(19)
(11)EP 2 970 284 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
01.11.2017 Bulletin 2017/44

(21)Application number: 14712206.3

(22)Date of filing:  14.03.2014
(51)Int. Cl.: 
C07D 471/10  (2006.01)
A61P 25/04  (2006.01)
A61K 31/438  (2006.01)
(86)International application number:
PCT/EP2014/000682
(87)International publication number:
WO 2014/139681 (18.09.2014 Gazette  2014/38)

(54)

CRYSTALLINE CIS-(E)-4-(3-FLUOROPHENYL)-2',3',4',9'-TETRAHYDRO-N,N-DIMETHYL-2'-(1-OXO-3-PHENYL-2-PROPENYL)-SPIRO[CYCLOHEXANE-1,1'[1H]-PYRIDO[3,4-B]INDOL]-4-AMINE

KRISTALLINES CIS-(E)-4-(3-FLUORPHENYL)-2',3',4',9'-TETRA-HYDRO-N,N-DIMETHYL-2'-(1-OXO-3-PHENYL-2-PROPENYL)-SPIRO[CYCLOHEXAN-1,1'[1H]-PYRIDO[3,4-B]INDOL]-4-AMIN

FORME CRYSTALLINE DU CIS-(E)-4-(3-FLUOROPHENYL)-2',3',4',9'-TETRA-HYDRO-N,N-DIMETHYL-2'-(1-OXO-3-PHENYL-2-PROPENYL)-SPIRO[CYCLOHEXANE-1,1'[1H]-PYRIDO[3,4-B]INDOL]-4-AMINE


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 15.03.2013 EP 13001331

(43)Date of publication of application:
20.01.2016 Bulletin 2016/03

(73)Proprietor: Grünenthal GmbH
52078 Aachen (DE)

(72)Inventor:
  • GRUSS, Michael
    52062 Aachen (DE)


(56)References cited: : 
WO-A1-2006/108565
WO-A1-2012/013343
  
     
    Remarks:
    The file contains technical information submitted after the application was filed and not included in this specification
     
    Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


    Description

    FIELD OF THE INVENTION



    [0001] The invention relates to crystalline form A of cis-(E)-4-(3-Fluorophenyl)-2',3',4',9'-tetrahydro-N,N-dimethyl-2'-(1-oxo-3-phenyl-2-propenyl)-spiro[cyclohexane-1,1'[1H]-pyrido[3,4-b]indol]-4-amine, pharmaceutical compositions and medicaments comprising this crystalline form, the use of this crystalline form as well as to processes for producing this crystalline form.

    BACKGROUND OF THE INVENTION



    [0002] Pharmaceutically active drugs can exist in different solid forms. For example, a drug may exist in different crystalline forms which have different physical, physic-chemical and chemical properties.

    [0003] Different physical or physic-chemical properties can cause different crystalline forms of the same drug to have largely different processing and storage performance. Such physical or physico-chemical properties include, for example, thermodynamic stability, crystal morphology [form, shape, structure, particle size, particle size distribution, color, degree of crystallinity, ripple behavior, flowability, density, bulk density, powder density, apparent density, vibrated density, depletability, emptyability, 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], reconstitutability, hygroscopicity, tackiness, adhesiveness, tendency to electrostatic charging, and the like.

    [0004] 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, pp 235-242 and 251-252).

    [0005] 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.

    [0006] One particular drug that is of great interest especially for the use in treating pain, especially chronic and/or neuropathic pain is cis-(E)-4-(3-Fluorophenyl)-2',3',4',9'-tetrahydro-N,N-dimethyl-2'-(1-oxo-3-phenyl-2-propenyl)-spiro[cyclohexane-1,1'[1H]-pyrido[3,4-b]indol]-4-amine, which is described in WO2012013343-A1. The chemical structure of this drug is depicted below as the compound of formula (I):



    [0007] WO2006/108565 lists binding affinities at selected receptors for the compound 1,1-(3-dimethylamino-3-(3-fluorophenyl)-pentamethylene)-2-cinnamoyl-1,3,4,9-tetrahydro-2,9-diazafluorene without information regarding its stereochemistry and discusses the use of such compounds in the treatment of substance dependency.
    The solid forms of cis-(E)-4-(3-Fluorophenyl)-2',3',4',9'-tetrahydro-N,N-dimethyl-2'-(1-oxo-3-phenyl-2-propenyl)-spiro[cyclohexane-1,1'[1H]-pyrido[3,4-b]indol]-4-amine that are known so far are not satisfactory in every respect and consequently there is a demand for advantageous solid forms, especially crystalline forms. Especially, there is a demand for solid forms of cis-(E)-4-(3-Fluorophenyl)-2',3',4',9'-tetrahydro-N,N-dimethyl-2'-(1-oxo-3-phenyl-2-propenyl)-spiro[cyclohexane-1,1'[1H]-pyrido[3,4-b]indol]-4-amine that have advantageous properties for the use of this compound in pharmaceutical compositions and for use in methods of preparing such pharmaceutical compositions.

    [0008] This object has been achieved by the present invention. It has surprisingly been found that different crystalline forms of cis-(E)-4-(3-Fluorophenyl)-2',3',4',9'-tetrahydro-N,N-dimethyl-2'-(1-oxo-3-phenyl-2-propenyl)-spiro[cyclohexane-1,1'[1H]-pyrido[3,4-b]indol]-4-amine can be prepared which have advantageous properties, especially for the use in pharmaceutical compositions. These inventive crystalline forms are described herein.

    BRIEF DESCRIPTION OF THE DRAWINGS



    [0009] 

    Figures 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i, 1j, 1k and 1l show the PXRD patterns of crystalline forms A, B, C, D, E, F, G, H, I, J, K, L and Q.

    Figures 2a, 2b and 2d show the Raman spectra of crystalline forms A, B, and D.

    Figures 3a, b, c, d, and e show plots of DVS experiments for crystalline forms A, B, C, D, and E.


    DETAILED DESCRIPTION



    [0010] The compound according to general formula (I) depicted above can be systematically be referred to as cis-(E)-4-(3-Fluorophenyl)-2',3',4',9'-tetrahydro-N,N-dimethyl-2'-(1-oxo-3-phenyl-2-propenyl)-spiro[cyclohexane-1,1'[1H]-pyrido[3,4-b]indol]-4-amine, or as cis-(E)-2',3',4',9'-tetrahydro-N,N-dimethyl-4-(3-fluorophenyl)-2'-(2-phenylvinyl)carbonyl-spiro[cyclohexane-1,1'(1'H)-pyrido[3,4-b]indole]-4-amine or as (E)-1-((1s,4s)-4-(dimethylamino)-4-(3-fluorophenyl)-3',4'-dihydrospiro[cyclohexane-1,1'-pyrido[3,4-b]indol]-2'(9'H)-yl)-3-phenylprop-2-en-1-one, respectively.

    [0011] The compound according to general formula (I) may be present as the free base. The definition of the free base of the compound according to general formula (I) as used herein includes solvates, co-crystals and crystalline forms. For the purpose of the specification, "free base" preferably means that the compound according to general 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 group of the compound according to general formula (I) is its N,N-dimethylamino moiety, which thus according to the invention is preferably neither protonated nor quaternized. In other words, the free electron pair of the nitrogen atom of the N,N-dimethylamino moiety is 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.

    [0012] Unless explicitly stated otherwise, all 2Θ values refer to a X-ray powder diffractogram measured using CuKα radiation having a wavelength of 1.54060 A. The terms 2Θ values and degrees 2Θ are used synonymously.

    [0013] Unless explicitly stated otherwise, all values in ppm refer to ppm by weight, i.e. ppmw.

    [0014] In a first aspect, the present invention relates to crystalline form A of cis-(E)-4-(3-Fluorophenyl)-2',3',4',9'-tetrahydro-N,N-dimethyl-2'-(1-oxo-3-phenyl-2-propenyl)-spiro[cyclohexane-1,1'[1H]-pyrido[3,4-b]indol]-4-amine, which has
    X-ray powder diffraction peaks (CuKα radiation) at 8.7 ±0.2 (2Θ), 10.0 ±0.2 (2Θ), 11.9 ±0.2 (2Θ), 15.3 ±0.2 (2Θ), 15.8 ±0.2 (2Θ); 16.7 ±0.2 (2Θ); 17.4 ±0.2 (2Θ); 17.8 ±0.2 (2Θ), 18.3 ±0.2 (2Θ), 19.7 ±0.2 (2Θ); 20.3 ±0.2 (2Θ), 21.9 ±0.2 (2Θ), 22.2 ±0.2 (2Θ), and 27.1 ±0.2 (2Θ).

    [0015] Preferably, said X-ray powder diffraction peak exhibits a relative intensity of at least 10%, preferably of at least 20%, more preferably of at least 30%.

    [0016] Crystalline form A according to the invention is an ansolvate.

    [0017] In a further preferred embodiment of the invention, crystalline form A has one or more Raman peaks selected from the group consisting of at 1606 ±2 cm-1, 1175 ±2 cm-1, 1568 ±2 cm-1, 1574 ±2 cm-1 and 1650 ±2 cm-1
    In a preferred embodiment of the invention, the crystalline form A exhibits in DSC analysis an endothermal event with an onset temperature in the range of 227 °C to 247°C, preferably 240 °C to 245 °C and/or a peak temperature in the range of 235 °C to 255°C, preferably 245 °C to 250 °C.
    Crystalline form B exhibits in DSC analysis an endothermal event with a peak temperature in the range of 80°C to 110°C and/or an exothermal event with a peak temperature in the range of 204°C to 231 °C.
    Crystalline form B has X-ray powder diffraction peaks (CuKα radiation) at 6.8 ±0.2 (2Θ), 12.1 ±0.2 (2Θ), 28,3 ±0.2 (2Θ), and optionally at 18,7 ±0.2 (2Θ).

    [0018] It has been surprisingly found that some crystalline forms of cis-(E)-4-(3-Fluorophenyl)-2',3',4',9'-tetrahydro-N,N-dimethyl-2'-(1-oxo-3-phenyl-2-propenyl)-spiro[cyclohexane-1,1'[1H]-pyrido[3,4-b]indol]-4-amine 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.
    The stability is important. By using the most stable modification in a medicament it may specifically be ensured that, during storage, no crystalline conversion or polymorphic conversion of the active ingredient in the pharmaceutical formulation takes place. This is advantageous, because otherwise the properties of the medicament could change as a consequence of a conversion of a less stable modification into a more stable modification. In relation to the pharmacological properties of an administration form, this could lead for example to the solubility of the active ingredient changing, accompanied by a change in the release characteristics and thus also a change in the bioavailability. Lastly, this could result in inadequate storage stability of the medicament.
    It has been surprisingly found that crystalline form A combines this important property for the use in the formulation of dosage forms with the favorable property that it exists as an ansolvate. This is important because ansolvates represent the crystalline form of a compound which has the lowest weight per mol for that compound, thereby reducing the mass of compound required to achieve a certain dosage in a dosage form, such as a tablet, compared to crystalline forms which bind or cooperate residual solvent.
    Suprisingly, it has also been found that of the four crystalline ansolvate forms (A, D, E and H) found, that crystalline form A is the only form of these which shows no tendency to transform into another crystalline form when heated up to its melting point, which lies in the range of about 243-250°C. The relatively high melting point is an additional advantage of crystalline form A. It has furthermore been surprisingly found that crystalline form A exhibits a higher physical and/or chemical stability compared to crystalline ansolvate forms D and E during storage at selected storage conditions, i.e. elevated temperatures and/or high relative humidity. Additionally, crystalline form A was surprisingly found to be chemical more stable during storage at selected storage conditions in mixture with selected pharmaceutical excipients. Details of the properties of crystalline form A and of the other forms according the invention will be discussed in greater detail in the examples below

    [0019] In further preferred embodiments, crystalline form A comprises X-ray powder diffraction peaks of about 8.7 ±0.2 (2Θ), about 10.0 ±0.2 (2Θ), about 11.9 ±0.2 (2Θ), about 15.3 ±0.2 (2Θ), about 15.8 ±0.2 (2Θ), about 16.7 ±0.2 (2Θ), about 17.4 ±0.2 (2Θ), about 17.8 ±0.2 (2Θ), about 18.3 ±0.2 (2Θ), about 19.7 ±0.2 (2Θ), about 20.3 ±0.2 (2Θ), about 21.9 ±0.2 (2Θ), about 22.2 ±0.2 (2Θ), and about 27.1 ±0.2 (2Θ). Optionally, crystalline form A may further comprise one or more X-ray peaks selected from the group consisting of about 7.7 ±0.2 (2Θ), about 12.3 ±0.2 (2Θ), about 22.5 ±0.2 (2Θ) and about 26.2 ±0.2 (2Θ). In further preferred embodiments, crystalline form A additionally comprises all of the aforementioned optional X-ray peaks.

    [0020] Although in the X-ray diffractogram of crystalline form A of (E)-2',3',4',9'-Tetrahydro-N,N-dimethyl-4-(3-fluorophenyl)-2'-(2-phenylvinyl)carbonyl-spiro[cyclohexane-1,1'(1'H)-pyrido[3,4-b]indole]-4-amine measured using CuKa radiation having a wavelength of 1.54060 A the five peaks with the highest relative intensity were found to be about 11.9 ±0.2 (2Θ), about 15.3 ±0.2 (2Θ), about 17.4 ±0.2 (2Θ), about 17.8 ±0.2 (2Θ) and about 18.3 ±0.2 (2Θ), in order to discriminate between form A and crystalline forms D, E and H it might be more advantageous to alternatively or additionally look at unique peaks in the X-ray diffractogram, i.e. peaks of sufficient relative intensity at 2Θ-values where forms D, E and H do not show lines with significant intensity. Such characteristic X-ray peaks are besides those of about 15.3 ±0.2 (2Θ), about 17.4 ±0.2 (2Θ) and about 18.3 ±0.2 (2Θ) X-ray peaks of about 7.7±0.2 (2Θ), about 10.0 ±0.2 (2Θ), about 15.8 ±0.2 (2Θ), about 21.9 ±0.2 (2Θ), about 22.2 ±0.2 (2Θ) and about 27.1 ±0.2 (2Θ).
    Similarly, the X-ray peaks about 16.7 ±0.2 (2Θ), about 17.4 ±0.2 (2Θ), about 20.3 ±0.2 (2Θ), about 22.5 ±0.2 (2Θ), and about 27.1 ±0.2 (2Θ) might be more advantageously used to discriminate between crystalline form A and crystalline forms B, C, F and G. Similarly, the X-ray powder diffraction peaks of about 7.7 ±0.2 (2Θ), about 18.3 ±0.2 (2Θ), about 21.9 ±0.2 (2Θ), about 22.2 ±0.2 (2Θ), about 22.5 ±0.2 (2Θ), about 26.2 ±0.2 (2Θ), and about 27.1 ±0.2 (2Θ) might be more advantageously used to discriminate form A from forms F, I, J, K and L. To discriminate between crystalline form A and crystalline B it might be more advantageous to use the X-ray powder diffraction peaks of about 8.7 ±0.2 (2Θ), about 10.0 ±0.2 (2Θ), about 16.7 ±0.2 (2Θ), about 17.4 ±0.2 (2Θ), about 26.2 ±0.2 (2Θ), and about 27.1 ±0.2 (2Θ).
    To discriminate between crystalline form A and crystalline form C the X-ray peaks of about 7.7 ±0.2 (2Θ), about 8.7 ±0.2 (2Θ), about 15.3 ±0.2 (2Θ), about 15.8 ±0.2 (2Θ), about 16.7 ±0.2 (2Θ), about 17.4 ±0.2 (2Θ), about 19.7 ±0.2 (2Θ), about 20.3 ±0.2 (2Θ), about 21.9 ±0.2 (2Θ), about 22.2 ±0.2 (2Θ), about 22.5 ±0.2 (2Θ) and about 27.1 ±0.2 (2Θ) might be more advantageously used.
    To discriminate between crystalline form A and crystalline form D the X-ray peaks of about 7.7 ±0.2 (2Θ), about 10.0 ±0.2 (2Θ), about 12.3 ±0.2 (2Θ), about 15.3 ±0.2 (2Θ), about 17.8 ±0.2 (2Θ), about 18.3 ±0.2 (2Θ), and about 21.9 ±0.2 (2Θ) might be more advantageously used
    In order to discriminate between crystalline form A and crystalline form E it might be more advantageous not to rely on the the X-ray peak of about 18.3 ±0.2 (2Θ), because both polymorphic form A and E show an X-ray peak of high intensity in this area.

    [0021] To discriminate between crystalline form A and crystalline form F, the X-ray peaks of about 7.7 ±0.2 (2Θ), about 10.0 ±0.2 (2Θ), about 11.9 ±0.2 (2Θ), about 15.3 ±0.2 (2Θ), about 15.8 ±0.2 (2Θ), about 17.4 ±0.2 (2Θ), about 17.8 ±0.2 (2Θ), about 19.7 ±0.2 (2Θ), about 20.3 ±0.2 (2Θ), about 21.9 ±0.2 (2Θ), about 22.2 ±0.2 (2Θ), about 22.5 ±0.2 (2Θ) and about 27.1 ±0.2 (2Θ) might be more advantageously used.
    To discriminate between crystalline form A and crystalline form G, the X-ray peaks of about 7.7 ±0.2 (2Θ), about 16.7 ±0.2 (2Θ), about 20.3 ±0.2 (2Θ), about 21.9 ±0.2 (2Θ), about 22.2 ±0.2 (2Θ), about 22.5 ±0.2 (2Θ), about 26.2 ±0.2 (2Θ) and about 27.1 ±0.2 (2Θ) might be more advantageously used.
    To discriminate between crystalline form A and crystalline form H, the X-ray peaks of about 7.7 ±0.2 (2Θ), about 8.7 ±0.2 (2Θ), about 11.9 ±0.2 (2Θ), about 12.3 ±0.2 (2Θ), about 15.3 ±0.2 (2Θ), about 15.8 ±0.2 (2Θ), about 16.7 ±0.2 (2Θ), about 21.9 ±0.2 (2Θ), about 22.2 ±0.2 (2Θ), about 26.2 ±0.2 (2Θ) and about 27.1 ±0.2 (2Θ) might be more advantageously used.
    To discriminate between crystalline form A and crystalline form I, the X-ray peaks of about 7.7 ±0.2 (2Θ), about 8.7 ±0.2 (2Θ), about 20.3 ±0.2 (2Θ), about 22.2 ±0.2 (2Θ), and about 27.1 ±0.2 (2Θ) might be more advantageously used.
    To discriminate between crystalline form A and crystalline form J, the X-ray peaks of about 7.7 ±0.2 (2Θ), about 8.7 ±0.2 (2Θ), about 10.0 ±0.2 (2Θ), about 11.9 ±0.2 (2Θ), about 15.8 ±0.2 (2Θ), about 21.9 ±0.2 (2Θ), about 22.2 ±0.2 (2Θ), about 22.5 ±0.2 (2Θ), and about 27.1 ±0.2 (2Θ) might be more advantageously used.
    To discriminate between crystalline form A and crystalline form K, the X-ray peaks of about 7.7 ±0.2 (2Θ), about 8.7 ±0.2 (2Θ), about 11.9 ±0.2 (2Θ), about 12.3 ±0.2 (2Θ), about 17.4 ±0.2 (2Θ), about 17.8 ±0.2 (2Θ), about 18.3 ±0.2 (2Θ), about 21.9 ±0.2 (2Θ), and about 26.2 ±0.2 (2Θ) might be more advantageously used
    To discriminate between crystalline form A and crystalline form L, the X-ray peaks of about 8.7 ±0.2 (2Θ), about 10.0 ±0.2 (2Θ), about 15.3 ±0.2 (2Θ), about 15.8 ±0.2 (2Θ), about 22.5 ±0.2 (2Θ), and about 27.1 ±0.2 (2Θ) might be more advantageously used. Crystalline form A according to the invention may further be characterized that it has a Raman peak at about 1606 cm-1 and/or at least one Raman peak selected from the group of about 1175 cm-1, about 1568 cm-1, about 1574 cm-1 and about 1650 cm-1.
    Crystalline form A according to the invention may further be characterized that it has a Raman peak at about 1606 cm-1 and/or at least one Raman peak selected from the group of about 1175 cm-1, about 1568 cm-1, about 1574 cm-1 and about 1650 cm-1 and/or at least one Raman peak selected from the group of about 98 cm-1 and about 1001 cm-1. Additionally, it may have at least one Raman peak selected from the group consisting of about 128 cm-1, about 170 cm-1, about 676 cm-1, about 1183 cm-1, about 1204 cm-1, about 1268 cm-1, about 1294 cm-1, about 1447 cm-1, about 1462 cm-1, about 1584 cm-1, about 2910 cm-1, about 3062 cm-1, and about 3075 cm-1. Also additionally, crystalline form A may have at least one Raman peak selected from the group consisting of about 189 cm-1, about 227 cm-1, about 272 cm-1, about 310 cm-1, about 355 cm-1, about 417 cm-1, about 461 cm-1, about 485 cm-1, about 509 cm-1, about 543 cm-1, about 589 cm-1, about 611 cm-1, about 620 cm-1, about 644 cm-1, about 697 cm-1, about 725 cm-1, about 746 cm-1, about 783 cm-1, about 801 cm-1, about 831 cm-1, about 865 cm-1, about 893 cm-1, about 927 cm-1, about 955 cm-1, about 978 cm-1, about 1012 cm-1, about 1028 cm-1, about 1048 cm-1, about 1074 cm-1, about 1111 cm-1, about 1155 cm-1, about 1244 cm-1, about 1343 cm-1, about 1368 cm-1, about 1385 cm-1, about 1407 cm-1, about 1493 cm-1, about 2782 cm-1, about 2834 cm-1, about 2878 cm-1, about 2946 cm-1, about 2960 cm-1, about 2980 cm-1, about 2999 cm-1, about 3026 cm-1 and about 3449 cm-1.

    [0022] In DSC analyses, crystalline form A according to the present invention preferably exhibits an endothermal event with a peak temperature of about 235-255 °C (i.e. the crystalline form has a melting endotherm at about 235-255 °C), more preferably of about 237-250 °C, still more preferably of about 240-248 °C. In some preferred embodiments crystalline form A exhibits an endothermal event with a peak temperature of about 242-248 °C.

    [0023] According to another aspect of the present invention a process is provided for the preparation of crystalline form A. This process comprises the steps of

    (a-1') suspending cis-(E)-4-(3-Fluorophenyl)-2',3',4',9'-tetrahydro-N,N-dimethyl-2'-(1-oxo-3-phenyl-2-propenyl)-spiro[cyclohexane-1,1'[1H]-pyrido[3,4-b]indol]-4-amine for at least 0.3h in a solvent at a temperature in the range of 20°C and the boiling point of the solvent, wherein the solvent is selected from the group consisting of isopropanol and a mixture of isopropanol and water, wherein the mixture may comprise up to 75 vol-% water;

    (b-1') separating, preferably filtering off the solid obtained in step (a-1'), and

    (c-1') drying the solid obtained in step (b-1') at a temperature in the range of 0° to 75°C, preferably at a temperature in the range of 20 to 55°C, more preferably at 50°C.



    [0024] Preferably, step (b-1 ") comprises the additional step of cooling the suspension obtained in step (a-1'), preferably to ambient temperature, prior to separating the solid from the solvent. Furthermore, drying step (c-1") is preferably conducted under reduced pressure.

    [0025] By a more preferred embodiment of the process according to the present invention crystalline form A can be obtained. This embodiment comprises the steps of

    (a-1''') suspending cis-(E)-4-(3-Fluorophenyl)-2',3',4',9'-tetrahydro-N,N-dimethyl-2'-(1-oxo-3-phenyl-2-propenyl)-spiro[cyclohexane-1,1'[1H]-pyrido[3,4-b]indol]-4-amine for at least 0.3h in a solvent at a temperature in the range of 20°C and the boiling point of the solvent, wherein the solvent is selected from the group consisting of isopropanol and a mixture of isopropanol and water, wherein the mixture may comprise up to 75 vol-% water;

    (b-1''') separating, preferably filtering off the solid obtained in step (a-1'), and

    (c-1''') drying the solid obtained in step (b-1'), preferably at a temperature in the range of 0° to 75°C, more preferably at a temperature in the range of 20 to 55°C, even more preferably at 50°C.



    [0026] Preferably, step (b-1''') comprises the additional step of cooling the suspension obtained in step (a-1'''), preferably to ambient temperature, prior to separating the solid from the solvent. Furthermore, drying step (c-1''') is preferably conducted under reduced pressure.

    [0027] A further aspect of the invention relates to crystalline form A obtainable by the process as described above.

    [0028] Mixtures of the crystalline form A with crystalline forms B, C, D, E, F, G, H, I, J, K, L and Q, preferably mixtures of two of these crystalline forms, are also included within the scope of the present invention.

    [0029] For example, such mixtures of two crystalline forms may be obtained from one or more of the crystalline forms A, B, C, D, E, F, G, H, I, J, K, L and Q 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).

    [0030] Furthermore, such mixtures of two crystalline forms may be obtained from one or more of crystalline forms A, B, C, D, E, F, G, H, I, J, K, L or Q by a partial uptake of hydrate water or respectively by a partial loss of hydrate water, or respectively by a solvent/water exchange.

    [0031] Another aspect of the invention relates to a composition comprising a mixture of at least two crystalline forms as described herein, wherein said mixture comprises crystalline form A; or a mixture of at least crystalline form as described herein with an amorphous form; or a mixture of at least crystalline form as described herein with a salt of cis-(E)-4-(3-Fluorophenyl)-2',3',4',9'-tetrahydro-N,N-dimethyl-2'-(1-oxo-3-phenyl-2-propenyl)-spiro[cyclohexane-1,1'[1H]-pyrido[3,4-b]indol]-4-amine with fumaric acid; in any mixing ratio.

    [0032] Preferably, the degree of crystallinity, i.e. the content of crystalline form A of cis-(E)-4-(3-Fluorophenyl)-2',3',4',9'-tetrahydro-N,N-dimethyl-2'-(1-oxo-3-phenyl-2-propenyl)-spiro[cyclohexane-1,1'[1H]-pyrido[3,4-b]indol]-4-amine relative to the total content of cis-(E)-4-(3-Fluorophenyl)-2',3',4',9'-tetrahydro-N,N-dimethyl-2'-(1-oxo-3-phenyl-2-propenyl)-spiro[cyclohexane-1,1'[1H]-pyrido[3,4-b]indol]-4-amine (crystalline form(s) + amorphous form(s)) 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.-%.

    [0033] Yet a further aspect the invention relates to a pharmaceutical composition comprising at least crystalline form A according to the invention.

    [0034] The term pain as used herein preferably includes but is not limited to pain selected from the group consisting of neuropathic pain, diabetic neuropathic pain, chronic neuropathic pain.

    [0035] In another aspect the present invention relates to a pharmaceutical composition comprising a crystalline form as described herein and optionally one or more suitable additives and/or adjuvants such as described below.

    [0036] Preferably said pharmaceutical composition may be used for the treatment of pain.

    [0037] In still another aspect the present invention relates to a medicament comprising a crystalline form as described herein, preferably a pharmaceutical composition as described herein. In a preferred embodiment, the medicament is a solid drug form. The medicament is preferably manufactured for oral administration. However, other forms of administration are also possible, e.g. for buccal, sublingual, transmucosal, rectal, intralumbal, intraperitoneal, transdermal, intravenous, intramuscular, intragluteal, intracutaneous and subcutaneous application.

    [0038] Depending on the configuration, the medicament (dosage form) preferably contains suitable additives and/or adjuvants. Suitable additives and/or adjuvants in the sense of the invention are all substances known to a person skilled in the art for the formation of galenic formulations. The choice of these adjuvants and also the quantities to be used are dependent on how the medication is to be administered, i.e. orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or locally.

    EXAMPLES



    [0039] The following abbreviations are used in the examples:

    The following abbreviations are used in the examples:

    d
    day
    DMSO
    dimethylsulfoxid
    EtOAc
    ethyl acetate
    EtOH
    ethanol
    Ex
    example
    FT-Raman
    Fourier transformation Raman spectroscopy
    H
    hour
    IPE
    diisopropyl ether
    MeCN
    acetonitril
    MEK
    2-butanone
    MeOH
    methanol
    min
    minute
    NMP
    N-methyl-2-pyrrolidone
    1PrOH
    n-propanol (1-propanol)
    2PrOH
    iso-propanol (2-propanol)
    PXRD
    powder x-ray diffraction
    r.h.
    relative humidity
    RT
    room temperature, preferably 20-25°C
    SCXRD
    single crystal X-ray diffraction
    sec
    seconds
    t
    time (duration)
    T
    Temperature
    TBME
    tert-butyl methyl ether
    TG-FTIR
    thermogravimetry coupled with Fourier transform infrared spectroscopy
    THF
    tetrahydrofuran
    XRPD
    X-ray powder diffraction



    [0040] In the following "compound (1)" denotes cis-(E)-4-(3-Fluorophenyl)-2',3',4',9'-tetrahydro-N,N-dimethyl-2'-(1-oxo-3-phenyl-2-propenyl)-spiro[cyclohexane-1,1'[1H]-pyrido[3,4-b]indol]-4-amine.

    [0041] Unless otherwise specified, solvent mixtures are always volume/volume.

    [0042] The synthesis of compound (1) is described in WO2012/013343 A1, page 48-49.

    A) Crystalline form A


    General procedure for syntheses:



    [0043] A quantity of compound (1) is charged into a vial or flask and an amount of solvent is added. The resulting suspension/solution is stirred (e.g. orbital shaker or overhead-stirrer) for a given time at a specific temperature. Subsequently, if the suspension/solution was stirred at an elevated temperature, it is allowed to cool to room temperature or any other predetermined temperature to precipitate or crystallize the product and the solvent is removed by filtration. The thus obtained solid is dried, preferably at room temperature.

    [0044] In table 1 below, specific reaction conditions for syntheses of crystalline form A are listed.
    Table 1
    ExampleCrystalline form of starting materialAmount [mg]Solvent / amountT [°C]Reaction time [d]Comment
    A1 D 227.7 2-propanol / 5 ml RT 5d Day 5 without stirring
    A2 D 190 2-propanol / 10ml RT 3d ---
    A3 D 206.1 1-propanol / 5ml RT 5d Day 5 without stirring
    A4 E 101 1-pentane / 2.5 ml 40 0.75d ---
    A5 E 102 1-propanol / 2.5 ml 40 0.75d ---
    A6.1 E 110.5 TBME / 2.5 ml 40 0.75d ---
    A6.2 E 102.8 n-hexane / 2.5 ml 30 0.75d ---
    A6.3 E 102 n-pentane / 2.5 ml 30 0.75d ---
    A6.4 E 107 1-propanol / 2.5 ml 40 0.75d ---
    A10.1 D 206.1 1-propanol / 5 ml RT 4d ---
    A10.2 D 227.7 2-propanol / 5 ml RT 4d ---
    A12 B 8300 2-propanol / 120 ml Water / 280 ml (3:7) 52 5d After cooling to RT the suspension was stirred for an additional hour.

    Example A13:



    [0045] Crystalline form H of compound (1) can be transformed into form A by heating a sample of crystalline form H, which was filled into a quartz capillary to a temperature between 150°C to 250°C. The sample remained crystalline form A upon cooling the sample to 20 °C.

    Example A 17: Interconversion / Slurry experiments



    [0046] About 25 mg of a specific crystalline form of compound (1) and 25 mg of the same or another crystalline form of compound (1) were charged into a vial and 1.0 mL of 2-Propanol was added. The vials were closed and the mixtures were stirred (via shaking using an Eppendorf Thermomixer, starting with 750 rpm, increased to 1000 rpm after 1 day) at an elevated temperature (30 ±2 °C) for 7 days. Subsequently the mixtures were cooled to 20 ±2 °C and stirred for an additional 2 hours.
    The solids were then separated via filtration using a suction filter. To dry the thus obtained solid material an air flow was applied for 2 to 3 hours.

    [0047] The crystalline form of the obtained materials was determined using XRPD. The experiments are summarized below in table 2 below.
    Table 2:
    IDAmount compound (1)/ [mg] and crystalline forms in starting materialResulting crystalline form
    A17.1 24,8 mg D A
    26,2 mg D
    A17.2 21,8 mg E A
    24,8 mg A
    A17.3 24,0 mg E A
    23,8 mg D
    A17.4 22,9 mg E A
    21,4 mg 63*
    A17.5 20,7 mg E A
    22,1 mg G
    A17.6 23,1 mg E H
    22,6 mg C
    A17.8 24,5 mg E A
    24,2 mg 58*
    A17.9 22,6 mg E A + H
    22,2 mg L
    A17.10 23,0 mg E A + H
    34,7 mg 64*
    A17.11 24,0 mg E A
      24,4 mg A+Pks*  
    A17.12 23,6 mg E A
    23,3 mg P
    A17.13 25,9 mg E A
    24,1 mg O
    A17.14 24,7 mg D A
    25,6 mg D
    A17.15 20,9 mg E A
    23,2 mg A
    A17.16 21,8 mg E A
    20,9 mg D
    A17.17 20,6 mg E A
    20,7 mg 63*
    A17.18 23,3 mg E A
    22,7 mg G
    A17.19 23,3 mg E H
    24,2 mg C
    A17.20 25,1 mg E A
    25,3 mg 58*
    A17.21 22,8 mg E A + H
    23,4 mg L
    A17.22 22,6 mg E A + H
    22,2 mg 64*
    A17.23 24,1 mg E A
    25,4 mg A+Pks*
    A17.24 26,2 mg E A
    26,2 mg P
    A17.25 25,2 mg E A
    24,3 mg O
    [* denote crystalline material in a polymorphic form not further characterized but most likely other than the ones described herein]


    [0048] From the above interconversion 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 compositions.

    Example A15



    [0049] 100 mg of crystalline form A of compound (1) was charged into a vial and 10 mL of a mixture ethylacetate/water 70:30 (vol/vol, i.e. 7 mL ethylacetate, 3 mL water) was added. The vial was closed and the mixture (a white suspension) was stirred (by means of shaking, 400 rpm, PLS Synthesiser) at room temperature (22 ±2 °C) for 13 days.

    [0050] The solid was separated using a suction filter and dried by applying an air flow for additional 5 to 30 minutes (until the solid appeared to be dry). The resulting material was identified via x-ray powder diffraction to be crystalline form A of compound (1).

    Example A16



    [0051] 0,99 g of crystalline form A of compound (1) was charged into a vial and 25 mL of ethanol p.a. was added. The vial was closed and the suspension was stirred (by means of shaking, PLS shaker, 400 rpm) at an elevated temperature (40°C ±2) for 20 h.
    The mixture was cooled to 20 ±2 °C. The solid was separated using a suction filter (G4) and dried by applying an air flow until the sample appeared to be dry. The white solid was subsequently left for 1 h at ambient conditions. Subsequently, it was identified via x-ray powder diffractometry to be crystalline form A of compound (1).

    Example A18



    [0052] Crystalline form A of compound (1) can be obtained by suspending in the flask fitted with a reflux condenser 34.6 g of compound (1) (e.g. as crystalline form C, E, G and/H, or any other form) in a mixture of 260 ml water and 606 ml isopropanol. The suspension is subsequently heated and stirred at 100°C for 30 minutes which leads to the formation of a very fine suspension of crystalline material which settles very quickly after stirring is stopped. The reaction slurry is cooled to 20°C and the solvent mixture is removed by filtration (suction filter). The solid crystalline material is dried over night at 50°C under reduced pressure Yield: 26 g (75 %)

    B) Crystalline form B (comparative)



    [0053] General procedure for syntheses: See general procedure for syntheses of crystalline form A.

    [0054] In table 3 below, specific reaction conditions for syntheses of crystalline form B are listed.
    Table 3
    Ex.Crystalline form of starting materialAmount [mg]Solvent / amountT [°C]Reaction time [d]Comment
    B1 D 224.7 Ethanol / 5 ml RT 5 Day 5 without stirring
    B2 D 165.3 Ethanol 10.5 ml / water 4.5 ml (7:3) RT 3 ---
    B3 D 176.4 Ethanol 10.5 ml / water 4.5 ml (7:3) 50 3 ---
    B4 D 225 Ethanol / 5 ml RT 4 ---
    B6 D 488 Ethanol 21 ml / water 9 ml (7:3) 50 4,83 For the final 20h, the suspension is stirred at RT.
    B7 A 101 Ethanol 7 ml / water 3 ml (7:3) RT 13  
    B9.1 Q 30.7 1-Propanol:water (8:2) 1.5 ml RT 7  
    B9.2 Q 30.0 2-Propanol:water (8:2) 1.5 ml RT 7  

    Example B8: Stability of crystalline form B



    [0055] Two samples (100 mg each) of crystalline form B of compound (1) were charged into a petri dish and dried at 50 ±2 °C at reduced pressure (about 7 mBar) for 72 hours. The samples were let to cool to room temperature under ambient conditions before they were analyzed. The analysis revealed that the obtained material was still compound (1) in crystalline form B.

    [0056] This example and example B7 demonstrate that in the presence of water, crystalline form B may form as a relatively stable polymorph or hydratealthough the water content may vary and/or change. The formation of form A (ansolvate) or form B (hydrate) in the presence of water depends on the organic co-solvent used as the reaction medium (preferably ethanol) and the reaction temperature (preferable room temperature).

    C) Crystalline form C (comparative)



    [0057] General procedure for syntheses: See general procedure for syntheses of crystalline form A. In table 4 below, specific reaction conditions for syntheses of crystalline form B are listed.
    Table 4
    Ex.Crystalline form of starting materialAmount [mg]Solvent / amountT [°C]Reaction time [d]Comment
    C1 E 100 Methanol / 2.5 ml 40 0.75  
    C2 A 1010 Methanol / 25 ml 40 0.83  
    C3 E 103 Methanol / 2.5 ml 40 0.75  
    C4 A 53.7 Methanol / 2 ml 30 19  
    C5.1 A 100 Methanol / 5ml 50 1  
    C5.2 A 100 Methanol / 3.5 ; Water / 1.5 ml 50 1  
    C6 A 100 Methanol / 7ml; Water / 3 ml RT 13  
    C7 D 650 Methanol / 150 ml 56 5  
    C8 D 280 Methanol / 150 ml 80 0.125 (3h) Reflux
    C9 D 778 Methanol / 250 ml 80 0.17 (4h) Reflux
    C10 E 150 Methanol / 50 ml 70 0.125 (3h) Solid was filtered from hot suspension.
    C11 H 75 Methanol / 75 ml 50 14  

    D) Crystalline form D (Comparative)



    [0058] General procedure for syntheses: See general procedure for syntheses of crystalline form A. In table 5 below, specific reaction conditions for syntheses of crystalline form D are listed.
    Table 5
    Ex.Crystalline form of starting materialAmount [mg]Solvent / amountT [°C]Reaction time [d]Comment
    D6.1 E 116.6 Acetone / 2.5 ml 40 0.75 ---
    D6.2 E 113 Acetonitrile / 2.5 ml 40 0.75 ---
    D6.3 E 106.4 Diethylether / 7.5 ml 40 0.75 ---
    D6.4 E 104.5 Dichloromethane / 7.5 ml 40 0.75 ---
    D6.5 E 105.2 Ethylmethylketone / 2.5 ml 40 0.75 ---
    D8.1 A 49.7 Dichloromethane / 2 ml 30 19  
    D8.2 A 53.6 Diethylether / 2 ml 30 19  
    D8.3 A 73.7 Acetone / 1 ml 30 19  
    D8.4. A 95.9 THF / 0.5 ml 30 19 Solvent was removed by evaporation under ambient conditions instead of filtration.
    D8.5 A 51.5 Acetonitrile / 2ml 30 19  
    D9.1 A 100 Acetone / 5 ml 50 1  
    D9.2 A 100 Acetone / 3.5 ml; Water / 1.5 ml 50 1  
    D12.1 G 55 Acetone / 1.5 ml RT 1  
    D12.2 G 51 Dichloromethane RT 1  

    Examples D1, D2, D3, D4, D10, D11 and D13



    [0059] In the above mentioned examples, which were carried out as described in the general procedure for syntheses of polymorph D under reaction conditions listed below in table 6, crystalline form D did not transform into another polymorphic form.
    Table 6: Stability of crystalline form D
    Ex.Crystalline form of starting materialAmount [mg]Solvent / amountT [°C]Reaction time [d]
    D1 D 207.6 Acetonitrile / 5 RT 5d*
    D2 D 170.7 Acetone / 10.5 ml; Water / 4.5 ml RT 3d
    D3 D 188.6 Acetone / 10.5 ml; Water / 4.5 ml 50 3d
    D4 D 196 Water / 10 ml RT 3d
    D10 D 208 Acetonitrile / 5ml RT 4d
    D11 D 196 Water / 10 ml RT 4d
    D13 D 517 Acetonitrile / 20 50 5d**
    * Day 5 without stirring. ** Day 5 at RT.

    Example D14



    [0060] 238 g of crystalline form E of compound (1) are charged into a suitable reaction vessel under inert conditions (N2-atmosphere) and 17 I of acetone are added. Whilst stirring at 130 rpm the suspension is heated to reflux (55 °C) for 30 min. The suspended solid is thereby completely dissolved. The heating is switched off and the solution is slowly cooled to 18 °C. The precipitated solid is filtered off under suction via a glass frit (G3) and dried for 3 h in the air flow. The solid is further dried at 50°C in a vacuum oven under reduced pressure (p< 2mbar) for 35 h.

    [0061] The dried product (136.6 g) was analyzed and identified to be crystalline form D or compound (1).

    E) Crystalline form E (comparative)


    Example E1



    [0062] Crystalline form can be obtained by drying crystalline form G for 2h at 100°C in ambient atmosphere and pressure (e.g. in an oven).

    Example E2



    [0063] Crystalline form E of compound (1) can be obtained in high purity by reaction compound (1) with fumaric acid to give the corresponding fumarate salt and subsequently reacting the isolated salt with a base to give free compound (1) again.

    71 ethylacetate are charged into a reaction vessel and 1.1 equivalent of fumaric acid (728,5mmol = 84,7g) are added to the solvent. The solvent is heated to 60°C thereby dissolving the fumaric acid to a large degree. One equivalent of compound (1) (336 g) dissolved in 10 I ethylacetate are added stepwise. A white suspension is quickly formed. The reaction mixture is stirred for 90 minutes then the mixture is allowed to cool to ambient temperature and stirred for another 2 days. The precipitated solid is isolated via filtration (G3 glass frit), washed three times with about 700 ethylacetate, dried by applying a strong air flow with the suction pump and then further dried at 40°C in a vacuum oven at a pressure of below 2mbar until no further loss of mass was observed.

    The thus obtained solid (293g) was charged into a reaction vessel together with 8 I distilled water. Whilst stirring at 150 rpm 610 diethylamine are added to the resulting white suspension. Subsequently, 200 of ethanol are added and the reaction mixture is stirred at 24°C for 16h. Then, the solid is isolated from the suspension via filtration (G3 glass frit) and slurryied 4 times in 1 I of water. The resulting solid is dried overnight on a nutsch filter with suction. The resulting white solid was further dried for 2 days in a vacuum oven at 70°C. 250 g of (1) are isolated (74.4%).
    XRPD analysis of the dried solid revealed it to be crystalline form E of compound (1).

    F) Crystalline form F (comparative)



    [0064] Crystalline form F was observed during an experiment in a multi-well plate. Approximately 5 mg of either crystalline forms D or A, or a mixture of crystalline forms D and E were charged into respective wells. 0.25 of a specific solvent were added to each well and the lid of the plate closed. The plate was shaken at 30°C for 16h. Subsequently, the plate was allowed to cool to RT. Upon opening, it was found, that part of the solid had been spread all over the plate. Residual solvent was removed by evaporation from the plate and the solid samples in the respective wells analyzed. The results are listed below in table 7.
    Table 7: Multiwell experiment
     Starting with polymorph D and EStarting with polymorph AStarting with polymorph E
    Acetone F 83* F
    Acetonitrile D 83* D
    Dichloromethane F D 83*
    Ethylacetate F M 75*
    Diethylether M F F
    Hexane F F M
    Methy-ethyl-ketone M F M
    Methanol K K K
    Pentane F F D + peaks
    1-Propanol am** F 77
    2- Propanol am** A F
    Ethanol am** F M
    Tetrahydrofurane am** E + peaks D + peaks
    Toluene M D + peaks am**
    tBME F F M
    Water M D E + peaks
    Acetone/Water F F F
    Acetone/Water_1 F F F
    Acetone/Water_2 M M F
    Tetrahydrofurane/Hexane am** M M
    * numbers denote crystalline forms which were not further characterized
    ** am = amorphous or of poor crystallinity
    "+ peaks" means that additional peaks were found in the XRPD of the solid, which were considered not to belong to the indicated crystalline form.

    G) Crystalline form G (comparative)



    [0065] General procedure for syntheses: See general procedure for syntheses of crystalline form A. In table 8 below, specific reaction conditions for syntheses of crystalline form G are listed.
    Table 8
    Ex.Crystalline form of starting materialAmount [mg]Solvent / amountT [°C]Reaction time [d]
    G1 E 176.4 Ethanol / 15 ml; water / 4.5 ml 50 3
    G3 L 1210 Ethanol / 25 ml 40 0.83 (20h)
    G4 A 1550 Ethanol / 175 ml 75 -->0* 0.65 (15.25h)*
    G5.1 E 106.1 Ethanol 40 0.75
    G5.2 E 115.7 1-Propanol / 2.5ml; Water / 2.5.ml 40 0.75
    * 15min heated to 75°C, cooled to 0°C during 6h, stirred at 0°C for 9h.

    H) Crystalline form H (comparative)



    [0066] General procedure for syntheses: See general procedure for syntheses of crystalline form A. In table 9 below, specific reaction conditions for syntheses of crystalline form H are listed.
    Table 9
    Ex.Crystalline form of starting materialAmount [mg]Solvent / amountT [°C]Reaction time [d]
    H3 E 105.8 2-Propanol / 2.5 40 0.75
    H5 E 103 2-Propanol / 2.5 ml 40 0.75

    Example H1: Interconversion experiments



    [0067] A mixture of two different crystalline forms of compound (1) was charged into a vial and 1.0 mL of 2-Propanol was added (details see table).

    [0068] The vials were closed and the mixtures were stirred (by means of shaking, Eppendorf Thermomixer, 750 rpm at first, increased to 1000 rpm after 1 d) at elevated temperature (30 ±2 °C) for 7 days.

    [0069] Susequently, the mixtures were cooled to 20 ±2 °C and stirred for additional 2 hours. The solids were then isolated via filtration using a suction filter. The air flow from the suction pump was applied for 2 to 3 hours to dry the isolated solid.

    [0070] The results of the experiments are listed below in table 10:
    Table 10
    Ex.Mixture of crystalline forms /[mg]Solvent (1ml)Temperature /°C (time)resulting crystalline form
      23,1 mg E   30 (7d) H
    H1.1 22,6 mg C 2-Propanol 20 (2 h)  
      22,6 mg E   30 (7d) A + H
    H1.2 22,2 mg L 2-Propanol 20 (2 h)  
      23,3 mg E   30 (7d) H
    H1.4 24,2 mg C 2-Propanol 20 (2 h)  
      22,8 mg E   30 (7d) A + H
    H1.5 23,4 mg L 2-Propanol 20 (2 h)  

    I) Crystalline form I (comparative)



    [0071] A sample of crystalline form C (characterized by X-ray diffraction) was stored for up to 4 months, during which, according to X-ray diffraction analysis, the sample converted to Polymorph I in three to four months.

    [0072] It was observed that under the conditions of a variable Temperature x-ray diffraction experiment (STOE diffractometer, radiation CuKα, sample filled in quartz capillary) starting from crystalline form I upon heating in a temperature range from 30°C to 100°C the sample remained crystalline form I until it transformed into crystalline form J at higher temperature in the range from 110°C to 130°C. Upon further heating in a temperature range from 140°C to 160 °C the sample became poorly crystalline to amorphous. The sample remained poorly crystalline to amorphous upon cooling to 20 °C.

    J) Crystalline form J (comparative)



    [0073] 45 mg or 78 mg crystalline form C were stored in a vacuum oven at reduced pressure (10 mbar) at 25°C for 24h, at 41 °C for 24h or at 65°C for 72 h. In all cases crystalline form C transformed into crystalline form J.

    K) Crystalline form K (comparative)


    Example K1



    [0074] 39.6 mg of crystalline form C were stored in a vacuum oven at reduced pressure (5 to 10 mbar) at 50°C for 16h. It was found that crystalline form C had transformed into crystalline form K.

    Example K2



    [0075] 99.5 mg of crystalline form C were stored in a vacuum oven C at reduced pressure (5 to 10 mbar) at 60°C for 16h. It was found that crystalline form C had transformed into crystalline form K.

    L) Crystalline form L (comparative)



    [0076] General procedure for syntheses: See general procedure for syntheses of crystalline form A. In table XXX below, specific reaction conditions for syntheses of crystalline form L are listed.
    Ex.Crystalline form of starting materialAmount [mg]Solvent / amountT [°C]Reaction time
    L1 E 102 Toluene / 2.5 ml 40 16 h
    L2 A 1110 Toluene / 30 ml 40 64 h
    L3 E 101 Toluene / 2.5 ml 40 16 h
    L4 A 83.9 Toluene / 1 ml 30 19 d

    Q) Crystalline form Q (comparative)


    Example Q1



    [0077] Compound (1) (6.6 g) was charged to a 250 mL flask and suspended in toluene p.a. (1.25 moles; 132.00mL; 115.00 g) and vigorously stirred with a magnetic stir bar for 3h at 21 °C. The solid was separated from the solvent by means of a suction filter, washed with 5 mL of toluene and subsequently washed again with another 10 mL of toluene.

    Example Q2



    [0078] 1,08 g of crystalline form A of compound (1) was charged into a vial and 30 mL of toluene p.a. were added. A thick suspension was formed. The vial was closed and the suspension was stirred (by means of shaking, PLS shaker, 400 rpm) at elevated temperature (40°C ±2) for 22 h. The mixture was cooled to 22 ±2 °C and shaken for another 30 min. The solid was separated using a suction filter (G4) and dried by applying the air flow from the suction pump for 10 min. A white fluffy solid was produced.

    1) Transformation of crystalline Q into amorphous material.



    [0079] 31.1 mg of crystalline form Q of compound (1) was charged into a vial and 1,5 mL of an acetone/water mixture (8:2 vol/vol) was added. The vial was closed and the mixture (a suspension) was stirred (by means of shaking, Eppendorf Thermomixer, 1000 rpm) at room temperature (23 ±2 °C) for 7 days.

    [0080] The solid was separated using a suction filter and dried by applying the air flow for an additional 15 minutes. The resulting solid was analyzed (SM1).

    [0081] The solvent from the filtrate was let to evaporate (23 ±2 °C) in a fume hood to give a second solid material (SM2). This was also analyzed.

    [0082] According to XRPD-analyses SM1 is a poorly crystalline material, SM2 amorphous.

    Example S1: Chemical stability of crystalline forms of compound (1)



    [0083] Samples of compound 1 in different crystalline forms were stored in open vials under controlled conditions at different temperatures and rel. humidities for 28 days. Prior to storage and after 14 and 28 days the content of compound (1) in the sample was determined via HPLC and the crystalline form was measured via XRPD.

    [0084] The results of this stability study are listed below in table 12:
    Table 12
    Ex-No.Initial solid formStorage [d]T[°C]Rel. humidity % r.H.Resulting solid formContent cmpd (1) [%]
    S1-A1 A 0 50   A 99,58
    A 14 50   A 99,49
    A 28 50   A 99,37
    S1-A2 A 0 40 75 A 99,58
    A 14 40 75 A 99,63
    A 28 40 75 A 99,39
    S1-B1 B* 0 50   B 84,85
    B* 14 50   B 82,63
    B* 28 50   B 81,26
    S1-B2 B* 0 40 75 B 84,85
    B* 14 40 75 B 84,21
    B* 28 40 75 B 83,74
    S1-C1 C* 0 50   C 99,67
    C* 14 50   P 99,57
    C* 28 50   P 99,20
    S1-C2 C* 0 40 75 C 99,67
    C* 14 40 75 J 99,68
    C* 28 40 75 J 99,44
    S1-D1 D* 0 50   D 84,61
    D* 14 50   D 84,65
    D* 28 50   D 83,54
    S1-D2 D* 0 40 75 D 84,61
    D* 14 40 75 D 84,27
    D* 28 40 75 D 83,92
    S1-E1 E* 0 50   E 99,76
    E* 14 50   E 97,25
    E* 28 50   E 95,53
    S1-E2 E* 0 40 75 E 99,76
    E* 14 40 75 G 99,80
    E* 28 40 75 B 99,50
    * comparative


    [0085] The data shows that the content of compound (1) of crystalline form A in the respective samples remains essentially unchanged after 28 days of open storage at the indicated temperatures and relative humidity.

    [0086] Contrary to this, the other two ansolvate crystalline forms show a higher degree of chemical degradation after 28 days storage at the respective storage conditions, wherein this effect is more pronounced at 50°C with crystalline form E than with D.

    [0087] Of the three ansolvate forms tested, crystalline form A is observed to be the chemically most stable one.

    [0088] Furthermore, it can be seen that crystalline form E transforms into different crystalline forms at 40°C and a relative humidity of 75%. This is a disadvantage of crystalline form E compared to A and D, because it is advantageous that in the formulation of solid dosage forms the pharmaceutical active ingredient retains the same crystalline form. Be it during formulation and storage of the dosage form so that the desired pharmacokinetic properties of the dosage form are achieved after formulation and remain essentially stable over the shelf-life of the dosage form. Crystalline form C shows a comparable chemical stability to crystalline form A, but transforms into other crystalline forms during storage over 28 days at the indicated conditions.

    [0089] Crystalline form B does not transform into different forms but it exhibits a higher degree of chemical degradation in the experiments, i.e. a lower chemical stability compared both to form A and C.

    Example S2: Chemical stability in pharmaceutical compositions



    [0090] To test the chemical stability, i.e. compatibility of different crystalline forms of compound (1), solid multi component mixtures were prepared comprising well established excipients used for solid oral dosage form and having different functions therein. The single components of each mixture were exactly weighed and intensively triturated using a mortar and a pestle.
    Subsequently, 10% (w/w) of compound (1) (either crystalline form A or B) were added to the respective mixtures and triturated using the same method as for preparation of the excipient mixtures.
    10 g of the final mixtures were separately filled into glass vials (open or closed) and stored under the conditions outlined below in table 13. Samples were taken and analyzed initially and after 1, 2 and 3 months with respect to the content of compound (1) within the mixtures.

    [0091] The comparison of the data obtained for the two different crystalline forms demonstrate that chemical degradation of compound (1) occurred to a lesser degree over the duration of storage at higher temperatures (e.g. 50°C) if the compound was present in crystalline form A. Consequently, crystalline form A demonstrates superior properties compared to crystalline form B with respect to chemical degradation, i.e. higher chemical stability, and therefore superior properties for the use in solid dosage forms.
    Table 13
    Examplecrystalline formTstoragehumidityexcipients0 month1 month2 months3 months
    S2-1A A 50°C dry Microcrystalline cellulose HPMC 6 mPas L-HPC LH21 magnesium stearate 99,64 99,59 99,59 99,62
    S2-1B B* 99,75 95,74 91,45 87,34
    S2-2A A 40°C 75% rel. hum. Microcrystalline cellulose HPMC 6 m Pas L-HPC LH21 magnesium stearate 99,64 99,61 99,60 99,66
    S2-2B B* 99,69 99,63 98,57 99,39
    S2-3A A 50°C dry Lactose monohydrate PVP25 Crospovidone Talcum 99,66 99,58 99,54 99,56
    S2-3B B* 99,57 95,82 91,04 85,33
    S2-4A A 40°C 75% rel. hum. Lactose monohydrate PVP25 Crospovidone Talcum 99,66 99,93 99,72 99,86
    S2-4B B* 99,57 99,22 99,05 96,87
    * comparative

    Example X1


    Analysis - XRPD (X-Ray Powder Diffraction) or PXRD (Powder X-Ray Diffraction)



    [0092] 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 CuKα 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 room temperature (i.e. 298 K (± 5 K)).

    [0093] In general a baseline correction of the measured diffractograms was done using the program WinXPow (STOE).

    Crystalline Form A



    [0094] Table 14 shows the peak list for crystalline form A. The uncertainty in the 2θ values is ±0.2° in 2θ; rel. I is the relative intensity of the respective peaks. Maximum relative intensity is 100.




    Crystalline Form B (comparative)



    [0095] Table 15 shows the peak list for crystalline form B. The uncertainty in the 2θ values is ±0.2° in 2θ; rel. I is the relative intensity of the respective peaks. Maximum intensity is 100.
    Table 15
    d value [Å]2θ [°]rel. I [%]
         
    12,9 6,8 40
    12,0 7,3 29
    8,8 10,0 4
    8,6 10,3 10
    7,6 11,6 9
    7,3 12,1 100
    6,8 13,0 15
    6,5 13,7 21
    6,3 14,1 39
    5,7 15,5 30
    5,6 15,8 4
    5,4 16,3 7
    5,3 16,8 11
    5,0 17,6 12
    4,9 18,0 56
    4,8 18,4 52
    4,7 18,7 81
    4,6 19,3 18
    4,5 19,5 14
    4,5 19,8 46
    4,4 20,2 3
    4,3 20,8 38
    4,0 22,1 28
    4,0 22,4 19
    3,9 22,7 9
    3,9 23,0 5
    3,8 23,3 12
    3,7 24,0 2
    3,6 24,4 10
    3,6 25,0 4
    3,5 25,4 12
    3,4 26,2 8
    3,3 26,9 7
    3,3 27,4 3
    3,2 27,8 8
    3,1 28,3 46
    3,1 29,2 5
    3,0 29,5 3
    3,0 29,7 5
    3,0 30,2 2
    2,9 30,8 4
    2,9 31,3 3
    2,8 31,9 4
    2,8 32,3 3
    2,7 33,4 4
    2,6 34,6 2
    2,5 36,4 3
    2,4 36,9 4
    2,4 37,3 4
    2,4 37,6 7
    2,3 39,9 6
    2,2 40,6 4
    2,2 41,3 3
    2,1 42,8 5
    2,0 44,3 3
    2,0 45,0 2
    1,9 48,7 2

    Crystalline Form C (comparative)



    [0096] Table 16 shows the peak list for crystalline form C. The uncertainty in the 2θ values is ±0.2° in 2θ; rel. I is the relative intensity of the respective peaks. Maximum relative intensity is 100.
    Table 16
    d value [Å]2θ [°]rel. I [%]
    12,7 7,0 30
    12,4 7,1 42
    10,7 8,3 6
    9,1 9,7 51
    7,8 11,3 31
    7,6 11,6 55
    7,1 12,5 46
    6,8 13,0 58
    6,3 13,9 60
    6,2 14,3 32
    5,9 15,1 16
    5,8 15,4 19
    5,1 17,5 8
    5,0 17,9 100
    4,5 19,8 6
    4,4 20,3 8
    4,2 21,0 30
    4,2 21,1 29
    4,0 22,2 5
    3,9 22,6 19
    3,9 23,0 13
    3,8 23,4 9
    3,8 23,6 16
    3,7 24,1 19
    3,5 25,1 6
    3,4 26,3 23
    3,3 26,7 8
    3,3 27,0 9
    3,2 27,7 4
    3,2 28,2 3
    3,1 29,2 6
    3,0 29,8 5
    2,9 31,3 4
    2,8 31,7 8
    2,7 33,3 5
    2,4 37,0 7
    2,3 39,7 4
    2,1 42,9 5
    1,9 47,4 4

    Crystalline Form D (comparative)



    [0097] Table 17 shows the peak list for crystalline form D. The uncertainty in the 2θ values is ±0.2° in 2θ; rel. I is the relative intensity of the respective peaks. Maximum relative intensity is 100.
    Table 17
    d value [Å]2θ [°]rel. I [%]
    10,2 8,7 100
    8,0 11,0 15
    7,8 11,3 10
    7,6 11,6 22
    7,1 12,5 10
    6,5 13,7 9
    5,6 15,8 3
    5,4 16,6 27
    5,1 17,2 23
    5,1 17,5 15
    4,9 18,2 11
    4,4 20,0 20
    4,2 20,9 4
    4,2 21,2 24
    4,1 21,7 7
    4,0 22,0 6
    3,9 22,7 10
    3,8 23,2 3
    3,7 23,9 5
    3,6 24,4 4
    3,6 25,0 6
    3,5 25,5 5
    3,4 26,0 4
    3,4 26,3 10
    3,3 27,1 2
    3,3 27,4 2
    3,2 27,7 5
    3,1 28,4 5
    3,1 28,8 6
    3,0 29,5 5
    2,7 33,3 3
    2,7 33,6 3
    2,1 42,4 3
    2,0 46,0 2

    Crystalline Form E (comparative)



    [0098] Table 18 shows the peak list for crystalline form E. The uncertainty in the 2θ values is ±0.2° in 2θ; rel. I is the relative intensity of the respective peaks. Maximum relative intensity is 100.
    Table 18
    d value [Å]2θ [°]rel. I [%]
    12,8 6,9 35
    10,9 8,1 29
    10,2 8,7 4
    9,2 9,6 6
    9,0 9,8 6
    8,5 10,4 18
    8,3 10,6 9
    7,3 12,1 10
    7,0 12,5 8
    6,4 13,8 17
    6,4 13,9 16
    6,2 14,3 7
    5,9 15,1 4
    5,6 15,9 2
    5,4 16,4 12
    5,3 16,6 14
    5,2 16,9 14
    5,0 17,7 6
    5,0 17,9 16
    4,8 18,3 100
    4,8 18,7 10
    4,7 18,8 4
    4,7 19,0 11
    4,6 19,2 6
    4,6 19,4 4
    4,5 19,6 8
    4,4 19,9 8
    4,3 20,8 22
    4,2 21,1 13
    4,1 21,9 3
    4,0 22,2 7
    3,9 22,6 5
    3,9 23,0 6
    3,8 23,7 7
    3,7 24,0 5
    3,6 24,6 3
    3,6 24,9 2
    3,5 25,3 4
    3,4 26,2 4
    3,3 27,2 3
    3,2 27,5 10
    3,2 27,8 9
    3,2 28,1 16
    3,1 29,0 2
    3,0 29,4 2
    2,8 32,3 2
    2,6 34,4 4
    2,5 36,2 1
    2,3 38,6 2
    2,2 40,5 2
    2,1 42,9 2

    Crystalline Form F (comparative)



    [0099] Table 19 shows the peak list for crystalline form F. The uncertainty in the 2θ values is ±0.2° in 2θ; rel. I is the relative intensity of the respective peaks. Maximum relative intensity is 100.
    Table 19
    d value [Å]2θ [°]rel. I [%]
    10,5 8,4 8
    10,2 8,7 38
    9,5 9,3 1
    7,8 11,3 16
    7,1 12,5 100
    6,5 13,6 1
    6,0 14,6 1
    5,6 15,7 1
    5,4 16,6 6
    5,3 16,7 15
    4,9 18,2 4
    4,8 18,4 11
    4,4 19,9 6
    4,2 20,9 47
    4,2 21,1 7
    4,1 21,7 4
    3,9 22,6 6
    3,7 23,9 4
    3,7 24,3 2
    3,5 25,2 14
    3,5 25,5 7
    3,4 25,9 13
    3,4 26,3 10
    3,3 27,1 2
    3,1 28,7 2
    3,0 29,4 5
    2,9 30,5 4
    2,9 31,1 1
    2,8 32,1 1
    2,7 33,2 8
    2,6 34,2 2
    2,6 34,6 1

    Crystalline Form G (comparative)



    [0100] Table 20 shows the peak list for crystalline form G. The uncertainty in the 2θ values is ±0.2° in 2θ; rel. I is the relative intensity of the respective peaks. Maximum relative intensity is 100.
    Table 20
    d value [Å]2θ [°]rel. I [%]
    13,3 6,6 100
    12,6 7,0 12
    11,0 8,0 30
    9,4 9,4 6
    8,5 10,4 11
    7,5 11,8 10
    7,1 12,4 14
    6,6 13,3 16
    6,4 13,9 18
    5,9 15,1 4
    5,7 15,5 11
    5,7 15,6 10
    5,0 17,6 13
    4,9 18,0 59
    4,8 18,4 43
    4,7 18,9 39
    4,6 19,3 27
    4,5 19,7 13
    4,4 19,9 8
    4,4 20,3 5
    4,3 20,6 7
    4,2 21,3 4
    4,1 21,6 5
    3,9 22,5 6
    3,8 23,3 10
    3,6 24,6 5
    3,5 25,3 3
    3,4 26,4 2
    3,3 27,0 8
    3,2 27,4 9
    3,2 27,7 10
    3,1 28,5 4

    Crystalline Form H (comparative)



    [0101] Table 21 shows the peak list for crystalline form H. The uncertainty in the 2θ values is ±0.2° in 2θ; rel. I is the relative intensity of the respective peaks. Maximum relative intensity is 100.




    Crystalline Form I (comparative)



    [0102] Table 22 shows the peak list for crystalline form I. The uncertainty in the 2θ values is ±0.2° in 2θ; rel. I is the relative intensity of the respective peaks. Maximum relative intensity is 100.
    Table 22
    d value [Å] [°]rel. I [%]
    12,5 7,1 99
    9,1 9,7 47
    8,0 11,0 34
    7,5 11,8 78
    7,0 12,7 74
    6,2 14,2 59
    6,1 14,6 51
    5,9 15,1 44
    5,6 15,7 50
    5,4 16,4 31
    5,1 17,5 100
    4,9 17,9 35
    4,7 18,9 32
    4,5 19,6 49
    4,2 21,2 41
    4,1 21,6 41
    3,9 22,9 42
    3,4 26,3 31

    Crystalline Form J (comparative)



    [0103] Table 23 shows the peak list for crystalline form J. The uncertainty in the 2θ values is ±0.2° in 2θ; rel. I is the relative intensity of the respective peaks. Maximum relative intensity is 100.
    Table 23
    d value [Å]2θ [°]rel. I [%]
    12,5 7,1 100
    11,8 7,5 18
    9,7 9,1 43
    7,9 11,1 73
    7,1 12,4 20
    6,1 14,5 73
    5,9 15,0 50
    5,8 15,3 34
    5,4 16,6 51
    5,3 16,8 61
    5,2 17,0 72
    5,0 17,9 29
    4,8 18,4 22
    4,5 19,7 97
    4,3 20,4 70
    4,2 21,3 29
    3,8 23,1 55
    3,5 25,3 21
    3,4 26,1 27
    3,4 26,4 28
    3,2 28,2 24
    3,1 28,8 25
    3,0 30,3 11
    2,6 34,1 13
    2,4 37,0 11
    2,3 39,3 12
    2,1 42,4 11
    2,1 43,9 10

    Crystalline Form K (comparative)



    [0104] Table 24 shows the peak list for crystalline form K. The uncertainty in the 2θ values is ±0.2° in 2θ; rel. I is the relative intensity of the respective peaks. Maximum relative intensity is 100.
    Table 24
    d value [Å]2θ [°]rel. I [%]
    12,4 7,1 100
    8,8 10,0 56
    7,9 11,2 42
    7,0 12,7 17
    6,2 14,3 83
    5,9 15,1 50
    5,8 15,4 53
    5,4 16,4 27
    5,3 16,8 23
    4,6 19,5 76
    4,5 19,9 52
    4,2 21,4 28
    4,0 22,4 21
    3,9 23,0 13
    3,6 24,4 17
    3,3 26,7 27
    3,2 27,7 30
    2,7 33,2 12
    2,4 37,0 11

    Crystalline Form L (comparative)



    [0105] Table 25 shows the peak list for crystalline form L. The uncertainty in the 2θ values is ±0.2° in 2θ; rel. I is the relative intensity of the respective peaks. Maximum relative intensity is 100.




    Crystalline Form Q (comparative)



    [0106] Table 26 shows the peak list for crystalline form Q. The uncertainty in the 2θ values is ±0.2° in 2θ; rel. I is the relative intensity of the respective peaks. Maximum relative intensity is 100.
    Table 26
    D value [Å]2θ [°]rel. I [%]
    10,7 8,2 49
    10,2 8,6 40
    8,1 11,0 23
    7,7 11,5 18
    7,3 12,0 26
    6,1 14,5 7
    5,9 15,0 10
    5,4 16,5 28
    5,2 17,2 100
    5,0 17,6 12
    4,9 18,0 12
    4,4 20,1 19
    4,2 21,3 18
    4,1 21,6 16
    4,0 22,0 13
    3,9 22,6 7
    3,6 24,4 18
    3,6 25,1 10
    3,4 26,0 10
    3,1 28,5 11
    3,1 29,2 5

    Calculated XRPD



    [0107] X-ray powder diffractogram (XRPD) may be calculated from a single crystal diffractogram (SCXRD) measured using MOK□ radiation having a wavelength of 0.71073 A at 100 K (± 5 K) or 130 K (± 5 K)or 230 K (± 5 K). Due to the fact that the SCXRD was determined at 100 K (± 5 K) or 130 K (± 5 K) or at 230 K (± 5 K), the peak positions determined by a XRPD measured at 298 K (± 5 K) may differ because of temperature dependent variations of the lattice parameters of the unit cell. Therefore, the uncertainty in the 2θ values is ±1.0°, preferably ±0.9°, more preferably ±0.8°, even more preferably ±0.7°, still more preferably ±0.6°, yet more preferably ±0.5°, still yet more preferably ±0.4°, particularly ±0.3°, most preferably ±0.2°, in 2θ.

    SCXRD (Sinale Crystal X-ray Diffraction)


    Polymorph A (measure at low temperature)



    [0108] SCXRD analyses of crystalline forms A was carried out with a Bruker D8-goniometer with SMART APEX CCD area detector at 100 K (± 5 K) using MoKα radiation (wavelength of 0.71073 Å, Incoatec microsource, multilayer optics).
    Table 27. Crystal data and structure refinement for ansolvat_lt.
    Empirical formula C33 H34 F N3 O
    Formula weight 507.63
    Temperature 100(2) K
    Wavelength .71073 A
    Crystal system Monoclinic
    Space group P 21/c
    Unit cell dimensions a = 12.1568(7) A alpha = 90 deg.
      b = 21.6289(12) A beta = 113.3610(10) deg
      c = 10.9424(6) A gamma = 90 deg.
    Volume 2641.3(3) A^3
    Z 4
    Density (calculated) 1.277 Mg/m^3
    Absorption coefficient 0.082 mm^-1
    F(000) 1080
    Crystal size 0.45 x 0.21 x 0.08 mm
    Theta range for data collection 1.82 to 28.30 deg.
    Index ranges -15<=h<=16, -27<=k<=28, -14<=l<=14
    Reflections collected 30878
    Independent reflections 6534 [R(int) = 0.0477]
    Absorption correction None
    Refinement method Full-matrix least-squares on F^2
    Data / restraints / parameters 6534/0/346
    Goodness-of-fit on F^2 1.000
    Final R indices [I>2sigma(I)] R1 = 0.0497, wR2 = 0.1281
    R indices (all data) R1 = 0.0643, wR2 = 0.1405
    Largest diff. peak and hole .496 and -.260 e.A^-3
    Table 28.
    Atomic coordinates (x 10^4) and equivalent isotropic displacement parameters (□^2 x 10^3). U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
     xyzU (eq)
    F (1) -1204 (1) 86 (1) 877 (1) 37 (1)
    O (1) 5159 (1) 2358 (1) 3238 (1) 21 (1)
    N (1) 496 (1) 2509 (1) 936 (1) 20 (1)
    N (2) 4304 (1) 1813 (1) 1278 (1) 17 (1)
    N (3) 4431 (1) 322 (1) 3012 (1) 18 (1)
    C (1) -626 (1) 567 (1) 1675 (2) 23 (1)
    C (2) -32 (1) 976 (1) 1184 (2) 20 (1)
    C (3) 611 (1) 1466 (1) 1983 (1) 18 (1)
    C (4) 1255 (1) 1945 (1) 1456 (1) 17 (1)
    C (5) -720 (1) 2372 (1) -34 (2) 25 (1)
    C (6) 389 (2) 2911 (1) 1959 (2) 23 (1)
    C (7) 1548 (1) 1693 (1) 300 (1) 18 (1)
    C (8) 2454 (1) 1166 (1) 685 (1) 18 (1)
    C (9) 3675 (1) 1347 (1) 1802 (1) 17 (1)
    C (10) 5036 (1) 2266 (1) 2081 (1) 16 (1)
    C (11) 5663 (1) 2682 (1) 1476 (1) 18 (1)
    C (12) 6456 (1) 3089 (1) 2250 (1) 19 (1)
    C (13) 7072 (1) 3566 (1) 1805 (2) 20 (1)
    C (14) 7665 (1) 4040 (1) 2684 (2) 26 (1)
    C (15) 8186 (2) 4527 (1) 2275 (2) 33 (1)
    C (16) 8115 (2) 4547 (1) 980 (2) 34 (1)
    C (17) 7544 (1) 4073 (1) 99 (2) 29 (1)
    C (18) 7032 (1) 3584 (1) 506 (2) 23 (1)
    C (19) 4616 (1) 1555 (1) 200 (1) 21 (1)
    C (20) 5609 (1) 1070 (1) 749 (2) 23 (1)
    C (21) 5339 (1) 652 (1) 1693 (1) 19 (1)
    C (22) 4483 (1) 790 (1) 2172 (1) 18 (1)
    C (23) 5276 (1) -121 (1) 3095 (1) 18 (1)
    C (24) 5862 (1) 74 (1) 2273 (1) 19 (1)
    C (25) 6781 (1) -296 (1) 2196 (2) 22 (1)
    C (26) 7101 (1) -831 (1) 2948 (2) 26 (1)
    C (27) 6502 (1) -1016 (1) 3749 (2) 25 (1)
    C (28) 5576 (1) -666 (1) 3830 (2) 22 (1)
    C (29) 3343 (1) 1574 (1) 2947 (1) 17 (1)
    C (30) 2476 (1) 2124 (1) 2558 (1) 17 (1)
    C (31) 607 (1) 1519 (1) 3261 (1) 20 (1)
    C (32) -3 (1) 1097 (1) 3720 (2) 23 (1)
    C (33) -630 (1) 608 (1) 2927 (2) 25 (1)
    Table 29. Bond lengths [A] and angles [deg]
    F(1)-C(1) 1.3620(18) C(20)-C(21) 1.503(2)
    O(1)-C(10) 1.2307(17) C(20)-H(20A) .9900
    N(1)-C(6) 1.4639(19) C(20)-H(20B) .9900
    N(1)-C(5) 1.4685(19) C(21)-C(22) 1.371(2)
    N(1)-C(4) 1.4991(18) C(21)-C(24) 1.432(2)
    N(2)-C(10) 1.3785(18) C(23)-C(28) 1.393(2)
    N(2)-C(19) 1.4855(18) C(23)-C(24) 1.415(2)
    N(2)-C(9) 1.5091(17) C(24)-C(25) 1.403(2)
    N(3)-C(23) 1.3802(18) C(25)-C(26) 1.385(2)
    N(3)-C(22) 1.3856(18) C(25)-H(25) .9500
    N(3)-H(3N) .8663 C(26)-C(27) 1.401(2)
    C(1)-C(33) 1.375(2) C(26)-H(26) .9500
    C(1)-C(2) 1.378(2) C(27)-C(28) 1.388(2)
    C(2)-C(3) 1.398(2) C(27)-H(27) .9500
    C(2)-H(2) .9500 C(28)-H(28) .9500
    C(3)-C(31) 1.405(2) C(29)-C(30) 1.533(2)
    C(3)-C(4) 1.542(2) C(29)-H(29A) .9900
    C(4)-C(7) 1.5436(19) C(29)-H(29B) .9900
    C(4)-C(30) 1.5447(19) C(30)-H(30A) .9900
    C(5)-H(5A) .9800 C(30)-H(30B) .9900
    C(5)-H(5B) .9800 C(31)-C(32) 1.389(2)
    C(5)-H(5C) .9800 C(31)-H(31) .9500
    C(6)-H(6A) .9800 C(32)-C(33) 1.388(2)
    C(6)-H(6B) .9800 C(32)-H(32) .9500
    C(6)-H(6C) .9800 C(33)-H(33) .9500
    C(7)-C(8) 1.523(2)    
    C(7)-H(7A) .9900 C(6)-N(1)-C(5) 107.70(12)
    C(7)-H(7B) .9900 C(6)-N(1)-C(4) 114.92(11)
    C(8)-C(9) 1.5518(19) C(5)-N(1)-C(4) 113.68(12)
    C(8)-H(8A) .9900 C(10)-N(2)-C(19) 117.99(11)
    C(8)-H(8B) .9900 C(10)-N(2)-C(9) 121.96(11)
    C(9)-C(22) 1.506(2) C(19)-N(2)-C(9) 112.14(11)
    C(9)-C(29) 1.5408(19) C(23)-N(3)-C(22) 108.75(12)
    C(10)-C(11) 1.4938(19) C(23)-N(3)-H(3N) 120.3
    C(11)-C(12) 1.332(2) C(22)-N(3)-H(3N) 130.5
    C(11)-H(11) .9500 F(1)-C(1)-C(33) 118.92(14)
    C(12)-C(13) 1.466(2) F(1)-C(1)-C(2) 117.24(14)
    C(12)-H(12) .9500 C(33)-C(1)-C(2) 123.80(14)
    C(13)-C(14) 1.396(2) C(1)-C(2)-C(3) 119.46(14)
    C(13)-C(18) 1.403(2) C(1)-C(2)-H(2) 120.3
    C(14)-C(15) 1.391(2) C(3)-C(2)-H(2) 120.3
    C(14)-H(14) .9500 C(2)-C(3)-C(31) 117.55(13)
    C(15)-C(16) 1.386(3) C(2)-C(3)-C(4) 121.08(13)
    C(15)-H(15) .9500 C(31)-C(3)-C(4) 121.32(13)
    C(16)-C(17) 1.389(3) N(1)-C(4)-C(7) 106.48(11)
    C(16)-H(16) .9500 N(1)-C(4)-C(3) 111.21(11)
    C(17)-C(18) 1.388(2) C(7)-C(4)-C(3) 112.67(12)
    C(17)-H(17) .9500 N(1)-C(4)-C(30) 110.43(11)
    C(18)-H(18) .9500 C(7)-C(4)-C(30) 105.39(11)
    C(19)-C(20) 1.531(2) C(3)-C(4)-C(30) 110.44(11)
    C(19)-H(19A) .9900 N(1)-C(5)-H(5A) 109.5
    C(19)-H(19B) .9900 N(1)-C(5)-H(5B) 109.5
    H(5A)-C(5)-H(5B) 109.5 N(2)-C(19)-H(19A) 109.5
    N(1)-C(5)-H(5C) 109.5 C(20)-C(19)-H(19A) 109.5
    H(5A)-C(5)-H(5C) 109.5 N(2)-C(19)-H(19B) 109.5
    H(5B)-C(5)-H(5C) 109.5 C(20)-C(19)-H(19B) 109.5
    N(1)-C(6)-H(6A) 109.5 H(19A)-C(19)-H(19B) 108.1
    N(1)-C(6)-H(6B) 109.5 C(21)-C(20)-C(19) 109.17(12)
    H(6A)-C(6)-H(6B) 109.5 C(21)-C(20)-H(20A) 109.8
    N(1)-C(6)-H(6C) 109.5 C(19)-C(20)-H(20A) 109.8
    H(6A)-C(6)-H(6C) 109.5 C(21)-C(20)-H(20B) 109.8
    H(6B)-C(6)-H(6C) 109.5 C(19)-C(20)-H(20B) 109.8
    C(8)-C(7)-C(4) 114.44(12) H(20A)-C(20)-H(20B) 108.3
    C(8)-C(7)-H(7A) 108.7 C(22)-C(21)-C(24) 106.88(13)
    C(4)-C(7)-H(7A) 108.7 C(22)-C(21)-C(20) 122.57(14)
    C(8)-C(7)-H(7B) 108.7 C(24)-C(21)-C(20) 130.55(13)
    C(4)-C(7)-H(7B) 108.7 C(21)-C(22)-N(3) 109.70(13)
    H(7A)-C(7)-H(7B) 107.6 C(21)-C(22)-C(9) 125.74(13)
    C(7)-C(8)-C(9) 112.98(12) N(3)-C(22)-C(9) 124.51(12)
    C(7)-C(8)-H(8A) 109.0 N(3)-C(23)-C(28) 130.03(13)
    C(9)-C(8)-H(8A) 109.0 N(3)-C(23)-C(24) 107.51(13)
    C(7)-C(8)-H(8B) 109.0 C(28)-C(23)-C(24) 122.45(14)
    C(9)-C(8)-H(8B) 109.0 C(25)-C(24)-C(23) 118.81(14)
    H(8A)-C(8)-H(8B) 107.8 C(25)-C(24)-C(21) 134.01(14)
    C(22)-C(9)-N(2) 105.22(11) C(23)-C(24)-C(21) 107.16(13)
    C(22)-C(9)-C(29) 112.91(12) C(26)-C(25)-C(24) 118.90(14)
    N(2)-C(9)-C(29) 115.53(11) C(26)-C(25)-H(25) 120.5
    C(22)-C(9)-C(8) 109.16(11) C(24)-C(25)-H(25) 120.5
    N(2)-C(9)-C(8) 109.87(11) C(25)-C(26)-C(27) 121.20(14)
    C(29)-C(9)-C(8) 104.10(11) C(25)-C(26)-H(26) 119.4
    O(1)-C(10)-N(2) 123.67(13) C(27)-C(26)-H(26) 119.4
    O(1)-C(10)-C(11) 118.88(13) C(28)-C(27)-C(26) 121.30(15)
    N(2)-C(10)-C(11) 117.37(12) C(28)-C(27)-H(27) 119.4
    C(12)-C(11)-C(10) 118.96(13) C(26)-C(27)-H(27) 119.4
    C(12)-C(11)-H(11) 120.5 C(27)-C(28)-C(23) 117.31(14)
    C(10)-C(11)-H(11) 120.5 C(27)-C(28)-H(28) 121.3
    C(11)-C(12)-C(13) 126.15(14) C(23)-C(28)-H(28) 121.3
    C(11)-C(12)-H(12) 116.9 C(30)-C(29)-C(9) 113.19(11)
    C(13)-C(12)-H(12) 116.9 C(30)-C(29)-H(29A) 108.9
    C(14)-C(13)-C(18) 118.60(14) C(9)-C(29)-H(29A) 108.9
    C(14)-C(13)-C(12) 118.72(14) C(30)-C(29)-H(29B) 108.9
    C(18)-C(13)-C(12) 122.58(13) C(9)-C(29)-H(29B) 108.9
    C(15)-C(14)-C(13) 120.71(16) H(29A)-C(29)-H(29B) 107.8
    C(15)-C(14)-H(14) 119.6 C(29)-C(30)-C(4) 111.40(11)
    C(13)-C(14)-H(14) 119.6 C(29)-C(30)-H(30A) 109.3
    C(16)-C(15)-C(14) 120.09(16) C(4)-C(30)-H(30A) 109.3
    C(16)-C(15)-H(15) 120.0 C(29)-C(30)-H(30B) 109.3
    C(14)-C(15)-H(15) 120.0 C(4)-C(30)-H(30B) 109.3
    C(17)-C(16)-C(15) 119.86(16) H(30A)-C(30)-H(30B) 108.0
    C(17)-C(16)-H(16) 120.1 C(32)-C(31)-C(3) 121.30(14)
    C(15)-C(16)-H(16) 120.1 C(32)-C(31)-H(31) 119.4
    C(18)-C(17)-C(16) 120.27(16) C(3)-C(31)-H(31) 119.4
    C(18)-C(17)-H(17) 119.9 C(33)-C(32)-C(31) 120.89(14)
    C(16)-C(17)-H(17) 119.9 C(33)-C(32)-H(32) 119.6
    C(17)-C(18)-C(13) 120.45(15) C(31)-C(32)-H(32) 119.6
    C(17)-C(18)-H(18) 119.8 C(1)-C(33)-C(32) 117.00(14)
    C(13)-C(18)-H(18) 119.8 C(1)-C(33)-H(33) 121.5
    N(2)-C(19)-C(20) 110.87(12) C(32)-C(33)-H(33) 121.5
    Table 30. Hydrogen coordinates (x 10^4) and isotropic displacement parameters (□^2 x 10^3).
     xyzU (eq)
    H (2) -60 926 310 24
    H (5A) -1181 2177 421 37
    H (5B) -677 2090 -715 37
    H (5C) -1115 2756 -457 37
    H (6A) -79 3279 1538 35
    H (6B) 1189 3037 2583 35
    H (6C) -15 2687 2441 35
    H (7A) 797 1547 -415 22
    H (7B) 1863 2036 -67 22
    H (8A) 2589 1034 -111 22
    H (8B) 2118 810 989 22
    H (11) 5498 2658 552 21
    H (12) 6640 3068 3177 23
    H (14) 7712 4031 3572 31
    H (15) 8592 4846 2884 40
    H (16) 8456 4884 695 40
    H (17) 7504 4084 -786 35
    H (18) 6652 3259 -98 27
    H (19A) 4886 1892 -227 25
    H (19B) 3896 1363 -487 25
    H (20A) 5657 824 9 28
    H (20B) 6391 1277 1221 28
    H (25) 7177 -180 1636 27
    H (26) 7737 -1078 2921 31
    H (27) 6734 -1389 4247 29
    H (28) 5164 -794 4365 26
    H (29A) 2973 1228 3242 20
    H (29B) 4085 1695 3709 20
    H (30A) 2832 2467 2239 21
    H (30B) 2352 2270 3351 21
    H (31) 1030 1850 3822 24
    H (32) 9 1144 4588 27
    H (33) -1043 315 3236 30
    H (3N) 4032 297 3514 39(6)
    Table 31. Anisotropic displacement parameters (□^2 x 10^3). The anisotropic displacement factor exponent takes the form: -2 pi^2 [h^2 a*^2 U11 + ... + 2 h k a* b* U12 ]
     U11U22U33U23U13U12
    F (1) 42 (1) 36 (1) 39 (1) -16 (1) 23 (1) -22 (1)
    O (1) 26 (1) 23 (1) 16 (1) -3 (1) 10 (1) -6 (1)
    N (1) 22 (1) 19 (1) 18 (1) 1 (1) 7 (1) 0 (1)
    N (2) 21 (1) 17 (1) 15 (1) -1 (1) 10 (1) -4 (1)
    N (3) 20 (1) 19 (1) 20 (1) 1 (1) 12 (1) 0(1)
    C (1) 22 (1) 21 (1) 28 (1) -6 (1) 11 (1) -5 (1)
    C (2) 20 (1) 23 (1) 19 (1) -2 (1) 8 (1) -1 (1)
    C (3) 16 (1) 18 (1) 18 (1) 1 (1) 6 (1) 1 (1)
    C (4) 19 (1) 17 (1) 15 (1) 0 (1) 7 (1) 0 (1)
    C (5) 22 (1) 27 (1) 23 (1) 2 (1) 6 (1) 2 (1)
    C (6) 28 (1) 19 (1) 23 (1) 0 (1) 11 (1) 2 (1)
    C (7) 20 (1) 21 (1) 14 (1) -1 (1) 7 (1) -2 (1)
    C (8) 21 (1) 19 (1) 16 (1) -4 (1) 8 (1) -4 (1)
    C (9) 21 (1) 15 (1) 16 (1) -1 (1) 9 (1) -3 (1)
    C (10) 17 (1) 15 (1) 15 (1) 0 (1) 6 (1) 0 (1)
    C (11) 20 (1) 17 (1) 16 (1) 1 (1) 7 (1) -1 (1)
    C (12) 20 (1) 20 (1) 18 (1) 2 (1) 7 (1) 0 (1)
    C (13) 16 (1) 18 (1) 24 (1) 2 (1) 6 (1) 0 (1)
    C (14) 23 (1) 24 (1) 31 (1) -3 (1) 10 (1) -4 (1)
    C (15) 26 (1) 21 (1) 51 (1) -4 (1) 14 (1) -5 (1)
    C (16) 26 (1) 24 (1) 51 (1) 11 (1) 17 (1) -3 (1)
    C (17) 21 (1) 33 (1) 32 (1) 13 (1) 10 (1) 1 (1)
    C (18) 19 (1) 25 (1) 22 (1) 3 (1) 6 (1) -2 (1)
    C (19) 30 (1) 22 (1) 16 (1) -4 (1) 13 (1) -7 (1)
    C (20) 28 (1) 23 (1) 24 (1) -5 (1) 17 (1) -6 (1)
    C (21) 20 (1) 19 (1) 19 (1) -6 (1) 10 (1) -5 (1)
    C (22) 20 (1) 17 (1) 18 (1) -2 (1) 9 (1) -4 (1)
    C (23) 17 (1) 19 (1) 19 (1) -5 (1) 7 (1) -3 (1)
    C (24) 18 (1) 20 (1) 20 (1) -7 (1) 8 (1) -5 (1)
    C (25) 19 (1) 25 (1) 25 (1) -10 (1) 10 (1) -4 (1)
    C (26) 20 (1) 27 (1) 28 (1) -10 (1) 7 (1) 1 (1)
    C (27) 26 (1) 19 (1) 24 (1) -3 (1) 5 (1) 2 (1)
    C (28) 22 (1) 21 (1) 21 (1) -3 (1) 8 (1) -2 (1)
    C (29) 19 (1) 19 (1) 14 (1) -1 (1) 8 (1) -3 (1)
    C (30) 19 (1) 18 (1) 15 (1) -2 (1) 7 (1) -2 (1)
    C (31) 21 (1) 22 (1) 17 (1) -1 (1) 7 (1) -1 (1)
    C (32) 23 (1) 26 (1) 21 (1) 1 (1) 11 (1) -1 (1)
    C (33) 24 (1) 25 (1) 29 (1) 1 (1) 14 (1) -4 (1)

    Example X2


    Polymorph A (measured at high temperature)


    SCXRD (Single Crystal X-ray Diffraction)



    [0109] SCXRD analyses of crystalline forms A was carried out with a Bruker D8-goniometer with SMART APEX CCD area detector at 230 K (± 5 K) using MoKα radiation (wavelength of 0.71073 Å, Incoatec microsource, multilayer optics).
    Table 32. Crystal data and structure refinement
    Empirical formula C33 H34 F N3 O
    Formula weight 507.63
    Temperature 230(2) K
    Wavelength .71073 A
    Crystal system Monoclinic
    Space group P 21/c
    Unit cell dimensions a = 12.2651(9) A alpha = 90 deg.
    b = 21.6265(16) A beta = 112.395(2) deg.
    c = 10.9590(8) A gamma = 90 deg.
    Volume 2687.6(3) A^3
    Z 4
    Density (calculated) 1.255 Mg/m^3
    Absorption coefficient 0.081 mm^-1
    F(000) 1080
    Crystal size 0.45 x 0.21 x 0.08 mm
    Theta range for data collection 1.80 to 28.27 deg.
    Index ranges -16<=h<=15, -27<=k<=28, -14<=l<=14
    Reflections collected 31943
    Independent reflections 6654 [R(int) = 0.1802]
    Absorption correction None
    Refinement method Full-matrix least-squares on F^2
    Data / restraints / parameters 6654/0/346
    Goodness-of-fit on F^2 0.946
    Final R indices [I>2sigma(I)] R1 = 0.0625, wR2 = 0.1445
    R indices (all data) R1 = 0.1004, wR2 = 0.1600
    Largest diff. peak and hole 0.323 and -0.319 e.A^-3
    Table 33. Atomic coordinates (x 10^4) and equivalent isotropic displacement parameters (□^2 x 10^3). U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
     xyzU (eq)
    F (1) -1154 (1) 73 (1) 906 (1) 80 (1)
    O (1) 5140 (1) 2339 (1) 3240 (1) 46 (1)
    N (1) 523 (1) 2490 (1) 956 (1) 44 (1)
    N (2) 4294 (1) 1814 (1) 1283 (1) 36 (1)
    N (3) 4436 (1) 321 (1) 3004 (1) 39 (1)
    C (1) -587 (2) 552 (1) 1706 (2) 49 (1)
    C (2) 4 (2) 961 (1) 1214 (2) 44 (1)
    C (3) 631 (2) 1448 (1) 1996 (2) 37 (1)
    C (4) 1271 (2) 1926 (1) 1468 (2) 38 (1)
    C (5) -666 (2) 2354 (1) -17 (2) 57 (1)
    C (6) 404 (2) 2894 (1) 1960 (2) 54 (1)
    C (7) 1583 (2) 1676 (1) 328 (2) 40 (1)
    C (8) 2481(2) 1157 (1) 705 (2) 39 (1)
    C (9) 3674 (2) 1343 (1) 1810 (2) 35 (1)
    C (10) 5019 (2) 2259 (1) 2092 (2) 34 (1)
    C (11) 5639 (2) 2682 (1) 1497 (2) 37 (1)
    C (12) 6430 (2) 3075 (1) 2249 (2) 40 (1)
    C (13) 7046 (2) 3554 (1) 1808 (2) 41 (1)
    C (14) 7639 (2) 4016 (1) 2688 (2) 54 (1)
    C (15) 8160 (2) 4500 (1) 2280 (3) 69 (1)
    C (16) 8091 (2) 4533 (1) 1016 (3) 73 (1)
    C (17) 7520 (2) 4072 (1) 132 (2) 64 (1)
    C (18) 7009 (2) 3583 (1) 532 (2) 50 (1)
    C (19) 4608 (2) 1562 (1) 205 (2) 45 (1)
    C (20) 5583 (2) 1082 (1) 734 (2) 49 (1)
    C (21) 5331 (2) 661 (1) 1678 (2) 40 (1)
    C (22) 4476 (2) 790 (1) 2163 (2) 37 (1)
    C (23) 5283 (2) -116 (1) 3077 (2) 39 (1)
    C (24) 5850 (2) 88 (1) 2250 (2) 40 (1)
    C (25) 6770 (2) -276 (1) 2165 (2) 48 (1)
    C (26) 7086 (2) -810 (1) 2904 (2) 55 (1)
    C (27) 6504 (2) -1002 (1) 3707 (2) 54 (1)
    C (28) 5592 (2) -658 (1) 3807 (2) 46 (1)
    C (29) 3323 (2) 1567 (1) 2941 (2) 37 (1)
    C (30) 2460 (2) 2108 (1) 2552 (2) 38 (1)
    C (31) 614 (2) 1497 (1) 3259 (2) 43 (1)
    C (32) 6 (2) 1079 (1) 3721 (2) 50 (1)
    C (33) - 606 (2) 594 (1) 2931 (2) 54 (1)
    Table 34. Bond lengths [A] and angles [deg].
    F(1)-C(1) 1.365(2) C(19)-H(19B) .9800
    O(1)-C(10) 1.2214(18) C(20)-C(21) 1.497(3)
    N(1)-C(6) 1.455(2) C(20)-H(20A) .9800
    N(1)-C(5) 1.472(2) C(20)-H(20B) .9800
    N(1)-C(4) 1.502(2) C(21)-C(22) 1.372(2)
    N(2)-C(10) 1.379(2) C(21)-C(24) 1.425(3)
    N(2)-C(19) 1.479(2) C(23)-C(28) 1.387(3)
    N(2)-C(9) 1.512(2) C(23)-C(24) 1.408(3)
    N(3)-C(22) 1.383(2) C(24)-C(25) 1.406(3)
    N(3)-C(23) 1.385(2) C(25)-C(26) 1.378(3)
    N(3)-H(3N) .8609 C(25)-H(25) .9400
    C(1)-C(33) 1.355(3) C(26)-C(27) 1.392(3)
    C(1)-C(2) 1.377(3) C(26)-H(26) .9400
    C(2)-C(3) 1.391(3) C(27)-C(28) 1.383(3)
    C(2)-H(2) .9400 C(27)-H(27) .9400
    C(3)-C(31) 1.396(2) C(28)-H(28) .9400
    C(3)-C(4) 1.537(3) C(29)-C(30) 1.527(3)
    C(4)-C(7) 1.537(2) C(29)-H(29A) .9800
    C(4)-C(30) 1.540(2) C(29)-H(29B) .9800
    C(5)-H(5A) .9700 C(30)-H(30A) .9800
    C(5)-H(5B) .9700 C(30)-H(30B) .9800
    C(5)-H(5C) .9700 C(31)-C(32) 1.384(3)
    C(6)-H(6A) .9700 C(31)-H(31) .9400
    C(6)-H(6B) .9700 C(32)-C(33) 1.385(3)
    C(6)-H(6C) .9700 C(32)-H(32) .9400
    C(7)-C(8) 1.515(3) C(33)-H(33) .9400
    C(7)-H(7A) .9800    
    C(7)-H(7B) .9800 C(6)-N(1)-C(5) 108.11(16)
    C(8)-C(9) 1.556(2) C(6)-N(1)-C(4) 115.41(14)
    C(8)-H(8A) .9800 C(5)-N(1)-C(4) 113.77(16)
    C(8)-H(8B) .9800 C(10)-N(2)-C(19) 118.05(15)
    C(9)-C(22) 1.502(3) C(10)-N(2)-C(9) 121.32(13)
    C(9)-C(29) 1.538(2) C(19)-N(2)-C(9) 112.20(14)
    C(10)-C(11) 1.490(2) C(22)-N(3)-C(23) 108.89(15)
    C(11)-C(12) 1.316(2) C(22)-N(3)-H(3N) 132.3
    C(11)-H(11) .9400 C(23)-N(3)-H(3N) 118.4
    C(12)-C(13) 1.469(3) C(33)-C(1)-F(1) 119.36(19)
    C(12)-H(12) .9400 C(33)-C(1)-C(2) 123.77(19)
    C(13)-C(18) 1.383(3) F(1)-C(1)-C(2) 116.85(17)
    C(13)-C(14) 1.387(3) C(1)-C(2)-C(3) 119.68(18)
    C(14)-C(15) 1.387(3) C(1)-C(2)-H(2) 120.2
    C(14)-H(14) .9400 C(3)-C(2)-H(2) 120.2
    C(15)-C(16) 1.357(3) C(2)-C(3)-C(31) 117.03(17)
    C(15)-H(15) .9400 C(2)-C(3)-C(4) 121.23(16)
    C(16)-C(17) 1.381(3) C(31)-C(3)-C(4) 121.69(16)
    C(16)-H(16) .9400 N(1)-C(4)-C(7) 106.69(14)
    C(17)-C(18) 1.383(3) N(1)-C(4)-C(3) 111.08(15)
    C(17)-H(17) .9400 C(7)-C(4)-C(3) 113.06(15)
    C(18)-H(18) .9400 N(1)-C(4)-C(30) 110.08(15)
    C(19)-C(20) 1.521(3) C(7)-C(4)-C(30) 105.17(15)
    C(19)-H(19A) .9800 C(3)-C(4)-C(30) 110.54(14)
    N(1)-C(5)-H(5A) 109.5 C(13)-C(18)-H(18) 119.6
    N(1)-C(5)-H(5B) 109.5 N(2)-C(19)-C(20) 110.73(15)
    H(5A)-C(5)-H(5B) 109.5 N(2)-C(19)-H(19A) 109.5
    N(1)-C(5)-H(5C) 109.5 C(20)-C(19)-H(19A) 109.5
    H(5A)-C(5)-H(5C) 109.5 N(2)-C(19)-H(19B) 109.5
    H(5B)-C(5)-H(5C) 109.5 C(20)-C(19)-H(19B) 109.5
    N(1)-C(6)-H(6A) 109.5 H(19A)-C(19)-H(19B) 108.1
    N(1)-C(6)-H(6B) 109.5 C(21)-C(20)-C(19) 109.80(16)
    H(6A)-C(6)-H(6B) 109.5 C(21)-C(20)-H(20A) 109.7
    N(1)-C(6)-H(6C) 109.5 C(19)-C(20)-H(20A) 109.7
    H(6A)-C(6)-H(6C) 109.5 C(21)-C(20)-H(20B) 109.7
    H(6B)-C(6)-H(6C) 109.5 C(19)-C(20)-H(20B) 109.7
    C(8)-C(7)-C(4) 114.70(15) H(20A)-C(20)-H(20B) 108.2
    C(8)-C(7)-H(7A) 108.6 C(22)-C(21)-C(24) 106.63(16)
    C(4)-C(7)-H(7A) 108.6 C(22)-C(21)-C(20) 122.25(19)
    C(8)-C(7)-H(7B) 108.6 C(24)-C(21)-C(20) 131.12(17)
    C(4)-C(7)-H(7B) 108.6 C(21)-C(22)-N(3) 109.58(17)
    H(7A)-C(7)-H(7B) 107.6 C(21)-C(22)-C(9) 125.71(17)
    C(7)-C(8)-C(9) 113.05(15) N(3)-C(22)-C(9) 124.67(16)
    C(7)-C(8)-H(8A) 109.0 N(3)-C(23)-C(28) 130.15(17)
    C(9)-C(8)-H(8A) 109.0 N(3)-C(23)-C(24) 106.96(17)
    C(7)-C(8)-H(8B) 109.0 C(28)-C(23)-C(24) 122.88(18)
    C(9)-C(8)-H(8B) 109.0 C(25)-C(24)-C(23) 118.18(19)
    H(8A)-C(8)-H(8B) 107.8 C(25)-C(24)-C(21) 133.87(18)
    C(22)-C(9)-N(2) 105.07(14) C(23)-C(24)-C(21) 107.94(16)
    C(22)-C(9)-C(29) 113.57(14) C(26)-C(25)-C(24) 118.92(19)
    N(2)-C(9)-C(29) 115.57(14) C(26)-C(25)-H(25) 120.5
    C(22)-C(9)-C(8) 108.97(15) C(24)-C(25)-H(25) 120.5
    N(2)-C(9)-C(8) 109.74(13) C(25)-C(26)-C(27) 121.6(2)
    C(29)-C(9)-C(8) 103.86(14) C(25)-C(26)-H(26) 119.2
    O(1)-C(10)-N(2) 123.79(16) C(27)-C(26)-H(26) 119.2
    O(1)-C(10)-C(11) 118.84(16) C(28)-C(27)-C(26) 120.9(2)
    N(2)-C(10)-C(11) 117.30(14) C(28)-C(27)-H(27) 119.5
    C(12)-C(11)-C(10) 120.00(16) C(26)-C(27)-H(27) 119.5
    C(12)-C(11)-H(11) 120.0 C(27)-C(28)-C(23) 117.43(19)
    C(10)-C(11)-H(11) 120.0 C(27)-C(28)-H(28) 121.3
    C(11)-C(12)-C(13) 126.77(17) C(23)-C(28)-H(28) 121.3
    C(11)-C(12)-H(12) 116.6 C(30)-C(29)-C(9) 113.18(14)
    C(13)-C(12)-H(12) 116.6 C(30)-C(29)-H(29A) 108.9
    C(18)-C(13)-C(14) 118.47(19) C(9)-C(29)-H(29A) 108.9
    C(18)-C(13)-C(12) 122.80(17) C(30)-C(29)-H(29B) 108.9
    C(14)-C(13)-C(12) 118.64(18) C(9)-C(29)-H(29B) 108.9
    C(15)-C(14)-C(13) 120.3(2) H(29A)-C(29)-H(29B) 107.8
    C(15)-C(14)-H(14) 119.9 C(29)-C(30)-C(4) 111.75(15)
    C(13)-C(14)-H(14) 119.9 C(29)-C(30)-H(30A) 109.3
    C(16)-C(15)-C(14) 120.7(2) C(4)-C(30)-H(30A) 109.3
    C(16)-C(15)-H(15) 119.6 C(29)-C(30)-H(30B) 109.3
    C(14)-C(15)-H(15) 119.6 C(4)-C(30)-H(30B) 109.3
    C(15)-C(16)-C(17) 119.8(2) H(30A)-C(30)-H(30B) 107.9
    C(15)-C(16)-H(16) 120.1 C(32)-C(31)-C(3)  
    C(17)-C(16)-H(16) 120.1 121.78(18)  
    C(16)-C(17)-C(18) 119.9(2) C(32)-C(31)-H(31) 119.1
    C(16)-C(17)-H(17) 120.0 C(3)-C(31)-H(31) 119.1
    C(18)-C(17)-H(17) 120.0 C(31)-C(32)-C(33)  
    C(17)-C(18)-C(13) 120.8(2) 120.36(19)  
    C(17)-C(18)-H(18) 119.6 C(31)-C(32)-H(32) 119.8
    C(33)-C(32)-H(32) 119.8 C(1)-C(33)-H(33) 121.3
    C(1)-C(33)-C(32) 117.4(2) C(32)-C(33)-H(33) 121.3
    Table 35. Hydrogen coordinates (x 10^4) and isotropic displacement parameters (□^2 x 10^3) for ansolvat_ht.
     xyzU (eq)
    H (2) -15 910 354 52
    H (5A) -1135 2167 427 85
    H (5B) -609 2069 -675 85
    H (5C) -1038 2734 -443 85
    H (6A) -22 3265 1545 81
    H (6B) 1181 3007 2588 81
    H (6C) -25 2681 2416 81
    H (7A) 859 1528 -372 49
    H (7B) 1889 2018 -36 49
    H (8A) 2624 1029 -79 47
    H (8B) 2154 802 1005 47
    H (11) 5465 2669 585 45
    H (12) 6620 3046 3163 49
    H (14) 7687 4001 3564 65
    H (15) 8565 4810 2886 82
    H (16) 8432 4868 744 88
    H (17) 7480 4090 -742 77
    H (18) 6631 3267 -70 60
    H (19A) 4872 1899 -215 54
    H (19B) 3911 1372 -464 54
    H (20A) 5633 841 0 59
    H (20B) 6341 1290 1184 59
    H (25) 7161 -157 1614 58
    H (26) 7711 -1050 2864 66
    H (27) 6735 -1372 4188 65
    H (28) 5196 -786 4349 56
    H (29A) 2964 1222 3235 44
    H (29B) 4036 1692 3687 44
    H (30A) 2806 2450 2234 45
    H (30B) 2326 2253 3331 45
    H (31) 1027 1822 3811 52
    H (32) 8 1125 4574 60
    H (33) -1017 304 3234 64
    H (3N) 4057 282 3518 72 (7)
    Table 36. Anisotropic displacement parameters (□^2 x 10^3). The anisotropic displacement factor exponent takes the form: -2 pi^2 [h^2 a*^2 U11 + ... + 2 h k a* b* U12 ]
     U11U22U33U23U13U12
    F (1) 80 (1) 78 (1) 96 (1) -37 (1) 50 (1) -45 (1)
    O (1) 51 (1) 53 (1) 37 (1) -8 (1) 20 (1) -15 (1)
    N (1) 51 (1) 43 (1) 43 (1) 1 (1) 12 (1) 3 (1)
    N (2) 42 (1) 37 (1) 34 (1) -5 (1) 17 (1) -11 (1)
    N (3) 38 (1) 39 (1) 49 (1) 1 (1) 25 (1) -3 (1)
    C (1) 42 (1) 47 (1) 62 (1) -13 (1) 23 (1) -13 (1)
    C (2) 38 (1) 49 (1) 47 (1) -4 (1) 19 (1) -5 (1)
    C (3) 32 (1) 37 (1) 40 (1) -1 (1) 12 (1) 1 (1)
    C (4) 38 (1) 37 (1) 38 (1) 0 (1) 14 (1) -2 (1)
    C (5) 42 (1) 60 (2) 60 (1) 5 (1) 10 (1) 5 (1)
    C (6) 60 (1) 44 (1) 59 (1) 3 (1) 24 (1) 9 (1)
    C (7) 39 (1) 45 (1) 36 (1) -1 (1) 13 (1) -6 (1)
    C (8) 40 (1) 40 (1) 39 (1) -6 (1) 17 (1) -9 (1)
    C (9) 37 (1) 34 (1) 36 (1) -3 (1) 17 (1) -9 (1)
    C (10) 34 (1) 35 (1) 32 (1) -1 (1) 11 (1) -1 (1)
    C (11) 37 (1) 40 (1) 34 (1) 2 (1) 12 (1) -3 (1)
    C (12) 38 (1) 42 (1) 40 (1) 1 (1) 13 (1) -6 (1)
    C (13) 31 (1) 39 (1) 48 (1) 4 (1) 10 (1) -1 (1)
    C (14) 45 (1) 49 (1) 68 (1) -6 (1) 20 (1) -11 (1)
    C (15) 54 (1) 46 (2) 106 (2) -7 (1) 30 (1) -15 (1)
    C (16) 54 (2) 52 (2) 113 (2) 26 (2) 33 (2) -8 (1)
    C (17) 45 (1) 72 (2) 75 (2) 30 (1) 22 (1) -3 (1)
    C (18) 36 (1) 57 (1) 52 (1) 9 (1) 12 (1) -8 (1)
    C (19) 60 (1) 44 (1) 37 (1) -9 (1) 26 (1) -18 (1)
    C (20) 57 (1) 47 (1) 55 (1) -11 (1) 35 (1) -13 (1)
    C (21) 41 (1) 42 (1) 45 (1) -12 (1) 24 (1) -11 (1)
    C (22) 35 (1) 38 (1) 40 (1) -3 (1) 18 (1) -8 (1)
    C (23) 33 (1) 39 (1) 45 (1) -7 (1) 15 (1) -5 (1)
    C (24) 33 (1) 43 (1) 45 (1) -13 (1) 17 (1) -9 (1)
    C (25) 37 (1) 53 (1) 58 (1) -20 (1) 24 (1) -9 (1)
    C (26) 38 (1) 60 (2) 64 (1) -20 (1) 15 (1) 5 (1)
    C (27) 48 (1) 48 (1) 60 (1) -4 (1) 12 (1) 5 (1)
    C (28) 42 (1) 45 (1) 51 (1) -2 (1) 17 (1) -2 (1)
    C (29) 38 (1) 38 (1) 36 (1) -2 (1) 16 (1) -7 (1)
    C (30) 38 (1) 37 (1) 38 (1) -3 (1) 15 (1) -5 (1)
    C (31) 39 (1) 46 (1) 45 (1) -4 (1) 16 (1) -6 (1)
    C (32) 46 (1) 59 (2) 49 (1) 0 (1) 24 (1) -6 (1)
    C (33) 47 (1) 55 (1) 67 (1) -2 (1) 31 (1) -12 (1)

    Analysis - FT Raman Spectroscopy



    [0110] FT Raman spectra were recorded on a Bruker RFS100/S Raman spectrometer (Nd-YAG 100 mW laser, excitation 1064 nm, Ge detector, 64 scans, 25-3500 cm-1, resolution 2 cm-1).

    [0111] Raman peak tables were generated using the ACD/SpecManager (Product Version12.5) software from ACD/Labs using the following parameters for the Auto Peak Picking:

    Noise Factor: 0.2 (for crystalline forms A and B) 0.5 (for crystalline form D) Minimum Peak Level: 0 % of max Intensity Peaks: positive FWHH Options: calculate automatically Area Baseline: zero



    [0112] For the intensity classification, the absolute intensity was used and the most intense peak was scaled to 100%. The classification is as follow: very strong (vs): I >90%; strong (s): 90% ≥ I >60%; medium (m): 60% ≥ I > 30%; weak (w): 30% ≥ I >10%; and very weak (vw): 10% ≥ I.



    Table 48: RAMAN peak-list of crystalline form B (comparative); spectrum shown in Fig. 2b
    Nocm-1Intensity
    1 84 S
    2 109 S
    3 166 W
    4 220 W
    5 272 W
    6 333 VW
    7 365 VW
    8 387 VW
    9 405 VW
    10 435 VW
    11 463 VW
    12 505 VW
    13 541 VW
    14 590 VW
    15 619 W
    16 643 VW
    17 676 W
    18 725 VW
    19 745 VW
    20 781 W
    21 802 VW
    22 834 VW
    23 862 W
    24 888 W
    25 929 VW
    26 976 W
    27 1001 S
    28 1010 W
    29 1029 W
    30 1047 W
    31 1087 VW
    32 1112 VW
    33 1158 W
    34 1180 W
    35 1203 W
    36 1266 W
    37 1300 W
    38 1326 VW
    39 1341 VW
    40 1373 VW
    41 1405 VW
    42 1441 W
    43 1449 W
    44 1465 W
    45 1563 M
    46 1578 W
    47 1601 VS
    48 1618 S
    49 1643 M
    50 1861 VW
    51 2136 VW
    52 2172 VW
    53 2328 VW
    54 2489 VW
    55 2519 VW
    56 2558 VW
    57 2772 VW
    58 2794 VW
    59 2843 VW
    60 2890 VW
    61 2935 W
    62 2967 W
    63 3001 W
    64 3063 M
    65 3153 VW
    66 3197 VW
    67 3243 VW
    68 3323 VW
    69 3459 VW
    Table XY3: RAMAN peak-list of crystalline form D (comparative): shown in figure 2d.
    Nocm-1Intensity
    1 84 VS
    2 121 M
    3 158 M
    4 237 W
    5 268 W
    6 294 W
    7 335 W
    8 372 W
    9 402 W
    10 434 W
    11 466 W
    12 489 W
    13 503 W
    14 542 W
    15 579 VW
    16 618 W
    17 646 VW
    18 675 W
    19 696 VW
    20 711 VW
    21 727 VW
    22 782 W
    23 799 VW
    24 834 VW
    25 867 VW
    26 886 W
    27 921 VW
    28 970 VW
    29 1000 M
    30 1011 W
    31 1030 W
    32 1056 W
    33 1085 VW
    34 1115 VW
    35 1154 W
    36 1171 W
    37 1199 W
    38 1263 W
    39 1289 W
    40 1325 W
    41 1343 VW
    42 1377 VW
    43 1406 VW
    44 1447 W
    45 1464 W
    46 1563 M
    47 1576 W
    48 1599 VS
    49 1612 S
    50 1644 W
    51 2792 VW
    52 2846 VW
    53 2895 VW
    54 2946 W
    55 2980 W
    56 3010 W
    57 3065 W
    58 3152 VW
    59 3196 VW

    Analysis-DSC



    [0113] Differential Scanning Calorimetry (DSC): device reference 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.

    [0114] In the following table, "ΔH" means "specific heat", "Tonset" means the "onset temperature", and "Tpeak" means the "peak temperature" of a thermal event.

    [0115] The values for ΔH, Tonset and Tpeak for each polymorph listed below are given as ranges derived from the measurement of different samples exhibiting essentially identical x-ray powder diffractograms. If a sample exhibited more than one thermal event ΔH, Tonset and Tpeak are listed for each event.
    Table 50: DSC data
     Tonset [°C]Tpeak [°C]ΔH [J/g]
    Crystalline Form A 227 - 247 235 - 255 > 80
    Crystalline Form B* 40 - 108 80 - 110 50 - 264
    133 - 140 142 - 148 -23 - 27
    194 - 224 204 - 231 -96 - -3
    230 - 250 230 - 255 80 - 110
    Crystalline Form C* 50 - 145 60 - 150 5 - 200
    145 - 150 150 - 165 0 - 2
    165 - 170 170 - 175 0 - 2
    170 - 210 175 - 220 -85 - -50
    220 - 245 230 - 255 75 - 95
    Crystalline Form D* 30 - 55 55 - 95 10 - 85
    135 - 160 150 - 170 30 - 90
    160 - 175 160 - 180 2 - 7
    190 - 215 205 - 225 -85 - -3
    225 - 245 230 - 250 5 - 95
    Crystalline Form E* 34 - 41 51 - 64 3 - 7
    120 - 122 125 - 127 1 - 20
    134 - 140 143 - 146 2 - 31
    153 - 154 168 - 169 2 - 6
    182 - 197 196 - 210 -74 - -48
    223 - 230 230 - 250 65 - 90
    Crystalline Form F* (n.d.) (n.d.) (n.d)
    Crystalline Form G* 35 - 143 67 - 149 34 - 269
    187 - 201 204 - 220 -112 - -62
    220 - 244 229 - 248 65 - 90
    Crystalline Form H* 135 - 145 145 - 160 40 - 80
    150 - 170 150 - 190 -60 - -20
    230 - 250 230 - 255 80 - 110
    Crystalline Form I* (n.d.) (n.d.) (n.d)
    Crystalline Form J* (one sample measured) 46,7 61,2 10
    123,0 130,3 11
    186,0 196,8 -84
    222,7 232,7 86
    Crystalline Form K* (n.d.) (n.d.) (n.d)
    Crystalline Form L* 100 - 120 115 - 125 4 - 50
    130 - 140 140 - 150 70 - 120
      150 - 160 155 - 175 4 - -50
    180 - 195 190 - 210 -80 - -20
    220 - 240 225 - 250 40 - 80
    Crystalline Form Q* 100 - 115 115 - 140 2 - 50
    130 - 140 130 - 140 2 - 50
    144 - 157 155 - 165 2 - 25
    175 - 190 185 - 205 -90 - -40
    210 - 225 220 - 250 20 - 105
    n.d. = not determined * comparative


    [0116] The above data shows for crystalline A that it has a relatively high melting point and that no transformations into other crystalline forms of compound (1) take place up to its melting point. Both of these properties are very favorable for the use of this crystalline form in the formulation of solid dosage forms.

    Analysis - TG



    [0117] Thermogravimetry analytical 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). Results of the measurements are discussed below.

    Analysis - DVS



    [0118] Crystalline forms were characterized by dynamic vapor sorption (DVS) using a Porotec DVS 1000 or a SMS DVS Intrinsic water vapor sorption analyzer. For the DVS analysis, a step width of 10 % r.h. was applied allowing the samples to equilibrate and reach weight constancy (± 0.002 %) for at least 10 min on each step. All measurements were performed according to the following program: 50 % r.h. → 90 % r.h., 90 → 0 % r.h., 0 % → 90 % r.h., 90 % → 50 % r.h. A cycle with increasing humidity is also known as a sorption cycle, a cycle with decreasing humidity is also known as a desorption cycle. The details of the respective DVS measurements are shown below in table 51 and discussed further below.

    [0119] The hygroscopicity of the respective crystalline forms 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.
    Table 51: DVS measurements
    Measurement no.Crystalline FormT [°C]Initial weight [mg]
    1 A 24.9 16.7255
    2 B 24.9 9.832
    3 C 25.4 21.2031
    4 D 24.9 7.2134
    5 E 24.9 3.8075

    Crystalline form A:



    [0120] TGA analysis performed with samples of crystalline form A revealed that these samples do not contain any significant quantities (i.e. weight loss in TGA is less or equal than 2.0%, preferably less or equal than 1.0 %, even more preferably less or equal than 0.5%, most preferably less than 0.2%) of residual solvents. This is in line with the assumption that crystalline form A is an ansolvate form.

    [0121] A sample of crystalline form A was analyzed via DVS. Crystalline form A showed no essential change, especially increase, in mass with increasing/decreasing relative humidity (-0.2 to 0.1%). Furthermore crystalline form A does not show a hysteresis bigger than 0.5 %, preferably bigger than 0.1% (see figure 3a).
    DVS measurements therefor revealed that crystalline form A is not hygroscopic or just slightly hygroscopic.

    Crystalline form B (comparative):



    [0122] TGA analyses performed with samples of crystalline form B revealed that these samples showed a weight loss between about 5-10 % of water agreeing with a sesqui-, di- or trihydrate form. In the majority of measurements the amount of water contained therein agreed with crystalline form B representing a trihydrate form.
    But the existence of crystalline form B being a hydrate with other variable or discrete states of moisture content (e.g. dihydrate) cannot be fully excluded, since dynamic vapor sorption (DVS) experiments show a significant hysteresis (i.e. > 0.5%, compare data in Figure 3b) between 10% to 40% relative humidity and a maximum weight gain, caused by moisture uptake, of about 7.4% to 10.6% in a range between 20% and 90% relative humidity.

    Crystalline form C (comparative):



    [0123] TGA analyses performed with samples of crystalline form C revealed that these samples exhibited a weight loss up to 9-10 % which is in accordance with the presence of two molecules of methanol per molecule of the title compound (see Figure 3c). Crystalline form C is therefore considered to be a dimethanol solvate.
    Dynamic vapor sorption (DVS) experiments shows two levels of maximum weight gain, indicating that initial amounts of solvent (e.g. methanol) may be exchanged by water.
    When Polymorph C is exposed to increasing moisture content (sorption cycle from 50% to 90% relative humidity) no major change in mass is observed. Upon decreasing moisture in its environment a weight loss of about 6.6 % can be observed (desorption cycle from 90 to 0% r.h.). This weight loss is not fully compensated in a subsequent sorption cycle, weight gain at 90% is only about 2.8 %. Furthermore, the next desorption cycle indicates that even more solvent is exchanged. Crystalline form C can rather easily loose or exchange solvent to form other crystalline forms (e.g. to yield crystalline form K or crystalline form J), therefore crystalline form C may also exist in crystalline states with varying solvent content.
    It cannot be excluded that crystalline form C has transformed to another crystalline form (e.g. crystalline form K or crystalline form J) under conditions of the DVS experiments.
    But the assumption that crystalline form C exists as a dimethanol solvate form is proven by x-ray single crystal structure analysis.

    Crystalline form D (comparative):



    [0124] TGA analyses performed with samples of crystalline form D obtained from solutions in different solvents, revealed residual solvent contents of between 0.1 - 4.7 %. Seen in conjunction with the results from the other analytical methods described herein, crystalline form D is considered to be an ansolvate form with varying amounts of residual solvent. Based on the DVS experiments the existence of crystalline form D with variable solvate or non-stoichiometric content cannot be fully excluded. Sorption and desorption behavior, which shows no significant hysteresis (see Figure 3d) is indicative of a channel-type crystal structure or another structure type that easily allows moisture exchange. The DVS experiments of crystalline form D showed a maximum weight gain of about 2.0 to 8.1 % at 90% relative humidity.
    It cannot be excluded that crystalline form D has transformed to another crystalline form (e.g. crystalline form G) under conditions of the DVS experiments.

    Crystalline form E (comparative):



    [0125] In TGA analysis performed with samples of crystalline form E, these showed a weight loss in a range from 0.1 to 5.3 %. Crystalline form E is considered to be an ansolvate form with varying amounts of residual solvent.
    The existence of crystalline form E being a variable or discrete solvate (e.g. sesqui hydrate) cannot be fully excluded, since dynamic vapor sorption (DVS) experiments show a significant hysteresis between 10% and 40% relative humidity and a maximum weight gain, caused by moisture uptake, of about 4.6 to 5.8 % in a range between 20% and 90% relative humidity (see Figure 3e).
    It cannot be excluded that crystalline form E has transformed to another crystalline form (e.g. crystalline form B) under conditions of the DVS experiments.

    [0126] TGA analysis performed with samples of crystalline form G revealed a two-step mass loss of 2 to 7 % which is, in conjunction with the data from the other analytic methods and/or knowledge about the synthesis conditions, indicative of crystalline form G being an ethanol solvate form, preferably a hemi- or mono ethanolate, or a hygroscopic form.
    The existence of crystalline form G existing in another variable or discrete solvated state cannot be excluded. Crystalline form G may contain alcohol (e.g. ethanol) or water as residual solvent.

    Crystalline form H (comparative):



    [0127] TGA analysis performed with a sample of crystalline form H revealed varying amount of residual solvent in the range of 2 to 8 wt-%, which in conjunction with the data from the other analytic methods suggests that polymorph H can be a non-stoichiometric or stoichiometric solvate. It cannot be excluded that crystalline form is an ansolvate.

    Crystalline form J (comparative):



    [0128] TGA analysis performed with a sample of crystalline form J revealed residual solvent between 2.8 % and 3.6 %, which is , in conjunction with the data from the other analytic methods and/or knowledge about the synthesis conditions, indicative of crystalline form J being a solvate or hygroscopic form.
    The existence of crystalline form J existing as variable or discrete solvated state cannot be excluded. Crystalline form J may contain alcohol (e.g. methanol) or water as residual solvent.

    Crystalline for K (comparative):



    [0129] According TGA analysis performed with a sample of crystalline form K this sample contained residual solvent in an amount between 2.1 % and 4.0 %, which is, in conjunction with the data from other analytic methods and/or knowledge about the synthesis conditions, indicative of crystalline form K being solvate or hygroscopic form.
    The existence of crystalline form K existing as variable or discrete solvated state cannot be excluded. Crystalline form K may contain alcohol (e.g. methanol) or water as residual solvent.

    Crystalline form L(comparative):



    [0130] TGA analysis performed with samples of crystalline form L revealed between 2 to 13% residual solvent (16.7% according to TGA), which is, in conjunction with data from other analytic methods and/or knowledge about the synthesis conditions, indicative of crystalline form J being solvate, preferably a variable or discrete toluene solvate.


    Claims

    1. Crystalline form A of cis-(E)-4-(3-Fluorophenyl)-2',3',4',9'-tetrahydro-N,N-dimethyl-2'-(1-oxo-3-phenyl-2-propenyl)-spiro[cyclohexane-1,1'[1H]-pyrido[3,4-b]indol]-4-amine, which has
    X-ray powder diffraction peaks (CuKα radiation) at 8.7 ±0.2 (2Θ), 10.0 ±0.2 (2Θ), 11.9 ±0.2 (2Θ), 15.3 ±0.2 (2Θ), 15.8 ±0.2 (2Θ); 16.7 ±0.2 (2Θ); 17.4 ±0.2 (2Θ); 17.8 ±0.2 (2Θ), 18.3 ±0.2 (2Θ), 19.7 ±0.2 (2Θ); 20.3 ±0.2 (2Θ), 21.9 ±0.2 (2Θ), 22.2 ±0.2 (2Θ), and 27.1 ±0.2 (2Θ).
     
    2. The crystalline form A according to claim 1, which, as determined in a single crystal X-ray diffraction analysis carried out at 100 K (± 5K) using MoKα radiation with a wavelength of 0.71073 A a monoclinic crystal system, has a P 21/c space group and unit cell dimensions of

    a = 12.1568(7) A, alpha = 90 deg.

    b = 21.6289(12) A, beta = 113.3610(10) deg. and

    c = 10.9424(6) A, gamma = 90 deg.


     
    3. Crystalline form A according to claim 1 or 2, which has one or more Raman peaks selected from the group consisting of at 1606 ±2 cm-1, 1175 ±2 cm-1, 1568 ±2 cm-1, 1574 ±2 cm-1 and 1650 ±2 cm-1.
     
    4. Crystalline form A according to any one of claims 1 to 3, which in DSC analysis exhibits an endothermal event with an onset temperature in the range of 227 °C to 247°C, preferably 240 °C to 245 °C and/or a peak temperature in the range of 235 °C to 255°C, preferably 245 °C to 250 °C.
     
    5. Crystalline form A according to any one of claims 1 to 4, which when measured at room temperature has essentially an X-ray powder diffraction peak pattern shown in the table below:




     
    6. Crystalline form A according to any one of claims 1 to 5, which has a X-ray powder diffraction peak pattern as shown in Figure 1a.
     
    7. A pharmaceutical composition comprising crystalline form A according to any one of claims 1 to 6 and one or more suitable additives and/or adjuvants.
     
    8. A process for preparing crystalline form A of cis-(E)-4-(3-Fluorophenyl)-2',3',4',9'-tetrahydro-N,N-dimethyl-2'-(1-oxo-3-phenyl-2-propenyl)-spiro[cyclohexane-1,1'[1H]-pyrido[3,4-b]indol]-4-amine according to any of claims 1 to 6, comprising the steps of

    (a-1') suspending cis-(E)-4-(3-Fluorophenyl)-2',3',4',9'-tetrahydro-N,N-dimethyl-2'-(1-oxo-3-phenyl-2-propenyl)-spiro[cyclohexane-1,1'[1H]-pyrido[3,4-b]indol]-4-amine for at least 0.3h in a solvent at a temperature in the range of 20°C and the boiling point of the solvent, wherein the solvent is selected from the group consisting of isopropanol and a mixture of isopropanol and water, wherein the mixture may comprise up to 75 vol-% water;

    (b-1') separating, preferably filtering off the solid obtained in step (a-1'), and

    (c-1') drying the solid obtained in step (b-1') at a temperature in the range of 0° to 75°C, preferably at a temperature in the range of 20 to 55°C, more preferably at 50°C.


     
    9. The process according to claim 8, comprising the steps of

    (a-1''') suspending cis-(E)-4-(3-Fluorophenyl)-2',3',4',9'-tetrahydro-N,N-dimethyl-2'-(1-oxo-3-phenyl-2-propenyl)-spiro[cyclohexane-1,1'[1H]-pyrido[3,4-b]indol]-4-amine for at least 0.3h in a solvent at a temperature in the range of 20°C and the boiling point of the solvent, wherein the solvent is selected from the group consisting of isopropanol and a mixture of isopropanol and water, wherein the mixture may comprise up to 75 vol-% water;

    (b-1''') separating, preferably filtering off the solid obtained in step (a-1'), and

    (c-1''') drying the solid obtained in step (b-1'), preferably at a temperature in the range of 0° to 75°C, more preferably at a temperature in the range of 20 to 55°C, even more preferably at 50°C.


     


    Ansprüche

    1. Kristalline Form A von cis-(E)-4-(3-Fluorphenyl)-2',3',4',9'-tetrahydro-N,N-dimethyl-2'-(1-oxo-3-phenyl-2-propenyl)-spiro[cyclohexan-1,1'[1H]-pyrido[3,4-b]indol]-4-amin, die Röntgenbeugungsreflexe (CuKα-Strahlung) bei 8,7 ±0,2 (2Θ), 10,0 ±0,2 (2Θ), 11,9 ±0,2 (2Θ), 15,3 ±0,2 (2Θ), 15,8 ±0,2 (2Θ); 16,7 ±0,2 (2Θ); 17,4 ±0,2 (2Θ); 17,8 ±0,2 (2Θ), 18,3 ±0,2 (2Θ), 19,7 ±0,2 (2Θ); 20,3 ±0,2 (2Θ), 21,9 ±0,2 (2Θ), 22,2 ±0,2 (2Θ) und 27,1 ±0,2 (2Θ) aufweist.
     
    2. Kristalline Form A nach Anspruch 1, die, wie in einer Röntgenstrukturanalyse am Einzelkristall, ausgeführt bei 100 K (± 5K) unter Verwendung von MoKα-Strahlung mit einer Wellenlänge von 0.71073 Å eines monoklinischen Kristallsystems, bestimmt, eine P 21/c-Raumgruppe und Einheitszelldimensionen von

    a = 12,1568(7) Å, alpha = 90°

    b = 21,6289(12) Å, beta = 113,3610(10)° und

    c = 10,9424(6) Å, gamma = 90° aufweist.


     
    3. Kristalline Form A nach Anspruch 1 oder 2, die eine oder mehrere Raman-Banden aufweist, die aus der Gruppe ausgewählt sind, die aus 1606 ±2 cm-1, 1175 ±2 cm-1, 1568 ±2 cm-1, 1574 ±2 cm-1 und 1650 ±2 cm-1 besteht.
     
    4. Kristalline Form A nach einem der Ansprüche 1 bis 3, die bei der DSC-Analyse ein endothermes Ereignis mit einer Anfangstemperatur in der Spanne von 227 °C bis 247°C, bevorzugt 240 °C bis 245 °C und/oder einer Spitzentemperatur in der Spanne von 235 °C bis 255°C, bevorzugt 245 °C bis 250 °C, aufweist.
     
    5. Kristalline Form A nach einem der Ansprüche 1 bis 4, die, wenn bei Raumtemperatur gemessen, im Wesentlichen ein in der nachfolgenden Tabelle gezeigtes Röntgenbeugungsreflexmuster aufweist:




     
    6. Kristalline Form A nach einem der Ansprüche 1 bis 5, die ein Röntgenbeugungsreflexmuster wie in Figur 1a gezeigt aufweist.
     
    7. Pharmazeutische Zusammensetzung, umfassend die kristalline Form A nach einem der Ansprüche 1 bis 6 und ein oder mehrere geeignete Additive und/oder Adjuvanzien.
     
    8. Verfahren zur Herstellung der kristallinen Form A von cis-(E)-4-(3-Fluorphenyl)-2',3',4',9'- tetrahydro-N,N-dimethyl-2'-(1-oxo-3-phenyl-2-propenyl)-spiro[cyclohexan-1,1'[1H]-pyrido[3,4-b]indol]-4-amin nach einem der Ansprüche 1 bis 6, umfassend die Schritte:

    (a-1') Suspendieren von cis-(E)-4-(3-Fluorphenyl)-2',3',4',9'-tetrahydro-N,N-dimethyl-2'-(1 - oxo-3-phenyl-2-propenyl)-spiro[cyclohexan-1,1'[1H]-pyrido[3,4-b]indol]-4-amin über mindestens 0,3 h in einem Lösungsmittel bei einer Temperatur in der Spanne von 20°C und dem Siedepunkt des Lösungsmittels, wobei das Lösungsmittel aus der Gruppe ausgewählt ist, die aus Isopropanol und einem Gemisch aus Isopropanol und Wasser besteht, wobei das Gemisch bis zu 75 Vol.-% Wasser umfassen kann;

    (b-1') Trennen, bevorzugt Abfiltrieren des in Schritt (a-1') erhaltenen Feststoffes, und

    (c-1') Trocknen des in Schritt (b-1') erhaltenen Feststoffes bei einer Temperatur in der Spanne von 0° bis 75°C, bevorzugt bei einer Temperatur in der Spanne von 20 bis 55°C, bevorzugter bei 50°C.


     
    9. Verfahren nach Anspruch 8, umfassend die Schritte:

    (a-1''') Suspendieren von cis-(E)-4-(3-Fluorphenyl)-2',3',4',9'-tetrahydro-N,N-dimethyl-2'-(1 - oxo-3-phenyl-2-propenyl)-spiro[cyclohexan-1,1'[1H]-pyrido[3,4-b]indol]-4-amin über mindestens 0,3 h in einem Lösungsmittel bei einer Temperatur in der Spanne von 20°C und dem Siedepunkt des Lösungsmittels, wobei das Lösungsmittel aus der Gruppe ausgewählt ist, die aus Isopropanol und einem Gemisch aus Isopropanol und Wasser besteht, wobei das Gemisch bis zu 75 Vol.-% Wasser umfassen kann;

    (b-1''') Trennen, bevorzugt Abfiltrieren des in Schritt (a-1') erhaltenen Feststoffes, und

    (c-1''') Trocknen des in Schritt (b-1') erhaltenen Feststoffes bei einer Temperatur in der Spanne von 0° bis 75°C, bevorzugter bei einer Temperatur in der Spanne von 20 bis 55°C, noch bevorzugter bei 50°C.


     


    Revendications

    1. Forme cristalline A de cis-(E)-4-(3-fluorophényl)-2',3',4',9'-tétrahydro-N,N-diméthyl-2'-(1-oxo-3-phényl-2-propényl)-spiro[cyclohexane-1,1'[1H]-pyrido[3,4-b]indole]-4-amine, qui a
    des pics de diffraction des rayons X sur poudre (rayonnement CuKα) à 8,7 ± 0,2 (2Θ), 10,0 ± 0,2 (2Θ), 11,9 ± 0,2 (2Θ), 15,3 ± 0,2 (2Θ), 15,8 ± 0,2 (2Θ) ; 16,7 ± 0,2 (2Θ) ; 17,4 ± 0,2 (2Θ) ; 17,8 ± 0,2 (2Θ) ; 18,3 ± 0,2 (2Θ), 19,7 ± 0,2 (2Θ) ; 20,3 ± 0,2 (2Θ), 21,9 ± 0,2 (2Θ), 22,2 ± 0,2 (2Θ), et 27,1 ± 0,2 (2Θ).
     
    2. Forme cristalline A selon la revendication 1, qui, telle que déterminée dans une analyse de diffraction de rayons X d'un seul cristal réalisée à 100 K (± 5K) en utilisant le rayonnement MoKα avec une longueur d'onde de 0,71073 Å d'un système cristallin monoclinique, a un groupe d'espace P 21/c et des dimensions de cellule unitaire de :

    a = 12,1568(7) Å, alpha = 90 degrés

    b = 21,6289(12) Å, bêta = 113,3610(10) degrés et

    c = 10,9424(6) Å, gamma = 90 degrés.


     
    3. Forme cristalline A selon la revendication 1 ou 2, qui a un ou plusieurs pics Raman choisis dans le groupe constitué par 1606 ± 2 cm-1, 1175 ± 2 cm-1, 1568 ± 2 cm-1, 1574 ± 2 cm-1 et 1650 ± 2 cm-1.
     
    4. Forme cristalline A selon l'une quelconque des revendications 1 à 3, qui, dans une analyse DSC, présente un événement endothermique avec une température de déclenchement dans la plage de 227°C à 247°C, de préférence de 240°C à 245°C et/ou une température de pic dans la plage de 235°C à 255°C, de préférence de 245°C à 250°C.
     
    5. Forme cristalline A selon l'une quelconque des revendications 1 à 4, qui, quand elle est mesurée à température ambiante, a essentiellement un profil de pics de diffraction des rayons X sur poudre montré dans le tableau ci-dessous :
    Valeur de d [Å]2Θ [°]I rel. [%]
    11,5 7,7 27
    10,2 8,7 33
    9,3 9,5 9
    8,8 10,0 33
    7,9 11,2 6
    7,5 11,9 85
    7,2 12,3 25
    5,8 15,3 73
    5,6 15,8 34
    5,5 16,2 19
    5,3 16,7 53
    5,1 17,4 79
    5,0 17,8 100
    4,8 18,3 83
    4,7 18,8 14
    4,6 19,2 12
    4,5 19,7 35
    4,4 20,2 38
    4,2 21,3 19
    4,1 21,5 13
    4,0 21,9 58
    4,0 22,2 35
    3,9 22,5 29
    3,9 23,1 15
    3,7 23,9 18
    3,6 24,8 15
    3,5 25,2 7
    3,5 25,7 14
    3,4 26,2 29
    3,3 27,1 38
    3,2 27,9 7
    3,2 28,2 10
    3,1 28,5 14
    3,1 29,0 6
    3,1 29,2 5
    3,0 29,6 7
    3,0 30,0 4
    2,9 30,4 11
    2,9 31,1 13
    2,8 31,6 5
    2,7 32,7 10
    2,7 33,5 5
    2,6 34,1 9
    2,6 34,9 6
    2,5 36,5 5
    2,4 37,4 8
    2,4 38,2 6
    2,3 38,9 5
    2,3 39,1 4
    2,2 40,1 7
    2,2 41,2 5
    2,2 41,9 4
    2,1 42,6 5
    2,1 43,0 3
    2,1 43,7 11
    2,0 44,4 4
    2,0 45,0 2
    1,9 48,0 4

     
    6. Forme cristalline A selon l'une quelconque des revendications 1 à 5, qui a un profil de pics de diffraction des rayons X sur poudre tel que montré sur la figure 1a.
     
    7. Composition pharmaceutique comprenant la forme cristalline A selon l'une quelconque des revendications 1 à 6 et un ou plusieurs additifs et/ou adjuvants appropriés.
     
    8. Procédé de préparation de la forme cristalline A de cis-(E)-4-(3-fluorophényl)-2',3',4',9'-tétrahydro-N,N-di-méthyl-2'-(1-oxo-3-phényl-2-propényl)-spiro[cyclohexane-1,1'[1H]-pyrido[3,4-b]indole]-4-amine selon l'une quelconque des revendications 1 à 6, comprenant les étapes de :

    (a-1') mise en suspension de la cis-(E)-4-(3-fluorophényl)-2',3',4',9'-tétrahydro-N,N-diméthyl-2'-(1-oxo-3-phényl-2-propényl)-spiro[cyclohexane-1,1'[1H]-pyrido[3,4-b]-indole]-4-amine durant au moins 0,3 heure dans un solvant à une température dans la plage de 20°C et le point d'ébullition du solvant, où le solvant est choisi dans le groupe constitué par l'isopropanol et un mélange d'isopropanol et d'eau, le mélange pouvant comprendre jusqu'à 75 % en volume d'eau ;

    (b-1') séparation, de préférence récupération par filtration du solide obtenu dans l'étape (a-1'), et

    (c-1') séchage du solide obtenu dans l'étape (b-1') à une température dans la plage de 0° à 75°C, de préférence à une température dans la plage de 20° à 55°C, davantage de préférence à 50°C.


     
    9. Procédé selon la revendication 8, comprenant les étapes de :

    (a-1''') mise en suspension de la cis-(E)-4-(3-fluorophényl)-2',3',4',9'-tétrahydro-N,N-diméthyl-2'-(1-oxo-3-phényl-2-propényl)-spiro[cyclohexane-1,1'[1H]-pyrido[3,4-b]-indole]-4-amine durant au moins 0,3 heure dans un solvant à une température dans la plage de 20°C et le point d'ébullition du solvant, où le solvant est choisi dans le groupe constitué par l'isopropanol et un mélange d'isopropanol et d'eau, le mélange pouvant comprendre jusqu'à 75 % en volume d'eau ;

    (b-1''') séparation, de préférence récupération par filtration du solide obtenu dans l'étape (a-1'), et

    (c-1''') séchage du solide obtenu dans l'étape (b-1'), de préférence à une température dans la plage de 0° à 75°C, davantage de préférence à une température dans la plage de 20° à 55°C, encore davantage de préférence à 50°C.


     




    Drawing































































    REFERENCES CITED IN THE DESCRIPTION



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    Patent documents cited in the description




    Non-patent literature cited in the description