WO2017114596A1 - Formes cristallines du (cis)-n-(4-(diméthylamino)-1,4-diphénylcyclohexyl)-n-méthyl-cinnamamide - Google Patents

Formes cristallines du (cis)-n-(4-(diméthylamino)-1,4-diphénylcyclohexyl)-n-méthyl-cinnamamide Download PDF

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Publication number
WO2017114596A1
WO2017114596A1 PCT/EP2016/025181 EP2016025181W WO2017114596A1 WO 2017114596 A1 WO2017114596 A1 WO 2017114596A1 EP 2016025181 W EP2016025181 W EP 2016025181W WO 2017114596 A1 WO2017114596 A1 WO 2017114596A1
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crystalline form
ray powder
cuk
powder diffraction
radiation
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PCT/EP2016/025181
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English (en)
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Michael Gruss
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Grünenthal GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/41—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a crystalline form of the compound according to formula (I)
  • X-ray powder diffraction peak CuK a radiation
  • pharmaceutical dosage forms comprising at least one crystalline form of the compound according to formula (I), the use of these crystalline forms as well as to processes for producing these crystalline forms.
  • Pharmacologically active ingredients can exist in different solid forms, i.e. different crystalline forms having different physical, physicochemical and chemical properties.
  • Such physical or physicochemical properties can cause different crystalline forms of the same drug to have largely different processing and storage performance.
  • Such physical or physicochemical properties include, for example, thermodynamic stability, crystal morphology (form, shape, structure, particle size, particle size distribution, color, degree of crystallinity, flowability, density, bulk density, powder density, apparent density, vibrated density, hardness, deformability, grindability, compressability, compactability, brittleness, elasticity), caloric properties (particularly melting point), solubility (particularly equilibrium solubility, pH dependence of solubility), dissolution (particularly dissolution rate, intrinsic dissolution rate), hygroscopicity, tackiness, adhesiveness, tendency to electrostatic charging, and the like.
  • crystalline forms of the same drug can have largely different performance properties.
  • a crystalline form having a low hygroscopicity can have superior chemical stability and longer shelf-life stability (cf. R. Hilfiker, Polymorphism, 2006 Wiley VCH, p. 235-242 and 251 -252).
  • Figures 1 and 3 to 5 show the x-ray powder diffraction (XRPD) analyses of crystalline forms A, B, C and D, respectively.
  • Figure 2 shows the dynamic vapor sorption (DVS) isotherm plot of A1-7 (crystalline form A).
  • DVS dynamic vapor sorption
  • the present invention relates to a crystalline form of the compound according to formula (I)
  • CuK a radiation having at least one X-ray powder diffraction peak (CuK a radiation) in the range of from 16.5 ⁇ 0.2 to 18.5 ⁇ 0.2 (2 ⁇ ) and/or 17.0 ⁇ 0.2 to 19.5 ⁇ 0.2 (2 ⁇ ) and/or 22.5 ⁇ 0.2 to 24.5 ⁇ 0.2 (2 ⁇ ).
  • the crystalline form according to the present invention has at least one X-ray powder diffraction peak (CuK a radiation) in each of the ranges of from 16.5 ⁇ 0.2 to 18.5 ⁇ 0.2 (2 ⁇ ) and 17.0 ⁇ 0.2 to 19.5 ⁇ 0.2 (2 ⁇ ) and 22.5 ⁇ 0.2 to 24.5 ⁇ 0.2 (2 ⁇ ).
  • CuK a radiation X-ray powder diffraction peak
  • the compound according to formula (I) is preferably present in form of the free base.
  • the definition of the term "free base” as used herein shall include solvates, co-crystals and crystalline forms.
  • free base preferably means that the compound according to formula (I) is not present in form of a co-crystal or salt, particularly not in form of an acid-addition salt.
  • the most basic functional groups of the compound according to formula (I) are the two amino moieties, which according to the present invention are preferably neither protonated nor quaternized. In other words, the free electron pairs of the nitrogen atoms of the amino moieties are present as a Lewis base.
  • crystalline form according to the present invention is an ansolvate or a solvate.
  • the crystalline form according to the present invention is an ansolvate.
  • the crystalline form according to the present invention is a solvate, preferably selected from the group of hydrates, solvates of lower alcohols, such as methanol, ethanol, 1-propanol or 2-propanol or solvates of toluene or a solvate of solvate mixtures.
  • the solvate is selected from the group consisting of monosolvate, hemi- solvate, disolvate, trisolvate, and mixtures thereof.
  • the solvate preferably is a variable or non-stoichiometric solvate.
  • the crystalline form according to the present invention is not hygroscopic.
  • hygroscopicity is determined via DVS (dynamic vapor sorption), preferably by using a Porotec DVS at 25°C (cycles: 50-90% relative humidity/90-0% relative humidity/0-90% relative humidity/90-50% relative humidity).
  • the hygroscopicity is classified according to the ranges for mass increase defined in the European Pharmacopoeia: very hygroscopic (vh): increase of the mass ⁇ 15 %; hygroscopic (h): increase of the mass is less than 15 % and equal or greater than 2 %; slightly hygroscopic (sh): increase of the mass is less than 2 % and equal or greater than 0.2 %; not hygroscopic (nh): increase of the mass is less than 0.2 %; deliquescent (d): sufficient water is absorbed to form a liquid.
  • vh very hygroscopic
  • h increase of the mass is less than 15 % and equal or greater than 2 %
  • slightly hygroscopic (sh) increase of the mass is less than 2 % and equal or greater than 0.2 %
  • not hygroscopic (nh) increase of the mass is less than 0.2 %
  • deliquescent (d) sufficient
  • all 2 ⁇ values refer to an x-ray powder diffraction (XRPD) analysis measured at room temperature, preferably at a temperature between 20°C and 25°C, using CuK a radiation having a wavelength of 1.54060 A.
  • XRPD x-ray powder diffraction
  • the terms 2 ⁇ values and degrees 2 ⁇ are used synonymously.
  • a person skilled in the art knows how to realize XRPD analysis.
  • XRPD are carried out in transmission geometry with a STOE StadiP or a Panalytical X'Pert Pro X-ray powder diffracto meter in reflection geometry with monochromatised CuK a radiation.
  • the crystalline form has at least one X-ray powder diffraction peak (CuK a radiation) in the range of from 16.5 ⁇ 0.2 to 18.5 ⁇ 0.2 (2 ⁇ ) and/or 17.0 ⁇ 0.2 to 19.5 ⁇ 0.2 (2 ⁇ ) and/or 22.5 ⁇ 0.2 to 24.5 ⁇ 0.2 (2 ⁇ ). More preferably, the crystalline form has an X-ray powder diffraction peak (CuK a radiation) in the range of from 16.5 ⁇ 0.2 to 18.5 ⁇ 0.2 (2 ⁇ ). Still more preferably, the crystalline form has X-ray powder diffraction peaks (CuK a radiation) in the range of from 16.5 ⁇ 0.2 to 18.5 ⁇ 0.2 (2 ⁇ ) and 17.0 ⁇ 0.2 to 19.5 ⁇ 0.2 (2 ⁇ ).
  • the crystalline form has X-ray powder diffraction peaks (CuK a radiation) in the range of from 16.5 ⁇ 0.2 to 18.5 ⁇ 0.2 (2 ⁇ ) and 17.0 ⁇ 0.2 to 19.5 ⁇ 0.2 (2 ⁇ ) and 22.5 ⁇ 0.2 to 24.5 ⁇ 0.2 (2 ⁇ ).
  • the crystalline form has at least one additional X-ray powder diffraction peak (CuK a radiation) in the range of from 1 1 .5 ⁇ 0.2 to 13.5 ⁇ 0.2 (2 ⁇ ) and/or 14.5 ⁇ 0.2 to 16.5 ⁇ 0.2 (2 ⁇ ) and/or 19.0 ⁇ 0.2 to 21.0 ⁇ 0.2 (2 ⁇ ). More preferably, the crystalline form has an additional X-ray powder diffraction peak (CuK a radiation) in the range of from 1 1.5 ⁇ 0.2 to 13.5 ⁇ 0.2 (2 ⁇ ). Still more preferably, the crystalline form has additional X-ray powder diffraction peaks (CuK a radiation) in the range of from 1 1.5 ⁇ 0.2 to 13.5 ⁇ 0.2 (2 ⁇ ) and 14.5 ⁇ 0.2 to 16.5 ⁇ 0.2 (2 ⁇ ). In another preferred embodiment, the crystalline form has additional X-ray powder diffraction peaks (CuK a radiation) in the range of from 1 1 .5 ⁇ 0.2 to 13.5 ⁇ 0.2 (20) and 19.0 ⁇ 0.2 to 21.0 ⁇ 0.2 (2 ⁇ ).
  • the X-ray powder diffraction peaks exhibits a relative intensity of at least 10%, more preferably at least 20%, still more preferably at least 30%, yet more preferably at least 40%, even more preferably at least 50%, most preferably at least 60% or at least 70%, and in particular at least 80% or at least 90% or at least 95%.
  • the crystalline form according to the present invention is crystalline form A having at least one X-ray powder diffraction peak (CuK a radiation) selected from the group consisting of 18.9 ⁇ 0.2 (2 ⁇ ), 17.2 ⁇ 0.2 (2 ⁇ ), 23.4 ⁇ 0.2 (2 ⁇ ), 15.1 ⁇ 0.2 (2 ⁇ ), 12.2 ⁇ 0.2 (2 ⁇ ), 17.4 ⁇ 0.2 (2 ⁇ ), 17.7 ⁇ 0.2 (2 ⁇ ) and 12.5 ⁇ 0.2 (20); or crystalline form B having at least one X-ray powder diffraction peak (CuK a radiation) selected from the group consisting of 23.4 ⁇ 0.2 (20), 18.8 ⁇ 0.2 (20), 17.1 ⁇ 0.2 (20), 12.4 ⁇ 0.2 (20) and 15.1 ⁇ 0.2 (20); or
  • crystalline form C having at least one X-ray powder diffraction peak CuK a radiation) selected from the group consisting of 17.2 ⁇ 0.2 (20), 18.9 ⁇ 0.2 (20), 12.4 ⁇ 0.2 (20),
  • the crystalline form according to the present invention is crystalline form A having X-ray powder diffraction peaks (CuK a radiation) at 18.9 ⁇ 0.2 (2 ⁇ ), 17.2 ⁇ 0.2 (2 ⁇ ), 23.4 ⁇ 0.2 (2 ⁇ ), 15.1 ⁇ 0.2 (2 ⁇ ) and 12.2 ⁇ 0.2 (2 ⁇ ).
  • the crystalline form according to the present invention is crystalline form B having X-ray powder diffraction peaks (CuK a radiation) at 23.4 ⁇ 0.2 (2 ⁇ ), 18.8 ⁇ 0.2 (2 ⁇ ), 17.1 ⁇ 0.2 (2 ⁇ ), 12.4 ⁇ 0.2 (2 ⁇ ) and 15.1 ⁇ 0.2 (2 ⁇ ).
  • the crystalline form according to the present invention is crystalline form C having X-ray powder diffraction peaks (CuK a radiation) at 17.2 ⁇ 0.2 (2 ⁇ ), 18.9 ⁇ 0.2 (2 ⁇ ), 12.4 ⁇ 0.2 (2 ⁇ ), 12.2 ⁇ 0.2 (2 ⁇ ) and 23.4 ⁇ 0.2 (2 ⁇ ).
  • the crystalline form according to the present invention is crystalline form D having X-ray powder diffraction peaks (CuK a radiation) at 18.4 ⁇ 0.2 (2 ⁇ ), 19.7 ⁇ 0.2 (2 ⁇ ), 12.8 ⁇ 0.2 (2 ⁇ ), 17.9 ⁇ 0.2 (2 ⁇ ) and 17.7 ⁇ 0.2 (2 ⁇ ).
  • the crystalline form according to the present invention is crystalline form A.
  • the crystalline form preferably has an X- ray powder diffraction peak (CuK a radiation) at 18.9 ⁇ 0.2 (2 ⁇ ), more preferably the crystalline form has X-ray powder diffraction peaks (CuK a radiation) at 18.9 ⁇ 0.2 (2 ⁇ ) and 17.2 ⁇ 0.2 (2 ⁇ ), still more preferably the crystalline form has X-ray powder diffraction peaks (CuK a radiation) at 18.9 ⁇ 0.2 (2 ⁇ ), 17.2 ⁇ 0.2 (2 ⁇ ) and 23.4 ⁇ 0.2 (2 ⁇ ), even more preferably the crystalline form has X-ray powder diffraction peaks (CuK a radiation) at 18.9 ⁇ 0.2 (2 ⁇ ), 17.2 ⁇ 0.2 (2 ⁇ ), 23.4 ⁇ 0.2 (2 ⁇ ) and 15.1 ⁇ 0.2 (2 ⁇ ), yet more preferably the crystalline form has X-ray powder diffraction peaks (CuK a radiation) at 18.9 ⁇ 0.2 (2 ⁇ ), 17.2 ⁇ 0.2 (2 ⁇ ), 23.4
  • all aforementioned X-ray powder diffraction peaks preferably exhibit a relative intensity of at least 25%.
  • the peaks with the highest relative intensities of more than 50% were found to be 18.9 ⁇ 0.2 (2 ⁇ ), 17.2 ⁇ 0.2 (2 ⁇ ), 23.4 ⁇ 0.2 (2 ⁇ ) and 15.1 ⁇ 0.2 (2 ⁇ )
  • crystalline form A preferably comprises at least one X-ray powder diffraction peak (CuK a radiation) selected from the group consisting of 18.9 ⁇ 0.2 (2 ⁇ ), 17.2 ⁇ 0.2 (2 ⁇ ), 23.4 ⁇ 0.2 (2 ⁇ ), 15.1 ⁇ 0.2 (2 ⁇ ), 12.2 ⁇ 0.2 (2 ⁇ ), 17.4 ⁇ 0.2 (2 ⁇ ), 17.7 ⁇ 0.2 (2 ⁇ ) and 12.5 ⁇ 0.2 (2 ⁇ ) and at least one additional X-ray powder diffraction peak (CuK a radiation) selected from 7.8 ⁇ 0.2 (2 ⁇ ), 9.6 ⁇ 0.2 (2 ⁇ ), 26.2 ⁇ 0.2 (2 ⁇ ) and 28.7 ⁇ 0.2 (2 ⁇ ).
  • the crystalline form according to the present invention is crystalline form B.
  • the crystalline form preferably has an X-ray powder diffraction peak (CuK a radiation) at 23.4 ⁇ 0.2 (2 ⁇ ), more preferably the crystalline form has X-ray powder diffraction peaks (CuK a radiation) at 23.4 ⁇ 0.2 (2 ⁇ ) and 18.8 ⁇ 0.2 (2 ⁇ ), still more preferably the crystalline form has X-ray powder diffraction peaks (CuK a radiation) at 23.4 ⁇ 0.2 (2 ⁇ ), 18.8 ⁇ 0.2 (2 ⁇ ) and 17.1 ⁇ 0.2 (2 ⁇ ), even more preferably the crystalline form has X-ray powder diffraction peaks (CuK a radiation) at 23.4 ⁇ 0.2 (2 ⁇ ), 18.8 ⁇ 0.2 (2 ⁇ ), 17.1 ⁇ 0.2 (2 ⁇ ) and 12.4 ⁇ 0.2 (2 ⁇ ), most preferably the crystalline form has X-ray powder diffraction peaks (CuK a radiation) at 23.4 ⁇ 0.2 (2 ⁇ ), 18.8 ⁇ 0.2 (2 ⁇ ), 17.1 ⁇ 0.2 (2 ⁇ ) and 12.4 ⁇
  • the crystalline form according to the present invention is crystalline form C.
  • the crystalline form preferably has an X- ray powder diffraction peak (CuK a radiation) at 17.2 ⁇ 0.2 (2 ⁇ ), more preferably the crystalline form has X-ray powder diffraction peaks (CuK a radiation) at 17.2 ⁇ 0.2 (2 ⁇ ) and 18.9 ⁇ 0.2 (2 ⁇ ), still more preferably the crystalline form has X-ray powder diffraction peaks (CuK a radiation) at 17.2 ⁇ 0.2 (2 ⁇ ), 18.9 ⁇ 0.2 (2 ⁇ ) and 12.4 ⁇ 0.2 (2 ⁇ ), even more preferably the crystalline form has X-ray powder diffraction peaks (CuK a radiation) at 17.2 ⁇ 0.2 (2 ⁇ ), 18.9 ⁇ 0.2 (2 ⁇ ), 12.4 ⁇ 0.2 (2 ⁇ ) and 12.2 ⁇ 0.2 (2 ⁇ ), yet more preferably the crystalline form has X-ray powder diffraction peaks (CuK a radiation) at 17.2 ⁇ 0.2 (2 ⁇ ), 18.9 ⁇ 0.2 (2 ⁇ ), 12.4 ⁇ 0.2 (2 ⁇ ) and 12.2 ⁇ 0.2
  • X-ray diffractogram of crystalline form C the peaks with the highest relative intensities of more than 50% were found to be 17.2 ⁇ 0.2 (2 ⁇ ), 18.9 ⁇ 0.2 (2 ⁇ ) and 12.4 ⁇ 0.2 (2 ⁇ ), in order to differentiate crystalline form C from crystalline forms A, B and D it might be more advantageous to alternatively or additionally look at unique peaks in the X-ray diffractogram of crystalline C, i.e. peaks of sufficient relative intensity at 20-values where forms A, B and D do not show peaks with significant intensity.
  • Such characteristic X-ray powder diffraction peaks are 34.0 ⁇ 0.2 (2 ⁇ ), 35.8 ⁇ 0.2 (2 ⁇ ), 39.8 ⁇ 0.2 (2 ⁇ ) and 41.2 ⁇ 0.2 (2 ⁇ ).
  • crystalline form C preferably comprises at least one X-ray powder diffraction peak (CuK a radiation) selected from the group consisting of 17.2 ⁇ 0.2 (2 ⁇ ), 18.9 ⁇ 0.2 (2 ⁇ ), 12.4 ⁇ 0.2 (2 ⁇ ), 12.2 ⁇ 0.2 (2 ⁇ ), 23.4 ⁇ 0.2 (2 ⁇ ), 28.6 ⁇ 0.2 (2 ⁇ ) and 17.7 ⁇ 0.2 (2 ⁇ ) and at least one additional X-ray powder diffraction peak (CuK a radiation) selected from 34.0 ⁇ 0.2 (2 ⁇ ), 35.8 ⁇ 0.2 (2 ⁇ ), 39.8 ⁇ 0.2 (2 ⁇ ) and 41.2 ⁇ 0.2 (2 ⁇ ).
  • CuK a radiation selected from the group consisting of 17.2 ⁇ 0.2 (2 ⁇ ), 18.9 ⁇ 0.2 (2 ⁇ ), 12.4 ⁇ 0.2 (2 ⁇ ), 12.2 ⁇ 0.2 (2 ⁇ ), 23.4 ⁇ 0.2 (2 ⁇ ), 28.6 ⁇ 0.2 (2 ⁇ ) and 17.7 ⁇ 0.2 (2 ⁇ )
  • CuK a radiation selected from 34.0 ⁇ 0.2 (2 ⁇ ), 35.8 ⁇ 0.2 (2 ⁇ ), 39.8 ⁇ 0.2 (2 ⁇ ) and 41.2 ⁇ 0.2 (2 ⁇ ).
  • the crystalline form according to the present invention is crystalline form D.
  • the crystalline form preferably has an X- ray powder diffraction peak (CuK a radiation) at 18.4 ⁇ 0.2 (2 ⁇ ), more preferably the crystalline form has X-ray powder diffraction peaks (CuK a radiation) at 18.4 ⁇ 0.2 (2 ⁇ ) and 19.7 ⁇ 0.2 (2 ⁇ ), still more preferably the crystalline form has X-ray powder diffraction peaks (CuK a radiation) at 18.4 ⁇ 0.2 (2 ⁇ ), 19.7 ⁇ 0.2 (2 ⁇ ) and 12.8 ⁇ 0.2 (2 ⁇ ), even more preferably the crystalline form has X-ray powder diffraction peaks (CuK a radiation) at 18.4 ⁇ 0.2 (2 ⁇ ), 19.7 ⁇ 0.2 (2 ⁇ ), 12.8 ⁇ 0.2 (2 ⁇ ) and 17.9 ⁇ 0.2 (2 ⁇ ), most preferably the crystalline form has X-ray powder diffraction peaks (CuK a radiation) at 18.4 ⁇ 0.2 (2 ⁇ ), 19.7 ⁇ 0.2 (2 ⁇ ), 12.8 ⁇ 0.2 (2 ⁇ ) and 17.9 ⁇ 0.2 (2
  • all aforementioned X-ray powder diffraction peaks preferably exhibit a relative intensity of at least 20%.
  • the peaks with the highest relative intensities of more than 35% were found to be 18.4 ⁇ 0.2 (2 ⁇ ) and 19.7 ⁇ 0.2 (2 ⁇ ), in order to differentiate crystalline form D from crystalline forms A, B and C it might be more advantageous to alternatively or additionally look at unique peaks in the X-ray diffractogram of crystalline D, i.e. peaks of sufficient relative intensity at 26-values where forms A, B and C do not show peaks with significant intensity.
  • Such characteristic X-ray powder diffraction peaks are 10.6 ⁇ 0.2 (2 ⁇ ), 1 1.4 ⁇ 0.2 (2 ⁇ ), 1 1.7 ⁇ 0.2 (2 ⁇ ), 12.6 ⁇ 0.2 (2 ⁇ ), 12.8 ⁇ 0.2 (2 ⁇ ), 20.8 ⁇ 0.2 (2 ⁇ ), 24.0 ⁇ 0.2 (2 ⁇ ) and 28.2 ⁇ 0.2 (2 ⁇ ).
  • crystalline form D preferably comprises at least one X-ray powder diffraction peak (CuK a radiation) selected from the group consisting of 18.4 ⁇ 0.2 (2 ⁇ ) and 19.7 ⁇ 0.2 (2 ⁇ ) and at least one additional X-ray powder diffraction peak (CuK a radiation) selected from 10.6 ⁇ 0.2 (2 ⁇ ), 1 1.4 ⁇ 0.2 (2 ⁇ ), 1 1.7 ⁇ 0.2 (2 ⁇ ), 12.6 ⁇ 0.2 (2 ⁇ ), 12.8 ⁇ 0.2 (2 ⁇ ), 20.8 ⁇ 0.2 (2 ⁇ ), 24.0 ⁇ 0.2 (2 ⁇ ) and 28.2 ⁇ 0.2 (2 ⁇ ).
  • CuK a radiation selected from the group consisting of 18.4 ⁇ 0.2 (2 ⁇ ) and 19.7 ⁇ 0.2 (2 ⁇ ) and at least one additional X-ray powder diffraction peak (CuK a radiation) selected from 10.6 ⁇ 0.2 (2 ⁇ ), 1 1.4 ⁇ 0.2 (2 ⁇ ), 1 1.7 ⁇ 0.2 (2 ⁇ ), 12.6 ⁇ 0.2 (2 ⁇ ), 12.8 ⁇ 0.2 (2 ⁇ ), 20.8 ⁇ 0.2 (2 ⁇ ), 24.0 ⁇ 0.2 (2 ⁇ ) and 28.2 ⁇ 0.2 (2 ⁇ ).
  • the crystalline form according to the present invention exhibits at least one endothermic event in differential scanning calorimetry (DSC) analysis.
  • DSC differential scanning calorimetry
  • a person skilled in the art knows how to realize DSC analysis.
  • DSC measurements are realized using a Mettler Toledo DSC821 or Mettler Toledo DSC823 (nitrogen flow, temperature range: -50°C to 350°C, heating rate: 10°C/min).
  • the crystalline form according to the present invention is crystalline form A exhibiting in differential scanning calorimetry analysis an endothermic event with an onset temperature in the range of from 159°C to 172°C, more preferably 162°C to 1 0°C, most preferably 163°C to 168.5°C and/or a peak temperature in the range of from 161 °C to 175°C, more preferably 163°C to 172°C, most preferably 165°C to 170.5°C.
  • the crystalline form according to the present invention is crystalline form B exhibiting in differential scanning calorimetry analysis an endothermic event with an onset temperature in the range of from 162°C to 1 3°C, more preferably 164°C to 171 °C, most preferably 166°C to 169°C and/or a peak temperature in the range of from 165°C to 176°C, more preferably 167°C to 174°C, most preferably 169°C to 172°C.
  • the crystalline form according to the present invention is crystalline form C exhibiting in differential scanning calorimetry analysis an endothermic event with an onset temperature in the range of from 162°C to 172°C, more preferably 164°C to 170°C, most preferably 166°C to 169°C and/or a peak temperature in the range of from 168°C to 179°C, more preferably 170°C to 177°C, most preferably 172°C to 175°C.
  • the crystalline form according to the present invention is crystalline form D exhibiting in differential scanning calorimetry analysis a first endothermic event with an onset temperature in the range of from 46°C to 56°C, more preferably 48°C to 54°C, most preferably 50°C to 52.5°C and/or a peak temperature in the range of from 81 °C to 91 °C, more preferably 83°C to 89°C, most preferably 85°C to 87°C; and a second endothermic event with an onset temperature in the range of from 1 19°C to 129°C, more preferably 121 °C to 127°C, most preferably 122°C to 125°C and/or a peak temperature in the range of from 128°C to 138°C, more preferably 130°C to 136°C, most preferably 132°C to 135°C.
  • crystalline form A achieves significantly and surprisingly higher stability, e.g. physical and/or chemical stability than other crystalline forms. Therefore, in a preferred embodiment, the crystalline form according to the present invention is crystalline form A.
  • Drug stability plays an important role for pharmaceutical dosage forms.
  • the most stable modification of the pharmacologically active ingredient in a pharmaceutical dosage form it may specifically be ensured that, during storage, no crystalline conversion or polymorphic conversion of said pharmacologically active ingredient takes place.
  • This is advantageous, because otherwise the properties of the pharmaceutical dosage form could change as a consequence of a conversion of a less stable modification into a more stable modification.
  • this could lead e.g. to changes in the solubility of the pharmacologically active ingredient, accompanied by a change in the release characteristics and thus also a change in the bioavailability.
  • these effects could result in an inadequately decreased shelf life of the pharmaceutical dosage form.
  • crystalline form A which exists as an ansolvate exhibits a high stability which is advantageous for use in pharmaceutical dosage forms.
  • Ansolvate crystalline forms of a pharmacologically active ingredient have advantages due to the fact that they represent the crystalline form having the lowest weight per mol for that pharmacologically active ingredient, thereby reducing the mass of pharmacologically active ingredient required to achieve a certain dosage in a pharmaceutical dosage form, such as a tablet, compared to crystalline forms which bind or form complexes with residual solvent.
  • crystalline form A shows no tendency to transform into another crystalline form when heated up to its melting point, which lies in the range of about 165°C.
  • the relatively high melting point is an additional advantage of crystalline form A. It has furthermore been surprisingly found that crystalline form A is not hygroscopic.
  • Another aspect of the present invention relates to a process for preparing a crystalline form according to the present invention.
  • a process for preparing a crystalline form according to the present invention comprises the steps of
  • step (iv) separating the solid obtained in step (iii);
  • suitable solvents are conventional solvents known to persons skilled in the art, such as water or organic solvents selected from the group consisting of alcohols such as methanol, ethanol, n-propanol, iso-propanol and n-butanol; esters such as ethyl acetate, n- propyl acetate, iso-propyl acetate, n-butyl acetate and iso-butyl acetate; ketones such as acetone, methyl ethyl ketone (2-butanone), pentan-2-one, pentan-3-one, hexan-2-one and hexan-3-one; ethers such as tert-butyl methyl ether, diethylether, tetrahydrofuran, diisopropylether and 1 ,4-dioxane; nitriles such as acetonitril; aromatic hydrocarbons such as toluene;
  • Step (ii) can be realized at elevated temperatures.
  • elevated temperatures shall refer to any temperature above room temperature.
  • step (ii) is carried out at a temperature below the boiling point of the respective solvent, more preferably at room temperature.
  • step (ii) is carried out at the boiling point of the respective solvent.
  • the compound according to formula (I) remains undissolved or is partially dissolved or completely dissolved in the solvent.
  • step (ii) gives a suspension or a solution.
  • step (ii) of the process according to the invention relates to precipitating the compound according to formula (I).
  • step (iii) involves cooling, preferably in an ice bath, of the suspension or solution obtained in step (ii). Cooling is especially preferred, when step (ii) is realized at elevated temperatures and/or when the compound according to formula (I) is completely or partially dissolved in the solvent.
  • Step (iv) i.e. the separation of the solid obtained in step (iii) is preferably realized by filtering.
  • Step (v), i.e. the drying of the solid obtained in step (iv), is preferably carried out at ambient conditions.
  • step (v) is realized at temperatures in the range of from 25°C to 50°C, preferably in a drying cabinet, and/or under reduced pressure, more preferably at pressures of 0 to 900 mbar, even more preferably 1 to 500 mbar, and in particular 10 to 200 mbar.
  • such mixtures of two crystalline forms may be obtained from one or more of the crystalline forms A, B, C or D during a crystallization process (e.g. cooling or evaporation) or respectively during a separation process (e.g. filtration), or respectively during a process where heat is applied (e.g. drying), or respectively during a process where mechanical energy is inserted (e.g. milling or grinding).
  • a crystallization process e.g. cooling or evaporation
  • a separation process e.g. filtration
  • heat e.g. drying
  • mechanical energy inserted
  • such mixtures of two crystalline forms may be obtained from one or more of crystalline forms A, B, C or D by a partial uptake of hydrate water or respectively by a partial loss of hydrate water, or respectively by a solvent/water exchange.
  • Another aspect of the present invention relates to a mixture of at least two crystalline forms according to the present invention; or a mixture of at least one crystalline form according to the present invention with an amorphous form; or a mixture of at least one crystalline form according to the present invention with a salt of the compound according to formula (I), in any mixing ratio.
  • the degree of crystallinity i.e. the amount of crystalline form(s) relative to the total amount of the compound according to formula (I) containing crystalline form(s) and maybe also amorphous form is at least 40 wt.-%, more preferably at least 60 wt.-%, still more preferably at least 80 wt.-%, yet more preferably at least 90 wt.-%, even more preferably at least 95 wt.-%, most preferably at least 99 wt.-%, and in particular at least 99.5 wt.-%.
  • Another aspect of the present invention relates to a pharmaceutical dosage form comprising at least one crystalline form according to the present invention.
  • the term "at least one” shall preferably mean “one, two, three or four”.
  • the present invention relates to methods of treating pain, comprising administering a pharmaceutical dosage form that comprises a crystalline form according to the present invention to a patient in need thereof (for example, a patient who has been diagnosed with a pain disorder).
  • the present invention relates to the use of a crystalline form according to the present invention in the treatment of pain, wherein the pain is selected from the group consisting of acute, visceral, neuropathic or chronic pain.
  • the present invention relates to a pharmaceutical dosage form comprising a crystalline form according to the present invention and optionally one or more pharmaceutical excipients.
  • said pharmaceutical dosage form may be used for the treatment of pain.
  • the pharmaceutical dosage form is a solid drug form.
  • the pharmaceutical dosage form is preferably manufactured for oral administration.
  • other forms of administration are also possible, e.g. for buccal, sublingual, transmucosal and rectal administration.
  • the pharmaceutical dosage form comprises a crystalline form according to the present invention and one or more pharmaceutical excipients.
  • Preferred pharmaceutical excipients in the sense of the present invention are all substances known to a person skilled in the art which are suitable for use in galenic formulations. The choice of these pharmaceutical excipients and also their quantities are dependent on how the dosage form is to be administered, i.e. orally, sublingually, buccally, transmucosally or rectally.
  • the present invention relates to a method for treating pain in a patient, preferably in a mammal, which comprises administering an effective amount of a crystalline form according to the present invention to a patient.
  • RT room temperature preferably 20-25°C
  • Figure 1 shows the XRPD analysis of crystalline form A.
  • Table 1 below, the peak list of crystalline form A is summarized. Maximum relative intensity is 100.
  • VTXRPD Variable temperature x-rav powder diffraction
  • VTXRPD analysis of crystalline form A was performed in a temperature range from 25°C to 210°C. A heating rate of 10°C/min was applied and hold-time per step was 15 min.
  • a suspension of compound (1 ) (crystalline form A) in solvent was first stirred for 7 d at 30°C and then vortexed for 1 h at RT. Afterwards, in order to separate off the solid, the suspension was centrifuged for 1 min at 45 rpm (for A1-1 to A1-5, see Table 1 ), respectively filtered using a G4 suction filter (for A1 -6 and A1 -7, see Table 1 ). The thus obtained white solid was dried for 18 h at 40°C (2.5 mbar).
  • A1-7 was analyzed via DVS (dynamic vapor sorption) using a Porotec DVS at 25°C.
  • a step width of 10 % r.h. was applied allowing the sample to equilibrate and reach weight constancy ( ⁇ 0.002 %) for at least 10 min on each step.
  • the measurement was started with sorption from 50-90% rH followed by a full cycle 90-0-90% rH and finished by desorption 90-50% rH.
  • the hygroscopicity determined via the DVS measurements was classified according to the ranges for mass increase defined in the European Pharmacopoeia: very hygroscopic (vh): increase of the mass ⁇ 15 %; hygroscopic (h): increase of the mass is less than 15 % and equal or greater than 2 %; slightly hygroscopic (sh): increase of the mass is less than 2 % and equal or greater than 0.2 %; not hygroscopic (nh): increase of the mass is less than 0.2 %; deliquescent (d): sufficient water is absorbed to form a liquid.
  • the DVS isotherm plot of A1-7 is show in Figure 2.
  • A3-1 A mixture of compound (1 ) (crystalline form A; 9.77 mg) and MEK (0.6 mL) was subjected to ultrasound in an ultrasonic bath for app. 30 sec until a clear solution was obtained. The solvent was left to evaporate under ambient conditions over 3 d.
  • A3-3 A mixture of compound (1 ) (crystalline form A; 10.03 mg) and DCM (0.05 mL) was subjected to ultrasound in an ultrasonic bath until a clear solution was obtained. Subsequently, the solvent was evaporated under reduced pressure giving an oil that crystallized upon scratching.
  • A3-4 A mixture of compound (1 ) (crystalline form A; 48.29 mg) and MEK (3 mL) was subjected to ultrasound in an ultrasonic bath until a clear solution was obtained. Subsequently, the solvent was evaporated using a rotary evaporator at 60°C bath temperature.
  • Example A8 Compound (1 ) (crystalline form A) and solvent (1 mL) were charged into a 2 mL vial and vortexed in an Eppendorf Thermomixer for 7 d. Then, if necessary after cooling to RT, the white suspension was filtered (suction filter G4). The recovered white solid was dried at 40°C (3 mbar).
  • Figure 3 shows the XRPD analysis of crystalline form B.
  • Example B1 Approximately 10 mg of compound (1 ) (crystalline form A) were weighed into a 20 ml. vial. The respective solvent was added until a clear solution had formed. The addition of the solvent was performed in 50 ⁇ _ steps until 0.5 ml. had been added and was then continued in 100 ⁇ _ steps until 2 ml. had been added in total. In case the solid had not dissolved by then, further solvent was added up to a total volume of 3 ml_, 5 mL or 10 ml_. After each addition step, the vial was placed for 10 sec in an ultrasonic bath.
  • Figure 4 shows the XRPD analysis of crystalline form C.
  • Figure 5 shows the XRPD analysis of crystalline form D.
  • Table 10 the peak list of crystalline form D is summarized. Maximum relative intensity is 100.
  • the measurement was realized using a Mettler Toledo DSC821 or Mettler Toledo DSC823. Unless otherwise specified, the samples were weighed in a pierced aluminium crucible. The measurement took place in a nitrogen flow in a temperature range from -50°C up to 350°C with a heating rate of 10°C/min.
  • the temperatures specified in relation to DSC analyses are, unless otherwise specified, the temperatures of the peak onset.
  • ⁇ means “specific heat”
  • T onset means the “onset temperature”
  • T peak means the "peak temperature” of a thermal event.
  • ⁇ , T onset and T peak for crystalline form A listed below are given as ranges derived from the measurement of different samples exhibiting essentially identical x-ray powder diffractograms. Crystalline form D showed more than one thermal event, therefore ⁇ , T onS et and T peak are listed for each event.
  • TGA experiments were recorded with a Mettler Toledo TGA/DSC1 (open aluminium oxide crucible nitrogen atmosphere, heating rate 10°C/min, 25 up to 350°C). The results are summarized in the table below.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une forme cristalline du composé de formule (I) présentant au moins un pic de diffraction des rayons X sur poudre (rayonnement CuKα) dans la plage de 16,5 ± 0,2 à 18,5 ± 0,2 (2Θ) et/ou de 17,0 ± 0,2 à 19,5 ± 0,2 (2Θ) et/ou de 22,5 ± 0,2 à 24,5 ± 0,2 (2Θ).
PCT/EP2016/025181 2015-12-28 2016-12-21 Formes cristallines du (cis)-n-(4-(diméthylamino)-1,4-diphénylcyclohexyl)-n-méthyl-cinnamamide WO2017114596A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009118168A1 (fr) 2008-03-27 2009-10-01 Grünenthal GmbH Dérivés substitués du 4-aminocyclohexane
WO2015007388A1 (fr) * 2013-07-17 2015-01-22 Grünenthal GmbH Sels de (e)-n-((1s,4s)-4-(diméthylamino)-1,4-diphénylcyclohexyl)-n-méthylcinnamamide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009118168A1 (fr) 2008-03-27 2009-10-01 Grünenthal GmbH Dérivés substitués du 4-aminocyclohexane
WO2015007388A1 (fr) * 2013-07-17 2015-01-22 Grünenthal GmbH Sels de (e)-n-((1s,4s)-4-(diméthylamino)-1,4-diphénylcyclohexyl)-n-méthylcinnamamide

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
R. HILFIKER: "Polymorphism", 2006, WILEY VCH, pages: 235 - 242,251-

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