20.0° and 23.8° ⁇ 0.2° (2 ⁇ ) and x-ray powder diffraction pattern substantially as same as shown in Fig. 4.
  • the crystalline form of sacubitril sodium is further characterized by differential scanning calorimetry (DSC) substantially as same as shown in Fig. 5 and thermogravimetric analysis (TGA) substantially as same as shown in Fig. 6.
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the solvent is selected from one or more of alcohols selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-octanol and isopentanol; ketones selected from acetone, methyl ethyl ketone and methyl isobutyl ketone; esters selected from methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate; other solvents selected from methylenedichloride, acetonitrile, dimethylformamide, dimethyl sulfoxide; and N- methylpyrrolidone or mixture thereof.
  • the solvent acetone may be used.
  • the sodium source is selected from sodium carbonate, sodium bicarbonate, sodium hydroxide and sodium 2-ethyl hexanoate.
  • the solvent from the solution of sacubitril sodium may be removed by one or more techniques selected from filtration, decantation, centrifugation, and evaporation to obtain crystalline sacubitril sodium.
  • the solvent from the solution of sacubitril sodium may be removed by one or more techniques selected from rotational distillation device (e.g. Buchi Rotavapor), spray drying, agitated thin film drying ("ATFD”), and freeze drying (lyophilization) to obtain amorphous form of sacubitril sodium.
  • rotational distillation device e.g. Buchi Rotavapor
  • spray drying agitated thin film drying
  • freeze drying lyophilization
  • the valsartan disodium used for the preparation of trisodium salt of valsartan sacubitril complex may be amorphous.
  • amorphous form of valsartan disodium is characterized by x-ray powder diffraction pattern substantially as same as shown in Fig. 7.
  • amorphous form of valsartan disodium is further characterized by differential scanning calorimetry (DSC) substantially as same as shown in Fig. 8 and thermogravimetric analysis (TGA) substantially as same as shown in Fig. 9.
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the solvent is selected from one or more of alcohols selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-octanol and isopentanol; ketones selected from acetone, methyl ethyl ketone and methyl isobutyl ketone; esters selected from methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate; other solvents selected from methylenedichloride, acetonitrile, dimethylformamide, dimethyl sulfoxide; N- methylpyrrolidone, water or mixture thereof.
  • the solvent acetone may be used.
  • the sodium source is selected from sodium carbonate, sodium bicarbonate, sodium hydroxide and sodium 2-ethyl hexanoate.
  • the solvent from the solution of valsartan disodium may be removed by one or more techniques selected from filtration, decantation, centrifugation, and evaporation to obtain amorphous valsartan disodium.
  • a process for the preparation of a trisodium salt of valsartan sacubitril complex comprising reacting sacubitril sodium and valsartan disodium in one or more of solvents to obtain the solution and obtaining the trisodium salt of valsartan sacubitril complex by the removal of the solvent.
  • the solvents comprises one or more of alcohols selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-octanol and isopentanol; ketones selected from acetone, methyl ethyl ketone and methyl isobutyl ketone; esters selected from methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate; other solvents selected from toluene, methylenedichloride, acetonitrile, dimethylformamide, dimethyl sulfoxide; and N- methylpyrrolidone, water or mixture thereof.
  • alcohols selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-octanol and isopentanol
  • ketones selected from acetone, methyl ethyl ket
  • a crystalline Form-I of trisodium salt of valsartan sacubitril complex is characterized by x-ray powder diffraction pattern having characteristic peaks expressed in terms of 2-theta at about 4.2°, 5.3°, 12.5°, 17.0°, and 19.4° ⁇ 0.2° (2 ⁇ ) and x-ray powder diffraction pattern substantially as same as shown in Fig. 1.
  • the crystalline Form-I of trisodium salt of valsartan sacubitril complex is further characterized by differential scanning calorimetry (DSC) substantially as same as shown in Fig. 2 and thermogravimetric analysis (TGA) substantially as same as shown in Fig. 3.
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • a crystalline Form-II of trisodium salt of valsartan sacubitril complex in another general aspect, is provided a crystalline Form-II of trisodium salt of valsartan sacubitril complex.
  • the crystalline Form-II of trisodium salt of valsartan sacubitril complex is characterized by x-ray powder diffraction pattern having characteristic peaks expressed in terms of 2-theta at about 4.1°, 4.9°, 9.8°, 12.5° and 14.7° ⁇ 0.2° (2 ⁇ ) and x-ray powder diffraction pattern substantially as shown in Fig. 10.
  • the crystalline Form-II of trisodium salt of valsartan sacubitril complex is further characterized by differential scanning calorimetry (DSC) substantially as same as shown in Fig. 1 1 and thermogravimetric analysis (TGA) substantially as same as shown in Fig. 12.
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • reaction mixture (a) reacting valsartan and sacubitril in the presence of a sodium ion source in one or more solvents to obtain a reaction mixture;
  • the solvent is selected from one or more of alcohols selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-octanol and isopentanol; ketones selected from acetone, methyl ethyl ketone and methyl isobutyl ketone; esters selected from methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate; other solvents selected from methylene dichloride, acetonitrile, dimethylformamide, dimethyl sulfoxide; N-methyl pyrrolidone, water or mixture thereof.
  • the solvent methanol, ethanol, acetone, methylene dichloride may be used.
  • the sodium source is selected from sodium carbonate, sodium bicarbonate, sodium hydroxide and sodium 2-ethyl hexanoate.
  • the ester solvents in step (c) comprise one or more of methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate.
  • isopropyl acetate may be used.
  • the heating in step (c) comprises temperature from about 40°C to reflux temperature of solvent and cooling in step (d) comprises from about 0°C to about 35°C.
  • the crystalline Form-Ill of trisodium salt of valsartan sacubitril complex is characterized by x-ray powder diffraction pattern having characteristic peaks expressed in terms of 2-theta at about 4.1°, 5.0°, 9.7°, 12.4°, 14.8°, 16.8° and 22.6° ⁇ 0.2° (2 ⁇ ) and x-ray powder diffraction pattern substantially as same as shown in Fig. 13.
  • the crystalline Form-Ill of trisodium salt of valsartan sacubitril complex is further characterized by differential scanning calorimetry (DSC) substantially as same as shown in Fig. 14 and thermogravimetric analysis (TGA) substantially as same as shown in Fig. 15.
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • reaction mixture (a) reacting sacubitril and valsartan in the presence of sodium ion source in one or more first solvents to obtain a reaction mixture;
  • the solvent is selected from one or more of alcohols selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-octanol and isopentanol; ketones selected from acetone, methyl ethyl ketone and methyl isobutyl ketone; esters selected from methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate; other solvents selected from methylenedichloride, acetonitrile, dimethylformamide, dimethyl sulfoxide; N- methylpyrrolidone, water or mixture thereof.
  • the solvent acetone may be used.
  • the sodium source is selected from sodium carbonate, sodium bicarbonate, sodium hydroxide and sodium 2-ethyl hexanoate.
  • the ether solvents in step (c) comprise one or more of diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane and tetrahydrofuran.
  • the solvent methyl tert-butyl ether may be used.
  • the heating in step (c) comprises temperature from about 40°C to reflux temperature of solvent and cooling in step (d) comprises from about 0°C to about 35°C.
  • the crystalline Form-IV of trisodium salt of valsartan sacubitril complex is characterized by x-ray powder diffraction pattern having characteristic peaks expressed in terms of 2-theta at about 3.0°, 6.0°, 7.0°, 11.7°, 12.5°, 16.2°, 18.1° and 19.6° ⁇ 0.2° (2 ⁇ ) and x-ray powder diffraction pattern substantially as same as shown in Fig. 16.
  • the non-polar solvent comprises one or more of hexane, heptane, cyclohexane, toluene, xylene, ethylbenzene, diisopropyl ether, diethyl ether, and methyl tert-butyl ether.
  • cyclohexane may be used.
  • the solvent from the solution of trisodium salt of valsartan sacubitril complex may be removed by one or more techniques selected from filtration, decantation, centrifugation and evaporation to obtain crystalline Form- IV of trisodium salt of valsartan sacubitril complex.
  • HX is an acid addition salt
  • the sacubitril of Formula (II) prepared by the process of the present invention is further converted to trisodium salt of valsartan sacubitril complex by one or more process as disclosed herein above.
  • staring compound of Formula (V) may be prepared by the known methods disclosed in WO 2008/031567 Al or J. Med. Chem. Vol. 38 Pg. 1689-1700 (1995) which are incorporated herein as reference.
  • the compound of Formula (V) is treated with an acid selected from one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, and triflouroacetic acid.
  • an acid selected from one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, and triflouroacetic acid.
  • hydrochloric acid may be used.
  • reaction of compound of Formula (V) with an acid may be performed in one or more solvents selected from methanol, ethanol, isopropanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, butyl acetate, isopropyl acetate, methylene di chloride, ethylene di chloride, chloroform, and carbon tetrachloride.
  • solvents selected from methanol, ethanol, isopropanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, butyl acetate, isopropyl acetate, methylene di chloride, ethylene di chloride, chloroform, and carbon tetrachloride.
  • solvents selected from methanol, ethanol, isopropanol, butanol, acetone, methyl
  • the reaction may be performed at an ambient temperature from about 0°C to 25°C. In particular, the reaction is performed at 0°C to 10°C.
  • the compound of Formula (IV) is a hydrochloride salt.
  • the compound of Formula (IV) as hydrochloride salt is further treated with a chlorinating agent selected from thionyl chloride or oxalyl chloride in the presence of ethanol solvent to obtain the compound of Formula (III) or its acid addition salt.
  • a chlorinating agent selected from thionyl chloride or oxalyl chloride in the presence of ethanol solvent to obtain the compound of Formula (III) or its acid addition salt.
  • the compound of Formula (III) is a hydrochloride salt.
  • the compound of Formula (III) as hydrochloride salt is further reacted with succinic anhydride in presence of a base selected from one or more of diethylamine, triethylamine, diisopropylamine, diisopropylethylamine, pyridine, piperidine, morpholine, and DBU.
  • a base selected from one or more of diethylamine, triethylamine, diisopropylamine, diisopropylethylamine, pyridine, piperidine, morpholine, and DBU.
  • triethylamine may be used.
  • the reaction may be performed in presence of solvent selected from one or more of dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methyl pyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, and methylene dichloride.
  • the solvent is acetonitrile.
  • the compound sacubitril of Formula (II) obtained may be converted to pharmaceutically acceptable salts.
  • the compound sacubitril of Formula (II) obtained may be converted to trisodium salt of valsartan sacubitril complex by the methods as disclosed herein above.
  • a pharmaceutical composition comprising an amorphous trisodium salt of valsartan sacubitril complex having one or more of pharmaceutically acceptable carrier, diluents and excipients.
  • a pharmaceutical composition comprising crystalline Form-II of trisodium salt of valsartan sacubitril complex having one or more of pharmaceutically acceptable carrier, diluents and excipients.
  • a pharmaceutical composition comprising crystalline Form-Ill of trisodium salt of valsartan sacubitril complex having one or more of pharmaceutically acceptable carrier, diluents and excipients.
  • composition comprising crystalline Form-IV of trisodium salt of valsartan sacubitril complex having one or more of pharmaceutically acceptable carrier, diluents and excipients.
  • the amorphous trisodium salt of valsartan sacubitril complex of present invention has a purity of more than 98% measured as area percentage by UPLC.
  • the amorphous trisodium salt of valsartan sacubitril complex has purity of more than 99%, preferably more than 99.5%, more preferably 99.8% measured as area percentage by UPLC.
  • the crystalline Form-II of trisodium salt of valsartan sacubitril complex of present invention has a purity of more than 98% measured as area percentage by HPLC.
  • the crystalline Form-II of trisodium salt of valsartan sacubitril complex compound has purity of more than 99%, preferably more than 99.5%, more preferably 99.8% measured as area percentage by HPLC.
  • the crystalline Form-Ill of trisodium salt of valsartan sacubitril complex of present invention has a purity of more than 98% measured as area percentage by HPLC.
  • the crystalline Form-Ill of trisodium salt of valsartan sacubitril complex compound has purity of more than 99%), preferably more than 99.5%, more preferably 99.8% measured as area percentage by HPLC.
  • the crystalline Form-IV of trisodium salt of valsartan sacubitril complex of present invention has a purity of more than 98% measured as area percentage by HPLC.
  • the crystalline Form-Ill of trisodium salt of valsartan sacubitril complex compound has purity of more than 99%), preferably more than 99.5%, more preferably 99.8% measured as area percentage by HPLC.
  • the trisodium salt of valsartan sacubitril complex has particle size distribution as characterized by 90% particles having particle size (D90) less than 250 ⁇ , 50% particles having particle size (D50) less than 100 ⁇ and 10% particles having particle size (D10) less than 50 ⁇ .
  • the trisodium salt of valsartan sacubitril complex has particle size distribution as characterized by 90% particles having particle size (D90) less than 100 ⁇ , 50% particles having particle size (D50) less than 50 ⁇ and 10% particles having particle size (D10) less than 25 ⁇ .
  • the amorphous trisodium salt of valsartan sacubitril complex has particle size distribution as characterized by 90% particles having particle size (D90) less than 250 ⁇ , 50% particles having particle size (D50) less than 100 ⁇ and 10% particles having particle size (D10) less than 50 ⁇ .
  • the crystalline Form-II of trisodium salt of valsartan sacubitril complex has particle size distribution as characterized by 90% particles having particle size (D90) less than 250 ⁇ , 50% particles having particle size (D50) less than 100 ⁇ and 10% particles having particle size (D10) less than 50 ⁇ .
  • the crystalline Form-Ill of trisodium salt of valsartan sacubitril complex has particle size distribution as characterized by 90% particles having particle size (D90) less than 250 ⁇ , 50% particles having particle size (D50) less than 100 ⁇ and 10% particles having particle size (D10) less than 50 ⁇ .
  • the crystalline Form-IV of trisodium salt of valsartan sacubitril complex has particle size distribution as characterized by 90% particles having particle size (D90) less than 250 ⁇ , 50% particles having particle size (D50) less than 100 ⁇ and 10% particles having particle size (D10) less than 50 ⁇ .
  • the trisodium salt of valsartan sacubitril complex may be micronized to achieve the better particle size distribution in order to make suitable Formulation.
  • the starting compound ethyl (2R,4S)-5-([l, l'-biphenyl]-4-yl)-4- amino-2-methylpentanoate hydrochloride for the preparation of sacubitril and thereby trisodium salt of valsartan sacubitril complex may be prepared by the process disclosed hereinafter in the examples.
  • Example-1 Preparation of ethyl (2R,4S)-5-([l,l'-biphenyl]-4-yl)-4-amino-2- methylpentanoate hydrochloride
  • the white solid compound obtained was filtered and washed with diisopropyl ether.
  • the wet-cake was dried at 50-55°C under vacuum for 4 hours to obtain 41.69 g (91.5%) titled compound having 99.10% purity and 158-159°C melting point.
  • Example-3 Preparation of ethyl (2R,4S)-5-([l,l'-biphenyl]-4-yl)-4-amino-2- meth lpentanoate hydrochloride
  • Example-4 Preparation of 4-(((2S,4R)-l-([l,l'-biphenyl]-4-yl)-5-ethoxy-4- methyl -5-oxopentan-2-yl)amino)-4-oxobutanoic acid
  • Example-5 Preparation of 4-(((2S,4R)-l-([l,l'-biphenyl]-4-yl)-5-ethoxy-4- methy -5-oxopentan-2-yl)amino)-4-oxobutanoic acid
  • the reaction mixture was concentrated at 30°C under vacuum. 15 mL isopropyl acetate (15.87 mmol) was added and the reaction mixture was concentrated to half the volume at 30°C. 15 mL isopropyl acetate (15.87 mmol) was again added and the reaction mixture was concentrated to half the volume at 30°C. The suspension was stirred for 1 hour at 20-25°C and white solid was obtained. The product was filtered and washed with isopropyl acetate. The wet-cake was dried at 30-35°C under vacuum for 4 hours to obtain 1.982 g (90.13%) trisodium salt of valsartan sacubitril complex having 99.42% purity. The compound was characterized as crystalline trisodium hemipentahydrate (Form -I).
  • the product was dried at 30- 35°C under vacuum for 4 hours to obtain 2.2 g (91.66%) valsartan disodium having 99.07% purity.
  • the compound was characterized as amorphous powder with disodium salt. Sodium content: 9.13% by IC.
  • the wet-cake was dried at 30-35°C under vacuum for 5 hours to obtain 1 g (90.83%) trisodium salt of valsartan sacubitril complex having 99.92%) purity with onset at 114.85°C and melting endotherm at 127.23°C in DSC.
  • the compound was characterized as crystalline trisodium hemipentahydrate.
  • Example-10 Preparation of crystalline Form-Ill of trisodium salt of valsartan sacubitril complex
  • the wet-cake was dried at 30-35°C under vacuum for 5 hours to obtain 0.95 g (81.54%) crystalline trisodium salt of valsartan sacubitril complex having with onset at 109.48°C and melting endotherm at 133.20°C in DSC.
  • the compound was characterized as crystalline trisodium hemipentahydrate.
  • Example-11 Preparation of crystalline Form-IV of trisodium salt of valsartan sacubitril complex
  • Example-12 Preparation of crystalline Form of trisodium salt of valsartan sacubitril complex
  • Example- 13 Preparation of Preparation of trisodium salt of valsartan sacubitril complex Form-I
  • X-ray powder diffraction is similar to FIG.1.
  • DSC is similar to FIG.2
  • TGA is similar to FIG.3
  • Example-14 Preparation of amorphous trisodium salt of valsartan sacubitril complex
  • reaction mixture spray dried in JISL Mini spray drier LSD-48 with feed pump running at 30-35 rpm, inlet temperature 50-55°C, out let temperature 45-50°C, aspiration rate 1200-1300 rpm, hot air supply 1.8-2.2 Kg/cm 2 and vacuum for conveying the dry product 80 mm (of Hg).
  • the product collected from cyclone was found to be amorphous by XRD; and was further dried to obtain the amorphous form of trisodium salt of valsartan sacubitril complex (Fig.17).
  • Example- 15 Preparation of amorphous trisodium salt of valsartan sacubitril complex
  • Example-16 Preparation of amorphous trisodium salt of valsartan sacubitril complex
  • Example- 18 Preparation of amorphous sacubitril sodium by spray drying

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Abstract

La présente invention concerne une forme amorphe de sel trisodique d'un complexe de valsartan et sacubitril et un procédé pour la préparation de celui-ci consistant à : faire réagir sacubitril sodique et du valsartan disodique ou du sacubitril et du valsartan en présence d'une source d'ions sodium dans un ou plusieurs solvants pour obtenir une solution; et obtenir le sel trisodique d'un complexe de valsartan et de sacubitril par l'élimination du solvant de la solution ou par l'ajout d'un anti-solvant à la solution. La forme cristalline du sacubitril sodique est caractérisée par un diagramme de diffraction des rayons X sur poudre ayant des pics caractéristiques exprimés en termes de 2-thêta à environ 6,3°, 12,0°, 13,8°, 16,5°, 18,3°, 20,0° et 23,8° ± 0,2° (2θ).
PCT/IB2016/054173 2015-07-14 2016-07-13 Formes à l'état solide de sel de trisodium du complexe valsartan/sacubitril et de sacubitril Ceased WO2017009784A1 (fr)

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EP3117823A1 (fr) * 2015-07-17 2017-01-18 Quimica Sintetica, S.A. Dispersion solide amorphe comprenant un bloqueur du récepteur de l'angiotensine et d'un inhibiteur d'endopeptidase neutre
CN107082746A (zh) * 2017-03-23 2017-08-22 广州隽沐生物科技有限公司 一种ahu钠盐晶型的制备方法
WO2018069833A1 (fr) 2016-10-10 2018-04-19 Laurus Labs Limited Forme amorphe stable d'un complexe de sacubitril-valsartan trisodique et ses procédés de préparation
CN108530371A (zh) * 2017-12-27 2018-09-14 浙江天宇药业股份有限公司 一种沙库比曲钠盐、沙库比曲游离酸与乙酸的共晶物、其晶型、晶型的制备方法及用途
US20180273493A1 (en) * 2015-02-06 2018-09-27 Mylan Laboratories Limited Amorphous trisodium sacubitril valsartan and a process for the preparation thereof
WO2018178295A1 (fr) 2017-03-31 2018-10-04 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Extrudat thermofusible stable contenant du valsartan et du sacubitril
CN109265406A (zh) * 2018-09-03 2019-01-25 石药集团中奇制药技术（石家庄）有限公司 一种沙库巴曲缬沙坦钠新晶型及其制备方法和用途
WO2019073062A1 (fr) 2017-10-13 2019-04-18 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Comprimé contenant du valsartan et du sacubitril
EP3498698A1 (fr) 2017-12-15 2019-06-19 Mankind Pharma Ltd Formes solides de valsartan disodium et son procédé de préparation
CN110041217A (zh) * 2019-03-29 2019-07-23 东北制药集团股份有限公司 一种沙库比曲酸的制备方法
WO2019239432A1 (fr) 2018-06-14 2019-12-19 Cipla Limited Complexe de valsartan et de sacubitril trisodique et composition pharmaceutique extrudée à chaud comprenant celui-ci
WO2020039386A1 (fr) 2018-08-23 2020-02-27 Novartis Ag Nouvelle utilisation pharmaceutique pour le traitement d'une insuffisance cardiaque
WO2020039394A1 (fr) 2018-08-24 2020-02-27 Novartis Ag Nouvelles combinaisons de médicaments
US11096918B2 (en) 2005-11-09 2021-08-24 Novartis Pharmaceuticals Corporation Amorphous solid form of compounds containing S—N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and sodium cations
CN113754565A (zh) * 2021-11-09 2021-12-07 南京威凯尔生物医药科技有限公司 一种连续流微反应器中制备沙库巴曲中间体的方法
US11382866B2 (en) 2017-07-06 2022-07-12 Mankind Pharma Ltd. Fixed dose pharmaceutical composition of valsartan and sacubitril
EP4088715A1 (fr) 2021-05-14 2022-11-16 KRKA, d.d., Novo mesto Formulation pharmaceutique de valsartan et sacubitril
CN117164474A (zh) * 2023-08-30 2023-12-05 九江市中医医院 一种沙库巴曲缬沙坦钠工艺杂质及其制备方法

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US11096918B2 (en) 2005-11-09 2021-08-24 Novartis Pharmaceuticals Corporation Amorphous solid form of compounds containing S—N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and sodium cations
US11642329B2 (en) 2005-11-09 2023-05-09 Novartis Pharmaceuticals Corporation Amorphous solid form of compounds containing S—N-valeryl-N- {[2′-( 1 H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and sodium cations
US20180273493A1 (en) * 2015-02-06 2018-09-27 Mylan Laboratories Limited Amorphous trisodium sacubitril valsartan and a process for the preparation thereof
US10562866B2 (en) * 2015-02-06 2020-02-18 Mylan Laboratories Limited Amorphous trisodium sacubitril valsartan and a process for the preparation thereof
EP3117823A1 (fr) * 2015-07-17 2017-01-18 Quimica Sintetica, S.A. Dispersion solide amorphe comprenant un bloqueur du récepteur de l'angiotensine et d'un inhibiteur d'endopeptidase neutre
WO2018069833A1 (fr) 2016-10-10 2018-04-19 Laurus Labs Limited Forme amorphe stable d'un complexe de sacubitril-valsartan trisodique et ses procédés de préparation
US10857132B2 (en) 2016-10-10 2020-12-08 Laurus Labs Limited Stable amorphous form of sacubitril valsartan trisodium complex and processes for preparation thereof
US11318116B2 (en) 2016-10-10 2022-05-03 Laurus Labs Limited Stable amorphous form of sacubitril valsartan trisodium complex and processes for preparation thereof
CN107082746A (zh) * 2017-03-23 2017-08-22 广州隽沐生物科技有限公司 一种ahu钠盐晶型的制备方法
WO2018178295A1 (fr) 2017-03-31 2018-10-04 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Extrudat thermofusible stable contenant du valsartan et du sacubitril
US11382866B2 (en) 2017-07-06 2022-07-12 Mankind Pharma Ltd. Fixed dose pharmaceutical composition of valsartan and sacubitril
US11819577B2 (en) 2017-07-06 2023-11-21 Mankind Pharma Ltd. Fixed dose pharmaceutical composition of valsartan and sacubitril
WO2019073062A1 (fr) 2017-10-13 2019-04-18 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Comprimé contenant du valsartan et du sacubitril
EP3498698A1 (fr) 2017-12-15 2019-06-19 Mankind Pharma Ltd Formes solides de valsartan disodium et son procédé de préparation
CN108530371A (zh) * 2017-12-27 2018-09-14 浙江天宇药业股份有限公司 一种沙库比曲钠盐、沙库比曲游离酸与乙酸的共晶物、其晶型、晶型的制备方法及用途
WO2019239432A1 (fr) 2018-06-14 2019-12-19 Cipla Limited Complexe de valsartan et de sacubitril trisodique et composition pharmaceutique extrudée à chaud comprenant celui-ci
WO2020039386A1 (fr) 2018-08-23 2020-02-27 Novartis Ag Nouvelle utilisation pharmaceutique pour le traitement d'une insuffisance cardiaque
WO2020039394A1 (fr) 2018-08-24 2020-02-27 Novartis Ag Nouvelles combinaisons de médicaments
CN109265406A (zh) * 2018-09-03 2019-01-25 石药集团中奇制药技术（石家庄）有限公司 一种沙库巴曲缬沙坦钠新晶型及其制备方法和用途
CN109265406B (zh) * 2018-09-03 2020-09-22 石药集团中奇制药技术（石家庄）有限公司 一种沙库巴曲缬沙坦钠新晶型及其制备方法和用途
CN110041217B (zh) * 2019-03-29 2022-05-17 东北制药集团股份有限公司 一种沙库比曲酸的制备方法
CN110041217A (zh) * 2019-03-29 2019-07-23 东北制药集团股份有限公司 一种沙库比曲酸的制备方法
EP4088715A1 (fr) 2021-05-14 2022-11-16 KRKA, d.d., Novo mesto Formulation pharmaceutique de valsartan et sacubitril
WO2022238563A1 (fr) 2021-05-14 2022-11-17 Krka, D.D., Novo Mesto Formulation pharmaceutique de valsartan et de sacubitril
CN113754565B (zh) * 2021-11-09 2022-02-22 南京威凯尔生物医药科技有限公司 一种连续流微反应器中制备沙库巴曲中间体的方法
CN113754565A (zh) * 2021-11-09 2021-12-07 南京威凯尔生物医药科技有限公司 一种连续流微反应器中制备沙库巴曲中间体的方法
CN117164474A (zh) * 2023-08-30 2023-12-05 九江市中医医院 一种沙库巴曲缬沙坦钠工艺杂质及其制备方法

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