WO2017037596A1 - Amorphous solid dispersion of lcz-696 - Google Patents

Amorphous solid dispersion of lcz-696 Download PDF

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Publication number
WO2017037596A1
WO2017037596A1 PCT/IB2016/055106 IB2016055106W WO2017037596A1 WO 2017037596 A1 WO2017037596 A1 WO 2017037596A1 IB 2016055106 W IB2016055106 W IB 2016055106W WO 2017037596 A1 WO2017037596 A1 WO 2017037596A1
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Prior art keywords
lcz
solid dispersion
amorphous solid
pharmaceutically acceptable
acceptable carrier
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PCT/IB2016/055106
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French (fr)
Inventor
Ramanaiah CHENNURU
Vishweshwar Peddy
Naga Lakshmi Ramana SUSARLA
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Dr. Reddy's Laboratories Limited
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Publication of WO2017037596A1 publication Critical patent/WO2017037596A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • 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

Definitions

  • the present application relates to amorphous form of a complex of valsartan and Sacubitril, known as LCZ-696.
  • the present application relates to amorphous solid dispersion of a complex of valsartan and Sacubitril, known as LCZ-696.
  • US Patent No. 8877938 discloses a crystalline form of supramolecular complex of valsartan and Sacubitril. It is known in the literature as LCZ-696 (Tetrahedron Letters 53, 2012, 275-276).
  • the US'938 patent characterizes the crystalline form of LCZ-696 by XRD having peaks at 4.5, 5.5, 5.6, 9.9, 12.8, 15.7, 17.0, 17.1 , 17.2, 18.3, 18.5, 19.8, 21 .5, 21 .7, 23.2, 23.3, 24.9, 25.3, 27.4, 27.9, 28.0 and 30.2 °2 ⁇ . But the US'938 patent does not provide the XRD figure of the said compound.
  • Tetrahedron Letters 53, 2012, 275-276 discloses the XRD figure of LCZ-696.
  • Amorphous material generally offers interesting properties such as higher dissolution rate and solubility than crystalline forms, typically resulting in improved bioavailability.
  • An amorphous form of cefuroxime axetil is a good example for exhibiting higher bioavailability than the crystalline form.
  • One aspect of the present application relates to process for preparing amorphous form of LCZ-696 comprising:
  • step b) optionally filtering the un-dissolved particles; (c) removing the solvent from the filtrate of step b) by suitable technique;
  • Another aspect of the present application relates to amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier.
  • Yet another aspect of the present application relates to amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier that can be characterized by a PXRD pattern substantially as illustrated in Figure 2 or Figure 3 or Figure 4 or Figure 5 or Figure 6.
  • Still another aspect of the present application relates to a process for preparing amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier or mixture thereof comprising:
  • Another aspect of the present application relates to a process for preparation of amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier or mixture thereof comprising:
  • Another aspect of the present application relates to a process for preparation of amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier comprising mixing amorphous LCZ-696 with one or more pharmaceutically acceptable carrier.
  • Another aspect of the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising amorphous solid dispersion of LCZ-696.
  • Figure 1 is an illustration of a PXRD of amorphous form of LCZ-696 obtained by the Example 1 .
  • Figure 2 is an illustration of a PXRD of amorphous solid dispersion of LCZ-696 obtained by the Example 3A.
  • Figure 3 is an illustration of a PXRD of amorphous solid dispersion of LCZ-696 obtained by the Example 3B.
  • Figure 4 is an illustration of a PXRD of amorphous solid dispersion of LCZ-696 obtained by the Example 3C.
  • Figure 5 is an illustration of a PXRD of amorphous solid dispersion of LCZ-696 obtained by the Example 3D.
  • Figure 6 is an illustration of a PXRD of amorphous solid dispersion of LCZ-696 obtained by the Example 3J.
  • One aspect of the present application relates to amorphous solid dispersion of LCZ- 696 with one or more pharmaceutically acceptable carrier.
  • Yet another aspect of the present application relates to amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier that can be characterized by a PXRD substantially as illustrated in Figure 2 or Figure 3 or Figure 4 or Figure 5 or Figure 6.
  • the pharmaceutically acceptable carrier may be any suitable carrier reported in the literature.
  • the pharmaceutically acceptable carrier includes, but not restricted to methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl cellulose, polysaccharides, heteropolysaccharides (pectins), poloxamers, poloxamines, ethylene vinyl acetates, polyethylene glycols, dextrans, polyvinylalcohols, propylene glycols, polyvinylacetates, phosphatidylcholines (lecithins), miglyols, polylactic acid, polyhydroxybutyric acid, polyvinylpyrrolidones (PVP), copovidone, methacrylic acid, silicon dioxide (syloid), neusilin mixtures of two or more thereof, copolymers thereof and derivatives thereof. More specifically, the pharmaceutically acceptable carrier may be selected from a group of hydroxypropyl methylcellulose phthalate and
  • silicon dioxide may be added to the amorphous solid dispersion of LCZ- 696, prepared by the process of this application, in order to increase the stability and reduce hygroscopicity of the amorphous solid dispersion.
  • the ratio (weight/weight) of LCZ-696 and pharmaceutically acceptable carrier in amorphous solid dispersion may be about 5:95, or about 10:90, or about 15:85, or about 20:80, or about 25:75, or about 30:70, or about 35:65, or about 40:60, or about 45:55, or about 50:50 and vice versa.
  • One specific aspect of the present application relates to amorphous solid dispersion of LCZ-696 with HPMC phthalate.
  • Another specific aspect of the present application relates to amorphous solid dispersion of LCZ-696 with HPMC phthalate and silicon dioxide (syloid).
  • Yet another specific aspect of the present application relates to amorphous solid dispersion of LCZ-696 with PVP K-30. Still another specific aspect of the present application relates to amorphous solid dispersion of LCZ-696 with PVP K-30 and silicon dioxide (syloid). Still another specific aspect of the present application relates to amorphous solid dispersion of LCZ-696 with silicon dioxide (syloid). Any known grade of silicon dioxide (syloid) may be used for the preparation of amorphous solid dispersion of LCZ-696 with silicon dioxide (syloid), e.g. 244 FP, aeropearl, AL-1 FP and the like.
  • the ratio of LCZ-696 with silicon dioxide (syloid) may be about 1 :1 or 1 :0.9, or 1 :0.8, or 1 :0.7, or 1 :0.6, or 1 :0.5, or 1 :04, or 1 :0.3, or 1 :0.2 or 1 :0.1 .
  • Another specific aspect of the present application relates to amorphous solid dispersion of LCZ-696 with neusilin.
  • Yet another specific aspect of the present application relates to amorphous solid dispersion of LCZ-696 with a mixture of silicon dioxide (syloid) and neusilin.
  • Still another aspect of the present application relates to a process for preparation of amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier or mixture thereof comprising:
  • LCZ-696 used in step (a) may be of any crystalline nature or a crude product.
  • LCZ-696 used in step (a) may be obtained by a reaction of valsartan and sacubitril in an organic solvent or mixture thereof in presence of sodium hydroxide and evaporating the solvent.
  • the suitable solvent for dissolving LCZ-696 in step (a) include, but are not limited to ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol and the like; and mixture thereof.
  • the mixture of step (a) may be heated at a temperature of about 30 °C to about the boiling point of the solvent to provide a solution.
  • the solution comprising LCZ-696 and a pharmaceutically acceptable carrier in a suitable solvent may be prepared at a temperature of about 40 °C to about 70 °C.
  • Isolation of amorphous solid dispersion of LCZ-696 may involve one or more methods including removal of solvent by techniques known in the art e.g. evaporation, distillation, filtration of precipitated solid and the like, cooling, concentrating the reaction mass, and the like. Stirring or other alternate methods such as shaking, agitation, and the like, may also be employed for the isolation. Distillation of the solvent may be conducted at atmospheric pressure or above, or under reduced pressures and at a temperatures less than about 120°C, less than about 100°C, less than about 90°C, or any other suitable temperatures. Any temperature and vacuum conditions can be used as long as there is no increase in the impurity levels of the product due to decomposition.
  • Suitable techniques which can be used for the distillation include, but not limited to, distillation using a rotary evaporator device such as a rotavapor, spray drying, agitated thin film drying ("ATFD"), and the like.
  • a rotary evaporator device such as a rotavapor, spray drying, agitated thin film drying ("ATFD"), and the like.
  • techniques providing a rapid solvent removal may be utilized to provide the desired amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier.
  • distillation using a rotavapor device such as a rotavapor or a spray drying technique may be used for the isolation of amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier.
  • the solid may be collected using techniques such as by scraping, or by shaking the container, or other techniques specific to the equipment used.
  • the isolated solid may be optionally further dried to afford amorphous solid dispersion of LCZ-696.
  • Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer and the like.
  • the drying may be carried out at atmospheric pressure or above, or under reduced pressures, at temperatures less than about 120°C, less than about 100°C, less than about 80°C, or any other suitable temperatures.
  • the drying may be carried out for any time period required for obtaining a desired product quality, such as from about 30 minutes to about 24 hours, or longer.
  • the obtained amorphous solid dispersion of LCZ-696 may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the amorphous solid dispersions.
  • Equipment that may be used for particle size reduction include, but not limited to, ball, roller, and hammer mills, jet mills and the like.
  • Another aspect of the present application relates to a process for preparation of amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier or mixture thereof comprising:
  • LCZ-696 used in step (a) may be of any crystalline nature or a crude product.
  • LCZ-696 used in step (a) may be obtained by a reaction of valsartan and sacubitril in an organic solvent or mixture thereof in presence of sodium hydroxide and evaporating the solvent.
  • LCZ-696 may be dissolved in a suitable solvent for dissolving LCZ-696 in step (a) include, but are not limited to ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol and the like; and mixture thereof.
  • the mixture of LCZ-696 and the suitable solvent may be heated at a temperature of about 30 °C to about the boiling point of the solvent to provide a solution.
  • the solution comprising LCZ-696 in a suitable solvent may be prepared at a temperature of about 40 °C to about 70 °C.
  • a suitable pharmaceutically acceptable carrier may be added to the solution of LCZ-696 in a suitable solvent.
  • Isolation of amorphous solid dispersion of LCZ-696 may involve one or more methods including removal of solvent by techniques known in the art e.g. evaporation, distillation, concentrating the reaction mass, and the like. Distillation of the solvent may be conducted at atmospheric pressure or above, or under reduced pressures and at a temperatures less than about 120°C, less than about 100°C, less than about 90°C, or any other suitable temperatures. Any temperature and vacuum conditions can be used as long as there is no increase in the impurity levels of the product due to decomposition.
  • Suitable techniques which can be used for the distillation include, but not limited to, distillation using a rotary evaporator device such as a rotavapor, spray drying, agitated thin film drying ("ATFD"), and the like.
  • a rotary evaporator device such as a rotavapor, spray drying, agitated thin film drying ("ATFD"), and the like.
  • techniques providing a rapid solvent removal may be utilized to provide the desired amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier.
  • distillation using a rotavapor device such as a rotavapor or a spray drying technique may be used for the isolation of amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier.
  • the solid may be collected using techniques such as by scraping, or by shaking the container, or other techniques specific to the equipment used.
  • the isolated solid may be optionally further dried to afford amorphous solid dispersion of LCZ-696.
  • Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer and the like.
  • the drying may be carried out at atmospheric pressure or above, or under reduced pressures, at temperatures less than about 120°C, less than about 100°C, less than about 80°C, or any other suitable temperatures.
  • the drying may be carried out for any time period required for obtaining a desired product quality, such as from about 30 minutes to about 24 hours, or longer.
  • the obtained amorphous solid dispersion of LCZ-696 may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the amorphous solid dispersions.
  • Equipment that may be used for particle size reduction include, but not limited to, ball, roller, and hammer mills, jet mills and the like.
  • Another aspect of the present application relates to a process for preparation of amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier comprising mixing amorphous LCZ-696 with one or more pharmaceutically acceptable carrier.
  • the mixing may be carried out by any known methods in the art. Specifically, the mixing may be carried out by blending. Blending of amorphous LCZ- 696 and one or more pharmaceutically acceptable carrier may be carried out in a suitable equipment known in the art. Specifically, blending may be carried out in a V- blender, double cone blender, rotatory cone vacuum drier (RCVD). The blending may further comprise unit operations such as Rapid Mix Granulation (RMG), milling, co- milling, grinding and the like.
  • RMG Rapid Mix Granulation
  • the mixing of amorphous LCZ-696 with one or more pharmaceutically acceptable carrier may be carried out by physical blending.
  • Physical blending may be carried out by blending amorphous LCZ-696 with one or more pharmaceutically acceptable carrier in a petri-dish or mortar pestle.
  • amorphous solid dispersion of LCZ-696 of the present application is stable and has good physico-chemical properties.
  • the amorphous solid dispersion of the present application may be easily formulated into a pharmaceutical composition comprising LCZ-696 along with one or more pharmaceutically acceptable excipients.
  • Pure amorphous form of LCZ-696 is highly hygroscopic in nature and has a tendency to absorb large amounts of moisture even at 30% RH/25 °C, as observed in DVS and humidification studies. It has been seen that pure amorphous form of LCZ-696 absorbs about 8% moisture within 3 hours at 30% RH/25 °C and becomes a sticky material .
  • pure amorphous form of LCZ-696 becomes deliquescent. Hence, pure amorphous form of LCZ-696 may not be suitable for developing a pharmaceutical composition comprising LCZ-696.
  • the pharmaceutically acceptable carrier stabilizes the amorphous LCZ-696 by acting as a protective barrier. It was observed by DVS and humidification studies that the amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier of the present application is stable up to 60% RH/25 °C. Hence, amorphous solid dispersion of LCZ-696 with silicon dioxide may be easily formulated into a pharmaceutical composition comprising LCZ-696.
  • Amorphous solid dispersion of LCZ-696 together with one or more pharmaceutically acceptable excipients of the present application may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions.
  • Formulations may be in the forms of immediate release, delayed release, or modified release.
  • immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems.
  • the compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization.
  • Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.
  • Still another aspect of the present application relates to process for preparing amorphous form of LCZ-696 comprising:
  • the solvent of step (a) includes but not limited to ketone solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol and the like.
  • LCZ-696 used in step (a) may be of any crystalline nature or a crude product.
  • LCZ-696 used in step (a) may be obtained by a reaction of valsartan and sacubitril in an organic solvent or mixture thereof in presence of sodium hydroxide and evaporating the solvent.
  • the reaction mixture of step (a) may be stirred for about 5 minutes to about 5 hours at a temperature of about 15 °C to about boiling point of the solvent. Specifically, the reaction mixture of step (a) may be stirred for about 15 minutes at about 25 °C.
  • Suitable techniques that may be used for the removal of solvent include but are not limited to rotational distillation using a device such as rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization) and the like, optionally under reduced pressure.
  • a solution comprising LCZ-696 is subjected to spray-drying or freeze-drying technique, to provide amorphous form of LCZ-696.
  • a solution comprising LCZ-696 is subjected to rotational distillation using a device such as rotavapor, optionally under reduced pressure, to provide amorphous form of LCZ-696.
  • the resulting solid may be collected by using techniques such as by scraping, or by shaking the container, or by other techniques specific to the equipment used.
  • the isolated solid may be optionally further dried to afford amorphous form of LCZ-696.
  • Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like.
  • the drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C.
  • the drying may be carried out for any time period required for obtaining a desired product quality, such as from about 30 minutes to about 24 hours, or longer.
  • the obtained amorphous form of LCZ-696 may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of amorphous form of LCZ-696.
  • Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.
  • the amorphous form of LCZ-696 of the instant application may contain less than about 10 % of crystalline form of LCZ-696. Specifically, the amorphous form of LCZ-696 may contain less than about 5 % of any crystalline form of LCZ-696. More specifically, the amorphous form of LCZ-696 may contain less than about 3 % of any crystalline form of LCZ-696.
  • Fig. 1 illustrates PXRD of amorphous form of LCZ-696 obtained by a process of Example 1 .
  • the PXRD conditions of the present application are as follows:
  • Range 3° 2 ⁇ to 40° 2 ⁇ in conventional reflection mode
  • Source Copper K-alpha radiation (1 .5418 Angstrom).
  • Example 3B Preparation of amorphous solid dispersion of LCZ-696
  • Example 3C Preparation of amorphous solid dispersion of LCZ-696
  • Example 3D Preparation of amorphous solid dispersion of LCZ-696
  • Example 3G Preparation of amorphous solid dispersion of LCZ-696
  • Amorphous LCZ-696 (50 g) and syloid (50 g) was mixed thoroughly in a rotavapor at 30 °C (160 RPM) to afford the title compound.
  • Amorphous LCZ-696 (125 g) and syloid (125 g) was mixed in a Rapid Mix Granulator for 1 hour under the following conditions to provide the title compound.
  • Example 3J Preparation of amorphous solid dispersion of LCZ-696
  • Amorphous LCZ-696 (1 g) and syloid (1 g) was mixed well in a petri-dish to provide the title compound.

Abstract

The present application relates to amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier. Specifically, the present application relates to amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier selected from a group of hydroxypropyl methylcellulose phthalate, povidone, silicon dioxide (syloid) and mixtures thereof. The present application also relates to process for preparation of amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier. Further the present application relates to pharmaceutical composition comprising amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier.

Description

AMORPHOUS SOLID DISPERSION OF LCZ-696
FIELD OF INVENTION
The present application relates to amorphous form of a complex of valsartan and Sacubitril, known as LCZ-696. The present application relates to amorphous solid dispersion of a complex of valsartan and Sacubitril, known as LCZ-696.
BACKGROUND OF INVENTION
US Patent No. 8877938 discloses a crystalline form of supramolecular complex of valsartan and Sacubitril. It is known in the literature as LCZ-696 (Tetrahedron Letters 53, 2012, 275-276). The US'938 patent characterizes the crystalline form of LCZ-696 by XRD having peaks at 4.5, 5.5, 5.6, 9.9, 12.8, 15.7, 17.0, 17.1 , 17.2, 18.3, 18.5, 19.8, 21 .5, 21 .7, 23.2, 23.3, 24.9, 25.3, 27.4, 27.9, 28.0 and 30.2 °2Θ. But the US'938 patent does not provide the XRD figure of the said compound. Tetrahedron Letters 53, 2012, 275-276 discloses the XRD figure of LCZ-696.
It has been disclosed earlier that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to crystalline forms [Konne T., Chem pharm Bull., 38, 2003(1990)]. Typically, the more crystalline the pharmaceutical agent, the lower is its bioavailability or vice varsa, reducing the degree of crystallinity has a positive effect on bioavailability. Amorphous material generally offers interesting properties such as higher dissolution rate and solubility than crystalline forms, typically resulting in improved bioavailability. An amorphous form of cefuroxime axetil is a good example for exhibiting higher bioavailability than the crystalline form.
Hence, there remains a need for alternate solid forms of LCZ-696 and processes for preparing them.
SUMMARY OF INVENTION
One aspect of the present application relates to process for preparing amorphous form of LCZ-696 comprising:
(a) dissolving LCZ-696 in a suitable solvent or mixture thereof;
(b) optionally filtering the un-dissolved particles; (c) removing the solvent from the filtrate of step b) by suitable technique; and
(d) optionally, drying the product at suitable temperature.
Another aspect of the present application relates to amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier.
Yet another aspect of the present application relates to amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier that can be characterized by a PXRD pattern substantially as illustrated in Figure 2 or Figure 3 or Figure 4 or Figure 5 or Figure 6.
Still another aspect of the present application relates to a process for preparing amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier or mixture thereof comprising:
(a) dissolving LCZ-696 and a pharmaceutically acceptable carrier in suitable solvent or mixtures thereof;
(b) optionally filtering the un-dissolved particles;
(c) isolating amorphous solid dispersion of LCZ-696 with a pharmaceutically acceptable carrier;
(d) optionally drying the amorphous solid dispersion of LCZ-696.
Another aspect of the present application relates to a process for preparation of amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier or mixture thereof comprising:
(a) mixing LCZ-696 and a pharmaceutically acceptable carrier in suitable solvent or mixtures thereof;
(b) isolating amorphous solid dispersion of LCZ-696 with a pharmaceutically acceptable carrier;
(c) optionally drying the amorphous solid dispersion of LCZ-696. Another aspect of the present application relates to a process for preparation of amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier comprising mixing amorphous LCZ-696 with one or more pharmaceutically acceptable carrier.
Another aspect of the present application relates to a pharmaceutical composition comprising amorphous solid dispersion of LCZ-696.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustration of a PXRD of amorphous form of LCZ-696 obtained by the Example 1 .
Figure 2 is an illustration of a PXRD of amorphous solid dispersion of LCZ-696 obtained by the Example 3A.
Figure 3 is an illustration of a PXRD of amorphous solid dispersion of LCZ-696 obtained by the Example 3B.
Figure 4 is an illustration of a PXRD of amorphous solid dispersion of LCZ-696 obtained by the Example 3C.
Figure 5 is an illustration of a PXRD of amorphous solid dispersion of LCZ-696 obtained by the Example 3D.
Figure 6 is an illustration of a PXRD of amorphous solid dispersion of LCZ-696 obtained by the Example 3J.
DETAILED DESCRIPTION OF INVENTION
One aspect of the present application relates to amorphous solid dispersion of LCZ- 696 with one or more pharmaceutically acceptable carrier.
Yet another aspect of the present application relates to amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier that can be characterized by a PXRD substantially as illustrated in Figure 2 or Figure 3 or Figure 4 or Figure 5 or Figure 6. The pharmaceutically acceptable carrier may be any suitable carrier reported in the literature. Specifically, the pharmaceutically acceptable carrier includes, but not restricted to methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl cellulose, polysaccharides, heteropolysaccharides (pectins), poloxamers, poloxamines, ethylene vinyl acetates, polyethylene glycols, dextrans, polyvinylalcohols, propylene glycols, polyvinylacetates, phosphatidylcholines (lecithins), miglyols, polylactic acid, polyhydroxybutyric acid, polyvinylpyrrolidones (PVP), copovidone, methacrylic acid, silicon dioxide (syloid), neusilin mixtures of two or more thereof, copolymers thereof and derivatives thereof. More specifically, the pharmaceutically acceptable carrier may be selected from a group of hydroxypropyl methylcellulose phthalate and povidone.
Optionally, silicon dioxide may be added to the amorphous solid dispersion of LCZ- 696, prepared by the process of this application, in order to increase the stability and reduce hygroscopicity of the amorphous solid dispersion.
The ratio (weight/weight) of LCZ-696 and pharmaceutically acceptable carrier in amorphous solid dispersion may be about 5:95, or about 10:90, or about 15:85, or about 20:80, or about 25:75, or about 30:70, or about 35:65, or about 40:60, or about 45:55, or about 50:50 and vice versa.
One specific aspect of the present application relates to amorphous solid dispersion of LCZ-696 with HPMC phthalate. Another specific aspect of the present application relates to amorphous solid dispersion of LCZ-696 with HPMC phthalate and silicon dioxide (syloid).
Yet another specific aspect of the present application relates to amorphous solid dispersion of LCZ-696 with PVP K-30. Still another specific aspect of the present application relates to amorphous solid dispersion of LCZ-696 with PVP K-30 and silicon dioxide (syloid). Still another specific aspect of the present application relates to amorphous solid dispersion of LCZ-696 with silicon dioxide (syloid). Any known grade of silicon dioxide (syloid) may be used for the preparation of amorphous solid dispersion of LCZ-696 with silicon dioxide (syloid), e.g. 244 FP, aeropearl, AL-1 FP and the like. In amorphous solid dispersion of LCZ-696 with silicon dioxide (syloid), the ratio of LCZ-696 with silicon dioxide (syloid) may be about 1 :1 or 1 :0.9, or 1 :0.8, or 1 :0.7, or 1 :0.6, or 1 :0.5, or 1 :04, or 1 :0.3, or 1 :0.2 or 1 :0.1 .
Another specific aspect of the present application relates to amorphous solid dispersion of LCZ-696 with neusilin.
Yet another specific aspect of the present application relates to amorphous solid dispersion of LCZ-696 with a mixture of silicon dioxide (syloid) and neusilin.
Still another aspect of the present application relates to a process for preparation of amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier or mixture thereof comprising:
(a) dissolving LCZ-696 and a pharmaceutically acceptable carrier in suitable solvent or mixtures thereof;
(b) optionally filtering the un-dissolved particles;
(c) isolating amorphous solid dispersion of LCZ-696 with a pharmaceutically acceptable carrier;
(d) optionally drying the amorphous solid dispersion of LCZ-696.
The LCZ-696 used in step (a) may be of any crystalline nature or a crude product. Alternatively, LCZ-696 used in step (a) may be obtained by a reaction of valsartan and sacubitril in an organic solvent or mixture thereof in presence of sodium hydroxide and evaporating the solvent.
The suitable solvent for dissolving LCZ-696 in step (a) include, but are not limited to ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol and the like; and mixture thereof. The mixture of step (a) may be heated at a temperature of about 30 °C to about the boiling point of the solvent to provide a solution. Specifically, the solution comprising LCZ-696 and a pharmaceutically acceptable carrier in a suitable solvent may be prepared at a temperature of about 40 °C to about 70 °C.
Isolation of amorphous solid dispersion of LCZ-696 may involve one or more methods including removal of solvent by techniques known in the art e.g. evaporation, distillation, filtration of precipitated solid and the like, cooling, concentrating the reaction mass, and the like. Stirring or other alternate methods such as shaking, agitation, and the like, may also be employed for the isolation. Distillation of the solvent may be conducted at atmospheric pressure or above, or under reduced pressures and at a temperatures less than about 120°C, less than about 100°C, less than about 90°C, or any other suitable temperatures. Any temperature and vacuum conditions can be used as long as there is no increase in the impurity levels of the product due to decomposition.
Suitable techniques which can be used for the distillation include, but not limited to, distillation using a rotary evaporator device such as a rotavapor, spray drying, agitated thin film drying ("ATFD"), and the like. Specifically, techniques providing a rapid solvent removal may be utilized to provide the desired amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier. More specifically, distillation using a rotavapor device such as a rotavapor or a spray drying technique may be used for the isolation of amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier.
The solid may be collected using techniques such as by scraping, or by shaking the container, or other techniques specific to the equipment used. The isolated solid may be optionally further dried to afford amorphous solid dispersion of LCZ-696.
Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, at temperatures less than about 120°C, less than about 100°C, less than about 80°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 30 minutes to about 24 hours, or longer.
The obtained amorphous solid dispersion of LCZ-696 may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the amorphous solid dispersions. Equipment that may be used for particle size reduction include, but not limited to, ball, roller, and hammer mills, jet mills and the like.
Another aspect of the present application relates to a process for preparation of amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier or mixture thereof comprising:
(a) mixing LCZ-696 and a pharmaceutically acceptable carrier in suitable solvent or mixtures thereof;
(b) isolating amorphous solid dispersion of LCZ-696 with a pharmaceutically acceptable carrier;
(c) optionally drying the amorphous solid dispersion of LCZ-696.
The LCZ-696 used in step (a) may be of any crystalline nature or a crude product. Alternatively, LCZ-696 used in step (a) may be obtained by a reaction of valsartan and sacubitril in an organic solvent or mixture thereof in presence of sodium hydroxide and evaporating the solvent.
In one specific aspect, LCZ-696 may be dissolved in a suitable solvent for dissolving LCZ-696 in step (a) include, but are not limited to ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol and the like; and mixture thereof. The mixture of LCZ-696 and the suitable solvent may be heated at a temperature of about 30 °C to about the boiling point of the solvent to provide a solution. Specifically, the solution comprising LCZ-696 in a suitable solvent may be prepared at a temperature of about 40 °C to about 70 °C. A suitable pharmaceutically acceptable carrier may be added to the solution of LCZ-696 in a suitable solvent. Isolation of amorphous solid dispersion of LCZ-696 may involve one or more methods including removal of solvent by techniques known in the art e.g. evaporation, distillation, concentrating the reaction mass, and the like. Distillation of the solvent may be conducted at atmospheric pressure or above, or under reduced pressures and at a temperatures less than about 120°C, less than about 100°C, less than about 90°C, or any other suitable temperatures. Any temperature and vacuum conditions can be used as long as there is no increase in the impurity levels of the product due to decomposition.
Suitable techniques which can be used for the distillation include, but not limited to, distillation using a rotary evaporator device such as a rotavapor, spray drying, agitated thin film drying ("ATFD"), and the like. Specifically, techniques providing a rapid solvent removal may be utilized to provide the desired amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier. More specifically, distillation using a rotavapor device such as a rotavapor or a spray drying technique may be used for the isolation of amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier.
The solid may be collected using techniques such as by scraping, or by shaking the container, or other techniques specific to the equipment used. The isolated solid may be optionally further dried to afford amorphous solid dispersion of LCZ-696.
Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, at temperatures less than about 120°C, less than about 100°C, less than about 80°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 30 minutes to about 24 hours, or longer.
The obtained amorphous solid dispersion of LCZ-696 may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the amorphous solid dispersions. Equipment that may be used for particle size reduction include, but not limited to, ball, roller, and hammer mills, jet mills and the like.
Another aspect of the present application relates to a process for preparation of amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier comprising mixing amorphous LCZ-696 with one or more pharmaceutically acceptable carrier. The mixing may be carried out by any known methods in the art. Specifically, the mixing may be carried out by blending. Blending of amorphous LCZ- 696 and one or more pharmaceutically acceptable carrier may be carried out in a suitable equipment known in the art. Specifically, blending may be carried out in a V- blender, double cone blender, rotatory cone vacuum drier (RCVD). The blending may further comprise unit operations such as Rapid Mix Granulation (RMG), milling, co- milling, grinding and the like. Alternatively, the mixing of amorphous LCZ-696 with one or more pharmaceutically acceptable carrier may be carried out by physical blending. Physical blending may be carried out by blending amorphous LCZ-696 with one or more pharmaceutically acceptable carrier in a petri-dish or mortar pestle.
It was found that the amorphous solid dispersion of LCZ-696 of the present application is stable and has good physico-chemical properties. The amorphous solid dispersion of the present application may be easily formulated into a pharmaceutical composition comprising LCZ-696 along with one or more pharmaceutically acceptable excipients. Pure amorphous form of LCZ-696 is highly hygroscopic in nature and has a tendency to absorb large amounts of moisture even at 30% RH/25 °C, as observed in DVS and humidification studies. It has been seen that pure amorphous form of LCZ-696 absorbs about 8% moisture within 3 hours at 30% RH/25 °C and becomes a sticky material . On increasing the relative humidity of the environment further, pure amorphous form of LCZ-696 becomes deliquescent. Hence, pure amorphous form of LCZ-696 may not be suitable for developing a pharmaceutical composition comprising LCZ-696. On the other hand, it was observed that in amorphous solid dispersion of LCZ-696 of the present application, the pharmaceutically acceptable carrier stabilizes the amorphous LCZ-696 by acting as a protective barrier. It was observed by DVS and humidification studies that the amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier of the present application is stable up to 60% RH/25 °C. Hence, amorphous solid dispersion of LCZ-696 with silicon dioxide may be easily formulated into a pharmaceutical composition comprising LCZ-696.
Yet another aspect of the present application relates to a pharmaceutical composition comprising amorphous solid dispersion of LCZ-696. Amorphous solid dispersion of LCZ-696 together with one or more pharmaceutically acceptable excipients of the present application may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.
Still another aspect of the present application relates to process for preparing amorphous form of LCZ-696 comprising:
(a) dissolving LCZ-696 in a suitable solvent or mixture thereof;
(b) optionally filtering the un-dissolved particles;
(c) removing the solvent from the filtrate of step b) by suitable technique; and
(d) optionally, drying the product at suitable temperature. The solvent of step (a) includes but not limited to ketone solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol and the like.
The LCZ-696 used in step (a) may be of any crystalline nature or a crude product. Alternatively, LCZ-696 used in step (a) may be obtained by a reaction of valsartan and sacubitril in an organic solvent or mixture thereof in presence of sodium hydroxide and evaporating the solvent.
The reaction mixture of step (a) may be stirred for about 5 minutes to about 5 hours at a temperature of about 15 °C to about boiling point of the solvent. Specifically, the reaction mixture of step (a) may be stirred for about 15 minutes at about 25 °C.
Suitable techniques that may be used for the removal of solvent include but are not limited to rotational distillation using a device such as rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization) and the like, optionally under reduced pressure. One specific aspect of the present application relates to a solution comprising LCZ-696 is subjected to spray-drying or freeze-drying technique, to provide amorphous form of LCZ-696. Another specific aspect of the present application relates to a solution comprising LCZ-696 is subjected to rotational distillation using a device such as rotavapor, optionally under reduced pressure, to provide amorphous form of LCZ-696.
The resulting solid may be collected by using techniques such as by scraping, or by shaking the container, or by other techniques specific to the equipment used. The isolated solid may be optionally further dried to afford amorphous form of LCZ-696.
Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 30 minutes to about 24 hours, or longer. The obtained amorphous form of LCZ-696 may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of amorphous form of LCZ-696. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.
In one embodiment, the amorphous form of LCZ-696 of the instant application may contain less than about 10 % of crystalline form of LCZ-696. Specifically, the amorphous form of LCZ-696 may contain less than about 5 % of any crystalline form of LCZ-696. More specifically, the amorphous form of LCZ-696 may contain less than about 3 % of any crystalline form of LCZ-696.
Fig. 1 illustrates PXRD of amorphous form of LCZ-696 obtained by a process of Example 1 .
The PXRD conditions of the present application are as follows:
Range: 3° 2Θ to 40° 2Θ in conventional reflection mode
Instrument: PANalytical X-ray Diffractometer
Detector: X'celerator
Source: Copper K-alpha radiation (1 .5418 Angstrom).
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
The terms "about," "general, 'generally," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. 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. All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms "comprising" and "comprises" mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
The term "optional" or "optionally" is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner.
EXAMPLES
Example 1 : Preparation of amorphous form of LCZ-696
LCZ-696 (1 g) was dissolved in a mixture of acetone (30 ml_) and methanol (5 ml_) at 25°C and stirred for about 5 minutes. The solvent was evaporated by the help of rotavapor at 60°C and the solid was dried for 10 minutes to afford the title compound.
Example 2: Preparation of amorphous form of LCZ-696
LCZ-696 (1 g) was dissolved in methanol (20 ml_) at 25°C and stirred for about 5 minutes. The solvent was evaporated by the help of rotavapor at 60°C to afford the title compound. Example 3A: Preparation of amorphous solid dispersion of LCZ-696
A mixture of LCZ-696 (2 g) and HPMC phthalate (2 g) in methanol (50 imL) was stirred for 10 minutes at 25°C and then at 60°C for 10 minutes. The solvent was evaporated by the help of rotavapor at 60°C to provide the title compound.
Example 3B: Preparation of amorphous solid dispersion of LCZ-696
Syloid (500 mg) was blended with amorphous solid dispersion of LCZ-696 (500 mg) obtained through Example 3.
Example 3C: Preparation of amorphous solid dispersion of LCZ-696
A mixture of LCZ-696 (2 g) and PVP K-30 (2 g) in methanol (50 imL) was stirred for 10 minutes at 25°C and then at 60°C for 10 minutes. The solvent was evaporated by the help of rotavapor at 60°C to provide the title compound.
Example 3D: Preparation of amorphous solid dispersion of LCZ-696
Syloid (500 mg) was blended with amorphous solid dispersion of LCZ-696 (500 mg) obtained through Example 4.
Example 3E: Preparation of amorphous solid dispersion of LCZ-696
(LCZ/PPE/FEA/4-031)
A mixture of LCZ-696 (5 g) in methanol (100 mL) was heated up to a temperature of 65 °C for 10 minutes to afford a clear solution. The solution was filtered to remove any extraneous particle and cooled to 30 °C. Syloid (5 g) was added to the filtrate. The solvent was evaporated under vacuum at 65 °C and dried in a vacuum tray drier for about 3 hours at 40 °C to afford the title compound.
Example 3F: Preparation of amorphous solid dispersion of LCZ-696
A mixture of LCZ-696 (7.5 g) in methanol (150 mL) was heated up to a temperature of 65 °C for 10 minutes to afford a clear solution. The solution was filtered to remove any extraneous particle and cooled to 30 °C. Neusilin (3.75 g) was added to the filtrate. The solvent was evaporated under vacuum at 65 °C and dried in a vacuum tray drier for about 3 hours at 40 °C to afford the title compound.
Example 3G: Preparation of amorphous solid dispersion of LCZ-696
A mixture of amorphous LCZ-696 (70 g) and syloid (70 g) was blended in a RCVD (RPM: 12) for almost 1 hour to provide the title compound.
Example 3H: Preparation of amorphous solid dispersion of LCZ-696
Amorphous LCZ-696 (50 g) and syloid (50 g) was mixed thoroughly in a rotavapor at 30 °C (160 RPM) to afford the title compound.
Example 3I: Preparation of amorphous solid dispersion of LCZ-696
Amorphous LCZ-696 (125 g) and syloid (125 g) was mixed in a Rapid Mix Granulator for 1 hour under the following conditions to provide the title compound.
Cycle Time: 900 seconds
Chopper Impeller: 2700 RPM
Main Impeller: 100 RPM
Example 3J: Preparation of amorphous solid dispersion of LCZ-696
Amorphous LCZ-696 (1 g) and syloid (1 g) was mixed well in a petri-dish to provide the title compound.

Claims

CLAIMS We Claim:
1. An amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier.
2. The amorphous solid dispersion of LCZ-696 of claim 1 , wherein pharmaceutically acceptable carrier is selected from a group of hydroxypropyl methylcellulose phthalate, povidone, silicon dioxide (syloid) and mixtures thereof.
3. The amorphous solid dispersion of LCZ-696 of claim 1 , wherein pharmaceutically acceptable carrier is a mixture of hydroxypropyl methylcellulose phthalate and silicon dioxide (syloid).
4. The amorphous solid dispersion of LCZ-696 of claim 1 , wherein pharmaceutically acceptable carrier is a mixture of povidone and silicon dioxide (syloid).
5. The amorphous solid dispersion of LCZ-696 of claim 1 , wherein pharmaceutically acceptable carrier is silicon dioxide (syloid).
6. The amorphous solid dispersion of LCZ-696 of claim 1 , wherein pharmaceutically acceptable carrier is neusilin.
7. The amorphous solid dispersion of LCZ-696 of claim 1 , wherein the ratio of LCZ-696 and pharmaceutically acceptable carrier is about 5:95 to about 95:5.
8. A process for the preparation of amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier or mixture thereof comprising:
(a) dissolving LCZ-696 and a pharmaceutically acceptable carrier in suitable solvent or mixtures thereof;
(b) optionally filtering the un-dissolved particles;
(c) isolating amorphous solid dispersion of LCZ-696 with a pharmaceutically acceptable carrier;
(d) optionally drying the amorphous solid dispersion of LCZ-696.
9. A process for preparation of amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier or mixture thereof comprising:
(a) mixing LCZ-696 and a pharmaceutically acceptable carrier in suitable solvent or mixtures thereof; (b) isolating amorphous solid dispersion of LCZ-696 with a pharmaceutically acceptable carrier;
(c) optionally drying the amorphous solid dispersion of LCZ-696.
10. The process for preparing amorphous solid dispersion of LCZ-696 of claims 8 and 9, wherein the solvent used in step (a) is selected from a group of ketone solvent, alcohol solvent and mixture thereof.
11. The process for preparing amorphous solid dispersion of LCZ-696 of claims 8 and 9, wherein the solvent used in step (a) is methanol.
12. The process for preparing amorphous solid dispersion of LCZ-696 of claims 8 and 9, wherein LCZ-696 used in step (a) is crystalline.
13. A process for preparation of amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier comprising mixing amorphous LCZ-696 with one or more pharmaceutically acceptable carrier.
14. The process for preparing amorphous solid dispersion of LCZ-696 of claim 13, wherein mixing of amorphous LCZ-696 with one or more pharmaceutically acceptable carrier is carried out by blending.
15. A pharmaceutical composition comprising amorphous solid dispersion of LCZ-696 with one or more pharmaceutically acceptable carrier.
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WO2018069833A1 (en) 2016-10-10 2018-04-19 Laurus Labs Limited Stable amorphous form of sacubitril valsartan trisodium complex and processes for preparation thereof
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WO2018178295A1 (en) 2017-03-31 2018-10-04 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Stable hot-melt extrudate containing valsartan and sacubitril
WO2019073062A1 (en) 2017-10-13 2019-04-18 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Tablet containing valsartan and sacubitril
WO2019239432A1 (en) 2018-06-14 2019-12-19 Cipla Limited Trisodium sacubitril valsartan complex and hot-melt extruded pharmaceutical composition comprising thereof
WO2020039386A1 (en) 2018-08-23 2020-02-27 Novartis Ag New pharmaceutical use for the treatment of heart failure
WO2020039394A1 (en) 2018-08-24 2020-02-27 Novartis Ag New drug combinations

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