WO2018163114A1 - Panobinostat amorphe et son sel de lactate - Google Patents

Panobinostat amorphe et son sel de lactate Download PDF

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Publication number
WO2018163114A1
WO2018163114A1 PCT/IB2018/051544 IB2018051544W WO2018163114A1 WO 2018163114 A1 WO2018163114 A1 WO 2018163114A1 IB 2018051544 W IB2018051544 W IB 2018051544W WO 2018163114 A1 WO2018163114 A1 WO 2018163114A1
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WO
WIPO (PCT)
Prior art keywords
panobinostat
amorphous
amorphous form
lactate
solvent
Prior art date
Application number
PCT/IB2018/051544
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English (en)
Inventor
Sriram RAMPALLI
Lav Kumar UPALLA
Veera Venkatarao DAKARAPU
Chandra Sekhar DANGUDUBIYYAM
Purohit PRASHANT
Purandhar CHILUVURU
Original Assignee
Shilpa Medicare Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shilpa Medicare Limited filed Critical Shilpa Medicare Limited
Publication of WO2018163114A1 publication Critical patent/WO2018163114A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines

Definitions

  • the present invention relates to an amorphous form of Panobinostat Lactate.
  • the present invention relates to processes for the preparation of amorphous form of Panobinostat Lactate.
  • the present invention relates to the pharmaceutical composition comprising an amorphous Panobinostat Lactate and one or more of pharmaceutically acceptable carriers, excipients or diluents used for the treatment of Multiple myeloma.
  • the present invention particularly relates to amorphous Panobinostat lactate hydrate.
  • Panobinostat Lactate is chemically known as 2-Hydroxypropanoic acid, compound with 2-(E)-N-hydroxy-3-[4-4[[[2-(2-methyl-lH-indol-3-yl)ethyl]amino]methyl]phenyl]-2- propenamide (1 : 1) having Formula (1).
  • Panobinostat Lactate is indicated for the treatment of Multiple myeloma, patients have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent. It is available under the trade name of FARYDAK ® and its Capsules are supplied in 10, 15, and 20 mg base strengths for oral administration.
  • Valuable pharmacological properties are attributed to this compound; thus, it can be used, for example, as a histone deacetylase inhibitor useful in therapy for diseases which respond to inhibition of histone deacetylase activity.
  • Knowledge of the potential polymorphic forms of N- hydroxy-3-[4-[[[2-(2-methy!-l H-indol-3-yl)ethyl]amino]- mclh 1 ] phenyl ] -2E-2-propenamide 2- Hydroxypropanoic acid is useful in the development of a suitable dosage form. Once chosen, it is important that a polymorphic form can be reproducibly prepared and remain unchanged for prolonged time periods in the dosage form developed.
  • Remiszewski et al in US6552065 provides no information at all about possible crystal modifications and amorphous of N-hydroxy-3-[4-[[[2-(2-methyl-l H-indol-3-yl)ethyl]amino] methyl]phenyl]-2E-2-propenamide or its Lactate (2-Hydroxypropanoic acid) salts.
  • Acemoglu et al in US 7989494 discloses crystalline Form A (anhydrous) and crystalline Form H A (Monohydrate) and crystalline Form S A ( Monomethanol solvate) of the DL-lactate salt of Panobinostat and other salts thereof. Further, this patent also disclosed that the salts of compounds disclosed in US '494 are sticky amorphous materials or amorphous gels.
  • polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density and dissolution rates (important in determining bioavailability). Stability differences may result from changes in more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e.g., capsules crumble on storage as a kinetically favored crystalline form converts to thermodynamically more stable crystalline form) or both (e.g., capsules of one polymorph are more susceptible to breakdown at high humidity).
  • An amorphous form generally prov ides better solubility and bioavailabil ity than the crystalline form and may be useful for formulations which can have better stability, solubility and compressibility etc which are important for formulation and product manufacturing.
  • amorphous form of Panobinostat Lactate is stable under ordinary stability conditions with respect to purity and storage.
  • the main aspect of the present invention is to provide an amorphous form of Panobinostat Lactate.
  • an amorphous form of solid Panobinostat Lactate wherein the amorphous Panobinostat Lactate is hydrate.
  • a process for the preparation of an amorphous form of Panobinostat Lactate wherein the amorphous form is prepared by milling Panobinostat Lactate for sufficient time.
  • an amorphous solid dispersion of Panobinostat Lactate and a polymer in another aspect, there is provided an amorphous solid dispersion of Panobinostat Lactate and a polymer.
  • an amorphous solid dispersion of Panobinostat Lactate wherein the amorphous solid dispersion of Panobinostat Lactate is prepared by a process comprising grinding a solid-solid mixture of Panobinostat Lactate and a polymer.
  • a process for preparing an amorphous solid dispersion of Panobinostat Lactate wherein the step of grinding a solid-solid mixture of Panobinostat Lactate and a polymer comprises grinding a solid-solid mixture of crystalline Panobinostat Lactate and a polymer.
  • step (c) removing the solvent from the solution as obtained in step (b);
  • a stable amorphous form of Panobinostat Lactate wherein the stability is measured by an absence of conversion of the amorphous form of Panobinostat Lactate to a crystalline form of Panobinostat Lactate after the amorphous Panobinostat Lactate is exposed to a relative humidity of at 25 °C ⁇ 2 °C/60% RH ⁇ 5% RH for a period of at least six months.
  • an amorphous solid dispersion of Panobinostat Lactate and a polymer wherein the amorphous solid dispersion of Panobinostat Lactate is prepared by a process comprising grinding a solid-solid mixture of Panobinostat Lactate and a polymer under controlled humidity.
  • a pharmaceutical composition comprising an amorphous form of Panobinostat Lactate and one or more pharmaceutically acceptable carriers, excipients or diluents.
  • a pharmaceutical composition further comprising at least one polymer selected from hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methyl cellulose, methacrylic acid copolymers, and polyvinyl pyrrolidone.
  • the present invention further related to amorphous Panobinostat
  • a process for the preparation of an amorphous form of Panobinostat comprising:
  • FIG. 1 discloses the x-ray diffractogram (XRD) o the amorphous form of Panobinostat Lactate.
  • FIG. 2 discloses the x-ray di ffractogram (XRD) f the amorphous form of Panobinostat.
  • FIG. 3 discloses the Thermo Gravametric analysis (TGA) of the amorphous form of Panobinostat Lactate.
  • the above and other objects of the present invention are achieved by the process of the present invention, which leads to amorphous Panobinostat Lactate suitable for pharmaceutical use and having greater stability.
  • the invention provides a process for preparing amorphous form of Panobinostat Lactate.
  • the present invention particularly provides an amorphous form of solid Panobinostat Lactate wherein the amorphous Panobinostat Lactate is hydrate.
  • the solution prior to any solids formation, can be filtered to remove any undissolved solids and/or solid impurities prior to the removal of the solvent.
  • Any filtration system and techniques known in the art can be used.
  • controlled humidity refers to a relative humidity in the range of 50 ⁇ 10%.
  • the controlled humidity includes grinding process performed under controlled humidity followed by drying under controlled humidity for the preparation of an amorphous form of Panobinostat Lactate.
  • the term “grinder” includes mixers, mills, blenders, and micronizers, or a combination thereof.
  • the terms “grinding”, “milling”, “mixing”, and “blending “ and the like are interchangeable for achiev ing the homogeneous solid-solid mixture.
  • ball milling means a process wherein shear forces are applied to a starting material by means of so-called milling balls located in a milling vessel. Typically and preferably, the milling vessel is rotated, wherein the milling balls collide with each other and with the API particles provided as the starting material.
  • the ball mill preferred, may be planetary ball mill with model No. PM 100 and make of Retsch, Germany.
  • stable Panobinostat Lactate includes an amorphous Panobinostat Lactate measured by an absence of conversion of the amorphous form of Panobinostat Lactate to a crystalline form of Panobinostat Lactate after the amorphous Panobinostat Lactate is exposed to a relative humidity of 75% at 40° C. or 60% at 25° C for a period of at least three months.
  • solid dispersion means any solid composition having at least two components.
  • a solid dispersion as disclosed herein includes r uiuumus u
  • the term "immobilize" with reference to the immobilization of the Panobinostat Lactate in the polymer matrix means that molecules of the Panobinostat Lactate interact with molecules of the polymer in such a way that the molecules of the Panobinostat Lactate are held in the aforementioned matrix and prevented from crystal nucleation due to lack of mobility.
  • an amorphous form of Panobinostat Lactate is provided.
  • an amorphous form of Panobinostat Lactate wherein the amorphous Panobinostat Lactate is hydrate.
  • an amorphous form of solid Panobinostat Lactate wherein the amorphous Panobinostat Lactate is hydrate.
  • an amorphous form of Panobinostat Lactate wherein the amorphous form is prepared by milling Panobinostat Lactate for sufficient time.
  • the step of milling Panobinostat Lactate comprises milling crystalline Panobinostat Lactate.
  • the amorphous form of Panobinostat Lactate is stable and has not detectable quantity of the crystalline form of Panobinostat Lactate after the amorphous form of Panobinostat Lactate is exposed to a relative humidity of 75% at 40° C. or 60% at 25° C. for a period of at least three months.
  • an amorphous solid dispersion of Panobinostat Lactate and a polymer in another aspect, there is provided an amorphous solid dispersion of Panobinostat Lactate and a polymer.
  • the amorphous solid dispersion of Panobinostat Lactate is prepared by a process comprising grinding a solid-solid mixture of Panobinostat Lactate and a polymer.
  • the step of grinding a solid-solid mixture of Panobinostat Lactate and a polymer comprises grinding a solid-solid mixture of crystalline Panobinostat Lactate and a polymer.
  • the polymer may be a non-ionic polymer or an ionic polymer.
  • the polymer comprises of hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose, methacrylic acid copolymers, and polyvinylpyrrolidone.
  • polyvinylpyrrolidone of different grades comprises of K-15, K-30, K-60, K-90 and K-120 which may be used for the preparation of amorphous composition. More particular, hydroxypropylmethyl cellulose acetate succinate and polyvinylpyrrolidone K-30 may be used.
  • the solid-solid mixture of Panobinostat Lactate and a polymer may be m i l led by grinding action between two surfaces.
  • milling machines that work on substantially the same principle may be used in the present process.
  • milling machines include various makes of ball mills, roller mills, gyratory mills, multi-mills, Jet-mills, and the like.
  • a mill such as a Micros Super Fine Mill, Multi-Mill Sr. No. G.1.132, Ret sch (Planetary ball mill), Jet-Mill from Midas Micronizer M-100 Aerosol (No. 154/07-08 or a common mixer grinder can be used.
  • a mill such as a Micros Super Fine Mill, Multi-Mill Sr. No. G.1.132, Ret sch (Planetary ball mill), Jet-Mill from Midas Micronizer M-100 Aerosol (No. 154/07-08 or a common mixer grinder can be used.
  • Alternatively another commercially available milling machine can be used.
  • the process parameter includes adding a solid-solid mixture of Panobinostat Lactate and hydroxypropylmethyl cellulose acetate succinate in a grinder.
  • a specific grinder used can be small-scale to large-scale mixer grinder which can easily prepare the homogeneous mixture of two solids.
  • Quadro dry mixing apparatus for providing lump-free homogenous blending to ensure proper mixing.
  • the varieties of mills and mixers provided in Perry's Chemical Engineers' I landbook Seventh Edition by Robert 11. Perry and Don W. Green can be used based on suitability are incorporated herein by reference in its entirety.
  • This grinding apparatus may consists of a water cooled jacketed bowl with the inside surface made of a suitable material such as Zirconium oxide, stainless steel, tungsten carbide, or aluminum oxide. Depending on the size of the grinder, the speed of rotation of the main shaft
  • ctiiu me ciic ⁇ ii v c vuiuiiic lilt gi ii iuing ⁇ ⁇ v ai y . i nt uitwi v i v i uiiiv ⁇ iv ⁇ grinding chamber may be in the range from about 0.45 liters to about 30 liters.
  • the speed of rotation of the main shaft is typically in the range from about 200 rpm to about 2000 rpm.
  • the grinder may be a typical milling apparatus.
  • This milling apparatus may be typically charged with feed material such that from about 10% to 30% of the effective volume of the grinding chamber is occupied.
  • Examples o methods of transferring materials well known in the art include manual transfer, gravity feed, pneumatic conveying (using a high velocity air stream), and vacuum transfer. Such methods, well known in the art, may be used with the process of this invention to charge the feed material into the grinding volume available between the bowl and the sub-shafts.
  • the Panobinostat Lactate and hydroxypropylmethyl cellulose acetate succinate may be mixed in a wide range of ratios.
  • the period of mill ing using the mil l may vary depending on the size of the mill, the speed of rotation of the main shaft, the type of feed material, and the quantity of feed material. The effects of these variables are well known in the art and the invention may be worked over a range of these variables. Typically, the period of milling ranges from about 15 minutes to 300 minutes. In general, the Panobinostat Lactate is subjected to grinding involving attrition of the particles and machine surfaces.
  • the Panobinostat Lactate may be dispersed within a matrix formed by a polymer in its solid state such that it is immobilized in its amorphous form.
  • the polymer may prevent intramolecular hydrogen bonding or weak dispersion forces between two or more drug molecules of Panobinostat Lactate.
  • the solid dispersion provides for a large surface area, thus further allowing for improved dissolution and bioavailability of Panobinostat Lactate.
  • the ratio of the amount of weight of Panobinostat Lactate within the solid dispersion to the amount by weight of the polymer therein is from about 1 : 1 to about 1 : 10.
  • the composition of Panobinostat Lactate with polymer, particularly hydroxypropylmethyl cellulose acetate succinate or polyvinylpyrrolidone may be prepared by using about 1 : 1 to about 1 : 10 polymers with respect to Panobinostat Lactate.
  • a process for the preparation of an amorphous solid dispersion of Panobinostat Lactate and a polymer comprising mixing Panobinostat Lactate with a polymer in one or more solvents and obtaining the amorphous solid dispersion of Panobinostat Lactate by the removal of the solvent.
  • the compound Panobinostat Lactate and a polymer may be dissolved in one or more solvents selected from methanol, ethanol, isopropanol, acetone, ethyl acetate or mixture thereof with water.
  • the amorphous solid dispersion may be obtained by the removal of the solvent.
  • the removal of the solvent comprises one or more of evaporation by rotational distillation, evaporation under reduced pressure, spray drying, agitated thin film drying ("ATFD”), freeze drying (lyophilization ). flash evaporation, and vacuum distillation thereby leaving the amorphous solid dispersion precipitated in a matrix formed by the polymer.
  • the present invention provides a process for the preparation of an amorphous form of Panobinostat Lactate, the process comprising:
  • step (c) removing the solvent from the solution as obtained in step (b);
  • the solvents that may be used in step a) comprises one or more of alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1 -butanol, and t-butyl alcohol, trifluoroethanol and/or mixture thereof; ketones selected from acetone, butanone, and methyl ethyl ketone, methyl isobutyl ketone and/or mixture thereof; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate, chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene and/or mixture thereof; acetonitrile; and polar aprotic solvents selected from dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, Tetrahydrofuran, Dioxane, Dirnethoxy ethane, Acet
  • Step-b involves aqueous lactic acid added to the solution obtained in step-a.
  • Lactic acid addition involves slow addition, wherein slow addition involves the drop wise addition (or) direct charging/adding in a single lot at a temperature ranging from 25-30°C.
  • Step c) involves removing the solvent from the solution obtained in step b). The isolation may be affected by removing the solvent.
  • the techniques which may be used for the removal of solvent comprises one or more of evaporation by rotational distillation, evaporation under reduced pressure, spray drying, agitated thin film drying ("ATFD”), freeze drying (lyophi lization). flash evaporation, and vacuum distillation.
  • the present invention provides a process for the preparation of an amorphous form of Panobinostat Lactate having water content in the range between 3. 1 to 4.9 % w/w, the process comprising:
  • step (b) removing the solvent from the solution as obtained in step (b);
  • Panobinostat Lactate obtained as per the present invention is hydrate, particularly monohydrate having water content in the range between 3.1 to 4.9 % w/w.
  • the solvents that may be used in step a) comprises one or more of alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1 -butanol, and t-butyl alcohol, trifluoroethanol and/or mixture thereof; ketones selected from acetone, butanone, and methyl ethyl ketone, methyl isobutyl ketone and/or mixture thereof; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate, chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene and/or mixture thereof; acetonitrile; and polar aprotic solvents selected from dimethylformamide, dimethyiacetarnide, N-methylpyrrolidone, dimethyl sulfoxide, Tetrahydrofuran, Dioxane, Dimethoxyethane
  • Step-b involves aqueous lactic acid added to the solution obtained in step-a.
  • Lactic acid addition involves slow addition, wherein slow addition involves the drop wise addition (or) direct charging/adding in a single lot at a temperature ranging from 25-30°C.
  • Step c) involves removing the solvent from the solution obtained in step b). The isolation may be affected by removing the solvent.
  • the techniques which may be used for the removal of solvent comprises one or more of evaporation by rotational distillation, evaporation under reduced pressure, spray drying, agitated thin film drying ("ATFD”), freeze drying (Syophilization), flash evaporation, and vacuum distillation.
  • solvent in step d) comprises one or more of methanol, ethanol. isopropanol. 2-propanol, 1 -butanol. and t-butyl alcohol, trifluoroethanol ketones selected from acetone, butanone, and methyl ethyl ketone, methyl isobutyl ketone esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate, chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene and/or mixture thereof; acetonitrile; and polar aprotic solvents selected from dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, Tetrahydrofuran, Dioxane, Dimethoxyethane, Acetonitrile, Toluene, x
  • the solvents that may be used in step a) comprises one or more of alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1 -butanol, and t-butyl alcohol, trifluoroethanol and/or mixture thereof; ketones selected from acetone, butanone, and methyl ethyl ketone, methyl isobutyl ketone and/or mixture thereof; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate, chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene and/or mixture thereof; acetonitrile; and polar aprotic solvents selected from dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, Tetrahydrofuran, Dioxane, Dimethoxyethane ⁇ Aceton
  • Step b) involves removing the solvent from the solution obtained in step a).
  • the isolation may be affected by removing the solvent.
  • the techniques which may be used for the removal of solvent comprises one or more of evaporation by rotational distillation, evaporation under reduced pressure, spray drying, agitated thin fi lm drying ("ATFD”), freeze drying (lyophilization), flash evaporation, and vacuum distillation.
  • the present invention further relates to solid dispersion of Panobinostat amorphous using the process as described in the foregoing description for amorphous Panobinostat lactate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne une forme amorphe d'hydrate de lactate de panobinostat. La présente invention concerne particulièrement des procédés de préparation de forme amorphe de lactate de panobinostat. La présente invention concerne plus particulièrement, une composition pharmaceutique comprenant un lactate de panobinostat amorphe et un ou plusieurs porteurs, excipients ou diluants pharmaceutiquement acceptables utilisés pour le traitement du myélome multiple. La présente invention concerne une forme amorphe de panobinostat et son procédé de préparation.
PCT/IB2018/051544 2017-03-10 2018-03-09 Panobinostat amorphe et son sel de lactate WO2018163114A1 (fr)

Applications Claiming Priority (2)

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IN201741008517 2017-03-10
IN201741008517 2017-03-10

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WO2018163114A1 true WO2018163114A1 (fr) 2018-09-13

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007146716A2 (fr) * 2006-06-12 2007-12-21 Novartis Ag Polymorphes de n-hydroxy-3-[4-[[[2-(2-méthyl-1h-indol-3-yl)éthyl]amino]méthyl]phényl]-2e-2-propénamide
US20090187029A1 (en) * 2006-06-12 2009-07-23 Bajwa Joginder S Process for making salts of n-hydroxy-3-[4-[[[2-(2-methyl-1h-indol-3-yl)ethyl]amino]methyl]phenyl]-2e-2-propenamide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007146716A2 (fr) * 2006-06-12 2007-12-21 Novartis Ag Polymorphes de n-hydroxy-3-[4-[[[2-(2-méthyl-1h-indol-3-yl)éthyl]amino]méthyl]phényl]-2e-2-propénamide
US20090187029A1 (en) * 2006-06-12 2009-07-23 Bajwa Joginder S Process for making salts of n-hydroxy-3-[4-[[[2-(2-methyl-1h-indol-3-yl)ethyl]amino]methyl]phenyl]-2e-2-propenamide

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