WO2016203436A1 - Amorphous and amorphous solid dispersion of lesinurad and their preparation - Google Patents

Amorphous and amorphous solid dispersion of lesinurad and their preparation Download PDF

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Publication number
WO2016203436A1
WO2016203436A1 PCT/IB2016/053605 IB2016053605W WO2016203436A1 WO 2016203436 A1 WO2016203436 A1 WO 2016203436A1 IB 2016053605 W IB2016053605 W IB 2016053605W WO 2016203436 A1 WO2016203436 A1 WO 2016203436A1
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Prior art keywords
lesinurad
amorphous
solid dispersion
mixture
solvent
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PCT/IB2016/053605
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French (fr)
Inventor
Bhaskar KANDAGATLA
Srinivas ORUGANTI
Subbareddy Peddireddy
Ajit Prabhakar WALKE
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Dr. Reddy's Laboratories Limited
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Publication of WO2016203436A1 publication Critical patent/WO2016203436A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms

Definitions

  • Present application relates to process for preparation of amorphous form of lesinurad. Another aspect of the present invention is directed to amorphous lesinurad characterized by X-ray diffractogram. Another aspect of the present application is directed to amorphous solid dispersion of lesinurad. Still another aspect of the present application relates to process for the preparation of amorphous solid dispersion of lesinurad.
  • Lesinurad is a selective uric acid re-absorption inhibitor (SURI). Lesinurad or its salt is used for reducing serum uric acid level and for the treatment of gout and hyperurecemia. Lesinurad is chemically known as 2-(5-bromo-4-(4-cyclopropyl naphthalen-1 -yl)-4H-1 ,2,4-triazol-3-ylthio)acetic acid and has following structural formula (I):
  • US8546436B2 discloses crystalline Forms I and 2 of lesinurad and their processes for preparation. Similarly, US8524754B2 discloses crystalline forms A, B, B', C, D and E of lesinurad sodium and their processes for preparation.
  • polymorphism refers to the ability of a substance to exist as two or more crystalline phases that have different spatial arrangements and/or conformations of molecules in their crystal lattices.
  • polymorphs refer to different crystalline forms of the same pure substance in which the molecules have different spatial arrangements of the molecules, atoms, and/or ions forming the crystal. Different polymorphs may have different physical properties such as melting points, solubilities, X-ray diffraction patterns, etc.
  • the variation in solid forms may appreciably influence the pharmaceutical properties, such as bioavailability, handling properties, dissolution rate, and stability, and in turn such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorphic form.
  • pharmaceutical properties such as bioavailability, handling properties, dissolution rate, and stability
  • regulatory authorities require drug manufacturing companies to put efforts into identifying all polymorphic forms, e.g., crystalline, amorphous, solvates, stable dispersions with a pharmaceutically acceptable carriers, etc., of new drug substances.
  • amorphous form and amorphous solid dispersion form of a drug may exhibit a higher bioavailability than its crystalline counterparts, which leads to the selection of the amorphous or its solid dispersion form as the final drug substance for pharmaceutical dosage form development.
  • the solubility of crystalline form is lower than its amorphous or amorphous solid dispersion in some instances, particularly aqueous solubility, which may result in the difference in their in-vivo bioavailability. Therefore, it is desirable to have amorphous or amorphous solid dispersion form of a drug to meet the needs of drug development and also a reproducible process for their preparation. Hence, it is desirable to provide amorphous or amorphous solid dispersion of lesinurad.
  • the present application relates to amorphous form of lesinurad which may be characterized by a PXRD pattern substantially as illustrated in figure-1 .
  • the present application relates to process for preparing amorphous form of lesinurad comprising:
  • the present application relates to process for preparing amorphous form of lesinurad comprising:
  • the present application relates to amorphous solid dispersion of lesinurad together with at least one pharmaceutically acceptable excipient.
  • the present application relates to amorphous solid dispersion of lesinurad together with HPMC which may be characterized by X-ray diffractogram as shown in figure-3.
  • the present application relates to amorphous solid dispersion of lesinurad together with PVP K-30.
  • the present application relates to process for preparing amorphous solid dispersion of lesinurad comprising: a) dissolving lesinurad and one or more pharmaceutically acceptable excipients in a suitable solvent or mixture thereof;
  • the present application relates to process for preparing amorphous solid dispersion of lesinurad comprising blending of lesinurad with one or more pharmaceutically acceptable excipients.
  • the present application provides pharmaceutical formulations comprising amorphous form of lesinurad, together with one or more pharmaceutically acceptable carrier, diluents and excipients.
  • the present application provides pharmaceutical composition comprising amorphous solid dispersion of lesinurad with a pharmaceutically acceptable excipient, together with one or more pharmaceutically acceptable excipients.
  • Figure 1 is an illustration of a PXRD pattern of amorphous form of lesinurad obtained by the example 1 .
  • Figure 2 is an illustration of a PXRD pattern of amorphous form of lesinurad obtained by the example 2.
  • Figure 3 is an illustration of a PXRD pattern of amorphous form of solid dispersion of lesinurad obtained by the example 5.
  • Figure 4 is an illustration of a PXRD pattern of amorphous form of solid dispersion of lesinurad obtained by the example 7.
  • Figure 5 is an illustration of a PXRD pattern of amorphous form of solid dispersion of lesinurad obtained by the example 8.
  • Figure 6 is an illustration of a PXRD pattern of amorphous form of solid dispersion of lesinurad obtained by the example 9.
  • Figure 7 is an illustration of a PXRD pattern of amorphous form of solid dispersion of lesinurad obtained by the example 10.
  • the present application relates to amorphous form of lesinurad which may be characterized by a PXRD pattern substantially as illustrated in Figure 1 .
  • the present application relates to process for preparing amorphous form of lesinurad comprising:
  • Any crystalline form or amorphous form of lesinurad sodium or mixture thereof may be used as starting material for preparing amorphous form of lesinurad.
  • Lesinurad sodium may be prepared by methods known in the art.
  • Suitable solvents of step a) for dissolving lesinurad sodium include, but are not limited to water, dimethylformamide; dimethylacetamide; dimethyl sulphoxide; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone; ethers such as tetrahydrofuran, dioxane; esters such as ethyl acetate, isopropyl acetate; halogenated hydrocarbons such as chloroform, dichloromethane; alcohols such as methanol, ethanol, propanol, isopropanol; and mixtures thereof.
  • Suitable acid of step c) include, but are not limited to hydrochloric acid, sulfuric acid, nitric acid, acetic acid, hydrobromic acid and the like.
  • the isolation of the crude compound after the step (c) may be carried out by solvent extraction.
  • suitable solvents that may be used for extraction include, but are not limited to, ethers such as tetrahydrofuran, dioxane; esters such as ethyl acetate, isopropyl acetate; aromatic hydrocarbons such as toluene, xylene, ethylbenzene; halogenated hydrocarbons such as chloroform, dichloromethane and the like.
  • Suitable techniques that may be used for the removal of solvent include but are not limited to rotational distillation using a device such as Buchi Rotavapor, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization) and the like, optionally under reduced pressure.
  • a device such as Buchi Rotavapor, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization) and the like, optionally under reduced pressure.
  • ATFD agitated thin film drying
  • freeze drying lyophilization
  • the isolation and purification can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.
  • suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.
  • the resulting solid may be collected by 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 form of lesinurad.
  • Drying in the embodiments of the present invention may be suitably carried out by 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 steps of the above embodiment may be performed at a temperature of about 0°C to about the boiling point of the solvent.
  • lesinurad sodium may be dissolved in a suitable solvent at a temperature of about 0°C to about 70°C.
  • the dried product 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 product.
  • 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 lesinurad of the present invention is substantially free of any crystalline form of lesinurad.
  • Amorphous form of lesinurad of the present invention does not contain more than about 10 % of any crystalline form of lesinurad.
  • amorphous form of lesinurad does not contain more than about 5 % of any crystalline form of lesinurad.
  • amorphous form of lesinurad does not contain more than about 3 % of any crystalline form of lesinurad.
  • amorphous form of lesinurad does not contain more than about 1 % of any crystalline form of lesinurad.
  • Fig. 1 illustrate PXRD pattern of amorphous lesinurad obtained by process of example 1 .
  • the amorphous form of lesinurad is stable and has excellent physico-chemical properties.
  • the amorphous form of lesinurad of the present application may be easily formulated into a pharmaceutical composition along with suitable pharmaceutically acceptable excipients.
  • the amorphous form of lesinurad obtained in the present invention may be converted to either crystalline or amorphous form of lesinurad sodium by following the methods known in the art.
  • the present application relates to process for preparing amorphous form of lesinurad comprising:
  • Suitable solvents of step a) for dissolving lesinurad include, but are not limited to ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone; alcohols such as methanol, ethanol, propanol, isopropanol; halogenated hydrocarbons such as chloroform, dichloromethane; and mixtures thereof.
  • Suitable techniques that may be used for the removal of solvent in step c) include but are not limited to rotational distillation using a device such as Buchi Rotavapor, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization) and the like, optionally under reduced pressure.
  • a device such as Buchi Rotavapor, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization) and the like, optionally under reduced pressure.
  • the isolation and purification can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.
  • the resulting solid may be collected by 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 form of lesinurad.
  • the steps of the above embodiment may be performed at a temperature of about 0°C to about the boiling point of the solvent. Specifically, lesinurad may be dissolved in a suitable solvent at a temperature of about 0°C to about 1 10°C.
  • the present application relates to amorphous solid dispersion of lesinurad together with at least one pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient may include but not limited 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, mixtures of two or more thereof, copolymers thereof and derivatives thereof.
  • PVP polyvinylpyrrolidones
  • the present application relates to amorphous solid dispersion of Lesinurad with polyvinylpyrrolidones (PVP). More specifically, the present application relates to amorphous solid dispersion of lesinurad with PVP K-30 or HPMC.
  • PVP polyvinylpyrrolidones
  • the weight/weight ratio of lesinurad and pharmaceutically acceptable excipient 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.
  • the present application relates to amorphous solid dispersion of lesinurad together with HPMC which may be characterized by X-ray diffractogram as shown in figure-3.
  • the present application relates to amorphous solid dispersion of lesinurad together with PVP K-30.
  • the present application relates to process for preparing amorphous solid dispersion of lesinurad comprising:
  • Suitable solvents of step a) for dissolving lesinurad include, but are not limited to water, dimethylformamide; dimethylacetamide; dimethyl sulphoxide; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone; alcohols such as methanol, ethanol, propanol, isopropanol; halogenated hydrocarbons such as chloroform, dichloromethane; ethers such as tetrahydrofuran, dioxane; esters such as ethyl acetate, isopropyl acetate; and mixtures thereof.
  • the pharmaceutically acceptable excipient of step a) may include but not limited 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, mixtures of two or more thereof, copolymers thereof and derivatives thereof.
  • PVP polyvinylpyrrolidones
  • the present application relates to amorphous solid dispersion of Lesinurad with polyvinylpyrrolidones (PVP). More specifically, the present application relates to amorphous solid dispersion of lesinurad with PVP K-30 or HPMC.
  • PVP polyvinylpyrrolidones
  • silicon dioxide may be added to the amorphous solid dispersion of lesinurad, prepared by the process of this application, in order to increase the stability and to reduce the hygroscopicity of the amorphous solid dispersion.
  • Suitable techniques that may be used for the removal of solvent in step c) include but are not limited to rotational distillation using a device such as Buchi Rotavapor, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization) and the like, optionally under reduced pressure.
  • a device such as Buchi Rotavapor, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization) and the like, optionally under reduced pressure.
  • step (d) may be same as used in step (a) or mixtures thereof
  • the blending may be carried out by known processes in the literature.
  • the processes which include but are not limited to physical blending, blending in rotatory equipment such as rotatory cone vacuum drier, mortar-pestle or similar suitable methods or combinations of any of these methods.
  • the isolation and purification can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.
  • suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.
  • the resulting solid may be collected by 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 form of lesinurad.
  • the steps of the above embodiment may be performed at a temperature of about 0°C to about the boiling point of the solvent. Specifically, lesinurad may be dissolved in a suitable solvent at a temperature of about 0°C to about 1 10°C.
  • the present application relates to process for preparing amorphous solid dispersion of lesinurad comprising blending of lesinurad with one or more pharmaceutically acceptable excipients.
  • the blending may be carried out by known processes in the literature.
  • the processes which include but are not limited to physical blending, blending in rotatory equipment such as rotatory cone vacuum drier, mortar-pestle or similar suitable methods or combinations of any of these methods.
  • Any crystalline form or amorphous form of lesinurad or mixture thereof may be used as starting material for preparing amorphous form of lesinurad or amorphous solid dispersion of lesinurad.
  • Drying in all the embodiments discussed above of the present invention may be suitably carried out by 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 dried product in all the embodiments discussed above 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 product.
  • 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 solid dispersion of lesinurad of the present invention is substantially free of any crystalline form of lesinurad.
  • Amorphous solid dispersion of lesinurad of the present invention does not contain more than about 10 % of any crystalline form of lesinurad.
  • amorphous solid dispersion of lesinurad does not contain more than about 5 % of any crystalline form of lesinurad.
  • amorphous solid dispersion of lesinurad does not contain more than about 1 % of any crystalline form of lesinurad.
  • the solid dispersion of amorphous form of lesinurad is stable and has excellent physico-chemical properties.
  • the solid dispersion of amorphous form of lesinurad of the present application may be easily formulated into a pharmaceutical composition along with suitable pharmaceutically acceptable excipients.
  • the present application provides pharmaceutical formulations comprising amorphous form of lesinurad, together with one or more pharmaceutically acceptable excipients, carrier and diluents.
  • the present application provides pharmaceutical composition comprising amorphous solid dispersion of lesinurad with a pharmaceutically acceptable excipient, together with one or more pharmaceutically acceptable excipients.
  • Amorphous lesinurad or solid dispersion of amorphous lesinurad together with one or more pharmaceutically acceptable excipients, carrier and diluents 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, extrusion and spheronization.
  • Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.
  • the PXRD data reported herein are obtained using a PANalytical X-ray Diffractometer, with copper Ka radiation.
  • Syloid 250 mg was blended with Lesinurad (250 mg) at 30°C using a mortar pestle to afford the title compound.
  • Example 8 Preparation of amorphous solid dispersion of lesinurad

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Abstract

The present invention provides amorphous form of lesinurad, amorphous solid dispersion of lesinurad and processes for preparation thereof. The present invention also provides a pharmaceutical composition comprising amorphous or amorphous solid dispersion of lesinurad and one or more pharmaceutically acceptable excipient or carrier.

Description

AMORPHOUS AND AMORPHOUS SOLID DISPERSION OF LESINURAD AND
THEIR PREPARATION
FIELD OF THE APPLICATION
Present application relates to process for preparation of amorphous form of lesinurad. Another aspect of the present invention is directed to amorphous lesinurad characterized by X-ray diffractogram. Another aspect of the present application is directed to amorphous solid dispersion of lesinurad. Still another aspect of the present application relates to process for the preparation of amorphous solid dispersion of lesinurad.
BACKGROUND
Lesinurad is a selective uric acid re-absorption inhibitor (SURI). Lesinurad or its salt is used for reducing serum uric acid level and for the treatment of gout and hyperurecemia. Lesinurad is chemically known as 2-(5-bromo-4-(4-cyclopropyl naphthalen-1 -yl)-4H-1 ,2,4-triazol-3-ylthio)acetic acid and has following structural formula (I):
Figure imgf000002_0001
US8546436B2 discloses crystalline Forms I and 2 of lesinurad and their processes for preparation. Similarly, US8524754B2 discloses crystalline forms A, B, B', C, D and E of lesinurad sodium and their processes for preparation.
WO2015075561 A1 assigned to Crystal Pharmatech Co Ltd & Suzhou pengxu harmatech co. ltd., discloses crystalline forms III, IV, V, and VI of lesinurad and their process for preparation. In general, polymorphism refers to the ability of a substance to exist as two or more crystalline phases that have different spatial arrangements and/or conformations of molecules in their crystal lattices. Thus, "polymorphs" refer to different crystalline forms of the same pure substance in which the molecules have different spatial arrangements of the molecules, atoms, and/or ions forming the crystal. Different polymorphs may have different physical properties such as melting points, solubilities, X-ray diffraction patterns, etc. The variation in solid forms may appreciably influence the pharmaceutical properties, such as bioavailability, handling properties, dissolution rate, and stability, and in turn such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorphic form. For these reasons, regulatory authorities require drug manufacturing companies to put efforts into identifying all polymorphic forms, e.g., crystalline, amorphous, solvates, stable dispersions with a pharmaceutically acceptable carriers, etc., of new drug substances.
The existence and possible numbers of polymorphic forms for a given compound cannot be predicted, and there are no "standard" procedures that can be used to prepare polymorphic forms of a substance. This is well-known in the art, as reported, for example, by A. Goho, "Tricky Business," Science News, Vol. 166(8), August 2004.
However there remains a need for alternate solid forms of lesinurad and preparative processes thereof. Particularly, amorphous form and amorphous solid dispersion form of a drug may exhibit a higher bioavailability than its crystalline counterparts, which leads to the selection of the amorphous or its solid dispersion form as the final drug substance for pharmaceutical dosage form development. Additionally, the solubility of crystalline form is lower than its amorphous or amorphous solid dispersion in some instances, particularly aqueous solubility, which may result in the difference in their in-vivo bioavailability. Therefore, it is desirable to have amorphous or amorphous solid dispersion form of a drug to meet the needs of drug development and also a reproducible process for their preparation. Hence, it is desirable to provide amorphous or amorphous solid dispersion of lesinurad. SUMMARY OF THE APPLICATION
In first embodiment, the present application relates to amorphous form of lesinurad which may be characterized by a PXRD pattern substantially as illustrated in figure-1 .
In second embodiment, the present application relates to process for preparing amorphous form of lesinurad comprising:
a) dissolving lesinurad sodium in a suitable solvent or mixture thereof;
b) optionally filtering the un-dissolved particles;
c) adding the acid to the mixture;
d) removing the solvent from the mixture; and
e) optionally, drying the product at suitable temperature.
In third embodiment, the present application relates to process for preparing amorphous form of lesinurad comprising:
a) dissolving lesinurad in a suitable solvent or mixture thereof;
b) optionally filtering the un-dissolved particles;
c) removing the solvent from the mixture; and
d) drying the product at suitable temperature.
In fourth embodiment, the present application relates to amorphous solid dispersion of lesinurad together with at least one pharmaceutically acceptable excipient.
In fifth embodiment, the present application relates to amorphous solid dispersion of lesinurad together with HPMC which may be characterized by X-ray diffractogram as shown in figure-3.
In sixth embodiment, the present application relates to amorphous solid dispersion of lesinurad together with PVP K-30.
In seventh embodiment, the present application relates to process for preparing amorphous solid dispersion of lesinurad comprising: a) dissolving lesinurad and one or more pharmaceutically acceptable excipients in a suitable solvent or mixture thereof;
b) optionally filtering the un-dissolved particles;
c) removing the solvent from the mixture;
d) optionally, blending the mixture with an excipient
e) drying the product at suitable temperature.
In eighth embodiment, the present application relates to process for preparing amorphous solid dispersion of lesinurad comprising blending of lesinurad with one or more pharmaceutically acceptable excipients.
In ninth embodiment, the present application provides pharmaceutical formulations comprising amorphous form of lesinurad, together with one or more pharmaceutically acceptable carrier, diluents and excipients.
In tenth embodiment, the present application provides pharmaceutical composition comprising amorphous solid dispersion of lesinurad with a pharmaceutically acceptable excipient, together with one or more pharmaceutically acceptable excipients.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustration of a PXRD pattern of amorphous form of lesinurad obtained by the example 1 .
Figure 2 is an illustration of a PXRD pattern of amorphous form of lesinurad obtained by the example 2.
Figure 3 is an illustration of a PXRD pattern of amorphous form of solid dispersion of lesinurad obtained by the example 5.
Figure 4 is an illustration of a PXRD pattern of amorphous form of solid dispersion of lesinurad obtained by the example 7.
Figure 5 is an illustration of a PXRD pattern of amorphous form of solid dispersion of lesinurad obtained by the example 8.
Figure 6 is an illustration of a PXRD pattern of amorphous form of solid dispersion of lesinurad obtained by the example 9. Figure 7 is an illustration of a PXRD pattern of amorphous form of solid dispersion of lesinurad obtained by the example 10.
DETAILED DESCRIPTION
In first embodiment, the present application relates to amorphous form of lesinurad which may be characterized by a PXRD pattern substantially as illustrated in Figure 1 .
In second embodiment, the present application relates to process for preparing amorphous form of lesinurad comprising:
a) dissolving lesinurad sodium in a suitable solvent or mixture thereof;
b) optionally filtering the un-dissolved particles;
c) adding the acid to the mixture;
d) removing the solvent from the mixture; and
e) optionally, drying the product at suitable temperature.
Any crystalline form or amorphous form of lesinurad sodium or mixture thereof may be used as starting material for preparing amorphous form of lesinurad. Lesinurad sodium may be prepared by methods known in the art.
Suitable solvents of step a) for dissolving lesinurad sodium include, but are not limited to water, dimethylformamide; dimethylacetamide; dimethyl sulphoxide; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone; ethers such as tetrahydrofuran, dioxane; esters such as ethyl acetate, isopropyl acetate; halogenated hydrocarbons such as chloroform, dichloromethane; alcohols such as methanol, ethanol, propanol, isopropanol; and mixtures thereof.
Suitable acid of step c) include, but are not limited to hydrochloric acid, sulfuric acid, nitric acid, acetic acid, hydrobromic acid and the like.
Optionally, the isolation of the crude compound after the step (c) may be carried out by solvent extraction. The suitable solvents that may be used for extraction include, but are not limited to, ethers such as tetrahydrofuran, dioxane; esters such as ethyl acetate, isopropyl acetate; aromatic hydrocarbons such as toluene, xylene, ethylbenzene; halogenated hydrocarbons such as chloroform, dichloromethane and the like. Suitable techniques that may be used for the removal of solvent include but are not limited to rotational distillation using a device such as Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization) and the like, optionally under reduced pressure.
The isolation and purification can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.
The resulting solid may be collected by 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 form of lesinurad.
Drying in the embodiments of the present invention may be suitably carried out by 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 steps of the above embodiment may be performed at a temperature of about 0°C to about the boiling point of the solvent. Specifically, lesinurad sodium may be dissolved in a suitable solvent at a temperature of about 0°C to about 70°C.
The dried product 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 product. 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 lesinurad of the present invention is substantially free of any crystalline form of lesinurad. Amorphous form of lesinurad of the present invention does not contain more than about 10 % of any crystalline form of lesinurad. Specifically, amorphous form of lesinurad does not contain more than about 5 % of any crystalline form of lesinurad. More specifically, amorphous form of lesinurad does not contain more than about 3 % of any crystalline form of lesinurad. Most specifically, amorphous form of lesinurad does not contain more than about 1 % of any crystalline form of lesinurad. Fig. 1 illustrate PXRD pattern of amorphous lesinurad obtained by process of example 1 .
It was found that the amorphous form of lesinurad is stable and has excellent physico-chemical properties. The amorphous form of lesinurad of the present application may be easily formulated into a pharmaceutical composition along with suitable pharmaceutically acceptable excipients.
The amorphous form of lesinurad obtained in the present invention may be converted to either crystalline or amorphous form of lesinurad sodium by following the methods known in the art.
In third embodiment, the present application relates to process for preparing amorphous form of lesinurad comprising:
a) dissolving lesinurad in a suitable solvent or mixture thereof;
b) optionally filtering the un-dissolved particles;
c) removing the solvent from the mixture; and
d) drying the product at suitable temperature.
Suitable solvents of step a) for dissolving lesinurad include, but are not limited to ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone; alcohols such as methanol, ethanol, propanol, isopropanol; halogenated hydrocarbons such as chloroform, dichloromethane; and mixtures thereof.
Suitable techniques that may be used for the removal of solvent in step c) include but are not limited to rotational distillation using a device such as Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization) and the like, optionally under reduced pressure.
The isolation and purification can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures. The resulting solid may be collected by 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 form of lesinurad.
The steps of the above embodiment may be performed at a temperature of about 0°C to about the boiling point of the solvent. Specifically, lesinurad may be dissolved in a suitable solvent at a temperature of about 0°C to about 1 10°C.
In fourth embodiment, the present application relates to amorphous solid dispersion of lesinurad together with at least one pharmaceutically acceptable excipient.
In an embodiment the pharmaceutically acceptable excipient may include but not limited 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, mixtures of two or more thereof, copolymers thereof and derivatives thereof. Specifically, the present application relates to amorphous solid dispersion of Lesinurad with polyvinylpyrrolidones (PVP). More specifically, the present application relates to amorphous solid dispersion of lesinurad with PVP K-30 or HPMC.
The weight/weight ratio of lesinurad and pharmaceutically acceptable excipient 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.
In fifth embodiment, the present application relates to amorphous solid dispersion of lesinurad together with HPMC which may be characterized by X-ray diffractogram as shown in figure-3.
In sixth embodiment, the present application relates to amorphous solid dispersion of lesinurad together with PVP K-30. In seventh embodiment, the present application relates to process for preparing amorphous solid dispersion of lesinurad comprising:
a) dissolving lesinurad and one or more pharmaceutically acceptable excipients in a suitable solvent or mixture thereof;
b) optionally filtering the un-dissolved particles;
c) removing the solvent from the mixture;
d) optionally, blending the mixture with an excipient;
e) drying the product at suitable temperature.
Suitable solvents of step a) for dissolving lesinurad include, but are not limited to water, dimethylformamide; dimethylacetamide; dimethyl sulphoxide; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone; alcohols such as methanol, ethanol, propanol, isopropanol; halogenated hydrocarbons such as chloroform, dichloromethane; ethers such as tetrahydrofuran, dioxane; esters such as ethyl acetate, isopropyl acetate; and mixtures thereof.
The pharmaceutically acceptable excipient of step a) may include but not limited 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, mixtures of two or more thereof, copolymers thereof and derivatives thereof. Specifically, the present application relates to amorphous solid dispersion of Lesinurad with polyvinylpyrrolidones (PVP). More specifically, the present application relates to amorphous solid dispersion of lesinurad with PVP K-30 or HPMC.
Optionally, silicon dioxide (Syloid) may be added to the amorphous solid dispersion of lesinurad, prepared by the process of this application, in order to increase the stability and to reduce the hygroscopicity of the amorphous solid dispersion.
Suitable techniques that may be used for the removal of solvent in step c) include but are not limited to rotational distillation using a device such as Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization) and the like, optionally under reduced pressure.
The additional excipient used in step (d) may be same as used in step (a) or mixtures thereof
The blending may be carried out by known processes in the literature. The processes which include but are not limited to physical blending, blending in rotatory equipment such as rotatory cone vacuum drier, mortar-pestle or similar suitable methods or combinations of any of these methods.
The isolation and purification can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.
The resulting solid may be collected by 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 form of lesinurad.
The steps of the above embodiment may be performed at a temperature of about 0°C to about the boiling point of the solvent. Specifically, lesinurad may be dissolved in a suitable solvent at a temperature of about 0°C to about 1 10°C.
In eighth embodiment, the present application relates to process for preparing amorphous solid dispersion of lesinurad comprising blending of lesinurad with one or more pharmaceutically acceptable excipients.
The blending may be carried out by known processes in the literature. The processes which include but are not limited to physical blending, blending in rotatory equipment such as rotatory cone vacuum drier, mortar-pestle or similar suitable methods or combinations of any of these methods.
Any crystalline form or amorphous form of lesinurad or mixture thereof may be used as starting material for preparing amorphous form of lesinurad or amorphous solid dispersion of lesinurad.
Drying in all the embodiments discussed above of the present invention may be suitably carried out by 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 dried product in all the embodiments discussed above 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 product. 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 solid dispersion of lesinurad of the present invention is substantially free of any crystalline form of lesinurad. Amorphous solid dispersion of lesinurad of the present invention does not contain more than about 10 % of any crystalline form of lesinurad. Preferably, amorphous solid dispersion of lesinurad does not contain more than about 5 % of any crystalline form of lesinurad. Preferably, amorphous solid dispersion of lesinurad does not contain more than about 1 % of any crystalline form of lesinurad.
It was found that the solid dispersion of amorphous form of lesinurad is stable and has excellent physico-chemical properties. The solid dispersion of amorphous form of lesinurad of the present application may be easily formulated into a pharmaceutical composition along with suitable pharmaceutically acceptable excipients.
In ninth embodiment, the present application provides pharmaceutical formulations comprising amorphous form of lesinurad, together with one or more pharmaceutically acceptable excipients, carrier and diluents.
In tenth embodiment, the present application provides pharmaceutical composition comprising amorphous solid dispersion of lesinurad with a pharmaceutically acceptable excipient, together with one or more pharmaceutically acceptable excipients.
Amorphous lesinurad or solid dispersion of amorphous lesinurad together with one or more pharmaceutically acceptable excipients, carrier and diluents 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, extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.
The PXRD data reported herein are obtained using a PANalytical X-ray Diffractometer, with copper Ka radiation.
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 lesinurad
Lesinurad sodium (43 g, 0.10 moles) was added to water (430 ml) under stirring in nitrogen atmosphere. The mixture was cooled to 0eC and 2N hydrochloric acid (25 ml) was added till pH of 2-3 was reached and stirred at 0eC for ten minutes. The mixture was extracted with dichloromethane (3x350ml). The combined dichloromethane layer was dried over sodium sulfate and solvent was evaporated at 40eC under vacuum to give crude brown color sticky solid. The crude compound was purified by silica gel column chromatography with 50-70% ethyl acetate/hexane to provide the title compound as off-white solid.
Yield: 30.25 g
Example 2: Preparation of amorphous form of lesinurad
Lesinurad (1 gm) was dissolved in of methanol (4ml) in a buchi rotavapor flask at 30°C. The solvent was evaporated under vacuum at 45°C and the solid was dried for 1 hour to afford the title compound.
Example 3: Preparation of amorphous form of lesinurad
Lesinurad (1 gm) was dissolved in of dichloromethane (4ml) in a buchi flask at 30°C. The solvent was evaporated under vacuum rotavapor at 45°C and the solid was dried for 15 minutes to afford the title compound.
Example 4: Preparation of amorphous form of lesinurad
Lesinurad (1 gm) was dissolved in of acetone (4ml) in a buchi flask at 30°C. The solvent was evaporated under vacuum rotavapor at 45°C and the solid was dried for 90 minutes to afford the title compound.
Example 5: Preparation of amorphous solid dispersion of lesinurad
A mixture of lesinurad (500mg) and HPMC VLV (500mg) was dissolved in dichloromethane (15 mL) at 30°C. The solvent was evaporated under vacuum rotavapor at 45°C and the solid was dried for 30 minutes to afford the title compound.
Example 6: Preparation of amorphous solid dispersion of lesinurad
A mixture of lesinurad (500mg) and PVP K-30 (500mg) was dissolved in dichloromethane (4 mL) at 30°C. The solvent was evaporated under vacuum rotavapor at 45°C and the solid was dried for 30 minutes to afford the title compound.
Example 7: Preparation of amorphous solid dispersion of lesinurad
Syloid (250 mg) was blended with Lesinurad (250 mg) at 30°C using a mortar pestle to afford the title compound.
Example 8: Preparation of amorphous solid dispersion of lesinurad
A mixture of lesinurad (500mg) and PVP K-30 (500mg) was dissolved in methanol (4 mL) at 30°C. To the resulting mixture, Syloid (50mg) was added and methanol (8ml) was added. The solvent was evaporated under vacuum rotavapor at 45°C and the solid was dried for 60 minutes to afford the title compound.
Example 9: Preparation of amorphous solid dispersion of lesinurad
A mixture of lesinurad (500mg) and PVP K-30 (500mg) was dissolved in methanol (4 mL) at 30°C. The solvent was evaporated under vacuum rotavapor at 45°C and the solid was dried for 30 minutes. Syloid (500 mg) was blended with the resulting mixture in a mortar pestle to afford the title compound.
Example 10: Preparation of amorphous form of lesinurad
Lesinurad (5gm) was dissolved in of methanol (20ml) at 30°C and filtered the solution to make it particle free. The clear solution was spray dried with 70% aspirator, flow rate of 3 mL/ minute and inlet temperature of 65°C and out let temperature of 47°C to obtain the title compound.

Claims

CLAIMS:
1 ) An amorphous form of Lesinurad.
2) Amorphous form of Lesinurad substantially as shown in figure 1 or 2.
3) A process for the preparation of amorphous form of lesinurad comprising: a) dissolving lesinurad sodium in a suitable solvent or mixture thereof;
b) optionally filtering the un-dissolved particles;
c) adding the acid to the mixture;
d) removing the solvent from the mixture; and
e) optionally, drying the product at suitable temperature.
4) The process according to claim 3, wherein the solvent used in step a) is selected from water, dimethylformamide, dimethylacetamide, dimethyl sulphoxide, nitriles, ketones, ethers, esters, halogenated hydrocarbons, alcohols and mixtures thereof.
5) The process according to claim 3, wherein the acid used in step c) is hydrochloric acid, sulfuric acid, nitric acid, acetic acid and hydrobromic acid.
6) A process for the preparation of amorphous form of lesinurad comprising : a) dissolving lesinurad in a suitable solvent or mixture thereof;
b) optionally filtering the un-dissolved particles;
c) removing the solvent from the mixture; and
d) drying the product at suitable temperature.
7) The process according to claim 6, wherein the solvent used in step a) is selected from ketones, alcohols, halogenated hydrocarbons and mixtures thereof.
8) An amorphous solid dispersion of lesinurad together with at least one pharmaceutically acceptable excipients. 9) The amorphous solid dispersion of Lesinurad according to claim 8, wherein pharmaceutically acceptable excipient is HPMC which is characterized by X- ray diffractogram as shown in figure-3.
10) The amorphous solid dispersion of Lesinurad according to claim 8, wherein pharmaceutically acceptable excipient is PVP K-30.
1 1 ) The amorphous solid dispersion of lesinurad according to claim 8, wherein the pharmaceutically acceptable carriers selected from 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, mixtures of two or more thereof.
12) A process for the preparation of amorphous solid dispersion of lesinurad comprising:
a) dissolving lesinurad and one or more pharmaceutically acceptable excipients in a suitable solvent or mixture thereof;
b) optionally filtering the un-dissolved particles;
c) removing the solvent from the mixture;
d) optionally, blending the mixture with an excipient
e) drying the product at suitable temperature.
13) The process according to claim 12, wherein the solvent used in step a) is selected from water, dimethylformamide, dimethylacetamide, dimethyl sulphoxide, nitriles, ketones, alcohols, halogenated hydrocarbons, ethers, esters and mixtures thereof.
14) The process according to claim 12, wherein additional excipient used in step (d) may be same as used in step (a) or mixtures thereof. 15) A process for the preparation of amorphous solid dispersion of lesinurad comprising blending of lesinurad with one or more pharmaceutically acceptable excipients.
16) The solid pharmaceutical formulation comprising the amorphous lesinurad or amorphous solid dispersion of lesinurad of any of claims 1 to 15 and one or more pharmaceutically acceptable carrier.
PCT/IB2016/053605 2015-06-19 2016-06-17 Amorphous and amorphous solid dispersion of lesinurad and their preparation WO2016203436A1 (en)

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