WO2010144675A1 - Polymorphes du chlorhydrate de bendamustine et leurs procédés de préparation - Google Patents

Polymorphes du chlorhydrate de bendamustine et leurs procédés de préparation Download PDF

Info

Publication number
WO2010144675A1
WO2010144675A1 PCT/US2010/038128 US2010038128W WO2010144675A1 WO 2010144675 A1 WO2010144675 A1 WO 2010144675A1 US 2010038128 W US2010038128 W US 2010038128W WO 2010144675 A1 WO2010144675 A1 WO 2010144675A1
Authority
WO
WIPO (PCT)
Prior art keywords
bendamustine hcl
xrd pattern
powder xrd
bendamustine
theta
Prior art date
Application number
PCT/US2010/038128
Other languages
English (en)
Inventor
Martin Kuchar
Romana Korytakova
Karel Pospisilik
Ales Gavenda
Pavel Vraspir
Alexandr Jegorov
Original Assignee
Plus Chemicals Sa
Teva Pharmaceuticals Usa, Inc.
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 Plus Chemicals Sa, Teva Pharmaceuticals Usa, Inc. filed Critical Plus Chemicals Sa
Publication of WO2010144675A1 publication Critical patent/WO2010144675A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to polymorphs of Bendamustine HCl, processes for preparing said polymorphs, and pharmaceutical compositions thereof.
  • Bendamustine HCl 4- ⁇ 5-[Bis(2-chloroethyl)amino]-l-methyl-lH- benzimidazol-2-yl ⁇ butanoic acid HCl, having the following formula I, belongs to the family of drugs named alkylating agents. Bendamustine HCl (BEM) of formula I
  • Formula I is used in the treatment of leukemia, chronic lymphocytic leukemia (CLL) and also being studied for the treatment of sarcoma.
  • CLL chronic lymphocytic leukemia
  • One of the advantages of Bendamustine HCl is that it is not cross resistant with other alkylating agents.
  • Bendamustine HCl received first marketing approval in Ge ⁇ nany under the trade name Ribomustin, by Astellas Pharma GmbH's licensee, Mundipharma International Corporation Limited, in which it is indicated as a single-agent or in combination with other anticancer agents for indolent Non-Hodgkin's Lymphomaand multiple myeloma, as well as CLL.
  • DD 34727 discloses synthesis of Bendamustine HCl from 4-nitro-2- amino-N-methylaniline, and the recrystallization of the product from water.
  • US 2006/159713, US 2006/128777 and WO2010036702 disclose formulations of Bendamustine HCl. These patent applications also include impurities of bendamustine.
  • Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, like Bendamustine HCl, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviours (e.g.
  • the present invention encompasses a crystalline
  • Bendamustine HCl characterized by data selected from the group consisting of: a powder XRD pattern with peaks at 3.3, 11.1, 12.0, 16.0 and 16.6 + 0.1 degrees 2-theta; a powder XRD pattern substantially as depicted in figure 11; and a combination thereof.
  • the present invention provides a process for preparing Bendamustine HCl characterized by data selected from the group consisting of: a powder XRD pattern with peaks at 7.4, 13.6, 15.0, 22.9 and 32.1 + 0.1 degrees 2-theta; a powder XRD pattern substantially as depicted in figure 4, a solid-state C NMR spectrum having signals at 150.3 and 130.8 ⁇ 0.2 ppm; a solid-state 13 C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift (at 109.6 ⁇ 1.0 ppm) and another in the chemical shift range of 100 to 180 ppm of 40.7 and 21.2 ⁇ 0.1 ppm; and a combination thereof, by preparing the above Bendamustine HCl characterized by data selected from the group consisting of: a powder XRD pattern with peaks at 3.3, 11.1, 12.0, 16.0 and 16.6 + 0.1 degrees 2-theta; a powder XRD pattern substantially as depicted in figure 11
  • the present invention refers to the use of the above described polymorphic form of Bendamustine HCl for the preparation of a formulation.
  • the present invention refers to a pharmaceutical composition comprising polymorphic form of Bendamustine HCl and at least one pharmaceutically acceptable excipient.
  • Figure 1 shows a powder XRD pattern of crystalline Bendamustine HCl form A.
  • Figure 2 shows a DSC thermogram of crystalline Bendamustine HCl form
  • Figure 3 shows a TGA thermogram of crystalline Bendamustine HCl form
  • Figure 4 shows a powder XRD pattern of crystalline Bendamustine HCl form B (the peak marked with "Si" belongs to silicon internal standard).
  • Figure 5 shows a powder XRD pattern of crystalline Bendamustine HCl form C (the peak marked with "Si" belongs to silicon internal standard).
  • Figure 6 shows a full-width solid state C NMR spectrum of
  • Figure 7 shows a detailed solid state C NMR spectrum of Bendamustine
  • Figure 8 shows a full-width solid state C NMR spectrum of
  • Figure 9 shows a detailed solid state 13 C NMR spectrum of Bendamustine
  • Figure 10 shows a powder XRD pattern of crystalline Bendamustine HCl form D (the peak marked with "Si” belongs to silicon internal standard; the amorphous bump is a result of presence of n-dodecane used for sample preparation).
  • Figure 11 shows a powder XRD pattern of crystalline Bendamustine HCl form E (the peak marked with "Si” belongs to silicon internal standard; the amorphous bump is a result of presence of «-dodecane used for sample preparation).
  • Figure 12 shows a powder XRD pattern of crystalline Bendamustine HCl form F (the peak marked with "Si” belongs to silicon internal standard; the amorphous bump is a result of presence of n-dodecane used for sample preparation).
  • Figure 13 illustrates an optical microscope photo of Bendamustine HCl form E.
  • the present invention relates to polymorphs of Bendamustine HCl process for preparing said polymorphs, and pharmaceutical compositions thereof.
  • a thing e.g., a reaction mixture
  • room temperature This expression means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located.
  • room temperature is from about 20° C to about 30° C, or about 25° C.
  • overnight This term refers to a time interval, e.g., for carrying out the process portion thereof, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, typically about 16 hours.
  • a crystal form may be referred to herein as being characterized by graphical data substantially "as depicted in" a Figure.
  • Such data include, for example, powder X-ray diffractograms and solid state NMR spectra.
  • the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms.
  • the present invention encompasses a crystalline
  • Bendamustine HCl characterized by data selected from the group consisting of: a powder XRD pattern with peaks at 3.3, 11.1, 12.0, 16.0 and 16.6 + 0.1 degrees 2-theta; a powder XRD pattern substantially as depicted in figure 11 ; and a combination thereof.
  • This form can be designated as form E.
  • the above crystalline form of Bendamustine HCl designated Form E may be further characterized by data selected from the group consisting of: a powder XRD pattern with additional peaks at 9.9, 13.3, 19.7, 19.9 and 26.0 + 0.1 degrees 2-theta.
  • the above crystalline Bendamustine HCl form E is a formamide solvate.
  • the crystalline Bendamustine HCl creates columnar particles of length between about 50 and 80 ⁇ m, which distinguishes it from all other forms of Bendamustine HCl as shown in Fig.13. Therefore, it is expected to have an excellent flowability. Thus, this form is exceptionally attractive for formulations.
  • the polymorph form E is substantially free of any other polymorph forms.
  • substantially free is meant 20% or less, preferably 10% or less, more preferably 5% or less, most preferably 2% or less, particularly 1% or less, more particularly 0.5% or less and most particularly 0.2% or less, for example, between about 0.01 and about 5% or between about 0.1 and about 1%.
  • the polymorph form E is substantially free of Bendamustine
  • HCl form A By “substantially free” is meant 20% or less, preferably 10% or less, more preferably 5% or less, most preferably 2% or less, particularly 1% or less, more particularly 0.5% or less and most particularly 0.2% or less, for example, between about 0.01 and about 5% or between about 0.1 and about 1%.
  • the content of the crystalline Bendamustine HCl having an X-ray powder diffraction pattern with peaks at about 8.4, 14.0, 17.5, 20.9 degrees two-theta ⁇ 0.2 degrees two-theta is measured by PXRD.
  • the above crystalline form of Bendamustine HCl can be prepared by a process comprising crystallizing Bendamustine HCl from formamide and ethylacetate. This process may comprise dissolving Bendamustine HCl in formamide and ethylacetate to obtain a solution comprising the crystalline form.
  • the volume ratio of formamide and ethylacetate is preferably between 1 : 1 and 1:10, more preferably between 1 :1.5 and 1 :9, yet more preferably between 1:2 and 1 :7, for example, 1:3, 1:4, and 1:6.25 and 1:7.5.
  • the Bendamustine HCl is dissolved in the formamide and then ethylacetate added, optionally, slowly (e.g. over a period of about 2 minutes to about 10 minutes) or drop wise.
  • the dissolution is done at a temperature that is in a range from about room temperature to about 70 0 C, preferably about 40 0 C to about 60 0 C, preferably about 50 0 C. Then, the solution may be stirred for a period of between about 5 minutes to about 5 days, preferably, about 30 minutes to about 1 day, more preferably about 1 hour to about 20 hours, yet more preferably about 2 hours to about 4 hours, most preferably about 3 hours at preferably about room temperature, during which a precipitation occurred forming a suspension.
  • the above crystalline form can be recovered from the suspension. Recovery can be done by filtering, washing and drying. Preferably, drying is done under nitrogen at room temperature.
  • the present invention provides a process for preparing Bendamustine HCl , designated form B, characterized by data selected from the group consisting of: a powder XRD pattern with peaks at 7.4, 13.6, 15.0, 22.9 and 32.1 + 0.1 degrees 2-theta; a powder XRD pattern substantially as depicted in figure 4, a solid- state C NMR spectrum having signals at 150.3 and 130.8 ⁇ 0.2 ppm; a solid-state C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift (at 109.6 ⁇ 1.0 ppm) and another in the chemical shift range of 100 to 180 ppm of 40.7 and 21.2 ⁇ 0.1 ppm; and a combination thereof, by preparing the above Bendamustine HCl form E according to the process of the present invention, and converting it to Bendamustine HCl form B.
  • a powder XRD pattern with peaks at 7.4, 13.6, 15.0, 22.9 and 32.1 + 0.1 degrees 2-theta
  • the present invention also provides a polymorphically pure crystalline
  • Bendamustine HCl This polymorph is a monohydrate form of Bendamustine HCl. This polymorph is also preferably chemically pure. In a preferred embodiment, it is free of a by-product where one Cl group is substituted by OH.
  • One embodiment is polymorphically pure crystalline Bendamustine HCl characterized by data selected from the group consisting of: a powder XRD pattern with peaks at 7.4, 13.6, 15.0, 22.9 and 32.1 + 0.1 degrees 2-theta; a powder XRD pattern substantially as depicted in figure 4, a solid-state 13 C NMR spectrum having signals at 150.3 and 130.8 ⁇ 0.2 ppm; a solid-state 13 C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift (at 109.6 ⁇ 1.0 ppm) and another in the chemical shift range of 100 to 180 ppm of 40.7 and 21.2 ⁇ 0.1 ppm; and a combination thereof, wherein the polymorphically pure crystalline Bendamustine HCl contains less than about 15% by weight of Bendamustine HCl, characterized by data selected from the group consisting of: a powder XRD pattern with peaks at 7.7, 10.2, 15.4, 19.4 and 25.5 + 0.1 degrees 2-theta; a
  • Form B This form can be designated as form B, which is a monohydrate form.
  • the above crystalline form of Bendamustine HCl designated Form B may be further characterized by data selected from the group consisting of: a powder XRD pattern with additional peaks at 10.6, 13.6, 15.0, 22.9 and 26.4 + 0.1 degrees 2-theta; a water content of about 4.7 % by weight as determined by Karl-Fischer titration; and a combination thereof.
  • crystalline Bendamustine HCl Form B contains less than about 10% by weight, preferably, less than about 5% by weight (for example, between about 0.01% and about 9%, between about 0.05% and about 5%, or between about 0.1% and 1%) of crystalline Bendamustine HCl, designated Form C, characterized by data selected from the group consisting of: a powder XRD pattern with peaks at 7.7, 10.2, 15.4, 19.4 and 25.5 + 0.1 degrees 2-theta; a powder XRD pattern substantially as depicted in figure 5; and a combination thereof.
  • the amount of form C in form B is measured by PXRD using any peak from the group of peaks at: 7.7, 10.2, 15.4, 19.4 and 25.5 deg ⁇ 0.1 degrees 2-theta.
  • the above form B is preferably polymorphically pure Bendamustine HCl.
  • This polymorph is a monohydrate form of Bendamustine HCl. This polymorph is also preferably chemically pure; especially free of a by product where one Cl group is substituted by OH.
  • dioxazaphosphocan HCl 4-[5-(2-hydroxy-2- oxido- 1 ,3 ,6,2-dioxazaphosphocan-6-yl)- 1 -methyl- lH-benzimidazol-2-yl]butanoic acid hydrochloride (BEMN07);
  • the crystallization from formamide-ethylacetate has high purification efficiency for removal of the ethyl bendamustine impurity.
  • the crystallization from diluted hydrochloric acid is efficient in removal of the polar impurities BEMN03 and BEMN07.
  • a crystalline Bendamustine HCl characterized by data selected from the group consisting of: a powder XRD pattern with peaks at 7.0, 9.8, 14.8, 19.7 and 21.6 + 0.1 degrees 2-theta; a powder XRD pattern substantially as depicted in figure 10; and a combination thereof.
  • This form can be designated as form D.
  • the above crystalline form of Bendamustine HCl designated Form D may be further characterized by a powder XRD pattern with additional peaks at 10.2, 10.6, 12.4, 22.0 and 30.1 + 0.1 degrees 2-theta.
  • a crystalline form of Bendamustine HCl characterized by data selected from the group consisting of: a powder XRD pattern with peaks at 8.4, 16.8, 17.5, 18.4 and 28.2 + 0.2 degrees 2-theta; a powder XRD pattern substantially as depicted in figure 1; a solid-state 13C NMR spectrum having signals at 152.8 and 132.4 ⁇ 0.2 ppm; a solid-state 13C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift (at 109.7 ⁇ 1.0 ppm) and another in the chemical shift range of 100 to 180 ppm of 43.1 and 22.7 ⁇ 0.1 ppm; and a combination thereof.
  • This form can be designated as form A.
  • the above crystalline form of Bendamustine HCl designated Form A may be further characterized by a powder XRD pattern with additional peaks at 8.7, 14.0, 22.0, 24.8 and 25.1 + 0.2 degrees 2-theta; a DSC thermogram substantially as depicted in figure 2; a TGA thermogram substantially as depicted in figure 3; and combinations thereof.
  • the above crystalline form of Bendamustine HCl can be prepared by a process comprising crystallizing Bendamustine HCl from a solvent mixture that is selected from the group consisting of: dimethylsulfoxide and toluene, dimethylsulfoxide and tetrahydrofuran, N,N-dimethylformamide and toluene, N,N-dimethylformamide and tetrahydrofuran, N,N-dimethylacetamide and tetrahydrofuran, N-methyl-2-pyrrolidone and toluene and mixtures thereof.
  • a solvent mixture that is selected from the group consisting of: dimethylsulfoxide and toluene, dimethylsulfoxide and tetrahydrofuran, N,N-dimethylformamide and toluene, N,N-dimethylformamide and tetrahydrofuran, N,N-dimethylacetamide and tetrahydrofuran, N-
  • the above process may comprise dissolving Bendamustine HCl in a first solvent selected from a group consisting of dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or mixtures thereof, and combining the solution with a second solvent (antisolvent) selected from a group consisting of toluene, tetrahydrofuran or mixtures thereof, to obtain a suspension comprising said crystalline form.
  • a first solvent selected from a group consisting of dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or mixtures thereof
  • a second solvent antisolvent
  • the dissolution is done at about 10 0 C to about 100 0 C, preferably about 15°C to about 90 0 C, yet more preferably at about room temperature to about 80 0 C.
  • the solution can be mixed with the second solvent; preferably the second solvent is added to the solution.
  • the combination of the solution with the second solvent such as toluene, tetrahydrofuran or mixtures thereof provides a suspension.
  • the addition of the second solvent, such as toluene, tetrahydrofuran or mixtures thereof is done over a period of about 2 minutes to about 10 minutes.
  • the suspension is stirred for a period of about 30 minutes to about 24 hours, preferably about 1 hour to about overnight.
  • additional amount of toluene, tetrahydrofuran or mixtures thereof can be added to the suspension to increase the amount of precipitated product.
  • the above suspension is further stirred for an additional amount of time. Preferably, stirring is done for a period of about 30 minutes to about 24 hours, preferably about 2 hours to about overnight. [0057]
  • the above crystalline form can be recovered from the suspension.
  • Recovery can be done by filtering, washing and drying.
  • drying is done at a temperature of about room temperature to about 50 0 C.
  • drying is done under vacuum.
  • the above crystalline form of Bendamustine HCl form A can be prepared by a process comprising crystallizing Bendamustine HCl from acetonitrile.
  • the crystallization comprises dissolving a Bendamustine HCl in acetonitrile and precipitating the crystalline form to obtain a suspension.
  • the solution of Bendamustine HCl and acetonitrile is provided, preferably, by combining Bendamustine HCl and acetonitrile, and heating the combination.
  • the combination can also contain formamide, for example from the starting material, which can be a solvate, like form E.
  • the combination is heated to a temperature of about 70 0 C to about 90 0 C, more preferably about 75 0 C to about 82 0 C, more preferably about 8O 0 C to about 82 0 C, more preferably about 8O 0 C.
  • cooling is to a temperature of about 15 0 C to about 25 0 C, more preferably about 15 0 C to about 2O 0 C.
  • the suspension is maintained prior to the recovering of
  • Bendamustine HCl form A e.g., at a temperature of about room temperature, preferably for a period of about 15 minutes to about 24 hours, more preferably about 30 minutes to about 20 hours, more preferably about 30 minutes to about 2 hours.
  • the process for preparing Bendamustine HCl form A can further comprise recovery of the polymorph from the suspension.
  • the recovery process may comprise, for example, filtering the crystalline form and drying, preferably, air drying.
  • drying is done at a temperature of about 4O 0 C to about 6O 0 C, more preferably about 5O 0 C.
  • drying is done for a period of about 10 hours to about 24 hours, more preferably about 12 hours to about 20 hours, more preferably about 15 hours to about 17 hours.
  • the above crystalline form A of Bendamustine HCl can also be prepared from crystalline Bendamustine HCl form E.
  • Bendamustine HCl form E is heated at a temperature of at least about 100 0 C, more preferably at least about 105 0 C under atmospheric pressure, for example between about 100 0 C and about 150 0 C. Preferably, the heating is done for a period of about 15 minutes to about 120 minutes, preferably about 30 minutes to about 60 minutes.
  • Bendamustine HCl form E is slurried in acetonitrile, acetone or propylacetate.
  • slurrying is done at a temperature about reflux temperature, preferably about 75 0 C to about 82 0 C, more preferably about 80° to about 82 0 C.
  • slurrying is done for a period of about 15 minutes to about 24 hours, more preferably about 30 minutes to about 24 hours, more preferably about 1 hour.
  • This process can further comprise recovering Bendamustine HCl form A from the slurry.
  • the recovery can comprise, for example, filtering the crystal form and drying, preferably, on air.
  • drying is done at a temperature of about 7O 0 C to about 8O 0 C, more preferably 75 0 C.
  • drying is done for a period of about 10 hours to about 24 hours, more preferably about 12 hours.
  • a polymorphically pure crystalline Bendamustine HCl characterized by data selected from the group consisting of: a powder XRD pattern with peaks at 7.7, 10.2, 15.4, 19.4 and 25.5 + 0.1 degrees 2-theta; a powder XRD pattern substantially as depicted in figure 5; and a combination thereof, wherein the polymorphically pure crystalline Bendamustine HCl contains less than about 15% by weight Bendamustine HCl Form B, preferably less than about 10%, more preferably less than about 10%, for example between about 0.5% and about 12% or between about 2% and about 8%.
  • This form can be designated as form C, which is an anhydrous form.
  • the above crystalline form of Bendamustine HCl designated Form C can be further characterized by data selected from the group consisting of: a powder XRD pattern with additional peaks at 3.9, 10.2, 10.7, 15.4 and 20.3 + 0.1 degrees 2-theta; a water content of less than 0.5% by weight, preferably less than 0.3% by weight, more preferably less than 0.1% by weight as determined by Karl-Fischer titration, for example between about 0.01% and about 0.4% or between about 0.02 and about 0.05%, and combinations thereof.
  • crystalline Bendamustine HCl Form C contains less than about 10% by weight, preferably, less than about 5% by weight of crystalline Bendamustine HCl Form B, for example between about 0.1% and about 8% or between about 2% and about 3%.
  • the amount of form B in form C is measured by PXRD using any peak from the group of peaks at: 7.4, 13.6, 15.0 and 32.1 deg ⁇ 0.1 degrees 2-theta.
  • Form C of Bendamustine HCl can be prepared by a process comprising slurrying Bendamustine HCl (preferably, Form B) in tetrahydrofuran.
  • the slurrying is performed for about 2 hours to about 8 hours, preferably about 4 hours at preferably room temperature.
  • the process for preparing form C of Bendamustine HCl may further comprise recovering the crystalline form.
  • the recovery can be done, for example, by filtering the suspension and drying.
  • drying is performed on a filter at room temperature under dry (relative humidity below 10 %) nitrogen flow and atmospheric pressure.
  • drying is performed at room temperature.
  • a crystalline Bendamustine HCl characterized by data selected from the group consisting of: a powder XRD pattern with peaks at 7.9, 10.5, 15.9, 21.3 and 27.8 + 0.1 degrees 2-theta; a powder XRD pattern substantially as depicted in figure 12; and a combination thereof.
  • This form can be designated as form F.
  • the above crystalline form of Bendamustine HCl designated Form F can be further characterized by data selected from the group consisting of: a powder XRD pattern with additional peaks at 19.5, 23.4, 25.4, 25.7 and 33.6 + 0.1 degrees 2-theta.
  • the above described forms of Bendamustine HCl can be used to prepare formulations by any method known in the art.
  • the present invention also includes a pharmaceutical composition comprising a crystalline form of Bendamustine HCl (preferably form E) and at least one pharmaceutically acceptable excipient, and optionally another active agent, preferably an anti-cancer agent.
  • a pharmaceutical composition comprising a crystalline form of Bendamustine HCl (preferably form E) and at least one pharmaceutically acceptable excipient, and optionally another active agent, preferably an anti-cancer agent.
  • Crystalline forms of Bendamustine HCl (preferably form E) and pharmaceutical compositions comprising them may be used for treating eukemia, chronic lymphocytic leukemia, sarcoma, indolent Non-Hodgkin's Lymphoma or multiple myeloma.
  • X'Celerator detector active length (2 theta) 2.122°, laboratory temperature 22-25° C.
  • Zero background sample holders Prior to analysis the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The sample might be mixed with «-dodecane in order to avoid the environmental contamination by airborne particles coming from the powder. The ground sample or its suspension with «-dodecane was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass. The presence of n-dodecane when used for a sample preparation usually causes an amorphous bump in the middle of the diffractogram.
  • a silicon internal standard can be used to calibrate peak positions and to eliminate an effect of sample preparation.
  • the internal standard possesses a diffraction with defined position at 28.44 degrees 2-theta.
  • the internal standard can be mixed with a sample, PXRD is then acquired and the current position of the aforementioned internal standard diffraction peak is determined. The difference between the current position of the diffraction and its nominal value of 28.44 degrees 2-theta is calculated. The current positions of all relevant sample peaks are then re-calculated by means of the above difference to obtain the true positions of the sample diffractions.
  • Scan range at least 3 - 40° 2-theta; Scan mode: continuous; Step size: 0.0167 °;
  • DSC823e Metal crucibles 40 ⁇ l with PIN were used for sample preparation. Usual weight of sample was 1.5 - 3.5 mg.
  • TGA851e (Mettler Toledo). Alumina crucibles 70 ⁇ l were used for sample preparation. Usual weight of sample was 7 - 13 mg.
  • Solvent B 1 ml/1 TFA in water-acetonitrile v/v 5:5;
  • BEM.HC1 (1.0 g) was dissolved in 2 ml DMSO at 24-25°C. Then 6 ml toluene was added to the solution over 5 minutes. Crystallization occurred after 2 hours of stirring. Toluene (ImI) was added into the consistent mixture, and then the mixture was further stirred overnight. The precipitated crystals were then separated by filtration. After filtration the white crystalline product that was obtained was washed with 3 ml toluene and dried under vacuum at 5O 0 C.
  • BEM.HC1 (1.0 g) was dissolved in 2 ml DMSO at 24-25°C. Then 6 ml of
  • BEM.HC1 (1.0 g) was dissolved in 4 ml DMF at 6O 0 C. The solution was then cooled to room temperature. Then 9 ml toluene was added over 5 minutes. A crystalline precipitate formed and this mixture was stirred overnight. The white product was then filtered, washed with 1 ml toluene and dried under vacuum at 5O 0 C overnight.
  • BEM.HC1 (1.0 g) was dissolved in 4 ml DMF at 6O 0 C. The solution was cooled to room temperature, and then 9 ml of THF was added over 5 minutes. A crystalline precipitate formed and this mixture was stirred overnight. The white product was then filtered, washed with 1 ml THF and dried under vacuum at 5O 0 C.
  • BEM.HC1 (2.2 g) was dissolved in 4.0 ml of concentrated HCl at room temperature. Then 30 ml distilled water was added to the solution. A crystalline precipitate formed and this mixture was stirred for 15 min. The precipitate was then separated by filtration. After filtration, the white product was washed with water, then with 4 ml THF, and then it was dried on the filter at room temperature.
  • BEM.HC1 (form B) (1 g) was stirred with THF for 4 hours to obtain a slurry comprising crystals. The crystals were filtered off and dried on the filter for 1 hour at room temperature under nitrogen flow and at atmospheric pressure.
  • BEM.HC1 (Form A) (3.3 g) was dissolved in 20 ml N,N- dimethylacetamide at 50 0 C. Then 30 ml THF was added to the solution. The solution was stirred at room temperature for 2 hours to form a suspension of crystalline material. The suspension was stirred for another 2 hours and then filtered. After filtration, the white crystalline product was washed with THF and dried on the filter at room temperature under nitrogen.
  • Example 9 Preparation of form A
  • a mixture of 1 g crude bendamustine hydrochloride and 20 ml 1 of ,4- dioxane was stirred and heated at 60 0 C. The solid part was dissolved after the addition of 680 ⁇ l water. Then, the clear solution was cooled in an ice bath and white crystals were formed slowly. The mixture was stirred for 1 hour, and then 5 ml 1 ,4-dioxane was added, followed by further 2 hrs of stirring. The product was then filtered off and dried on the filter for 1 hour at room temperature under nitrogen.
  • Bendamustine hydrochloride form E (100 mg) was heated in a closed vial at 105 0 C for 30 minutes under atmospheric pressure.
  • BEM.HC1 (crude bendamustine) (7.0 g) was dissolved in 7 ml formamide at 50 0 C. Ethylacetate (13 ml) was slowly added to form a cloudy mixture. The mixture was stirred for 20 hrs at RT to form a suspension. The product was filtered off, washed with ethylacetate (3 x 10 ml), and dried on the filter. The product was Form E as determined by XRD analysis.
  • BEM HCl form E (7.0 g) was refiuxed for 1 hour in a mixture of 600 ml of acetonitrile and 3 ml of formamide. The product was filtered off of this mixture at 75 0 C, and dried on filter at room temperature under nitrogen.
  • Example 18 Preparation of form A
  • BEM HCl (form E) 500 mg was suspended in 10 ml acetonitrile to form a slurry.
  • the slurry was stirred at 80 0 C for 20 h.
  • the slurry was then stirred at ambient temperature for 1 hour.
  • the crystals that were formed were filtered off and dried on the filter at room temperature under nitrogen. Yield 400 mg.
  • BEM HCl form E (590 mg) was dissolved in 60 ml acetonitrile at 80 0 C to form a clear solution. The solution was then stirred at room temperature for 20 hours (after 30 min crystallization occurred). The crystals were filtered off and dried on the filter at room temperature under nitrogen. Yield 430 mg.
  • Example 20 Preparation of crude Bendamustine hydrochloride (form B) [00103] A 5 L bottle was charged with 197 g of phosphorus oxychloride. The contents of the bottle were heated to 50 0 C and 150 g of ethyl 4- ⁇ 5-[bis(2- hydroxycthyl)amino]-l -methyl- lH-benzimidazol-2-yl ⁇ butanoatc("BBOH”) dissolved in 600 ml of dichloromethane was added. Reaction mixture was stirred at 75-85 0 C for 4-5 hours. The reaction mixture was then cooled to room temperature and diluted with 450 ml dichloromethane to form a solution.
  • Example 21 Preparation of form A through form E.
  • Bendamustine hydrochloride (crude) (2.5g) was dissolved in 3 ml of formamide at 70 0 C.
  • Ethyl acetate (12 ml) was added and the resulting solution was stirred at ambient temperature for 3 hours. Crystals formed and were filtered off and washed with 10 ml of ethylacetate.
  • the cake (form E) was dried in flow of nitrogen at room temperature for 1 hour.
  • Example 23 HPLC results indicating purification effect of the crystallization system: [00107] Step A) Recrystallization of crude bendamustine(Form B) from formamide-ethylacetate:
  • Bendamustine form E (the product of the above step A) (78 g of) was dissolved in 140 ml of 21 % hydrochloric acid at 50 0 C. The solution was stirred in an ice bath for 30 minutes. Then 600 ml of distilled water was added. Crystallization started after 2 minutes. The resulting suspension was stirred in an ice bath for 30 minutes (at +18 to + 12 0 C). The product was filtered off, washed twice with 250 ml ice water and dried on the filter. The filter cake was then washed twice with 250 ml cool acetone (- 10 0 C). The filter cake was then dried on the filter by a flow of wet nitrogen (relative humidity 35 - 60 %) for 4 hours.
  • BEMN03 hydroxybendamustine
  • BEM bendamustine
  • BEMMOl ethylbendamustine
  • Step A using formamide-ethylacetate crystallization purifies the material especially from BEMMO 1 which non-polar impurity.
  • Step B using diluted HCl is then purifying the product from BEMN03 which is polar impurity.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux polymorphes du chlorhydrate de bendamustine qui ont été préparés et caractérisés. Ces polymorphes et les compositions pharmaceutiques les contenant sont utiles, par exemple, dans le traitement de patients souffrant de cancers divers.
PCT/US2010/038128 2009-06-10 2010-06-10 Polymorphes du chlorhydrate de bendamustine et leurs procédés de préparation WO2010144675A1 (fr)

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
US18564609P 2009-06-10 2009-06-10
US61/185,646 2009-06-10
US22127209P 2009-06-29 2009-06-29
US61/221,272 2009-06-29
US24412209P 2009-09-21 2009-09-21
US61/244,122 2009-09-21
US24537509P 2009-09-24 2009-09-24
US61/245,375 2009-09-24
US30235610P 2010-02-08 2010-02-08
US61/302,356 2010-02-08

Publications (1)

Publication Number Publication Date
WO2010144675A1 true WO2010144675A1 (fr) 2010-12-16

Family

ID=42321158

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/038128 WO2010144675A1 (fr) 2009-06-10 2010-06-10 Polymorphes du chlorhydrate de bendamustine et leurs procédés de préparation

Country Status (1)

Country Link
WO (1) WO2010144675A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102351799A (zh) * 2011-10-24 2012-02-15 江苏奥赛康药业股份有限公司 一种盐酸苯达莫司汀晶型及其制备方法
WO2012106117A1 (fr) * 2011-01-31 2012-08-09 Cephalon, Inc. Procédé de préparation de bendamustine
CN103351346A (zh) * 2013-07-29 2013-10-16 东南大学 盐酸苯达莫司汀杂质hp1的制备方法
WO2014140929A1 (fr) 2013-03-14 2014-09-18 Johnson Matthey Public Limited Company Procédé de séchage de l'hydrochlorure de bendamustine monohydraté
US8987469B2 (en) 2012-07-24 2015-03-24 Heyl Chemisch-Pharmazeutische Fabrik Gmbh & Co. Kg Process for the preparation of bendamustine
US20150175554A1 (en) * 2010-11-01 2015-06-25 Shilpa Medicare Limited Highly pure bendamustine hydrochloride monohydrate
US10252999B2 (en) 2013-03-15 2019-04-09 Johnson Matthey Public Limited Company Process for preparing alkyl esters of 4-(5-(bis(2-hydroxyethyl)amino-1-methyl-1H-benzo[D]imidazol-2-yl)butyric acid
WO2019068904A1 (fr) 2017-10-05 2019-04-11 Tube Pharmaceuticals Gmbh Formulations de bendamustine à administration par voie orale

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD34727A1 (de) 1963-12-21 1964-12-28 Dietrich Krebs Verfahren zur Herstellung von 1-Stellung substituierten [5-Bis-(chloräthyl)-amino-benzimidazolyl-(2)]-alkancarbonsäuren
US20060128777A1 (en) 2004-11-05 2006-06-15 Bendall Heather H Cancer treatments
US20060159713A1 (en) 2005-01-14 2006-07-20 Cephalon, Inc. Bendamustine pharmaceutical compositions
WO2009120386A2 (fr) * 2008-03-26 2009-10-01 Cephalon, Inc. Nouvelles formes solides d'hydrochlorure de bendamustine
WO2010036702A1 (fr) 2008-09-25 2010-04-01 Cephalon, Inc. Formulations liquides de bendamustine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD34727A1 (de) 1963-12-21 1964-12-28 Dietrich Krebs Verfahren zur Herstellung von 1-Stellung substituierten [5-Bis-(chloräthyl)-amino-benzimidazolyl-(2)]-alkancarbonsäuren
US20060128777A1 (en) 2004-11-05 2006-06-15 Bendall Heather H Cancer treatments
US20060159713A1 (en) 2005-01-14 2006-07-20 Cephalon, Inc. Bendamustine pharmaceutical compositions
WO2009120386A2 (fr) * 2008-03-26 2009-10-01 Cephalon, Inc. Nouvelles formes solides d'hydrochlorure de bendamustine
WO2010036702A1 (fr) 2008-09-25 2010-04-01 Cephalon, Inc. Formulations liquides de bendamustine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANON.: "Crystalline form of 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2- yl]butanoic acid hydrochloride", IP.COM JOURNAL , 9(7A), 16 (NO. IPCOM000184385D), 23 JUN 2009 CODEN: IJPOBX; ISSN: 1533-0001, 2009, XP002592632 *
BYRN S ET AL: "PHARMACEUTICAL SOLIDS: A STRATEGIC APPROACH TO REGULATORY CONSIDERATIONS", PHARMACEUTICAL RESEARCH, KLUWER ACADEMIC PUBLISHERS, NEW YORK, NY, US LNKD- DOI:10.1023/A:1016241927429, vol. 12, no. 7, 1 July 1995 (1995-07-01), pages 945 - 954, XP000996386, ISSN: 0724-8741 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150175554A1 (en) * 2010-11-01 2015-06-25 Shilpa Medicare Limited Highly pure bendamustine hydrochloride monohydrate
WO2012106117A1 (fr) * 2011-01-31 2012-08-09 Cephalon, Inc. Procédé de préparation de bendamustine
CN103443084A (zh) * 2011-01-31 2013-12-11 赛福伦公司 制备苯达莫司汀的方法
CN102351799A (zh) * 2011-10-24 2012-02-15 江苏奥赛康药业股份有限公司 一种盐酸苯达莫司汀晶型及其制备方法
CN102351799B (zh) * 2011-10-24 2014-02-26 江苏奥赛康药业股份有限公司 一种盐酸苯达莫司汀晶型及其制备方法
US8987469B2 (en) 2012-07-24 2015-03-24 Heyl Chemisch-Pharmazeutische Fabrik Gmbh & Co. Kg Process for the preparation of bendamustine
WO2014140929A1 (fr) 2013-03-14 2014-09-18 Johnson Matthey Public Limited Company Procédé de séchage de l'hydrochlorure de bendamustine monohydraté
US9315469B2 (en) 2013-03-14 2016-04-19 Johnson Matthey Public Limited Company Process for drying bendamustine hydrochloride monohydrate
US10252999B2 (en) 2013-03-15 2019-04-09 Johnson Matthey Public Limited Company Process for preparing alkyl esters of 4-(5-(bis(2-hydroxyethyl)amino-1-methyl-1H-benzo[D]imidazol-2-yl)butyric acid
CN103351346A (zh) * 2013-07-29 2013-10-16 东南大学 盐酸苯达莫司汀杂质hp1的制备方法
WO2019068904A1 (fr) 2017-10-05 2019-04-11 Tube Pharmaceuticals Gmbh Formulations de bendamustine à administration par voie orale

Similar Documents

Publication Publication Date Title
WO2010144675A1 (fr) Polymorphes du chlorhydrate de bendamustine et leurs procédés de préparation
JP6081763B2 (ja) ダサチニブ多形体およびその調製プロセス
US7956048B2 (en) Polymorphs of eltrombopag and eltrombopag salts and processes for preparation thereof
JP5289948B2 (ja) ４−メチル−ｎ−［３−（４−メチル−イミダゾール−１−イル）−５−トリフルオロメチル−フェニル］−３−（４−ピリジン−３−イル−ピリミジン−２−イルアミノ）−ベンズアミドの結晶形態
US9174973B2 (en) Crystalline forms of azilsartan and preparation and uses thereof
US11149017B2 (en) Solid state forms of apalutamide
US20090298947A1 (en) Polymorphic and amorphous forms of lacosamide and amorphous compositions
US20040242556A1 (en) Novel crystalline form of cefdinir
WO2012068441A2 (fr) Sels d'intedanib et leurs formes à l'état solide
WO2010062715A2 (fr) Polymorphes de dasatinib et leur procédé de préparation
US20070203176A1 (en) Crystalline forms of dolasetron base and processes for preparation thereof
WO2013065063A1 (fr) Forme anhydre du dasatinib, son procédé de préparation et son utilisation
AU2011284341A1 (en) N-Methylformamide solvate of dasatinib
US20080262060A1 (en) Crystalline forms of Deferasirox
US9695147B2 (en) Process for the preparation of perampanel
JP7152122B2 (ja) エダラボン塩
EP4229057A1 (fr) Formes à l'état solide de lorécivivint
US20090030207A1 (en) Polymorphs of Dolasetron base and process for preparation thereof
WO2010046804A2 (fr) Procédé de préparation du losartan potassium forme i
WO2008081475A2 (fr) Nouvelles formes cristallines de zolmitriptan
SI21424A (sl) Postopek čiščenja losartana

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10726388

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10726388

Country of ref document: EP

Kind code of ref document: A1