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WO2019092752A2 - Nouveau sel de lénalidomide et ses formes polymorphes - Google Patents

Nouveau sel de lénalidomide et ses formes polymorphes Download PDF

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Publication number
WO2019092752A2
WO2019092752A2 PCT/IN2018/050741 IN2018050741W WO2019092752A2 WO 2019092752 A2 WO2019092752 A2 WO 2019092752A2 IN 2018050741 W IN2018050741 W IN 2018050741W WO 2019092752 A2 WO2019092752 A2 WO 2019092752A2
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WO
WIPO (PCT)
Prior art keywords
lenalidomide
trifluroacetic acid
acid salt
crystalline form
salt
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Ceased
Application number
PCT/IN2018/050741
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English (en)
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WO2019092752A3 (fr
Inventor
Venkata Rama Rao Alla
Chandrashekar Ramarao
Mukesh Padmakar SHEWALKAR
Sampath AMUDALA
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Avra Laboratories Pvt Ltd
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Avra Laboratories Pvt Ltd
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Publication date
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Publication of WO2019092752A2 publication Critical patent/WO2019092752A2/fr
Publication of WO2019092752A3 publication Critical patent/WO2019092752A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to novel pharmaceutical salt of Lenalidomide. More particularly, the invention relates to Trifluroacetic acid salt of Lenalidomide; polymorphic forms thereof and process for preparation thereof. The invention further relates to pharmaceutical composition comprising Trifluroacetic acid salt of Lenalidomide in association with one or more pharmaceutical excipients.
  • Lenalidomide is chemically known as 3-(4-amino-l-oxo-l,3-dihydro-2H-isoindol- 2-yl)piperidine-2,6-dione and structurally represented below.
  • Lenalidomide a Thalidomide analogue
  • the first therapeutic use of Lenalidomide, a Thalidomide analogue was for the treatment of multiple myeloma. Subsequently, the therapeutic efficacy of Lenalidomide has been established in the hematological disorders known as the myelodysplasia syndromes.
  • Lenalidomide was approved by the U.S. Food and Drug Administration for treating patients with low or intermediate- 1 risk MDS with 5q with or without additional cytogenetic abnormalities.
  • Lenalidomide is currently marketed under the trade name REVLIMID® by Celgene.
  • Lenalidomide was first disclosed in US5635517. The aqueous solubility of Lenalidomide is very low. Therefore continued search for suitable polymorphic forms with improved physical characteristics results in various patents/patent applications for various crystalline, amorphous polymorphic forms of Lenalidomide as well as solvate forms.
  • WO 2005/023192 disclose polymorphic forms of Lenalidomide, designated as forms A, B, C, D, E, F, G, and H.
  • US9108945 discloses an anhydrous unsolvated crystalline form of Lenalidomide (Form-I) having weight loss of up to 0.13% between 25 and 225° C. by thermogravimetric analysis and characterized by its Powder XRD having peaks at 10.175 ⁇ 0.2, 11.269 ⁇ 0.2, 15.772 ⁇ 0.2, 16.277 ⁇ 0.2, 17.646 ⁇ 0.2, 20.099 ⁇ 0.2, 24.098 ⁇ 0.2, 25.230 ⁇ 0.2, 25.987 ⁇ 0.2, 28.320 ⁇ 0.2, and 32.595 ⁇ 0.2 degrees 2 ⁇ .
  • WO2012127493 discloses a Lenalidomide N-methylpyrrolidone solvate which is characterized by peaks in the powder x-ray diffraction spectrum having 20 angle positions at about 8.5, 14.0, 14.5, 15.6, 16.1, 17.1, 17.6, 19.6, 21.6, 22.8 and 25.3 ⁇ 0.2 degrees.
  • polymorphism is defined as the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice.
  • different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. however, these properties will disappear once the compound is dissolved.
  • these physical properties can influence pharmaceutically relevant properties of the solid form, such as handling properties; dissolution rate and stability thereby significantly influence the processing, shelf life, therapeutic efficacy and thus commercial acceptance of a polymorph.
  • Trifluroacetic acid salt of Lenalidomide that has more solubility, dissolution rate and stability.
  • the present invention discloses a novel Trifluroacetic acid (TFA) salt of Lenalidomide of formula I, which is stable and exhibits more intrinsic dissolution to that of existing forms.
  • Trifluroacetic acid (TFA) salt of Lenalidomide of formula I is crystalline in nature.
  • the invention provides process for preparation of the novel Trifluroacetic acid (TFA) salt of Lenalidomide by reacting Lenalidomide with Trifluroacetic acid at ambient temperature to obtain Trifluroacetic acid (TFA) salt of Lenalidomide.
  • the present invention encompasses various crystalline polymorphic forms of Trifluroacetic acid (TFA) salt of Lenalidomide viz., Form I; Form II; Form III; Form IV and Form V.
  • TFA Trifluroacetic acid
  • the invention also encompasses mixtures of these forms.
  • this invention provides methods of making, isolating and characterizing these polymorphs.
  • the invention provides pharmaceutical compositions comprising therapeutically effective amount of crystalline Trifluroacetic acid (TFA) salt of Lenalidomide in association with one or more pharmaceutical carriers.
  • TFA Trifluroacetic acid
  • These compositions may be formulated into oral solid dosage forms such as tablets and capsules; liquid dosage forms such as syrups and solutions and injectable dosage forms, using suitable excipients by conventional methods.
  • the invention provides methods of using the TFA salt of Lenalidomide according to the invention for treatment of hematological disorders, which method comprises administering a therapeutically effective amounts of TFA salt of Lenalidomide or its crystalline polymorphic forms optionally in association with one or more pharmaceutical excipients to a subject in need thereof.
  • Fig 1 depicts PXRD of Trifluroacetic acid (TFA) salt of Lenalidomide resulted from Ethanol and DCM solvent system, referred as polymorphic form I
  • Fig 2 depicts PXRD Trifluroacetic acid (TFA) salt of Lenalidomide resulted from DCM as solvent, as well as resulted from Toluene referred as polymorphic form II
  • Fig 3 depicts PXRD Trifluroacetic acid (TFA) salt of Lenalidomide resulted from Ethyl acetate as solvent, referred as polymorphic form III
  • Fig 4 depicts PXRD Trifluroacetic acid (TFA) salt of Lenalidomide resulted from MTBE as solvent referred as polymorphic form IV
  • Fig 5 depicts PXRD Trifluroacetic acid (TFA) salt of Lenalidomide resulted from Acetonitrile as solvent referred as polymorphic form V
  • the present invention discloses a novel Trifluroacetic acid salt of Lenalidomide of formula I, which is structurally depicted below:
  • the invention provides process for preparation of the novel Trifluroacetic acid (TFA) salt of Lenalidomide by reacting Lenalidomide with Trifluroacetic acid at ambient temperature under stirring for about 2 to lOhrs. The reaction mass is concentrated to obtain residue containing Trifluroacetic acid salt of Lenalidomide.
  • TFA Trifluroacetic acid
  • the Trifluroacetic acid (TFA) salt of Lenalidomide of formula I is crystalline in nature.
  • purified crystals of Trifluroacetic acid salt of Lenalidomide can be obtained by treating the residue with organic solvent.
  • the present invention encompasses these crystalline polymorphic forms of formula I which are designated as Form 1, Form II, Form III, Form IV and Form V. All these forms exhibits characteristic peaks when subjected to PXRD.
  • the invention provides a process for preparation of the crystalline form I of Trifluroacetic acid salt of Lenalidomide which process comprises;
  • Trifluroacetic acid (TFA) salt of Lenalidomide Form I thus obtained from combination of ethanol and dichloromethane solvents is analyzed by PXRD, for its crystal characteristics.
  • the PXRD shows characteristic peaks at 8.4, 8.8, 9.3, 12.1, 14.6, 15.1, 15.5, 20.4, 21.4, 22.1, 22.5, 23.1, 23.4, 24, 24.4, 24.7 degrees 2 ⁇ , as shown in figure 1.
  • the invention provides process for preparation of novel crystalline form II of Trifluroacetic acid (TFA) salt of Lenalidomide which comprises;
  • the PXRD of this crystalline form having characteristic peaks at 5.2, 5.4, 8.3, 10.6, 10.8, 13.9, 13.8, 18, 18.7, 20.2, 20.7, 21.3, 21.7, 26.1, 27 degrees 2 ⁇ 0.2.
  • the PXRD of the crystalline form thus obtained from both toluene and dichloromethane is substantially as shown in figure 2.
  • the invention provides process for preparation of novel crystalline form III of Trifluroacetic acid (TFA) salt of Lenalidomide which process comprises;
  • the PXRD of the crystalline form III is substantially as shown in figure 3.
  • the invention provides process for preparation of novel crystalline form IV of Trifluroacetic acid (TFA) salt of Lenalidomide which process comprises;
  • the PXRD of the crystalline form IV obtained from MTBE exhibits characteristic peaks at 5.4, 8.3, 10.4, 10.8, 12.8, 13.2, 13.6, 14.5, 15.8, 16.3, 16.7, 18, 18.7, 19.4,
  • the PXRD of the crystalline form IV is substantially as shown in figure 4.
  • the invention provides process for preparation of novel crystalline form V of Trifluroacetic acid (TFA) salt of Lenalidomide which process comprises;
  • the PXRD of the crystalline form V obtained from acetonitrile exhibits characteristic peaks at 5.6, 6.1, 11.4, 124, 14, 14.7, 15.8, 16.6, 17.2, 17.9, 18.7, 19.7, 20.3, 21.2, 23.1, 25.9, 26.5, 27.1, 28.2, 29.1 degrees 2 ⁇ 0.2.
  • the PXRD of this novel crystalline form V is substantially as shown in figure 5.
  • the present invention encompasses various crystalline polymorphic forms of Trifluroacetic acid (TFA) salt of Lenalidomide referred as above- a) Crystalline polymorphic form I of Trifluroacetic acid (TFA) salt of Lenalidomide analyzed by PXRD having characteristic peaks at 8.4, 8.8, 9.3, 12.1, 14.6, 15.1, 15.5, 20.4, 21.4, 22.1, 22.5, 23.1, 23.4, 24, 24.4, 24.7 degrees 2 ⁇ 0.2, substantially as shown in figure 1; b) Crystalline polymorphic form II of Trifluroacetic acid (TFA) salt of Lenalidomide analyzed by PXRD having characteristic peaks at 5.2, 5.4, 8.3, 10.6, 10.8, 13.9, 13.8, 18, 18.7, 20.2, 20.7, 21.3, 21.7, 26.1, 27 degrees 2 ⁇ 0.2, substantially as shown in figure 2; c) Crystalline polymorphic form III of Trifluroacetic acid (TFA) salt of Lenalidomide analyzed by PXRD having characteristic
  • TFA salts of Lenalidomide of the present invention is observed to be in the range of 8.5mg/ml to 11 26mg/mL which is far greater than the Form I and Form B of Lenalidomide viz., 3.15mg/ml and 3.28 respectively as reported in US9108945.
  • the invention provides comparative evaluation study of acute toxicity of Lenalidomide Trifluroacetate and Lenalidomide free base by fixed dose method as per NCI guidelines. Accordingly, the study was conducted in Balb/c Mice as test subjects in order to derive the data with the test compounds for predicting the human response by strictly adhering to the regulatory guidelines NCI for testing the chemicals for acute oral toxicity by fixed dose method. These animals are widely used for pre-clinical toxicological studies for anticancer compounds. According to this study, mice of both the genders having uniform weight and age were used for acute toxicity testing to determine the effect of a single dose on the test subjects. In acute toxicological testing, the test product is administered at different dose levels, and the effect is observed for 14 days.
  • the fixed dose procedure (FDP) is used to assess the nonlethal toxicity rather than the lethal dose.
  • the Lenalidomide Trifluroacetate (test compound I) is administered to the mice at fixed dose levels of 100, 200 and 400mg/kg and mice is observed for a specified period of 14 days to notice the difference in the body weight, to assess the toxicity of the test compound.
  • test compound I Lenalidomide Trifluroacetate
  • test compound 2 Lenalidomide free base
  • Lenalidomide Trifluroacetate of the present invention is much safer than the Lenalidomide or at least comparable.
  • Lenalidomide Trifluroacetate having very good safety profile and 3 times greater solubility over the Lenalidomide of the prior art conclusively proves that Lenalidomide Trifluroacetate, if administered, provides enhanced therapeutic efficacy over the prior art product, Lenalidomide.
  • the present invention provides pharmaceutical compositions comprising novel TFA salt of Lenalidomide in therapeutically effective amounts along with one or more pharmaceutical carriers/ excipients.
  • compositions of present invention may comprise any one specific polymorphic form of TFA salt of Lenalidomide selected from polymorphic forms I to V according to the present invention along with one or more pharmaceutical excipients/carriers to attain desired therapeutic efficacy.
  • compositions of present invention may comprise mixture of one or more polymorphic forms of TFA salt of Lenalidomide selected from polymorphic forms I to V according to the present invention along with one or more pharmaceutical excipients/carriers to attain desired therapeutic efficacy.
  • the TFA salt of Lenalidomide according to the invention can be formulated into oral dosage forms such as tablets, capsules, oral liquids such as syrups and suspensions or injectable dosage forms using suitable pharmaceutical excipients.
  • the invention provides methods of using the TFA salt of Lenalidomide according to the invention for treatment of hematological disorders, which method comprises administering a therapeutically effective amounts of TFA salt of Lenalidomide or the crystalline polymorphic forms I to V according to the invention optionally in association with one or more pharmaceutical excipients to a subject in need thereof.
  • excipients are the conventional excipients which can be selected from the group consisting of binders, diluents, distintegrants, lubricants, polymers, gelatin, fillers etc.
  • the invention provides methods of using the TFA salt of Lenalidomide according to the invention for the preparation of medicament for treatment of hematological disorders.
  • Such methods of use involve preparation of variety of dosage forms of TFA salt of Lenalidomide optionally in association with one or more pharmaceutical excipients.
  • Lenalidomide free base (9g, 0.034mole) and TFA (45mL, 5V) were stirred at 25- 30° C for 5Hrs. TFA was concentrated and the residue was stirred with DCM (612mL, 68V) at 25-30° C for 12Hrs. The obtained solid (12.4g) was collected by filtration. The PXRD of the TFA salt of Lenalidomide thus obtained is shown as Fig.2.
  • Lenalidomide free base (5g, 0.019mole) and TFA (25mL, 5V) were stirred at 25- 30° C for 5Hrs. TFA was concentrated and the residue was stirred with Toluene (300mL, 60V) at 25-30° C for 48Hrs. The obtained solid (7g) was collected by filtration. The PXRD of the TFA salt of Lenalidomide thus obtained is corresponding Fig.2.
  • Lenalidomide free base (5g, 0.019mole) and TFA (25mL, 5V) were stirred at 25-
  • Lenalidomide free base (5g, 0.019mole) and TFA (25mL, 5V) were stirred at 25- 30° C for 4 Hrs. TFA was concentrated and the residue was stirred with Acetonitrile (150mL, 30V) at 25-30° C for 0.5Hr. The obtained solid (5.8g) was collected by filtration. PXRD of the TFA salt of Lenalidomide thus obtained is shown as Fig.5. Yield: 80%

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  • Chemical & Material Sciences (AREA)
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  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne un nouveau sel pharmaceutique De lénalidomide. Plus particulièrement, l'invention concerne un sel d'Acide trifluroacétique cristallin De lénalidomide; ses formes polymorphes et son procédé de préparation. L'invention concerne en outre une composition Pharmaceutique comprenant un sel d'Acide trifluroacétique cristallin de lénalidomide en association avec un ou plusieurs excipients pharmaceutiques.
PCT/IN2018/050741 2017-11-13 2018-11-13 Nouveau sel de lénalidomide et ses formes polymorphes Ceased WO2019092752A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN201741040454 2017-11-13
IN201741040454 2017-11-13
IN201841006631 2018-02-21
IN201841006631 2018-02-21

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WO2019092752A2 true WO2019092752A2 (fr) 2019-05-16
WO2019092752A3 WO2019092752A3 (fr) 2019-06-13

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Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20100124710A (ko) * 2008-03-11 2010-11-29 닥터 레디스 레보러터리즈 리미티드 레날리도미드의 제조
US20110060010A1 (en) * 2008-03-13 2011-03-10 Tianjin Hemay Bio-Tech Co., Ltd Salts of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)piperidine-2,6-dione and derivatives thereof, or polymorphs of salts, process for preparing same and use thereof
EA201270261A1 (ru) * 2009-08-12 2012-07-30 Синтон Б. В. Соли леналидомида
WO2011050962A1 (fr) * 2009-10-29 2011-05-05 Ratiopharm Gmbh Sels d'addition d'acide du lénalidomide

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