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WO2017114596A1 - Crystalline forms of (cis)-n-(4-(dimethylamino)-1,4-diphenylcyclohexyl)-n-methyl-cinnamamide - Google Patents

Crystalline forms of (cis)-n-(4-(dimethylamino)-1,4-diphenylcyclohexyl)-n-methyl-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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Prior art keywords
crystalline form
ray powder
cuk
powder diffraction
radiation
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PCT/EP2016/025181
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French (fr)
Inventor
Michael Gruss
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Grünenthal GmbH
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Publication of WO2017114596A1 publication Critical patent/WO2017114596A1/en

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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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Abstract

The present invention relates to a crystalline form of the compound according to formula (I) having at least one X-ray powder diffraction peak (CuKα radiation) in the range of from 16.5±0.2 to 18.5±0.2 (2Θ) and/or 17.0±0.2 to 19.5±0.2 (2Θ) and/or 22.5±0.2 to 24.5±0.2 (2Θ).

Description

Crystalline forms of (cis)-N-(4-(dimethylamino)-1 ,4-diphenylcyclohexyl)-N-methyl- cinnamamide
FIELD OF THE PRESENT INVENTION
The present invention relates to a crystalline form of the compound according to formula (I)
Figure imgf000002_0001
having at least one X-ray powder diffraction peak (CuKa radiation) in the range of from 16.5±0.2 to 18.5±0.2 (2Θ) and/or 17.0±0.2 to 19.5±0.2 (2Θ) and/or 22.5±0.2 to 24.5±0.2 (20); as well as 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.
BACKGROUND OF THE PRESENT INVENTION Pharmacologically active ingredients can exist in different solid forms, i.e. different crystalline forms having different physical, physicochemical and chemical properties.
Different 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. In addition, different chemical properties can cause different crystalline forms of the same drug to have largely different performance properties. For example, a crystalline form having a low hygroscopicity (relative to other crystalline forms) can have superior chemical stability and longer shelf-life stability (cf. R. Hilfiker, Polymorphism, 2006 Wiley VCH, p. 235-242 and 251 -252).
In medicine, the treatment of pain is of great importance and although a significant number of drugs are known for and established in the treatment of pain, there remains, for instance with regard to drug-related side-effects, a demand for improved pain medication, especially for the treatment of strong/severe and/or chronic and/or neuropathic pain. Consequently, a great deal of effort is still being invested by pharmaceutical companies into the development of new, improved analgesics. One particular drug that is of great interest especially for the use in treating pain, especially chronic and/or neuropathic pain is (cis)-N-(4-(dimethylamino)-1 ,4-diphenylcyclohexyl)-N- methylcinnamamide which is described in WO 2009/1 18168 and the chemical structure of which is depicted in formula (I) below:
Figure imgf000003_0001
The solid forms of (cis)-N-(4-(dimethylamino)-1 ,4-diphenylcyclohexyl)-N-methylcinnamamide that are known so far are not satisfactory in every respect and consequently there is a demand for advantageous solid forms, especially crystalline forms. In particular, there is a demand for crystalline forms of (cis)-N-(4-(dimethylamino)-1 ,4-diphenylcyclohexyl)-N-methyl- cinnamamide for use in pharmaceutical dosage forms.
This object has been achieved by the present invention. It has surprisingly been found that different crystalline forms of (cis)-N-(4-(dimethylamino)-1 ,4-diphenylcyclohexyl)-N-methyl- cinnamamide can be prepared which have advantageous properties, especially for the use in pharmaceutical dosage forms. These inventive crystalline forms are described herein. BRIEF DESCRIPTION OF THE DRAWINGS
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). DETAILED DESCRIPTION The present invention relates to a crystalline form of the compound according to formula (I)
Figure imgf000004_0001
having at least one X-ray powder diffraction peak (CuKa radiation) in the range of from 16.5±0.2 to 18.5±0.2 (2Θ) and/or 17.0±0.2 to 19.5±0.2 (2Θ) and/or 22.5±0.2 to 24.5±0.2 (2Θ).
In a preferred embodiment, the crystalline form according to the present invention has at least one X-ray powder diffraction peak (CuKa radiation) in each of the ranges of from 16.5±0.2 to 18.5±0.2 (2Θ) and 17.0±0.2 to 19.5±0.2 (2Θ) and 22.5±0.2 to 24.5±0.2 (2Θ). Herein below, the compound according to formula (I) is also referred to by the term "pharmacologically active ingredient".
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. For the purposes of this specification, "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. Methods to determine whether a chemical substance is present as the free base or as a salt are known to the skilled artisan such as 14N or 15N solid state NMR, x-ray diffraction, x-ray powder diffraction, IR, Raman, XPS. 1H-NMR recorded in solution may also be used to consider the presence of protonation. In further preferred embodiments, the crystalline form according to the present invention is an ansolvate or a solvate.
In a particularly preferred embodiment, the crystalline form according to the present invention is an ansolvate.
In another preferred embodiment, 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. Preferably, the solvate is selected from the group consisting of monosolvate, hemi- solvate, disolvate, trisolvate, and mixtures thereof. According to this embodiment, the solvate preferably is a variable or non-stoichiometric solvate.
Preferably, the crystalline form according to the present invention is not hygroscopic. The person skilled in the art knows how to determine hygroscopicity. Preferably, 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). Further preferably, 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.
Unless explicitly stated otherwise, all 2Θ 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 CuKa radiation having a wavelength of 1.54060 A. The terms 2Θ values and degrees 2Θ are used synonymously. A person skilled in the art knows how to realize XRPD analysis. Preferably, 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 CuKa radiation. According to the present invention, the crystalline form has at least one X-ray powder diffraction peak (CuKa radiation) in the range of from 16.5±0.2 to 18.5±0.2 (2Θ) and/or 17.0±0.2 to 19.5±0.2 (2Θ) and/or 22.5±0.2 to 24.5±0.2 (2Θ). More preferably, the crystalline form has an X-ray powder diffraction peak (CuKa radiation) in the range of from 16.5±0.2 to 18.5±0.2 (2Θ). Still more preferably, the crystalline form has X-ray powder diffraction peaks (CuKa radiation) in the range of from 16.5±0.2 to 18.5±0.2 (2Θ) and 17.0±0.2 to 19.5±0.2 (2Θ). Even more preferably, the crystalline form has X-ray powder diffraction peaks (CuKa radiation) in the range of from 16.5±0.2 to 18.5±0.2 (2Θ) and 17.0±0.2 to 19.5±0.2 (2Θ) and 22.5±0.2 to 24.5±0.2 (2Θ).
In a preferred embodiment, the crystalline form has at least one additional X-ray powder diffraction peak (CuKa radiation) in the range of from 1 1 .5±0.2 to 13.5±0.2 (2Θ) and/or 14.5±0.2 to 16.5±0.2 (2Θ) and/or 19.0±0.2 to 21.0±0.2 (2Θ). More preferably, the crystalline form has an additional X-ray powder diffraction peak (CuKa radiation) in the range of from 1 1.5±0.2 to 13.5±0.2 (2Θ). Still more preferably, the crystalline form has additional X-ray powder diffraction peaks (CuKa radiation) in the range of from 1 1.5±0.2 to 13.5±0.2 (2Θ) and 14.5±0.2 to 16.5±0.2 (2Θ). In another preferred embodiment, the crystalline form has additional X-ray powder diffraction peaks (CuKa 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 (2Θ).
Preferably, 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%.
In a preferred embodiment, the crystalline form according to the present invention is crystalline form A having at least one X-ray powder diffraction peak (CuKa radiation) selected from the group consisting of 18.9±0.2 (2Θ), 17.2±0.2 (2Θ), 23.4±0.2 (2Θ), 15.1 ±0.2 (2Θ), 12.2±0.2 (2Θ), 17.4±0.2 (2Θ), 17.7±0.2 (2Θ) and 12.5±0.2 (20); or crystalline form B having at least one X-ray powder diffraction peak (CuKa 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 CuKa radiation) selected from the group consisting of 17.2±0.2 (20), 18.9±0.2 (20), 12.4±0.2 (20),
12.2±0.2 (20), 23.4±0.2 (20), 28.6±0.2 (20) and 17.7±0.2 (20); or crystalline form D having at least one X-ray powder diffraction peak (CuKa radiation) selected from the group consisting of 18.4±0.2 (2Θ), 19.7±0.2 (2Θ), 12.8±0.2 (2Θ), 17.9±0.2 (2Θ), 17.7±0.2 (2Θ) and 10.6±0.2 (2Θ). Preferably, the crystalline form according to the present invention is crystalline form A having X-ray powder diffraction peaks (CuKa radiation) at 18.9±0.2 (2Θ), 17.2±0.2 (2Θ), 23.4±0.2 (2Θ), 15.1 ±0.2 (2Θ) and 12.2±0.2 (2Θ).
Preferably, the crystalline form according to the present invention is crystalline form B having X-ray powder diffraction peaks (CuKa radiation) at 23.4±0.2 (2Θ), 18.8±0.2 (2Θ), 17.1 ±0.2 (2Θ), 12.4±0.2 (2Θ) and 15.1 ±0.2 (2Θ).
Preferably, the crystalline form according to the present invention is crystalline form C having X-ray powder diffraction peaks (CuKa radiation) at 17.2±0.2 (2Θ), 18.9±0.2 (2Θ), 12.4±0.2 (2Θ), 12.2±0.2 (2Θ) and 23.4±0.2 (2Θ).
Preferably, the crystalline form according to the present invention is crystalline form D having X-ray powder diffraction peaks (CuKa radiation) at 18.4±0.2 (2Θ), 19.7±0.2 (2Θ), 12.8±0.2 (2Θ), 17.9±0.2 (2Θ) and 17.7±0.2 (2Θ).
In a particularly preferred embodiment, the crystalline form according to the present invention is crystalline form A. According to this embodiment, the crystalline form preferably has an X- ray powder diffraction peak (CuKa radiation) at 18.9±0.2 (2Θ), more preferably the crystalline form has X-ray powder diffraction peaks (CuKa radiation) at 18.9±0.2 (2Θ) and 17.2±0.2 (2Θ), still more preferably the crystalline form has X-ray powder diffraction peaks (CuKa radiation) at 18.9±0.2 (2Θ), 17.2±0.2 (2Θ) and 23.4±0.2 (2Θ), even more preferably the crystalline form has X-ray powder diffraction peaks (CuKa radiation) at 18.9±0.2 (2Θ), 17.2±0.2 (2Θ), 23.4±0.2 (2Θ) and 15.1 ±0.2 (2Θ), yet more preferably the crystalline form has X-ray powder diffraction peaks (CuKa radiation) at 18.9±0.2 (2Θ), 17.2±0.2 (2Θ), 23.4±0.2 (2Θ), 15.1 ±0.2 (2Θ) and 12.2±0.2 (2Θ), most preferably the crystalline form has X-ray powder diffraction peaks (CuKa radiation) at 18.9±0.2 (2Θ), 17.2±0.2 (2Θ), 23.4±0.2 (2Θ), 15.1 ±0.2 (2Θ), 12.2±0.2 (2Θ) and 17.4±0.2 (2Θ), and in particular the crystalline form has X-ray powder diffraction peaks (CuKa radiation) at 18.9±0.2 (2Θ), 17.2±0.2 (2Θ), 23.4±0.2 (2Θ), 15.1 ±0.2 (2Θ), 12.2±0.2 (2Θ), 17.4±0.2 (2Θ), 17.7±0.2 (2Θ) and 12.5±0.2 (2Θ). Further according to this embodiment, all aforementioned X-ray powder diffraction peaks preferably exhibit a relative intensity of at least 25%. Although in the X-ray diffractogram of crystalline form A the peaks with the highest relative intensities of more than 50% were found to be 18.9±0.2 (2Θ), 17.2±0.2 (2Θ), 23.4±0.2 (2Θ) and 15.1 ±0.2 (2Θ), in order to differentiate crystalline form A from crystalline forms B, C and D it might be more advantageous to alternatively or additionally look at unique peaks in the X-ray diffractogram of crystalline A, i.e. peaks of sufficient relative intensity at 20-values where forms B and/or C and/or D do not show peaks with significant intensity. Such characteristic X-ray powder diffraction peaks (CuKa radiation) are 7.8±0.2 (2Θ), 9.6±0.2 (2Θ), 26.2±0.2 (2Θ) and 28.7±0.2 (2Θ). Therefore, crystalline form A preferably comprises at least one X-ray powder diffraction peak (CuKa radiation) selected from the group consisting of 18.9±0.2 (2Θ), 17.2±0.2 (2Θ), 23.4±0.2 (2Θ), 15.1 ±0.2 (2Θ), 12.2±0.2 (2Θ), 17.4±0.2 (2Θ), 17.7±0.2 (2Θ) and 12.5±0.2 (2Θ) and at least one additional X-ray powder diffraction peak (CuKa radiation) selected from 7.8±0.2 (2Θ), 9.6±0.2 (2Θ), 26.2±0.2 (2Θ) and 28.7±0.2 (2Θ).
In another preferred embodiment, the crystalline form according to the present invention is crystalline form B. According to this embodiment, the crystalline form preferably has an X-ray powder diffraction peak (CuKa radiation) at 23.4±0.2 (2Θ), more preferably the crystalline form has X-ray powder diffraction peaks (CuKa radiation) at 23.4±0.2 (2Θ) and 18.8±0.2 (2Θ), still more preferably the crystalline form has X-ray powder diffraction peaks (CuKa radiation) at 23.4±0.2 (2Θ), 18.8±0.2 (2Θ) and 17.1 ±0.2 (2Θ), even more preferably the crystalline form has X-ray powder diffraction peaks (CuKa radiation) at 23.4±0.2 (2Θ), 18.8±0.2 (2Θ), 17.1 ±0.2 (2Θ) and 12.4±0.2 (2Θ), most preferably the crystalline form has X-ray powder diffraction peaks (CuKa radiation) at 23.4±0.2 (2Θ), 18.8±0.2 (2Θ), 17.1 ±0.2 (2Θ), 12.4±0.2 (2Θ) and 15.1 ±0.2 (2Θ), and in particular the crystalline form has X-ray powder diffraction peaks (CuKa radiation) at 23.4±0.2 (2Θ), 18.8±0.2 (2Θ), 17.1 ±0.2 (2Θ), 12.4±0.2 (2Θ), 15.1 ±0.2 (2Θ) and 12.2±0.2 (2Θ). Further according to this embodiment, all aforementioned X-ray powder diffraction peaks preferably exhibit a relative intensity of at least 10%. In still another preferred embodiment, the crystalline form according to the present invention is crystalline form C. According to this embodiment, the crystalline form preferably has an X- ray powder diffraction peak (CuKa radiation) at 17.2±0.2 (2Θ), more preferably the crystalline form has X-ray powder diffraction peaks (CuKa radiation) at 17.2±0.2 (2Θ) and 18.9±0.2 (2Θ), still more preferably the crystalline form has X-ray powder diffraction peaks (CuKa radiation) at 17.2±0.2 (2Θ), 18.9±0.2 (2Θ) and 12.4±0.2 (2Θ), even more preferably the crystalline form has X-ray powder diffraction peaks (CuKa radiation) at 17.2±0.2 (2Θ), 18.9±0.2 (2Θ), 12.4±0.2 (2Θ) and 12.2±0.2 (2Θ), yet more preferably the crystalline form has X-ray powder diffraction peaks (CuKa radiation) at 17.2±0.2 (2Θ), 18.9±0.2 (2Θ), 12.4±0.2 (2Θ), 12.2±0.2 (2Θ) and 23.4±0.2 (2Θ), most preferably the crystalline form has X-ray powder diffraction peaks (CuKa radiation) at 17.2±0.2 (2Θ), 18.9±0.2 (2Θ), 12.4±0.2 (2Θ), 12.2±0.2 (2Θ), 23.4±0.2 (2Θ) and 28.6±0.2 (2Θ), and in particular the crystalline form has X-ray powder diffraction peaks (CuKa radiation) at 17.2±0.2 (2Θ), 18.9±0.2 (2Θ), 12.4±0.2 (2Θ), 12.2±0.2 (2Θ), 23.4±0.2 (2Θ), 28.6±0.2 (2Θ) and 17.7±0.2 (2Θ). Further according to this embodiment, all aforementioned X-ray powder diffraction peaks preferably exhibit a relative intensity of at least 20%.
Although in the 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 (2Θ), 18.9±0.2 (2Θ) and 12.4±0.2 (2Θ), 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 (CuKa radiation) are 34.0±0.2 (2Θ), 35.8±0.2 (2Θ), 39.8±0.2 (2Θ) and 41.2±0.2 (2Θ).
Therefore, crystalline form C preferably comprises at least one X-ray powder diffraction peak (CuKa radiation) selected from the group consisting of 17.2±0.2 (2Θ), 18.9±0.2 (2Θ), 12.4±0.2 (2Θ), 12.2±0.2 (2Θ), 23.4±0.2 (2Θ), 28.6±0.2 (2Θ) and 17.7±0.2 (2Θ) and at least one additional X-ray powder diffraction peak (CuKa radiation) selected from 34.0±0.2 (2Θ), 35.8±0.2 (2Θ), 39.8±0.2 (2Θ) and 41.2±0.2 (2Θ).
In yet another preferred embodiment, the crystalline form according to the present invention is crystalline form D. According to this embodiment, the crystalline form preferably has an X- ray powder diffraction peak (CuKa radiation) at 18.4±0.2 (2Θ), more preferably the crystalline form has X-ray powder diffraction peaks (CuKa radiation) at 18.4±0.2 (2Θ) and 19.7±0.2 (2Θ), still more preferably the crystalline form has X-ray powder diffraction peaks (CuKa radiation) at 18.4±0.2 (2Θ), 19.7±0.2 (2Θ) and 12.8±0.2 (2Θ), even more preferably the crystalline form has X-ray powder diffraction peaks (CuKa radiation) at 18.4±0.2 (2Θ), 19.7±0.2 (2Θ), 12.8±0.2 (2Θ) and 17.9±0.2 (2Θ), most preferably the crystalline form has X-ray powder diffraction peaks (CuKa radiation) at 18.4±0.2 (2Θ), 19.7±0.2 (2Θ), 12.8±0.2 (2Θ), 17.9±0.2 (2Θ) and 17.7±0.2 (2Θ), and in particular the crystalline form has X-ray powder diffraction peaks (CuKa radiation) at 18.4±0.2 (2Θ), 19.7±0.2 (2Θ), 12.8±0.2 (2Θ), 17.9±0.2 (2Θ), 17.7±0.2 (2Θ) and 10.6±0.2 (2Θ). Further according to this embodiment, all aforementioned X-ray powder diffraction peaks preferably exhibit a relative intensity of at least 20%. Although in the X-ray diffractogram of crystalline form D the peaks with the highest relative intensities of more than 35% were found to be 18.4±0.2 (2Θ) and 19.7±0.2 (2Θ), 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 (CuKa radiation) are 10.6±0.2 (2Θ), 1 1.4±0.2 (2Θ), 1 1.7±0.2 (2Θ), 12.6±0.2 (2Θ), 12.8±0.2 (2Θ), 20.8±0.2 (2Θ), 24.0±0.2 (2Θ) and 28.2±0.2 (2Θ). Therefore, crystalline form D preferably comprises at least one X-ray powder diffraction peak (CuKa radiation) selected from the group consisting of 18.4±0.2 (2Θ) and 19.7±0.2 (2Θ) and at least one additional X-ray powder diffraction peak (CuKa radiation) selected from 10.6±0.2 (2Θ), 1 1.4±0.2 (2Θ), 1 1.7±0.2 (2Θ), 12.6±0.2 (2Θ), 12.8±0.2 (2Θ), 20.8±0.2 (2Θ), 24.0±0.2 (2Θ) and 28.2±0.2 (2Θ).
Preferably, the crystalline form according to the present invention exhibits at least one endothermic event in differential scanning calorimetry (DSC) analysis. A person skilled in the art knows how to realize DSC analysis. Preferably, 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).
In a preferred embodiment, 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.
In another preferred embodiment, 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.
In still another preferred embodiment, 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.
In yet another preferred embodiment, 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.
It has been surprisingly found that some crystalline forms of the compound according to formula (I) disclosed herein have surprisingly higher stability than other forms, as is demonstrated in the examples. For instance, 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. By using 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. Depending on the pharmacological properties of the pharmaceutical dosage form, 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. Thus, these effects could result in an inadequately decreased shelf life of the pharmaceutical dosage form.
It has been surprisingly found that 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.
Surprisingly, it has also been found that 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.
Details of the properties of crystalline form A and of the other forms according the present invention are disclosed in greater detail in the examples below.
Another aspect of the present invention relates to a process for preparing a crystalline form according to the present invention.
In a preferred embodiment, a process for preparing a crystalline form according to the present invention comprises the steps of
(i) mixing the compound according to formula (I) with a solvent;
(ii) stirring at room temperature or stirring at an elevated temperature the mixture obtained in step (i);
(iii) precipitating the compound according to formula (I);
(iv) separating the solid obtained in step (iii); and
(v) drying the solid obtained in step (iv).
In step (i), 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; saturated hydrocarbons such as n-pentane, n-hexane and n-heptane; chlorinated hydrocarbons such as dichloromethane and chloroform; and also N-methyl-2-pyrrolidone, dimethyl formamide and dimethyl sulfoxide; and mixtures thereof. Particularly preferred solvents are dichloromethane, tetrahydrofuran, toluene, ethanol, methyl ethyl ketone (2-butanone) and iso-propanol. Step (ii) can be realized at elevated temperatures. In this regard, elevated temperatures shall refer to any temperature above room temperature. In a preferred embodiment, step (ii) is carried out at a temperature below the boiling point of the respective solvent, more preferably at room temperature. In another preferred embodiment, step (ii) is carried out at the boiling point of the respective solvent. Preferably, in step (ii), the compound according to formula (I) remains undissolved or is partially dissolved or completely dissolved in the solvent. According to this embodiment, step (ii) gives a suspension or a solution. In a preferred embodiment, the stirring carried out in step (ii) is realized for a time period of at least 15 min, more preferably in a range of from 15 min to 7 days, still more preferably 15 min to 4 days, even more preferably 15 min to 2 days, yet more preferably 15 min to 1 day, most preferably 15 min to 12 h, and in particular 15 min to 2h. Step (iii) of the process according to the invention relates to precipitating the compound according to formula (I). Preferably, 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. In another preferred embodiment, 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.
Mixtures of the crystalline forms A, B, C and D, preferably mixtures of two of these crystalline forms, are also included within the scope of the present invention.
For example, 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). Furthermore, 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.
Preferably, 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. In this regard, the term "at least one" shall preferably mean "one, two, three or four".
In still another aspect, 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).
In a preferred embodiment, 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. In another aspect 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.
Preferably, said pharmaceutical dosage form may be used for the treatment of pain.
In a preferred embodiment, the pharmaceutical dosage form is a solid drug form. The pharmaceutical dosage form is preferably manufactured for oral administration. However, other forms of administration are also possible, e.g. for buccal, sublingual, transmucosal and rectal administration.
In a preferred embodiment, 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.
Furthermore, 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. EXAMPLES
The following examples serve to explain the present invention in more detail, but should not be interpreted as restrictive. The following abbreviations are used in the examples:
d day
DCM dichloromethane
Et20 diethyl ether
EtOH ethanol
Ex. example
h hour
MeCN acetonitril
MEK 2-butanone
MeOH methanol
min minute
MTBE methyl tert-butyl ether
2PrOH iso-propanol (2-propanol)
ret. reaction
rel. I relative intensity
rH relative humidity
RT room temperature, preferably 20-25°C
rpm rounds per minute sec seconds
t time (duration)
T temperature
T boiling point
XRPD X-ray powder diffraction
In the following "compound (1 )" denotes the compound according to formula (I) which synthesis is described in WO 2009/1 18168. XRPD analyses were carried out in transmission geometry with a STOE StadiP or a Panalytical X'Pert Pro X-ray powder diffractometer in reflection geometry, monochromatised CuKc radiation being used by means of a germanium monocrystal. Measurements were carried out in an angular range between 5° and 50° in 2Θ. In general, the 2Θ values have an error rate of ±0.2° in 2Θ. The samples were measured without any special treatment other than the application of slight pressure to get a flat surface. An ambient air atmosphere was used. Unless stated otherwise, measurements were performed at RT (i.e. 298 K (± 5 K)). In general a baseline correction of the measured diffractograms was done using the program WinXPow (STOE). A) Crystalline form A
XRPD
Figure 1 shows the XRPD analysis of crystalline form A. In Table 1 below, the peak list of crystalline form A is summarized. Maximum relative intensity is 100.
Table 1 :
2Θ rel I 2Θ rel I
7.80 13.36 19.12 6.44
9.60 8.6 21 .25 12.19
12.20 41 .41 21 .76 9.31
12.46 27 23.40 56.14
15.13 51 .17 23.73 10.48
17.15 97.1 25.04 6.1
17.39 31 .35 25.64 9.32
17.71 27.8 26.22 12.58
17.84 12.1 1 27.66 6.24
18.05 7.97 28.69 15.78 18.87 100
Variable temperature x-rav powder diffraction (VTXRPD)
The 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.
It was found that crystalline form A is present until the melting point. This crystalline form undergoes no transformation to another crystalline form. At a temperature of around 165°C, the crystalline form melts which is indicated by an amorphous x-ray pattern.
Synthesis of crystalline form A
Example A 1 :
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).
Table 2 below, used solvents and yields are summarized.
Table 2:
Figure imgf000017_0001
All of Examples A1-1 to A1 -7 gave a white solid that was determined by XRPD to be crystalline form A.
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. From the data it can be seen that crystalline form A is not hygroscopic (nh). The change in mass observed was around 0.1 %. This crystalline form is an ansolvate and did not show any uptake of water during all sorption cycles. Example A2:
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 μΙ_ steps until 0.5 ml. had been added and was then continued in 100 μΙ_ 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.
After the experiment, the mixtures were deposited in a fume hood and the solvents were left to evaporate at ambient conditions. When the solvent had completely evaporated, the solids were recovered and analyzed by XRPD.
In Table 3 below, used solvents and solubilities are summarized.
Table 3: solvent compound (1 )
Ex.
type V [ml_] m (weighed in) [mg] solubility [mg/mL]
A2-1 DCM 0.05 9.99 >199.80
A2-2 EtOH 0.90 10.44 1 1 .60
A2-3 MeOH 0.80 10.67 13.34
A2-4 toluene 0.50 1 1 .12 22.24
A2-5 Et20 10.00 1 1 .17 <1.12
A2-6 MTBE 10.00 1 1 .05 <1.1 1 A2-7 acetone 0.70 1 1 .23 16.04
A2-8 MeCN 2.00 10.29 5.15
All of Examples A2-1 to A2-8 gave a white solid that was determined by XRPD to be crystalline form A. Example A3:
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.
A3-2: A mixture of compound (1 ) (crystalline form A; 9.85 mg) and MEK (0.6 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.
A3-3: 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.
A3-5: A mixture of compound (1 ) (crystalline form A; 199.69 mg) and DCM (1 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.
All of Examples A3-1 to A3-5 gave a white solid that was determined by XRPD to be crystalline form A. Example A4:
A mixture of compound (1 ) (crystalline form A) and solvent was heated using an Eppendorf Thermomixer, wherein the starting temperature was 25°C. The temperature was raised in steps of 5°C and held a few minutes. In case the suspension had not become a clear solution, the temperature was raised again. This procedure was repeated until the solid had dissolved and a clear solution was obtained.
In Table 4 below, used solvents and solubilities are summarized.
Table 4:
Figure imgf000020_0001
After having obtained clear solutions, the solutions were cooled to 10°C. A4-1 : After 1 to 2 h, still no solid had precipitated. However, after 18 h a white solid had formed which was filtered off (suction filter G4) and dried (21 h at 23°C and 24 h at 40°C and 2.5 mbar).
A4-2: After 2.5 h, a white solid had precipitated. The suspension was left to stir over the weekend. Then, the solid was filtered off (suction filter G4) and dried (21 h at 23°C and 24 h at 40°C and 2.5 mbar). The yield was 23.89 mg (59.55%).
A4-3: There was no precipitation after 4.5 h, so the solution was left to stir over the weekend. After 74 h, a white solid had precipitated which was filtered off (suction filter G4) and dried (21 h at 23°C and 24 h at 40°C and 2.5 mbar). The yield was 27.01 mg (66.18%).
A4-4: After 4.5 h, a white solid had precipitated. The suspension was left to stir over the weekend. Then, the solid was filtered off (suction filter G4) and dried (21 h at 23°C and 24 h at 40°C and 2.5 mbar). The yield was 22.79 mg (74.45%). Example A5:
Compound (1 ) (crystalline form A; 50.81 mg) was ground in a mortar for 3 to 5 min. The obtained solid was determined by XRPD to be crystalline form A.
Example A6:
A mixture of compound (1 ) (crystalline form A; 1 .01062 g) and 2PrOH (13.07 mL) was heated and the temperature was kept at the boiling point until a clear solution was obtained. The solution was then stirred for 40 min at RT and another 30 min in an ice bath. Afterwards, the precipitated white solid was separated using a G4 suction filter (yield of moist solid: 0.94664 g) and was determined by XRPD to be crystalline form A.
Example A7:
A flask was charged with compound (1 ) (crystalline form A) and solvent. The mixture was heated up to the boiling point until a clear solution was obtained. At RT, water or pentane was added to the solution until crystallization was complete. The white solid was separated by filtration using a G4 suction filter.
In Table 5 below, used solvents and yields are summarized.
Table 5:
Figure imgf000021_0001
All of Examples A7-1 to A7-4 gave a white solid that was determined by XRPD to be crystalline form A.
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).
In Table 6 below, used solvents and yields are summarized. Table 6:
Figure imgf000022_0002
*The solid could not be transferred quantitatively and partially remained in the vials.
All of Examples A8-1 to A8-8 gave a white solid that was determined by XRPD to be crystalline form A.
From the above experiments, it becomes apparent that under these reaction conditions crystalline form A is predominantly formed, i.e. that crystalline form A is thermodynamically more stable than the other crystalline forms. This advantageous property makes crystalline form A an attractive material for use in pharmaceutical dosage forms.
B) Crystalline form B
XRPD
Figure 3 shows the XRPD analysis of crystalline form B.
In Table 7 below, the peak list of crystalline form B is summarized. Maximum relative intensity is 100.
Table 7:
Figure imgf000022_0001
17.13 32.03
18.84 34.48
23.36 100
Synthesis 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 μΙ_ steps until 0.5 ml. had been added and was then continued in 100 μΙ_ 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.
After the experiment, the mixtures were deposited in a fume hood and the solvents were left to evaporate at ambient conditions. When the solvent had completely evaporated, the solids were recovered and analyzed by XRPD.
In Table 8 below, used solvents and solubilities are summarized.
Table 8:
Figure imgf000023_0001
All of Examples B1-1 to B1 -3 gave a white solid that was determined by XRPD to be crystalline form B.
C) Crystalline form C XRPD
Figure 4 shows the XRPD analysis of crystalline form C.
In Table 9 below, the peak list of crystalline form C is summarized. Maximum relative intensity is 100. Table 9:
Figure imgf000024_0001
Synthesis of crystalline form C
Example C1:
A mixture of acetone (4 mL) and compound (1 ) (crystalline form A; 248.73 mg; concentration in acetone: 62.18 mg/mL) was heated, respectively cooled using an Avantium Crystalline. The starting temperature was RT and then the temperature was raised, respectively lowered in steps of 5 K/min in a range of from -15°C to +51 °C. The clear point, i.e. a clear solution was obtained, at a temperature of 50.8°C. After reaching 51 °C, the mixture was stepwise cooled down to -15°C. The precipitated solid was filtered off and dried using a P4 frit.
The solid was determined by XRPD to be crystalline form C. D) Crystalline form D
XRPD
Figure 5 shows the XRPD analysis of crystalline form D. In Table 10 below, the peak list of crystalline form D is summarized. Maximum relative intensity is 100.
Table 10:
2Θ rel I 2Θ rel I
10.59 21 .54 18.39 100
1 1.39 14.08 18.87 14.39
1 1.66 17.12 19.70 38.22 12.61 17.27 20.84 15.9
12.83 24.33 21 .91 18.66
17.70 21 .63 24.04 1 1.1 1
17.90 23.36 28.22 9.39
Synthesis of crystalline form D
Example D1:
A mixture of compound (1 ) (crystalline form A) and aqueous tartaric acid solution (1 .33 M) was vortexed for 5 h at 20°C. Then, the solid was separated by filtration (G4 suction filter) and dried for 16 h at 40°C and 3 mbar.
In Table 1 1 below, used solvents and solubilities are summarized.
Table 11 :
Figure imgf000025_0001
Both Examples D1-1 and D1-2 gave a white solid that was determined by XRPD to be crystalline form D.
X) Further Analyses of the crystalline forms A to D
Differential Scanning Calorimetry (DSC)
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.
In the following table, "ΔΗ" means "specific heat", "Tonset" means the "onset temperature", and "Tpeak" means the "peak temperature" of a thermal event. The values for ΔΗ, Tonset and Tpeak 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 ΔΗ, TonSet and Tpeak are listed for each event.
Table 12:
Figure imgf000026_0001
Thermoqravimetry analysis (TGA)
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.
Table 13:
Figure imgf000026_0002
From the above data it becomes clear that the samples do not contain any significant quantities of residual solvents. This is in line with the assumption that crystalline forms A, B and C are ansolvate forms.

Claims

Patent claims:
1. A crystalline form of the compound according to formula (I)
Figure imgf000027_0001
having at least one X-ray powder diffraction peak (CuKa radiation) in the range of from 16.5±0.2 to 18.5±0.2 (2Θ) and/or 17.0±0.2 to 19.5±0.2 (2Θ) and/or 22.5±0.2 to 24.5±0.2 (2Θ).
The crystalline form according to claim 1 , which is an ansolvate.
The crystalline form according to claim 1 or 2, which has at least one additional X-ray powder diffraction peak (CuKa radiation) in the range of from 1 1 .5±0.2 to 13.5±0.2 (2Θ) and/or 14.5±0.2 to 16.5±0.2 (2Θ) and/or 19.0±0.2 to 21 .0±0.2 (2Θ).
The crystalline form according to any of the preceding claims, which is crystalline form A having at least one X-ray powder diffraction peak (CuKa radiation) selected from the group consisting of 18.9±0.2 (2Θ), 17.2±0.2 (2Θ), 23.4±0.2 (2Θ), 15.1 ±0.2 (2Θ), 12.2±0.2 (2Θ), 17.4±0.2 (2Θ), 17.7±0.2 (2Θ) and 12.5±0.2 (20); or crystalline form B having at least one X-ray powder diffraction peak (CuKa radiation) selected from the group consisting of 23.4±0.2 (2Θ), 18.8±0.2 (2Θ), 17.1 ±0.2 (2Θ), 12.4±0.2 (2Θ) and 15.1 ±0.2 (26); or crystalline form C having at least one X-ray powder diffraction peak CuKa radiation) selected from the group consisting of 17.2±0.2 (2Θ), 18.9±0.2 (2Θ), 12.4±0.2 (2Θ), 12.2±0.2 (2Θ), 23.4±0.2 (2Θ), 28.6±0.2 (2Θ) and 17.7±0.2 (26); or crystalline form D having at least one X-ray powder diffraction peak (CuKa radiation) selected from the group consisting of 18.4±0.2 (2Θ), 19.7±0.2 (2Θ), 12.8±0.2 (2Θ), 17.9±0.2 (2Θ), 17.7±0.2 (2Θ) and 10.6±0.2 (2Θ). The crystalline form according to claim 4, which 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 and/or a peak temperature in the range of from 161 °C to 175°C.
The crystalline form according to claims 4 or 5, which has X-ray powder diffraction peaks (CuKa radiation) at 18.9±0.2 (2Θ), 17.2±0.2 (2Θ), 23.4±0.2 (2Θ), 15.1 ±0.2 (2Θ) and 12.2±0.2 (2Θ).
The crystalline form according to claim 4, which 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 173°C and/or a peak temperature in the range of from 165°C to 176°C.
The crystalline form according to claim 4 or 7, which has X-ray powder diffraction peaks (CuKa radiation) at 23.4±0.2 (2Θ), 18.8±0.2 (2Θ), 17.1 ±0.2 (2Θ), 12.4±0.2 (2Θ) and 15.1 ±0.2 (2Θ).
The crystalline form according to claim 4, which 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 and/or a peak temperature in the range of from 168°C to 179°C. 10. The crystalline form according to claim 4 or 9, which has X-ray powder diffraction peaks (CuKa radiation) at 17.2±0.2 (2Θ), 18.9±0.2 (2Θ), 12.4±0.2 (2Θ), 12.2±0.2 (2Θ) and 23.4±0.2 (2Θ).
The crystalline form according to claim 4, which 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 and/or a peak temperature in the range of from 81 °C to 91 °C; and a second endothermic event with an onset temperature in the range of from 1 19°C to 129°C and/or a peak temperature in the range of from 128°C to 138°C.
2. The crystalline form according to claim 4 or 1 1 , which has X-ray powder diffraction peaks (CuKa radiation) at 18.4±0.2 (2Θ), 19.7±0.2 (2Θ), 12.8±0.2 (2Θ), 17.9±0.2 (2Θ) and 17.7±0.2 (2Θ).
3. A pharmaceutical dosage form comprising at least one crystalline form according to any of claims 1 to 12.
4. A process for preparing a crystalline form according to any of claims 1 to 12, comprising the steps of
(i) mixing the compound according to formula (I) with a solvent;
(ii) stirring at room temperature or stirring at an elevated temperature the mixture obtained in step (i);
(iii) precipitating the compound according to formula (I);
(iv) separating the solid obtained in step (iii); and
(v) drying the solid obtained in step (iv).
PCT/EP2016/025181 2015-12-28 2016-12-21 Crystalline forms of (cis)-n-(4-(dimethylamino)-1,4-diphenylcyclohexyl)-n-methyl-cinnamamide WO2017114596A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009118168A1 (en) 2008-03-27 2009-10-01 Grünenthal GmbH Substituted 4-aminocyclohexane derivatives
WO2015007388A1 (en) * 2013-07-17 2015-01-22 Grünenthal GmbH Salts of (e)-n-((1s,4s)-4-(dimethylamino)-1,4-diphenylcyclohexyl)-n-methylcinnamamide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009118168A1 (en) 2008-03-27 2009-10-01 Grünenthal GmbH Substituted 4-aminocyclohexane derivatives
WO2015007388A1 (en) * 2013-07-17 2015-01-22 Grünenthal GmbH Salts of (e)-n-((1s,4s)-4-(dimethylamino)-1,4-diphenylcyclohexyl)-n-methylcinnamamide

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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