# Patent

## Title
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]

## Abstract

The present invention relates to 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, pharmaceutical compositions and medicaments comprising these modifications, the use of these modifications as well as to a process for making the crystalline forms.

## Background
FIELD OF THE INVENTION
The invention relates to 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, pharmaceutical compositions and medicaments comprising one or more of these crystalline forms, the use of these crystalline forms as well as to processes for producing these crystalline forms.
BACKGROUND OF THE INVENTION
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.
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.
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).
In medicine, the treatment of pain is of great importance and although a significant number of drugs are known for and established in the treatment of pain, there remains, for instance with regard to drug-related side-effects, a demand for improved pain medication, especially for the treatment of strong/severe and/or chronic and/or neuropathic pain. Consequently, a great deal of effort is still being invested by pharmaceutical companies into the development of new, improved analgesics.
One particular drug that is of great interest especially for the use in treating pain, especially chronic and/or neuropathic pain is cis-(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):




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.
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
FIGS. 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.
FIGS. 2a, 2b and 2d show the Raman spectra of crystalline forms A, B, and D.
FIGS. 3a, b, c, d, and e show plots of DVS experiments for crystalline forms A, B, C, D, and E.



DETAILED DESCRIPTION
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.
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.
Unless explicitly stated otherwise, all 2Θ values refer to a X-ray powder diffractogram measured using CuKα radiation having a wavelength of 1.54060 Å. The terms 2Θ values and degrees 2Θ are used synonymously.
Unless explicitly stated otherwise, all values in ppm refer to ppm by weight, i.e. ppmw.
In a first aspect, the present invention relates to a crystalline form of 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.
In a preferred embodiment of the invention, the crystalline form according to the invention has at least one X-ray powder diffraction peak (CuKα radiation) in the range of 6.5±0.2 to 8.9±0.2 (2Θ) and/or 17.2±0.2 to 18.3±0.2 (2Θ) and/or in the range of 19.7±0.2 to 20.9±0.2 (2Θ).
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%.
In further preferred embodiments the crystalline form according to the invention is an ansolvate or a solvate.
In some preferred embodiments the crystalline form according to the invention is an ansolvate. In other preferred embodiments the crystalline form according to the invention is a solvate, preferably selected from the group of hydrates, solvates of lower alcohols, such as methanol, ethanol, 1-propanol or 2-propanol or solvates of toluene or a solvate of solvate mixtures. Preferably, the solvate is selected from the group consisting of monosolvate, hemi-solvate, disolvate, trisolvate, and mixtures thereof. In another preferred embodiment the solvate is a variable or non-stoichiometric solvate.
In a preferred embodiment, the crystalline form is a hydrate, preferably selected from the group consisting of monohydrate, hemi-hydrate, dihydrate, trihydrate, and mixtures thereof. In some preferred embodiments, the crystalline form is a trihydrate. In another preferred embodiment the hydrate is a variable or non-stoichiometric hydrate. In another preferred embodiment the alcohol solvate is a variable or non-stoichiometric alcohol solvate.
In another preferred embodiment, the crystalline form is an alcohol solvate, preferably selected from the group consisting of methanol, ethanol or propanolate (1-propanol or 2-propanol) solvates, and the mixtures thereof, the 1-methanol solvate being particularly preferred.
In a further preferred embodiment of the invention, the crystalline form is one which has

    
    
        A: one or more X-ray powder diffraction peaks (CuKα radiation) selected from the group consisting of 8.7±0.2 (2Θ), 11.9±0.2 (2Θ), 18.3±0.2 (2Θ), and 27.1±0.2 (2Θ) and/or 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; or
        B: one or more X-ray powder diffraction peaks (CuKα radiation) selected from the group consisting of at 6.8±0.2 (2Θ), 12.1±0.2 (2Θ), 18.7±0.2 (2Θ), and 28.3±0.2 (2Θ); and/or one or more Raman peaks selected from the group consisting of at 1643±2 cm−1 and 1578±2 cm−1; or
        C: one or more X-ray powder diffraction peaks (CuKα radiation) selected from the group consisting of 9.7±0.2 (2Θ), 11.6±0.2 (2Θ), 14.0±0.2 (2Θ), and 17.9±0.2 (2Θ); or
        D: one or more X-ray powder diffraction peaks (CuKα radiation) selected from the group consisting of 8.7±0.2 (2Θ), 11.6±0.2 (2Θ), 16.6±0.2 (2Θ), and 21.2±0.2 (2Θ); and/or one or more Raman peaks selected from the group consisting of 1612±2 cm−1 and 1199 cm−1±2 cm−1; or
        E: one or more X-ray powder diffraction peaks (CuKα radiation) selected from the group consisting of 6.9±0.2 (2Θ), 8.1±0.2 (2Θ), 18.3±0.2 (2Θ) and 20.8±0.2 (2Θ); or
        F: one or more X-ray powder diffraction peaks (CuKα radiation) selected from the group consisting of 8.7±0.2 (2Θ), 12.5±0.2 (2Θ), 20.9±0.2 (2Θ); or
        G: one or more X-ray powder diffraction peaks (CuKα radiation) selected from the group consisting of 6.6±0.2 (2Θ), 8.0±0.2 (2Θ), 18.0±0.2 (2Θ), and 18.9±0.2 (2Θ);
        H: one or more X-ray powder diffraction peaks (CuKα radiation) selected from the group consisting of 7.1±0.2 (2Θ), 8.0±0.2 (2Θ), 18.2±0.2 (2Θ), and 28.3±0.2 (2Θ); or
        I: one or more X-ray powder diffraction peaks (CuKα radiation) selected from the group consisting of 7.1±0.2 (2Θ), 11.8±0.2 (2Θ), 17.6±0.2 (2Θ) and 19.6±0.2 (2Θ); or
        J: one or more X-ray powder diffraction peaks (CuKα radiation) selected from the group consisting of 7.1±0.2 (2Θ), 11.1±0.2 (2Θ), 14.5±0.2 (2Θ), and 19.7±0.2 (2Θ); or
        K: one or more X-ray powder diffraction peaks (CuKα radiation) selected from the group consisting of 7.1±0.2 (2Θ), 10.0±0.2 (2Θ), 14.3±0.2 (2Θ), and 19.5±0.2 (2Θ); or
        L: one or more X-ray powder diffraction peaks (CuKα radiation) selected from the group consisting of 8.1±0.2 (2Θ), 12.0±0.2 (2Θ), 17.1±0.2 (2Θ), and 20.1±0.2 (2Θ); or
        Q: one or more X-ray powder diffraction peaks (CuKα radiation) selected from the group consisting of 8.2±0.2 (2Θ), 8.6±0.2 (2Θ), 17.2±0.2 (2Θ), and 24.4±0.2 (2Θ).
    
    


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.
In another preferred embodiment of the invention, crystalline form A has X-ray powder diffraction peaks (CuKα radiation) of 8.7±0.2 (2Θ), 11.9±0.2 (2Θ), 18.3±0.2 (2Θ), and optionally 27.1±0.2 (2Θ).
In a further preferred embodiment of the invention the crystalline form has X-ray powder diffraction peaks (CuKα radiation) at 7.7±0.2 (2Θ) and/or 17.4±0.2 (2Θ) and/or 18.3±0.2 (2Θ) and at least one additional X-ray peak selected from 10.0±0.2 (2Θ), 15.3±0.2 (2Θ), 15.8±0.2 (2Θ), 21.9±0.2 (2Θ), 22.2±0.2 (2Θ) and 27.1±0.2 (2Θ).
In still further preferred embodiments, the crystalline form has X-ray powder diffraction peaks (CuKα radiation) at 8.7±0.2 (2Θ) and 17.4±0.2 (2Θ) and at least one additional peak selected from the group of 10.0±0.2 (2Θ), 16.7±0.2 (2Θ), 26.2±0.2 (2Θ), and 27.1±0.2 (2Θ).
In another preferred embodiment of the invention 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.
In a further preferred embodiment of the invention 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).
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
A further aspect of the invention relates to a process for obtaining a crystalline form 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, 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 in a solvent;
    (b-1) separating, preferably filtering off the solid obtained in step (a-1); and
    (c-1) drying of the solid obtained in step (b-1).


A further aspect of the present invention relates to a crystalline form A.
Preferably, the crystalline form A according to the invention has one or more X-ray powder diffraction peaks selected from the group consisting of about 8.7±0.2 (2Θ), about 11.9±0.2 (2Θ), about 18.3±0.2 (2Θ), and about 27.1±0.2 (2Θ). In a further embodiment the group of X-ray powder diffraction peaks further comprises a peak at about 27.1±0.2 (2Θ).
In some preferred embodiments, the crystalline form has an X-ray powder diffraction peak of about 17.8±0.2 (2Θ). In some preferred embodiments the crystalline form comprises X-ray powder diffraction peaks of about 17.8±0.2 (2Θ), about 11.9±0.2 (2Θ) and/or about 27.1±0.2 (2Θ).
In some preferred embodiments, crystalline form A comprises X-ray powder diffraction peaks of about 18.3±0.2 (2Θ), about 11.9±0.2 (2Θ) and about 27.1±0.2 (2Θ). In further preferred embodiments, crystalline form A may further comprise X-ray powder diffraction peaks of about 17.4±0.2 (2Θ), about 15.3±0.2 (2Θ), 21.9±0.2 (2Θ) and about 16.7±0.2 (2Θ).
In some preferred embodiments, crystalline form A comprises X-ray powder diffraction peaks of about 11.9±0.2 (2Θ), about 17.8±0.2 (2Θ), about 17.4±0.2 (2Θ) and about 18.3±0.2 (2Θ). Optionally, X-ray powder diffraction peaks of about 15.3±0.2 (2Θ), about 21.9±0.2 (2Θ), about 16.7±0.2 (2Θ) and about 27.1±0.2 (2Θ) are comprised.
In another preferred embodiment the crystalline form A according to the invention has one or more X-ray powder diffraction peaks selected from the group consisting of about 8.7±0.2 (2Θ), about 11.9±0.2 (2Θ), about 18.3±0.2 (2Θ), and about 27.1±0.2 (2Θ) and optionally one or more peaks selected from about 15.3±0.2 (2Θ), about 21.9±0.2 (2Θ), about 16.7±0.2 (2Θ) and about 27.1±0.2 (2Θ).
In further preferred embodiments, crystalline form A comprises X-ray powder diffraction peaks of 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). Optionally, an additional X-ray powder diffraction peak of about 27.1±0.2 (2Θ) may be comprised. Also optionally, additional X-ray powder diffraction peaks of about 21.9±0.2 (2Θ), about 16.7±0.2 (2Θ), about 20.3±0.2 (2Θ), and about 19.7±0.2 (2Θ) may be comprised, either in addition to the peak of about 27.1±02 (2Θ) or alternatively.
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.
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 CuKα radiation having a wavelength of 1.54060 Å 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).
Consequently, in some preferred embodiments of the invention crystalline form A comprises at least one X-ray peak selected from the group consisting of about 15.3±0.2 (2Θ), about 17.4±0.2 (2Θ) and about 18.3±0.2 (2Θ) and at least one additional X-ray peak selected from 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. Consequently, in some embodiments of the invention crystalline form A comprises at least one X-ray peak at about 17.4±0.2 (2Θ) in combination with at least one X-ray peak selected from about 16.7±0.2 (2Θ), about 20.3±0.2 (2Θ), about 22.5±0.2 (2Θ), and about 27.1±0.2 (2Θ).
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.
Consequently, in some preferred embodiments crystalline form A comprises X-ray powder diffraction peaks of about 18.3±0.2 (2Θ) and about 21.7±0.2 (2Θ) and at least one additional peak selected from the group consisting of about 7.7±0.2 (2Θ), about 21.9±0.2 (2Θ), about 22.2±0.2 (2Θ), about 22.5±0.2 (2Θ), and about 26.2±0.2 (2Θ).
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).
Consequently, in some preferred embodiments of the invention crystalline form A comprises an X-ray peak at about 17.4±0.2 (2Θ) and at least one additional peak selected from the group of about 8.7±0.2 (2Θ), about 10.0±0.2 (2Θ), about 16.7±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. Consequently, in a preferred embodiment of the invention, form A comprises the X-ray peak at about 17.4±0.2 (2Θ) and at least one additional peak selected from the group consisting of about 15.3±0.2 (2Θ), about 16.7±0.2 (2Θ), about 20.3±0.2 (2Θ) and about 27.1±0.2 (2Θ). Optionally, one or more X-ray peaks selected from the group consisting of about 7.7±0.2 (2Θ), about 8.7±0.2 (2Θ), about 15.3±0.2 (2Θ), about 19.7±0.2 (2Θ), about 22.2±0.2 (2Θ), and about 22.5±0.2 (2Θ).
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. Consequently, in a preferred embodiment of the invention, form A comprises at least one of the X-ray peaks selected from at 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) and at least one additional X-ray peak selected from the group consisting of about 7.7±0.2 (2Θ), about 10.0±0.2 (2Θ), about 12.3±0.2 (2Θ), and about 21.9±0.2 (2Θ).
In order to discriminate between crystalline form A and crystalline form E it might be more advantageous not to rely on 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. Consequently, in a preferred embodiment of the invention, form A comprises at least one X-ray peak selected about 11.9±0.2 (2Θ), about 15.3±0.2 (2Θ), about 17.4±0.2 (2Θ), and about 17.8±0.2 (2Θ), and at least one X-ray peak selected from the group consisting 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 12.3±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), about 26.2±0.2 (2Θ) and about 27.1±0.2 (2Θ).
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. Consequently, in a preferred embodiment of the invention, form A comprises at least one X-ray peak selected from about 11.9±0.2 (2Θ), about 15.8±0.2 (2Θ), and about 17.8±0.2 (2Θ) and at least one additional peak selected from the group consisting of about 7.7±0.2 (2Θ), about 10.0±0.2 (2Θ), about 15.3±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).
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. Consequently, in a preferred embodiment of the invention, form A comprises at least one or more X-ray powder diffraction peaks selected from the group consisting of 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 and at least one additional peak selected from the group consisting 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).
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. Consequently, in a preferred embodiment of the invention, form A comprises at least one or more X-ray powder diffraction peaks selected from the group consisting of about 11.9±0.2 (2Θ) and about 15.3±0.2 (2Θ) and at least one additional peak selected from the group consisting of about 7.7±0.2 (2Θ), about 8.7±0.2 (2Θ), about 12.3±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).
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. Consequently, in a preferred embodiment of the invention, form A comprises at least one or more X-ray powder diffraction peaks selected from the group consisting of 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), and at least one additional peak selected from the group consisting 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).
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. Consequently, in a preferred embodiment of the invention, form A comprises at least one or more X-ray powder diffraction peaks selected from the group consisting of about 11.9±0.2 (2Θ) and 15.8±0.2 (2Θ), and at least one additional peak selected from the group consisting of 7.7±0.2 (2Θ), about 8.7±0.2 (2Θ), about 10.0±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)
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. Consequently, in a preferred embodiment of the invention, form A comprises at least one or more X-ray powder diffraction peaks selected from the group consisting of 11.9±0.2 (2Θ), about 17.4±0.2 (2Θ), about 17.8±0.2 (2Θ) and about 18.3±0.2 and at least one additional peak selected from the group consisting of 7.7±0.2 (2Θ), about 8.7±0.2 (2Θ), about 12.3±0.2 (2Θ), about 21.9±0.2 (2Θ), and about 26.2±0.2 (2Θ).
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. Consequently, in a preferred embodiment of the invention, form A comprises an X-ray peak of about 15.3±0.2 and at least one additional peak selected from the group consisting of 8.7±0.2 (2Θ), about 10.0±0.2 (2Θ), about 15.8±0.2 (2Θ), about 22.5±0.2 (2Θ), and about 27.1±0.2 (2Θ).
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.
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.
A further aspect of the present invention relates to a crystalline form B
Preferably, the crystalline form B according to the invention has one or more X-ray powder diffraction peaks selected from the group consisting of about 6.8±0.2 (2Θ), about 12.1±0.2 (2Θ), about 18.7±0.2 (2Θ), and about 28.3±0.2 (2Θ).
In a further embodiment the group of X-ray powder diffraction peaks further comprises a peak at about 28.3±0.2 (2Θ). In some preferred embodiments, the crystalline form has an X-ray powder diffraction peak of about 12.1±0.2 (2Θ). In some preferred embodiments the crystalline form comprises X-ray powder diffraction peaks of about 12.1±0.2 (2Θ), about 18.7±0.2 (2Θ) and/or about 28.3±0.2 (2Θ).
In some preferred embodiments, crystalline form B comprises X-ray powder diffraction peaks of about 12.1±0.2 (2Θ), about 18.0±0.2 (2Θ) and about 18.7±0.2 (2Θ), and optionally, a further peak at about 28.3±0.2 (2Θ). In further preferred embodiments, crystalline form B may further comprise X-ray powder diffraction peaks of about 6.8±0.2 (2Θ), about 18.4±0.2 (2Θ), about 19.8±0.2 (2Θ).
Although in the X-ray diffractogram of crystalline form B 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 measured using CuKα radiation having a wavelength of 1.54060 Å the five peaks with the highest relative intensity were found to be about 12.1±0.2 (2Θ), about 18.0±0.2 (2Θ) and about 18.7±0.2 (2Θ), about 18.4±0.2 (2Θ), and about 19.8±0.2 (2Θ), in order to discriminate this form over crystalline forms A, 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 A, D, E and H do not show lines with significant intensity. Such characteristic X-ray peaks are those of about 13.7±0.2 (2Θ) and about 14.2±0.2 (2Θ).
Consequently, in some preferred embodiments of the invention crystalline form B comprises at least one X-ray peak selected from about 13.7±0.2 (2Θ) and about 14.2±0.2 (2Θ).
Similarly, the X-ray peaks of about 12.1±0.2 (2Θ), about 15.5±0.2 (2Θ), about 19.8±0.2 (2Θ), about 22.1±0.2 (2Θ), and about 28.3±0.2 (2Θ) might be more advantageously used to discriminate crystalline form B over crystalline forms C, F and G. Consequently, in some embodiments of the invention crystalline form B comprises at least one X-ray peak selected from the peaks of about 12.1±0.2 (2Θ) and about 19.8±0.2 (2Θ) in combination with at least one X-ray peak selected from the group of peaks consisting of about 15.5±0.2 (2Θ), about 22.1±0.2 (2Θ) and about 28.3±0.2 (2Θ).
To discriminate between crystalline form B and crystalline form A the X-ray peaks of about 6.8±0.2 (2Θ), about 13.7±0.2 (2Θ), about 14.2±0.2 (2Θ), about 18.7±0.2 (2Θ), and about 28.3±0.2 (2Θ) might be more advantageously used. Consequently, in a preferred embodiment of the invention, form B comprises the X-ray peak at about 18.7±0.2 (2Θ) in combination with one or more X-ray peaks from the group consisting of about 6.8±0.2 (2Θ), about 13.7±0.2 (2Θ), about 14.2±0.2 (2Θ) and about 28.3±0.2 (2Θ).
In some preferred embodiments, crystalline form B comprises X-ray powder diffraction peaks of about 12.1±0.2 (2Θ), about 18.0±0.2 (2Θ), about 18.4±0.2 (2Θ), and about 18.7±0.2 (2Θ). Optionally, X-ray powder diffraction peaks of about 6.8±0.2 (2Θ), about 14.2±0.2 (2Θ), about 19.8±0.2 (2Θ), and about 28.3±0.2 (2Θ), are comprised.
In further preferred embodiments, the crystalline form B according to the invention comprises the X-ray powder diffraction peaks of about 6.8±0.2 (2Θ), about 12.1±0.2 (2Θ), about 18.7±0.2 (2Θ), and about 28.3±0.2 (2Θ), optionally with one or more additional peaks selected from about 14.2±0.2 (2Θ), about 18.0±0.2 (2Θ), about 18.4±0.2 (2Θ), about 19.8±0.2 (2Θ), and about 28.3±0.2 (2Θ).
In further preferred embodiments, crystalline form B comprises X-ray powder diffraction peaks of about 12.1±0.2 (2Θ), about 18.0±0.2 (2Θ), about 18.4±0.2 (2Θ), about 18.7±0.2 (2Θ), and about 19.8±0.2 (2Θ). Optionally, an additional X-ray powder diffraction peak of about 28.3±0.2 (2Θ) may be comprised. Also optionally, additional X-ray powder diffraction peaks of about 6.8±0.2 (2Θ), about 14.2±0.2 (2Θ), about 20.8±0.2 (2Θ), and about 15.6±0.2 (2Θ) may be comprised, either in addition to the peak of about 28.3±02 (2Θ) or alternatively. Optionally, in some preferred embodiments, crystalline form B comprises at least one additional X-ray powder diffraction peak selected from of about 7.4±0.2 (2Θ), about 22.1±0.2 (2Θ) and about 13.7±0.2 (2Θ). In preferred embodiments, crystalline form A comprises all of the aforementioned optional additional X-ray peaks.
Crystalline form B according to the invention may further be characterized that it has a Raman peak at about 1643 cm−1 and/or one Raman peak at about 1578 cm−1.
Crystalline form B according to the invention may further be characterized that it has a Raman peak at about 1643 cm−1 and/or one Raman peak at about 1578 cm−1 and/or one peak selected from the group of about 1601 cm−1, about 84 cm−1, about 109 cm−1, about 1001 cm−1, about 1618 cm−1, about 1563 cm−1, about 1643 cm−1, and about 3063 cm−1.
Additionally, crystalline form B may have one or more Raman peaks selected from the group consisting of about 166 cm−1, about 220 cm−1, about 272 cm−1, about 619 cm−1, about 676 cm−1, about 781 cm−1, about 862 cm−1, about 888 cm−1, about 976 cm−1, about 1010 cm−1, about 1029 cm−1, about 1047 cm−1, about 1158 cm−1, about 1180 cm−1, about 1203 cm−1, about 1266 cm−1, about 1300 cm−1, about 1441 cm−1, about 1449 cm−1, about 1465 cm−1, about 1578 cm−1, about 2935 cm−1, about 2967 cm−1 and about 3001 cm−1.
Also additionally, crystalline form B may have one or more Raman peaks selected from the group consisting of about 333 cm−1, about 365 cm−1, about 387 cm−1, about 405 cm−1, about 435 cm−1, about 463 cm−1, about 505 cm−1, about 541 cm−1, about 590 cm−1, about 643 cm−1, about 725 cm−1, about 745 cm−1, about 802 cm−1, about 834 cm−1, about 929 cm−1, about 1087 cm−1, about 1112 cm−1, about 1326 cm−1, about 1341 cm−1, about 1373 cm−1, about 1405 cm−1, about 1861 cm−1, about 2136 cm−1, about 2172 cm−1, about 2328 cm−1, about 2489 cm−1, about 2519 cm−1, about 2558 cm−1, about 2772 cm−1, about 2794 cm−1, about 2843 cm−1, about 2890 cm−1, about 3153 cm−1, about 3197 cm−1, about 3243 cm−1, about 3323 cm−1 and about 3459 cm−1.
In DSC analyses, crystalline form B according to the present invention preferably exhibits an endothermal event with a peak temperature of about 80-110° C., preferably of about 80-95° C., and/or an endothermal event with a peak temperature of about 230 to 255, preferably of about 237-250° C., more preferably of about 240-248° C. In some preferred embodiments crystalline form B exhibits an endothermal event with a peak temperature of about 242-248° C. Additionally, crystalline form B preferably exhibits an exothermal event with a peak temperature of about 140-150° C., preferably 142 to 148° C., more preferably 143-147° C., and/or an exothermal event with a peak temperature of about 200-230° C., preferably about 205-230° C.
A further aspect of the present invention relates to a crystalline form C.
Preferably, the crystalline form C according to the invention has one or more X-ray powder diffraction peaks selected from the group consisting of about 9.7±0.2 (2Θ), about 11.6±0.2 (2Θ), about 14.0±0.2 (2Θ), and about 17.9±0.2 (2Θ).
In some preferred embodiments, the crystalline form C has an X-ray powder diffraction peak of about 17.9±0.2 (2Θ). In some preferred embodiments the crystalline form comprises X-ray powder diffraction peaks of about 17.9±0.2 (2Θ), about 14.0±0.2 (2Θ) and/or about 13.0±0.2 (2Θ).
In some preferred embodiments, crystalline form C comprises X-ray powder diffraction peaks of 17.9±0.2 (2Θ), about 14.0±0.2 (2Θ) and about 13.0±0.2 (2Θ). In further preferred embodiments, crystalline form C may further comprise X-ray powder diffraction peaks of about 7.1±0.2 (2Θ), about 9.7±0.2 (2Θ), about 11.6±0.2 (2Θ), and about 12.5±0.2 (2Θ).
To discriminate between crystalline form C and 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 it might be more advantageous to alternatively or additionally look at unique peaks in the X-ray diffraction diagram of C compared to the X-ray diffraction diagram of A. Such characteristic X-ray peaks are besides those of about 9.7±0.2 (2Θ), about 13.0±0.2 (2Θ), and about 14.0±0.2 (2Θ) X-ray peaks of about 7.0±0.2 (2Θ), about 7.1±0.2 (2Θ), at about 11.3±0.2 (2Θ), at about 14.3±0.2 (2Θ), at about 21±0.2 (2Θ) and at about 21.1±0.2 (2Θ).
Consequently, in some preferred embodiments of the invention crystalline form C comprises at least one X-ray peak selected from the group consisting of about 9.7±0.2 (2Θ), about 13.0±0.2 (2Θ), and about 14.0±0.2 (2Θ) and at least one additional X-ray peak selected from about 7.0±0.2 (2Θ), about 7.1±0.2 (2Θ), at about 11.3±0.2 (2Θ), at about 14.3±0.2 (2Θ), at about 21±0.2 (2Θ) and at about 21.1±0.2 (2Θ).
In some preferred embodiments, crystalline form C comprises X-ray powder diffraction peaks of about 17.9±0.2 (2Θ), about 14.0±0.2 (2Θ), about 13.0±0.2 (2Θ) and about 11.6±0.2 (2Θ). Optionally, X-ray powder diffraction peaks of about 7.1±0.2 (2Θ), of about 9.7±0.2 (2Θ), about 12.5±0.2 (2Θ) and of about 14.3±0.2 (2Θ) are further comprised.
In further preferred embodiments, the crystalline form C according to the invention comprises X-ray powder diffraction peaks at about 9.7±0.2 (2Θ), about 11.6±0.2 (2Θ), about 14.0±0.2 (2Θ), and about 17.9±0.2 (2Θ) and optionally one or more peaks selected from the group consisting of about 7.1±0.2 (2Θ), about 12.5±0.2 (2Θ), of about 13.0±0.2 (2Θ) and of about 14.3±0.2 (2Θ).
In further preferred embodiments, crystalline form C comprises X-ray powder diffraction peaks of about 17.9±0.2 (2Θ), about 14.0±0.2 (2Θ), 13.0±0.2 (2Θ), about 11.6±0.2 (2Θ) and about 9.7±0.2 (2Θ). Optionally, an additional X-ray powder diffraction peak of about 12.5±0.2 (2Θ) may be comprised. Also optionally, additional X-ray powder diffraction peaks of about 7.1±0.2 (2Θ), about 11.3±0.2 (2Θ), and about 14.3±0.2 (2Θ) may be comprised, either in addition to the peak of about 12.5±02 (2Θ) or alternatively.
In further preferred embodiments, crystalline form C comprises X-ray powder diffraction peaks of about 7.0±0.2 (2Θ), about 7.1±0.2 (2Θ), about 9.7±0.2 (2Θ), about 11.3±0.2 (2Θ), about 11.6±0.2 (2Θ), about 12.5±0.2 (2Θ), about 13.0±0.2 (2Θ), about 14.0±0.2 (2Θ), about 14.3±0.2 (2Θ), about 17.9±0.2 (2Θ), and about 21.0±0.2 (2Θ). Optionally, crystalline form C may further comprise one or more X-ray peaks selected from the group consisting of about 21.1±0.2 (2Θ) and/or about 26.3. In some preferred embodiments, crystalline form C additionally comprises all of the aforementioned optional X-ray peaks.
In DSC analyses, crystalline form C according to the present invention preferably exhibits an endothermal event with a peak temperature of about 60-150° C., preferably of about 100-150° C., more preferably of about 120-150° C., and/or an endothermal event with a peak temperature of about 230 to 255, preferably of about 237-250° C., more preferably of about 240-248° C. In some preferred embodiments crystalline form B exhibits an endothermal event with a peak temperature of about 242-248° C. Additionally, crystalline form C preferably exhibits an exothermal event with a peak temperature of about 175-220° C., preferably 175-215° C., more preferably 175-210° C.
A further aspect of the present invention relates to a crystalline form D.
Preferably, the crystalline form D according to the invention has one or more X-ray powder diffraction peaks selected from the group consisting of about 8.7±0.2 (2Θ), about 11.6±0.2 (2Θ), about 16.6±0.2 (2Θ), about and 21.2±0.2 (2Θ).
In some preferred embodiments, the crystalline form D has an X-ray powder diffraction peak of about 8.7±0.2 (2Θ). In some preferred embodiments the crystalline form comprises X-ray powder diffraction peaks of about 8.7±0.2 (2Θ), about 16.6±0.2 (2Θ) and/or about 21.2±0.2 (2Θ).
In some preferred embodiments, crystalline form D comprises X-ray powder diffraction peaks of about 8.7±0.2 (2Θ), about 16.6±0.2 (2Θ) and about 21.2±0.2 (2Θ). In further preferred embodiments, crystalline form D may further comprise X-ray powder diffraction peaks of about 17.2±0.2 (2Θ), about 11.6±0.2 (2Θ), about 20.0±0.2 (2Θ) and about 11.0±0.2 (2Θ).
To discriminate between crystalline form D and 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 it might be more advantageous to alternatively or additionally look at unique peaks in the X-ray diffraction diagram of D compared to the X-ray diffraction diagram of A. Such a characteristic X-ray peak is the one of about 21.2±0.2 (2Θ).
Consequently, in some preferred embodiments of the invention crystalline form D comprises at least one X-ray peak selected from the group consisting of about 8.7±0.2 (2Θ), about 11.6±0.2 (2Θ), about 16.6±0.2 (2Θ), about 17.2±0.2 (2Θ), and the additional X-ray peak of about and about 21.2±0.2 (2Θ).
In some preferred embodiments, crystalline form D comprises X-ray powder diffraction peaks of about 8.7±0.2 (2Θ), about 16.6±0.2 (2Θ), about 17.2±0.2 (2Θ) and about 21.2±0.2 (2Θ). Optionally, X-ray powder diffraction peaks of about 11.6±0.2 (2Θ), about 20.0±0.2 (2Θ), about 11.0±0.2 (2Θ), and about 17.6±0.2 (2Θ) may be further comprised.
In further preferred embodiments, crystalline form D comprises X-ray powder diffraction peaks of about 8.7±0.2 (2Θ), about 11.6±0.2 (2Θ), about 16.6±0.2 (2Θ), about and 21.2±0.2 (2Θ) and optionally, X-ray powder diffraction peaks of about 11.0±0.2 (2Θ), about 17.2±0.2 (2Θ), about 17.6±0.2 (2Θ), and about 20.0±0.2 (2Θ) may be further comprised.
In further preferred embodiments, crystalline form D comprises X-ray powder diffraction peaks of about 8.7±0.2 (2Θ), about 16.6±0.2 (2Θ), about 21.2±0.2 (2Θ), about 17.2±0.2 (2Θ) and about 11.6±0.2 (2Θ). Optionally, an additional X-ray powder diffraction peak of about 20.0±0.2 (2Θ) may be comprised. Also optionally, additional X-ray powder diffraction peaks of about 11.0±0.2 (2Θ), about 17.6±0.2 (2Θ), and/or about 18.2±0.2 (2Θ) and/or about 22.7±0.2 (2Θ) and/or about 11.3±0.2 (2Θ) and/or about 12.5±0.2 (2Θ) and/or about 26.4.2±0.2 (2Θ) may be comprised, either in addition to the peak of about 20.0±02 (2Θ) or alternatively.
Crystalline form D according to the invention may further be characterized that it has a Raman peak at about 1612 cm−1 and/or one Raman peak at about 1199 cm−1.
Crystalline form D according to the invention may further be characterized that it has a Raman peak at about 1612 cm−1 and/or one Raman peak at about 1199 cm−1 and/or one peak selected from the group of about 84 cm−1, about 121 cm−1, about 158 cm−1, about 1000 cm−1, about 1563 cm−1, and about 1599 cm−1.
Additionally, crystalline form D may have one or more Raman peaks selected from the group consisting of about 237 cm−1, about 268 cm−1, about 294 cm−1, about 335 cm−1, about 372 cm−1, about 402 cm−1, about 434 cm−1, about 466 cm−1, about 489 cm−1, about 503 cm−1, about 542 cm−1, about 618 cm−1, about 675 cm−1, about 782 cm−1, about 886 cm−1, about 1011 cm−1, about 1030 cm−1, about 1056 cm−1, about 1154 cm−1, about 1171 cm−1, about 1199 cm−1, about 1263 cm−1, about 1289 cm−1, about 1325 cm−1, about 1447 cm−1, about 1464 cm−1, about 1576 cm−1, about 1644 cm−1, about 2946 cm−1, about 2980 cm−1, about 3010 cm−1 and about 3065 cm−1.
Also additionally, crystalline form D may have one or more Raman peaks of about 579 cm−1, about 646 cm−1, about 696 cm−1, about 711 cm−1, about 727 cm−1, about 799 cm−1, about 834 cm−1, about 867 cm−1, about 921 cm−1, about 970 cm−1, about 1085 cm−1, about 1115 cm−1, about 1343 cm−1, about 1377 cm−1, about 1406 cm−1, about 2792 cm−1, about 2846 cm−1, about 2895 cm−1, about 3152 and about 3196 cm−1.
In DSC analyses, crystalline form D according to the present invention preferably exhibits an endothermal event with a peak temperature of about 140-180° C., preferably of about 145-170° C., more preferably of about 145-165° C., and/or an endothermal event with a peak temperature of about 230 to 255, preferably of about 237-250° C., more preferably of about 240-248° C. In some preferred embodiments crystalline form B exhibits an endothermal event with a peak temperature of about 242-248° C. Additionally, crystalline form D preferably exhibits an exothermal event with a peak temperature of about 200-230° C., preferably 205-225° C.
A further aspect of the present invention relates to a crystalline form E.
Preferably, the crystalline form E according to the invention has one or more X-ray powder diffraction peaks selected from the group consisting of about 6.9±0.2 (2Θ), about 8.1±0.2 (2Θ), about 18.3±0.2 (2Θ), and about 20.8±0.2 (2Θ).
In some preferred embodiments, the crystalline form E has an X-ray powder diffraction peak of about 18.3±0.2 (2Θ). In some preferred embodiments the crystalline form comprises X-ray powder diffraction peaks of about 18.3±0.2 (2Θ), about 6.9.0±0.2 (2Θ) and/or about 8.1±0.2 (2Θ).
In some preferred embodiments, crystalline form E comprises X-ray powder diffraction peaks of about 18.3±0.2 (2Θ), about 6.9±0.2 (2Θ), and about 8.1±0.2 (2Θ). In further preferred embodiments, crystalline form E may further comprise X-ray powder diffraction peaks of about 20.8±0.2 (2Θ), about 10.4±0.2 (2Θ), and about 13.8±0.2 (2Θ).
To discriminate between crystalline form E and crystalline form A 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 it might be more advantageous to alternatively or additionally look at unique peaks in the X-ray diffraction diagram of E compared to the X-ray diffraction diagram of A. Such characteristic X-ray peaks are besides those of about 6.9±0.2 (2Θ), about 8.1±0.2 (2Θ) and about 20.8±0.2 (2Θ) X-ray peaks of about 13.7±0.2 (2Θ), about 28.1±0.2 (2Θ), about 13.9±0.2 (2Θ), about 21.1±0.2 (2Θ), and about 19.0±0.2 (2Θ).
Consequently, in some preferred embodiments of the invention crystalline form C comprises at least one X-ray peak selected from the group consisting of about 6.9±0.2 (2Θ), about 8.1±0.2 (2Θ) and about 20.8±0.2 (2Θ) and at least one additional X-ray peak selected from about 13.7±0.2 (2Θ), about 28.1±0.2 (2Θ), about 13.9±0.2 (2Θ), about 21.1±0.2 (2Θ), and about 19.0±0.2 (2Θ).
In some preferred embodiments, crystalline form E comprises X-ray powder diffraction peaks of about 6.9±0.2 (2Θ), about 8.1±0.2 (2Θ), about 18.3±0.2 (2Θ) and about 20.8±0.2 (2Θ). Optionally, X-ray powder diffraction peaks of about 10.4±0.2 (2Θ), about 13.8±0.2 (2Θ), about 28.1±0.2 (2Θ), and/or about 13.9±0.2 (2Θ) and/or about 17.9±0.2 (2Θ) are further comprised.
In further preferred embodiments, crystalline form E comprises X-ray powder diffraction peaks of about 6.9±0.2 (2Θ), about 8.1±0.2 (2Θ), about 18.3±0.2 (2Θ), about 20.8±0.2 (2Θ), and about 10.4±0.2 (2Θ). Optionally, and X-ray powder diffraction peak of about 13.8±0.2 (2Θ) may be comprised. Also optionally, additional X-ray powder diffraction peaks of about 28.1±0.2 (2Θ), about 13.9±0.2 (2Θ), about 17.9±0.2 (2Θ) and about 16.9±0.2 (2Θ) may be comprised, either in addition to the peak of about 13.8±02 (2Θ) or alternatively.
In further preferred embodiments, crystalline form E comprises X-ray powder diffraction peaks of about 6.9±0.2 (2Θ), about 8.1±0.2 (2Θ), about 10.4±0.2 (2Θ), about 12.1±0.2 (2Θ), about 13.8±0.2 (2Θ), about 13.9±0.2 (2Θ), about 16.4±0.2 (2Θ), 16.6±0.2 (2Θ), about 16.9±0.2 (2Θ), about 17.9±0.2 (2Θ), about 18.3±0.2 (2Θ), about 18.7±0.2 (2Θ), about 19.0±0.2 (2Θ), about 20.8±0.2, about 21.1±0.2 (2Θ), about 27.5±0.2 (2Θ), and about 28.1±0.2 (2Θ).
In DSC analyses, crystalline form E according to the present invention preferably exhibits an endothermal event with a peak temperature of about 135-150° C., preferably of about 140-150° C., more preferably of about 143-146° C., and/or an endothermal event with a peak temperature of about 230 to 255, preferably of about 237-250° C., more preferably of about 240-248° C. In some preferred embodiments crystalline form E exhibits an endothermal event with a peak temperature of about 242-248° C. Additionally, crystalline form E preferably exhibits an exothermal event with a peak temperature of about 190-210° C., preferably about 197-212° C.
A further aspect of the present invention relates to a crystalline form F.
Preferably, the crystalline form F according to the invention has one or more X-ray powder diffraction peaks selected from the group consisting of about 8.7±0.2 (2Θ), about 12.5±0.2 (2Θ), and 20.9±0.2 (2Θ).
In some preferred embodiments, the crystalline form F has an X-ray powder diffraction peak of about 12.5±0.2 (2Θ). In some preferred embodiments the crystalline form comprises X-ray powder diffraction peaks of about 8.7±0.2 (2Θ), about 12.5±0.2 (2Θ) and/or about 20.9±0.2 (2Θ).
In some preferred embodiments, crystalline form F comprises X-ray powder diffraction peaks of about 8.7±0.2 (2Θ), about 12.5±0.2 (2Θ) and about 20.9±0.2 (2Θ). In further preferred embodiments, crystalline form F may further comprise one or more X-ray powder diffraction peaks selected from the groups consisting of about 11.3±0.2 (2Θ), about 16.7±0.2 (2Θ), about 25.2±0.2 (2Θ) and about 25.9±0.2 (2Θ).
In some preferred embodiments, crystalline form F comprises at least on X-ray powder diffraction peak selected from the group consisting of about 8.7±0.2 (2Θ), about 12.5±0.2 (2Θ), and about 20.9±0.2 (2Θ) and may optionally further comprise at least one X-ray peak selected from the group consisting of 11.3±0.2 (2Θ), about 16.7±0.2 (2Θ), about 18.4±0.2 (2Θ), about 25.2±0.2 (2Θ), about 25.9±0.2 (2Θ) and about 26.3±0.2 (2Θ).
To discriminate between crystalline form F and 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 it might be more advantageous to alternatively or additionally look at unique peaks in the X-ray diffraction diagram of F compared to the X-ray diffraction diagram of A. Such characteristic X-ray peaks are those of about 11.3±0.2 (2Θ), about 20.9±0.2 (2Θ), and about 25.2±0.2 (2Θ).
Consequently, in some preferred embodiments of the invention crystalline form F comprises at least one X-ray peak selected from the group consisting of about 11.3±0.2 (2Θ), about 20.9±0.2 (2Θ), and about 25.2±0.2 (2Θ), and may optionally comprise one or more X-ray peaks selected from the group consisting of 8.7±0.2 (2Θ), about 12.5±0.2 (2Θ), about 16.7±0.2 (2Θ), about 18.4±0.2 (2Θ), about 25.9±0.2 (2Θ) and about 26.3±0.2 (2Θ).
A further aspect of the present invention relates to a crystalline form G.
Preferably, the crystalline form G according to the invention has one or more X-ray powder diffraction peaks selected from the group consisting of about 6.6±0.2 (2Θ), about 8.0±0.2 (2Θ) about 18.0±0.2 (2Θ), and about 18.9±0.2 (2Θ).
In some preferred embodiments, the crystalline form G has an X-ray powder diffraction peak of about 6.6±0.2 (2Θ). In some preferred embodiments the crystalline form comprises X-ray powder diffraction peaks of about 6.6±0.2 (2Θ), about 18.0±0.2 (2Θ) and/or about 18.4±0.2 (2Θ).
In some preferred embodiments, crystalline form G comprises X-ray powder diffraction peaks of about 6.6±0.2 (2Θ), about 18.0±0.2 (2Θ) and about 18.4±0.2 (2Θ). In further preferred embodiments, crystalline form G may further comprise X-ray powder diffraction peaks of about 8.0±0.2 (2Θ), about 13.9±0.2 (2Θ), about 18.8±0.2 (2Θ) and about 19.3±0.2 (2Θ).
In some preferred embodiments, crystalline form G comprises X-ray powder diffraction peaks of about 6.6±0.2 (2Θ), about 8.0±0.2 (2Θ), about 18.0±0.2 (2Θ), and about 18.4±0.2 (2Θ). Optionally, X-ray powder diffraction peaks of about 13.3±0.2 (2Θ), 13.9±0.2 (2Θ), about 18.8±0.2 (2Θ), and about 19.3±0.2 (2Θ).
In further preferred embodiments crystalline form G comprises the X-ray powder diffraction peaks (CuKα radiation) of 6.6±0.2 (2Θ), 8.0±0.2 (2Θ), 18.0±0.2 (2Θ), and 18.9±0.2 (2Θ) and may optionally comprise one or more additional peaks selected from the group consisting of about 13.3±0.2 (2Θ), 13.9±0.2 (2Θ), about 18.4±0.2 (2Θ), about 18.8±0.2 (2Θ), and about 19.3±0.2 (2Θ)
In further preferred embodiments, crystalline form G comprises X-ray powder diffraction peaks of about 6.6±0.2 (2Θ), about 8.0±0.2 (2Θ), about 18.0±0.2 (2Θ), about 18.4±0.2 (2Θ), and about 18.9±0.2 (2Θ). Optionally, an additional X-ray powder diffraction peak of about 19.3±0.2 (2Θ) may be comprised. Also optionally, one or more additional X-ray powder diffraction peaks selected from the group consisting of about 7.0±0.2 (2Θ), about 10.4±0.2 (2Θ), about 11.8±0.2 (2Θ), about 12.4±0.2 (2Θ), about 13.3±0.2 (2Θ), about 13.9±0.2 (2Θ), about 15.5±0.2 (2Θ), about 15.6±0.2 (2Θ), about 17.6±0.2 (2Θ), and about 19.7±0.2 (2Θ).
To discriminate between crystalline form G and 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 it might be more advantageous to alternatively or additionally look at unique peaks in the X-ray diffraction diagram of G compared to the X-ray diffraction diagram of A. Such characteristic X-ray peaks are those of about 6.6±0.2 (2Θ), about 7.0±0.2 (2Θ), about 8.0±0.2 (2Θ), about 13.3±0.2 (2Θ), about 13.9±0.2 (2Θ), and about 19.3±0.2 (2Θ). Consequently, in some preferred embodiments of the invention crystalline form G comprises at least one X-ray peak selected from the group consisting of about 6.6±0.2 (2Θ), about 8.0±0.2 (2Θ), and about 19.3±0.2 (2Θ), and optionally at least one additional X-ray peak selected from the group consisting of about 7.0±0.2 (2Θ), about 13.3±0.2 (2Θ), and about 13.9±0.2 (2Θ).
In DSC analyses, crystalline form G according to the present invention preferably exhibits an endothermal event with a peak temperature of about 65-150° C., preferably of about 70-100° C., and/or an endothermal event with a peak temperature of about 230 to 255, preferably of about 237-250° C., more preferably of about 240-248° C. In some preferred embodiments crystalline form E exhibits an endothermal event with a peak temperature of about 242-248° C. Additionally, crystalline form E preferably exhibits an exothermal event with a peak temperature of about 200-220° C., preferably about 204-220° C.
A further aspect of the present invention relates to a crystalline form H
Preferably, the crystalline form H according to the invention has one or more X-ray powder diffraction peaks selected from the group consisting of about 7.1±0.2 (2Θ), about 8.0±0.2 (2Θ), about 18.2±0.2 (2Θ), and about 28.3±0.2 (2Θ).
In some preferred embodiments, the crystalline form H has an X-ray powder diffraction peak of about 18.2±0.2 (2Θ). In some preferred embodiments the crystalline form comprises X-ray powder diffraction peaks of about 8.0±0.2 (2Θ), about 18.2±0.2 (2Θ) and/or about 19.7±0.2 (2Θ).
In some preferred embodiments, crystalline form H comprises X-ray powder diffraction peaks of about 8.0±0.2 (2Θ), about 18.2±0.2 (2Θ), and about 19.7±0.2 (2Θ), and optionally, a further peak of about 18.1±0.2 (2Θ). In some preferred embodiments, crystalline form H may optionally further comprise X-ray powder diffraction peaks of about 17.7±0.2 (2Θ), about 18.8±0.2 (2Θ), and about 19.2±0.2 (2Θ).
In some preferred embodiments, crystalline form H comprises X-ray powder diffraction peaks of about 8.0±0.2 (2Θ), about 18.1±0.2 (2Θ), about 18.2±0.2 (2Θ), and about 19.7±0.2 (2Θ). Optionally, further X-ray peaks of about 17.7±0.2 (2Θ), about 18.8±0.2 (2Θ), about 19.2±0.2 (2Θ), and about 20.7±0.2 (2Θ) may be comprised.
In further preferred embodiments the crystalline form H according to the invention comprises the X-ray powder diffraction peaks of about 7.1±0.2 (2Θ), about 8.0±0.2 (2Θ), about 18.2±0.2 (2Θ), and about 28.3±0.2 (2Θ), and may optionally comprise one or more additional peaks selected from the group consisting of 17.7±0.2 (2Θ), about 18.1±0.2 (2Θ), about 18.3±0.2 (2Θ), about 18.8±0.2 (2Θ), about 19.2±0.2 (2Θ), about 19.7±0.2 (2Θ), and about 20.7±0.2 (2Θ).
In further preferred embodiments, crystalline form H comprises X-ray powder diffraction peaks of about 8.0±0.2 (2Θ), about 18.1±0.2 (2Θ), about 18.2±0.2 (2Θ), about 19.2±0.2 (2Θ), and about 19.7±0.2 (2Θ). Optionally, an additional X-ray powder diffraction peak of about 17.7±0.2 (2Θ) may be comprised. Also optionally, additional X-ray powder diffraction peaks of about 7.1±0.2 (2Θ), about 17.3±0.2 (2Θ), about 17.7±0.2 (2Θ), about 18.8±0.2 (2Θ), and about 20.7±0.2 (2Θ), may be comprised, either in addition to the peak of 17.7±02 (2Θ) or alternatively. Optionally, in some preferred embodiments, crystalline form H comprises at least one additional X-ray powder diffraction peak selected from about 10.4±02 (2Θ), about 17.5±02 (2Θ), about 20.9±02 (2Θ), about 22.3±02 (2Θ), and about 28.3±02 (2Θ). In further preferred embodiments, crystalline form H comprises all of the aforementioned optional additional X-ray peaks.
In order to discriminate between crystalline form H and crystalline form A it might be more advantageous to alternatively or additionally look at unique peaks in the X-ray diffractogram of crystalline form H where form A shows no lines with significant intensity. Such characteristic X-ray peaks are those of about 19.2±0.2 (2Θ), about 7.1±0.2 (2Θ), about 20.9±02 (2Θ), and about 28.3±02 (2Θ). Consequently, in some preferred embodiments of the invention crystalline form H comprises an X-ray peak of about 19.2±0.2 (2Θ), and at least one X-ray peak selected from the group consisting of about 7.1±0.2 (2Θ), about 20.9±02 (2Θ), and about 28.3±02 (2Θ).
In DSC analyses, crystalline form H according to the present invention preferably exhibits an endothermal event with a peak temperature of about 140-160° C., preferably of about 145-160° C., more preferably of about 153-156° C., and/or an endothermal event with a peak temperature of about 230 to 255, preferably of about 237-250° C., more preferably of about 240-248° C. In some preferred embodiments crystalline form H exhibits an endothermal event with a peak temperature of about 242-248° C. Additionally, crystalline form H preferably exhibits an exothermal event with a peak temperature of about 150-190° C., preferably about 163-175° C.
A further aspect of the present invention relates to a crystalline form I
Preferably, the crystalline form I according to the invention has one or more X-ray powder diffraction peaks selected from the group consisting of about 7.1±0.2 (2Θ), about 11.8±0.2 (2Θ), about 14.3±0.2 (2Θ), and about 17.5±0.2 (2Θ).
In some preferred embodiments, crystalline form I has an X-ray powder diffraction peak of about 17.5±0.2 (2Θ). In some preferred embodiments crystalline form I comprises X-ray powder diffraction peaks of about 7.1±0.2 (2Θ) and about 17.5±0.2 (2Θ).
In some preferred embodiments, crystalline form I comprises X-ray powder diffraction peaks of about 7.1±0.2 (2Θ), about 11.8±0.2 (2Θ) and about 17.5±0.2 (2Θ), and optionally, a further peak at about 12.7±0.2 (2Θ). In further preferred embodiments, crystalline form I may further comprise X-ray powder diffraction peaks of about 14.2±0.2 (2Θ), about 14.6±0.2 (2Θ), and about 15.7±0.2 (2Θ).
In some preferred embodiments, crystalline form I comprises X-ray powder diffraction peaks of about 7.1±0.2 (2Θ), about 11.8±0.2 (2Θ), about 12.7±0.2 (2Θ), and about 17.5±0.2 (2Θ). Optionally, X-ray powder diffraction peaks of about 14.2±0.2 (2Θ), about 14.6±0.2 (2Θ), about 15.7±0.2 (2Θ), and 19.6±0.2 (2Θ) are additionally comprised.
In further preferred embodiments, crystalline form I comprises X-ray powder diffraction peaks of about 7.1±0.2 (2Θ), about 11.8±0.2 (2Θ), about 14.3±0.2 (2Θ), and about 17.5±0.2 (2Θ) and may optionally comprise additional peaks selected from the group consisting of about 12.7±0.2 (2Θ), about 14.2±0.2 (2Θ), about 14.6±0.2 (2Θ), about 15.7±0.2 (2Θ), and 19.6±0.2 (2Θ).
In further preferred embodiments, crystalline form I comprises X-ray powder diffraction peaks of about 7.1±0.2 (2Θ), about 11.8±0.2 (2Θ), about 12.7±0.2 (2Θ), about 14.2±0.2 (2Θ), and about 17.5±0.2 (2Θ).
Optionally, an additional X-ray powder diffraction peak of about 14.6±0.2 (2Θ) may be comprised. Also optionally, additional X-ray powder diffraction peaks of about 9.7.±0.2 (2Θ), about 15.1±0.2 (2Θ), and about 15.7±0.2 (2Θ), and/or about 19.6±0.2 (2Θ) may be comprised. Optionally, in some preferred embodiments, crystalline form I comprises at least one additional X-ray powder diffraction peak selected from of about 11.0±0.2 (2Θ), about 16.4±0.2 (2Θ), about 17.9±0.2 (2Θ), about 18.9±0.2 (2Θ), about 21.2±0.2 (2Θ), about 21.6±0.2 (2Θ), about 22.9±0.2 (2Θ), and about 26.3±0.2 (2Θ). In some preferred embodiments, crystalline form I comprises all of the aforementioned optional additional X-ray peaks.
To discriminate between crystalline form I and crystalline form A the X-ray peaks of about 7.1±0.2 (2Θ), about 11.0±0.2 (2Θ), about 14.2±0.2 (2Θ), about 14.6±0.2 (2Θ), about 18.9±0.2 (2Θ), and about 21.2±0.2 (2Θ) might be more advantageously used.
Consequently, in a preferred embodiment of the invention, form I comprises at least one X-ray peak selected from the group consisting of 7.1±0.2 (2Θ), and about 14.2±0.2 (2Θ), and at least one X-ray peak selected from the group consisting of about 11.0±0.2 (2Θ), about 14.6±0.2 (2Θ), about 18.9±0.2 (2Θ), and about 21.2±0.2 (2Θ) 18.7±0.2 (2Θ).
A further aspect of the present invention relates to a crystalline form J
Preferably, the crystalline form J according to the invention has one or more X-ray powder diffraction peaks selected from the group consisting of about 7.1±0.2 (2Θ), about 11.1±0.2 (2Θ), about 14.5±0.2 (2Θ), and about 19.7±0.2 (2Θ).
In some preferred embodiments, the crystalline form has an X-ray powder diffraction peak of about 7.1±0.2 (2Θ). In some preferred embodiments the crystalline form comprises X-ray powder diffraction peaks of about 7.1±0.2 (2Θ), about 11.1±0.2 (2Θ) and/or about 14.5±0.2 (2Θ).
In some preferred embodiments, crystalline form A comprises X-ray powder diffraction peaks of about 7.1±0.2 (2Θ), about 11.1±0.2 (2Θ) and about 19.7±0.2 (2Θ), and optionally, a further peak at about 14.5±0.2 (2Θ). In further preferred embodiments, crystalline form A may further comprise X-ray powder diffraction peaks of about 16.8±0.2 (2Θ), about 17.0±0.2 (2Θ), and about 20.4±0.2 (2Θ).
In some preferred embodiments, crystalline form J comprises X-ray powder diffraction peaks of about 7.1±0.2 (2Θ), about 11.1±0.2 (2Θ), about 14.5±0.2 (2Θ), and about 19.7±0.2 (2Θ). Optionally, X-ray powder diffraction peaks of about 16.8±0.2 (2Θ), about 17.0±0.2 (2Θ), about 20.4±0.2 (2Θ), and 23.1±0.2 (2Θ) are additionally comprised.
In further preferred embodiments, crystalline form J comprises X-ray powder diffraction peaks of about 7.1±0.2 (2Θ), about 11.1±0.2 (2Θ), about 14.5±0.2 (2Θ), about 17.0±0.2 (2Θ), and about 19.7±0.2 (2Θ). Optionally, an additional X-ray powder diffraction peak of about 20.4±0.2 (2Θ) may be comprised. Also optionally, additional X-ray powder diffraction peaks of about 15.0±0.2 (2Θ), about 16.6±0.2 (2Θ), about 16.8±0.2 (2Θ), and about 23.1±0.2 (2Θ) may be comprised, either in addition to the peak of about 20.4±02 (2Θ) or alternatively. Optionally, in some preferred embodiments, crystalline form G comprises at least one additional X-ray powder diffraction peak selected from of about 9.1±0.2 (2Θ) and about 15.3±0.2 (2Θ). In further preferred embodiments, crystalline form J comprises all of the aforementioned optional additional X-ray peaks.
To discriminate between crystalline form J and crystalline form A the X-ray peaks of about 7.1±0.2 (2Θ), about 9.1±0.2 (2Θ), about 11.1±0.2 (2Θ), about 14.5±0.2 (2Θ), about 21.3±0.2 (2Θ), about 23.1±0.2 (2Θ), about 25.3±0.2 (2Θ), about 28.2±0.2 (2Θ), and about 28.8±0.2 (2Θ) might be more advantageously used. Consequently, in a preferred embodiment of the invention, form B comprises at least one X-ray peak selected from the group consisting of 7.1±0.2 (2Θ), about 11.1±0.2 (2Θ), and about 14.5±0.2 (2Θ), and at least one X-ray peak selected from at about 18.7±0.2 (2Θ) in combination with one or more X-ray peaks from the group consisting of about 9.1±0.2 (2Θ), about 21.3±0.2 (2Θ), about 23.1±0.2 (2Θ), about 25.3±0.2 (2Θ), about 28.2±0.2 (2Θ), and about 28.8±0.2 (2Θ).
In DSC analyses, crystalline form J according to the present invention preferably exhibits an endothermal event with a peak temperature of about 230 to 255, preferably of about 237-250° C., more preferably of about 240-248° C. In some preferred embodiments crystalline form J exhibits an endothermal event with a peak temperature of about 242-248° C. Additionally, crystalline form J preferably exhibits an exothermal event with a peak temperature of about 180-190° C., preferably about 183-187° C.
A further aspect of the present invention relates to a crystalline form K
Preferably, the crystalline form K according to the invention has one or more X-ray powder diffraction peaks selected from the group consisting of about 7.1±0.2 (2Θ), about 10.0±0.2 (2Θ), about 14.3±0.2 (2Θ), and about 19.5±0.2 (2Θ).
In some preferred embodiments, crystalline form K has an X-ray powder diffraction peak of about 7.1±0.2 (2Θ). In some preferred embodiments the crystalline form comprises X-ray powder diffraction peaks of about 7.1±0.2 (2Θ), about 14.3±0.2 (2Θ) and/or about 19.5±0.2 (2Θ).
In some preferred embodiments, crystalline form K comprises X-ray powder diffraction peaks of about 7.1±0.2 (2Θ), about 14.3±0.2 (2Θ) and about 19.5±0.2 (2Θ), and optionally, a further peak at about 10.0±0.2 (2Θ). In further preferred embodiments, crystalline form K may further comprise X-ray powder diffraction peaks of about 15.1±0.2 (2Θ), about 15.4±0.2 (2Θ), and about 19.9±0.2 (2Θ).
In some preferred embodiments, crystalline form K comprises X-ray powder diffraction peaks of about 7.1±0.2 (2Θ), about 10.0±0.2 (2Θ), about 14.3±0.2 (2Θ), and about 19.5±0.2 (2Θ). Optionally, X-ray powder diffraction peaks of about 11.2±0.2 (2Θ), 15.1±0.2 (2Θ), about 15.4±0.2 (2Θ), and about 19.9±0.2 (2Θ), are additionally comprised.
In further preferred embodiments, crystalline form K comprises X-ray powder diffraction peaks of about 7.1±0.2 (2Θ), about 10.0±0.2 (2Θ), about 14.3±0.2 (2Θ), about 15.4±0.2 (2Θ), and about 19.4±0.2 (2Θ). Optionally, an additional X-ray powder diffraction peak of about 15.1±0.2 (2Θ) may be comprised. Also optionally, additional X-ray powder diffraction peaks of about 11.2±0.2 (2Θ), about 15.1±0.2 (2Θ), and about 19.9±0.2 (2Θ), either in addition to the peak of about 15.1±02 (2Θ) or alternatively. Optionally, in some preferred embodiments, crystalline form K comprises at least one additional X-ray powder diffraction peak selected from of about 21.4±0.2 (2Θ) and about 27.7±0.2 (2Θ). In some preferred embodiments, crystalline form K comprises all of the aforementioned optional additional X-ray peaks.
To discriminate between crystalline form K and crystalline form A the X-ray peaks of about 7.1±0.2 (2Θ), about 11.2±0.2 (2Θ), about 14.3±0.2 (2Θ), about 21.4±0.2 (2Θ), about 26.7±0.2 (2Θ), and about 27.7 might be more advantageously used. Consequently, in a preferred embodiment of the invention, crystalline form K comprises at least one X-ray peak selected from the group consisting of about 7.1±0.2 (2Θ), about 11.2±0.2 (2Θ), and about 14.3±0.2 (2Θ), and at least one X-ray peak selected from about 21.4±0.2 (2Θ), about 26.7±0.2 (2Θ), and about 27.7 4±0.2 (2Θ).
In DSC analyses, crystalline form K according to the present invention preferably exhibits an endothermal event with a peak temperature of about 90-145° C., preferably of about 120-140° C., more preferably of about 130-140° C., and/or an endothermal event with a peak temperature of about 230 to 255, preferably of about 237-250° C., more preferably of about 240-248° C. In some preferred embodiments crystalline form K exhibits an endothermal event with a peak temperature of about 242-248° C. Additionally, crystalline form K preferably exhibits an exothermal event with a peak temperature of about 180-190° C.
A further aspect of the present invention relates to a crystalline form L.
Preferably, the crystalline form L according to the invention has one or more X-ray powder diffraction peaks selected from the group consisting of about 8.1±0.2 (2Θ), about 12.0±0.2 (2Θ), about 17.1±0.2 (2Θ), and about 20.1±0.2 (2Θ).
In some preferred embodiments, crystalline form L has an X-ray powder diffraction peak of about 8.1±0.2 (2Θ). In some preferred embodiments the crystalline form comprises X-ray powder diffraction peaks of about 8.1±0.2 (2Θ), about 17.1±0.2 (2Θ) and/or about 20.1±0.2 (2Θ).
In some preferred embodiments, crystalline form L comprises X-ray powder diffraction peaks of about 8.1±0.2 (2Θ), about 17.1±0.2 (2Θ) and about 20.1±0.2 (2Θ), and optionally, a further peak at about 12.0±0.2 (2Θ). In further preferred embodiments, crystalline form K may further comprise X-ray powder diffraction peaks of about 24.3±0.2 (2Θ), about 21.2±0.2 (2Θ), and about 21.9±0.2 (2Θ).
In some preferred embodiments, crystalline form L comprises X-ray powder diffraction peaks of about 8.1±0.2 (2Θ), about 12.0±0.2 (2Θ), about 17.1±0.2 (2Θ), and about 20.1±0.2 (2Θ). Optionally, X-ray powder diffraction peaks of about 16.4±0.2 (2Θ), 21.2±0.2 (2Θ), 21.9±0.2 (2Θ), about and 24.3±0.2 (2Θ), are additionally comprised.
In further preferred embodiments, crystalline form L comprises X-ray powder diffraction peaks of about 8.1±0.2 (2Θ), about 12.0±0.2 (2Θ), about 17.1±0.2 (2Θ), about 20.1±0.2 (2Θ), and about 24.3±0.2 (2Θ). Optionally, an additional X-ray powder diffraction peak of about 21.2±0.2 (2Θ) may be comprised. Also optionally, additional X-ray powder diffraction peaks of about 7.7±0.2 (2Θ), about 16.4±0.2 (2Θ), and about 21.9±0.2 (2Θ), either in addition to the peak of about 21.2±02 (2Θ) or alternatively. Optionally, in some preferred embodiments, crystalline form L comprises one additional X-ray powder diffraction peak of 18.0±0.2 (2Θ). In preferred embodiments, crystalline form L comprises all of the aforementioned optional additional X-ray peaks.
To discriminate between crystalline form L and crystalline form A the X-ray peaks of about 8.1±0.2 (2Θ), about 21.2±0.2 (2Θ), and about 24.3±0.2 (2Θ), might be more advantageously used. Consequently, in a preferred embodiment of the invention, crystalline form K comprises an X-ray peak of about 8.1±0.2 (2Θ), about 21.2±0.2 (2Θ) and/or about 24.3±0.2 (2Θ).
In DSC analyses, crystalline form L according to the present invention preferably exhibits an endothermal event with a peak temperature of about 135 to 150° C., preferably of about 140-150° C., and/or an endothermal event with a peak temperature of about 230 to 255, preferably of about 237-250° C., more preferably of about 240-248° C. In some preferred embodiments crystalline form L exhibits an endothermal event with a peak temperature of about 242-248° C. Additionally, crystalline form L preferably exhibits an exothermal event with a peak temperature of about 170-210° C., preferably about 190-210° C.
A further aspect of the present invention relates to a crystalline form Q.
Preferably, the crystalline form Q according to the invention has one or more X-ray powder diffraction peaks selected from the group consisting of about 8.2±0.2 (2Θ), about 8.6±0.2 (2Θ), about 17.2±0.2 (2Θ), and about 24.4±0.2 (2Θ).
In some preferred embodiments, crystalline form Q has an X-ray powder diffraction peak of about 8.2±0.2 (2Θ). In some preferred embodiments the crystalline form comprises X-ray powder diffraction peaks of about 8.2±0.2 (2Θ), about 17.2±0.2 (2Θ) and/or about 24.4±0.2 (2Θ).
In some preferred embodiments, crystalline form Q comprises X-ray powder diffraction peaks of about 8.2±0.2 (2Θ), about 17.2±0.2 (2Θ) and about 24.4±0.2 (2Θ), and optionally, a further peak at about 8.6±0.2 (2Θ). In further preferred embodiments, crystalline form Q may further comprise X-ray powder diffraction peaks of about 11.0±0.2 (2Θ), about 12.0±0.2 (2Θ), and about 16.5±0.2 (2Θ).
In some preferred embodiments, crystalline form Q comprises X-ray powder diffraction peaks of about 8.2±0.2 (2Θ), about 17.2±0.2 (2Θ), about 24.4±0.2 (2Θ), and about 8.6±0.2 (2Θ). Optionally, X-ray powder diffraction peaks of about 11.0±0.2 (2Θ), about 12.0±0.2 (2Θ), about 16.5±0.2 (2Θ) and about 20.1±0.2 (2Θ), are additionally comprised.
In further preferred embodiments, crystalline form Q comprises X-ray powder diffraction peaks of about 8.2±0.2 (2Θ), about 8.6±0.2 (2Θ), about 17.2±0.2 (2Θ), about 24.4±0.2 (2Θ), and about 16.5±0.2 (2Θ). Optionally, an additional X-ray powder diffraction peak of about 11.0±0.2 (2Θ) may be comprised. Also optionally, X-ray powder diffraction peaks of about 11.5±0.2 (2Θ), 12.0±0.2 (2Θ), about 16.5±0.2 (2Θ) and about 20.1±0.2 (2Θ) are additionally comprised.
Optionally, in some preferred embodiments, crystalline form Q comprises one additional X-ray powder diffraction peak of 21.3±0.2 (2Θ). In preferred embodiments, crystalline form Q comprises all of the aforementioned optional additional X-ray peaks.
To discriminate between crystalline form Q and crystalline form A the X-ray peaks of about 8.2±0.2 (2Θ), about 11.0±0.2 (2Θ), about 21.3±0.2 (2Θ), and about 24.4±0.2 (2Θ) might be more advantageously used. Consequently, in a preferred embodiment of the invention, crystalline form Q comprises an X-ray peak of about 8.2±0.2 (2Θ), about 11.0±0.2 (2Θ) and/or about 24.4±0.2 (2Θ) and may optionally comprise an X-ray peak of about 21.3±0.2 (2Θ).
In DSC analyses, crystalline form Q according to the present invention preferably exhibits at least one endothermal event with a peak temperature of about 115 to 140° C., preferably of about 130-140° C., and/or an endothermal event with a peak temperature of about 155 to 165 and/or an endothermal event with a peak temperature of about 230 to 255, preferably of about 237-250° C., more preferably of about 240-248° C. In some preferred embodiments crystalline form L exhibits an endothermal event with a peak temperature of about 242-248° C. Additionally, crystalline form Q preferably exhibits an exothermal event with a peak temperature of about 180-210° C., preferably about 185-205° C.
Another aspect of the present invention relates to a process for the production of the crystalline form according to the invention.
In a preferred embodiment, the process comprises the step 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 in a solvent.


In step (a-1) 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 partially or even completely dissolved in the solvent.
Conventional solvents known to persons skilled in the art may be used as solvents in a suspension of this type, such as water or organic solvents selected from the group consisting of alcohols such as methanol, ethanol, n-propanol, iso-propanol and n-butanol; esters such as ethyl acetate, n-propyl acetate, iso-propyl acetate, n-butyl acetate and iso-butyl acetate; ketones such as acetone, 2-butanone, pentan-2-one, pentan-3-one, hexan-2-one and hexan-3-one; ethers such as tert-butyl methyl ether, diethylether, tetrahydrofuran, diisopropylether and 1,4-dioxane; nitriles such as acetonitril; aromatic hydrocarbons such as toluene; saturated hydrocarbons such as n-pentane, n-hexane and n-heptane; chlorinated hydrocarbons such as dichloromethane and chloroform; and also N-methyl-2-pyrrolidone, dimethyl formamide and dimethyl sulfoxide; and mixtures thereof.
In a preferred embodiment, the solvent comprises at least one alcohol selected from the group consisting of methanol, ethanol, n-propanol and iso-propanol.
In another preferred embodiment, the solvent comprises at least one organic solvent selected from the group consisting of n-pentane, n-hexane, tert-butylmethylether, ethylacetate, acetone, acetonitrile, diethylether, dichloromethane, tetrahydrofurane, ethylmethylketone and toluene or mixtures thereof.
In yet another preferred embodiment, the solvent additionally comprises water.
In still another preferred embodiment, the solvent consists of isopropanol or a mixture of isopropanol and water.
Preferably, in the process according to the invention, step (a-1) is carried out at a temperature below or at the boiling point of the respective solvent, preferably at a temperature not higher than 120° C., more preferably not higher than 100° C., even more preferably not higher than 90° C., and in particular in a temperature range of 40° C. to 90° C.
Preferably, in the process according to the invention, the suspension/solution obtained in step (a-1) is stirred for a time period of at least 0.3 h, preferably in the range of 0.3 h to 5 days, preferably 0.3 h to 4 days, more preferably 0.3 h to 2 days, still more preferably 0.3 h to 1 day, even more preferably between 0.3 h to 12 h, especially preferably 0.3 to 2 h.
Preferably, the process according to the invention further comprises the step

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


In preferred embodiments of the process according to the invention separation step (b-1) comprises the addition step of cooling the suspension or solution obtained in step (a-1) prior to the separation of the solid. This is especially preferred if step (a-1) is carried out at elevated temperatures and/or if 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 is completely or partially dissolved in the solvent.
Preferably, the process according to the invention further comprises the step

    (c-1) drying of the solid obtained in step (b-1).


Preferably, in the process according to the invention, step (c-1) takes place under air. However, drying under vacuum, more preferably at a vacuum of 0 to 900 mbar, even more preferably at a vacuum of 1 to 500 mbar, and in particular at a vacuum of 10 to 200 mbar is also possible.
Preferably, in the process according to the invention, step (c-1) takes place in a temperature range from 0 to 75° C., preferably from 10° C. to 60° C. more preferably from 20 to 55° C.
By a preferred embodiment of the process according to the present invention crystalline form A can be obtained. This preferred 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 0.3 h 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.


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.
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 0.3 h 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.


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.
A further aspect of the invention relates to crystalline form A obtainable by the process as described above.
In another preferred embodiment of the process according to the present invention crystalline form B can be obtained. This preferred embodiment comprises the step of

    (a-2) 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 in a solvent at a temperature in the range of 20° C. to 60° C., wherein the solvent is a mixture of water and an alcohol selected from the group consisting of ethanol, n-propanol and isopropanol, wherein the mixture may comprise up to 50 vol.-% water, preferably up to 30% water;
    (b-2) separating, preferably filtering off the solid obtained in step (a-2), and
    (c-2) drying the solid obtained in step (b-2).


Preferably, on or more of crystalline forms A, D or Q 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 is suspended in step (a-2)
In a preferred embodiment of this process, the crystalline form is step (a-2) is suspended in the solvent for at least 2 h, preferably, at least 6 h, more preferably 12 h. In further preferred embodiments crystalline form B is suspended in the solvent for between 2 h and 14 d, preferably between 12 h and 7 d, more preferably between 1 d and 5 d.
In preferred embodiments of this process, the solvent is a mixture of ethanol and water, wherein the mixture may contain between 99.9 and 50 vol.-% of ethanol. Preferably, the mixture comprises 60 to 75 vol.-% ethanol. In additional preferred embodiments the solvent is a mixture of n-propanol and water or of isopropanol and water. Preferably, in these mixtures the n-propanol or isopropanol is present in 60 to 99 vol.-%, preferably in 75 to 97 vol.-%.
In further preferred embodiments, the solid obtained from step (b-2) is dried in step (c-2) at a temperature in the range of 20° C. and 60° C., preferably 30° to 55° C., more preferably at 50° C. Optionally, the solid obtained in step (b-2) is dried in step (c-2) at reduced pressure.
A further aspect of the invention relates to crystalline form B obtainable by the process as described above.
In another preferred embodiment of the process according to the present invention crystalline form C can be obtained. This preferred embodiment comprises the step of

    (a-3) 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 in a solvent at a temperature in the range of 20° C. and the boiling point of the solvent, wherein the solvent is methanol or a mixture of water and methanol, wherein the mixture may comprise up to 50 vol.-% water, preferably up to 25 vol.-% water;
    (b-3) separating, preferably filtering off the solid obtained in step (a-3), and
    (c-3) drying the solid obtained in step (b-3).


Preferably, one or more of crystalline forms A, D, and E 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 are suspended in step (a-2).
In a preferred embodiment of this process, the crystalline form in step a-3 is suspended in the solvent for a time between at least 2 h and up to 14 d, preferably for at least 2 h to 24 h. The lower the temperature applied to the suspension in step (a-3) the longer the stirring time should be.
In further preferred embodiments, the solid obtained from step (b-3) is dried in step (c-3) at a temperature in the range of 20° C. and 40° C., preferably 20° to 30° C., more preferably at 20° C. Preferably, the solid obtained in step (b-3) is in step (c-3) dried at ambient pressure.
A further aspect of the invention relates to crystalline form C obtainable by the process as described above.
In another preferred embodiment of the process according to the present invention crystalline form D can be obtained. This preferred embodiment comprises the step of
In another preferred embodiment of the process according to the present invention crystalline form D can be obtained. This preferred embodiment comprises the step of

    (a-4) 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 0.3 h 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 acetonitrile, acetone and water, or mixtures of acetonitrile or acetone with water;
    (b-4) separating, preferably filtering off the solid obtained in step (a-4), and
    (c-4) drying the solid obtained in step (b-3).


Preferably, crystalline forms A, E, or G are suspended in step (a-4).
Preferably, the solvent is acetone and the temperature at which the crystalline form is suspended is the boiling point of acetone. Preferable, the suspension is maintained at this temperature of 0.3 to 1 h, preferably 0.5 h.
In a preferred embodiment, step (b-4) comprises the step of cooling the suspension to ambient temperature prior to separation the solvent from the solid obtained in step (a-4).
A further aspect of the invention relates to crystalline form D obtainable by the process as described above.
Another aspect of the invention relates to a process for the production of crystalline form E 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.
This process comprises the step:

    
    
        (a-4) 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 fumarate in water;
        (b-4) adding an excess of an organic base to the suspension and stirring the reaction mixture of at least 2 h; and
        (c-4) separating, preferably filtering off the solid obtained in step (b-4), and
        (d-4) drying the solid obtained in step (c-4).
    
    


In a preferred embodiment the organic base in step (b-4) is a dialkyl- or trialkylamine, preferably triethylamine.
In a further preferred embodiment, step (c-4) comprises as additional step (c-4.1) at least once slurrying the isolated solid in water and separating, preferably filtering off the solid obtained in step (c-4.1).
In a preferred embodiment the solid obtained in step (c-4/c-4.1) is dried at 40° C. to 75° C., preferably at 70° C. and preferably at reduced pressure.
A further aspect of the invention relates to crystalline form E obtainable by the process as described above.
In a preferred embodiment the crystalline form according to the invention is subsequently transformed into an amorphous form.
Suitable methods for the preparation of amorphous forms are known to a person skilled in the art. For example, amorphous forms or amorphous mixtures may be obtained by means of the following methods or combinations thereof:

    i) precipitation from solution,
    ii) lyophilization,
    iii) spray drying,
    iv) melts extrusion,
    v) flash evaporation,
    vi) quench cooling of the melt,
    vii) grinding at ambient or liquid nitrogen temperatures,
    viii) working under protection of an inert atmosphere (e.g. gaseous nitrogen or argon), and/or
    ix) using capillary crystallization technology.


Another aspect of the invention relates to an amorphous form 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, preferably to an amorphous form that is obtainable by any of the above methods or combinations thereof.
Mixtures of the crystalline forms A, 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.
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).
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.
Another aspect of the invention relates to a composition comprising a mixture of at least two crystalline forms as described herein; or a mixture of at least one crystalline form as described herein with an amorphous form; or a mixture of at least one 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.
Preferably, the degree of crystallinity, i.e. the content of crystalline form(s) 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.-%.
Yet a further aspect the invention relates to a pharmaceutical composition comprising at least one crystalline form according to the invention.
In another aspect the present invention relates to methods of treating pain, comprising administering a pharmaceutical composition that comprises a crystalline form as described herein to a patient in need thereof (for example, a patient who has been diagnosed with a pain disorder).
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.
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.
Preferably said pharmaceutical composition may be used for the treatment of pain.
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.
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.
Furthermore, the present invention relates to a method for treating pain in a patient, preferably in a mammal, which comprises administering an effective amount of a crystalline form as described herein to a patient.
EXAMPLES
The following examples serve to explain the invention in more detail, but should not be interpreted as restrictive.
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


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.
Unless otherwise specified, solvent mixtures are always volume/volume.
The synthesis of compound (1) is described in WO2012/013343 A1, page 48-49.
A) Crystalline Form A
General Procedure for Syntheses:
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.
In table 1 below, specific reaction conditions for syntheses of crystalline form A are listed.













TABLE 1






Crystalline








form of



starting
Amount
Solvent/
T
Reaction


Example
material
[mg]
amount
[° C.]
time [d]
Comment





















A1
D
227.7
2-propanol/
RT
  5 d
Day 5 without





5 ml


stirring


A2
D
190
2-propanol/
RT
  3 d
—





10 ml


A3
D
206.1
1-propanol/
RT
  5 d
Day 5 without





5 ml


stirring


A4
E
101
1-pentane/
40
0.75 d
—





2.5 ml


A5
E
102
1-propanol/
40
0.75 d
—





2.5 ml


A6.1
E
110.5
TBME/2.5 ml
40
0.75 d
—


A6.2
E
102.8
n-hexane/
30
0.75 d
—





2.5 ml


A6.3
E
102
n-pentane/
30
0.75 d
—





2.5 ml


A6.4
E
107
1-propanol/
40
0.75 d
—





2.5 ml


A10.1
D
206.1
1-propanol/
RT
  4 d
—





5 ml


A10.2
D
227.7
2-propanol/
RT
  4 d
—





5 ml


A12
B
8300
2-propanol/
52
  5 d
After cooling to RT





120 ml


the suspension was





Water/280 ml


stirred for an





(3:7)


additional hour.









Example A13
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
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.
The crystalline form of the obtained materials was determined using XRPD. The experiments are summarized below in table 2 below.











TABLE 2








Amount compound (1)/[mg]





and crystalline forms
Resulting crystalline



ID
in starting material
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]






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
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.
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
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
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
General Procedure for Syntheses: See General Procedure for Syntheses of Crystalline Form A.
In table 3 below, specific reaction conditions for syntheses of crystalline form B are listed.













TABLE 3






Crystalline form








of starting
Amount


Reaction


Ex.
material
[mg]
Solvent/amount
T [° C.]
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
RT
3
—





(7:3)


B3
D
176.4
Ethanol 10.5 ml/water 4.5 ml
50
3
—





(7:3)


B4
D
225
Ethanol/5 ml
RT
4
—


B6
D
488
Ethanol 21 ml/water 9 ml
50
4.83
For the final





(7:3)


20 h, the








suspension is








stirred at RT.


B7
A
101
Ethanol 7 ml/water 3 ml
RT
13





(7:3)


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
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.
This example and example B7 demonstrate that in the presence of water, crystalline form B may form as a relatively stable polymorph or hydrate although 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
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






Crystalline








form of



starting
Amount


Reaction


Ex.
material
[mg]
Solvent/amount
T [° C.]
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/5 ml
50
1


C5.2
A
100
Methanol/3.5;
50
1





Water/1.5 ml


C6
A
100
Methanol/7 ml;
RT
13





Water/3 ml


C7
D
650
Methanol/150 ml
56
5


C8
D
280
Methanol/150 ml
80
0.125 (3 h)
Reflux


C9
D
778
Methanol/250 ml
80
 0.17 (4 h)
Reflux


C10
E
150
Methanol/50 ml
70
0.125 (3 h)
Solid was filtered








from hot








suspension.


C11
H
75
Methanol/75 ml
50
14









D) Crystalline Form D

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






Crystalline








form of



starting
Amount

T
Reaction


Ex.
material
[mg]
Solvent/amount
[° C.]
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/
40
0.75
—





7.5 ml


D6.5
E
105.2
Ethylmethylketone/
40
0.75
—





2.5 ml


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/2 ml
30
19


D9.1
A
100
Acetone/5 ml
50
1


D9.2
A
100
Acetone/3.5 ml;
50
1





Water/1.5 ml


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
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













Crystalline







form of starting
Amount


Reaction


Ex.
material
[mg]
Solvent/amount
T [° C.]
time [d]















D1
D
207.6
Acetonitrile/5 ml
RT
 5 d*


D2
D
170.7
Acetone/10.5 ml;
RT
3 d





Water/4.5 ml


D3
D
188.6
Acetone/10.5 ml;
50
3 d





Water/4.5 ml


D4
D
196
Water/10 ml
RT
3 d


D10
D
208
Acetonitrile/5 ml
RT
4 d


D11
D
196
Water/10 ml
RT
4 d


D13
D
517
Acetonitrile/20 ml
50
 5 d**





*Day 5 without stirring.


**Day 5 at RT.






Example D14
238 g of crystalline form E of compound (1) are charged into a suitable reaction vessel under inert conditions (N2-atmosphere) and 17 l 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<2 mbar) for 35 h.
The dried product (136.6 g) was analyzed and identified to be crystalline form D or compound (1).
E) Crystalline Form E
Example E1
Crystalline form can be obtained by drying crystalline form G for 2 h at 100° C. in ambient atmosphere and pressure (e.g. in an oven).
Example E2
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.
7 l ethylacetate are charged into a reaction vessel and 1.1 equivalent of fumaric acid (728.5 mmol=84.7 g) 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 l 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 ml 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 2 mbar until no further loss of mass was observed.
The thus obtained solid (293 g) was charged into a reaction vessel together with 8 l distilled water. Whilst stirring at 150 rpm 610 ml diethylamine are added to the resulting white suspension. Subsequently, 200 ml of ethanol are added and the reaction mixture is stirred at 24° C. for 16 h. Then, the solid is isolated from the suspension via filtration (G3 glass frit) and slurried 4 times in 1 l 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
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 ml of a specific solvent were added to each well and the lid of the plate closed. The plate was shaken at 30° C. for 16 h. 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
Starting with
Starting with



polymorph D and E
polymorph A
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/
am**
M
M


Hexane





*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

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






Crystalline form of
Amount


Reaction


Ex.
starting material
[mg]
Solvent/amount
T [° C.]
time [d]




















G1
E
176.4
Ethanol/15 ml; water/4.5 ml
50
3


G3
L
1210
Ethanol/25 ml
40
0.83 (20 h)


G4
A
1550
Ethanol/175 ml
75
0.65 (15.25 h)*






-->0*


G5.1
E
106.1
Ethanol
40
0.75


G5.2
E
115.7
1-Propanol/2.5 ml;
40
0.75





Water/2.5.ml





*15 min heated to 75° C., cooled to 0° C. during 6 h, stirred at 0° C. for 9 h.






H) Crystalline Form H

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






Crystalline form of
Amount

T
Reaction


Ex.
starting material
[mg]
Solvent/amount
[° C.]
time [d]




















H3
E
105.8
2-Propanol/2.5 ml
40
0.75


H5
E
103
2-Propanol/2.5 ml
40
0.75









Example H1
Interconversion Experiments
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).
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.
Subsequently, 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.
The results of the experiments are listed below in table 10:











TABLE 10






Mixture of






crystalline forms/

Temperature/
resulting


Ex.
[mg]
Solvent (1 ml)
° C. (time)
crystalline form







H1.1
23.1 mg E
2-Propanol
30 (7 d)
H



22.6 mg C

20 (2 h)


H1.2
22.6 mg E
2-Propanol
30 (7 d)
A + H



22.2 mg L

20 (2 h)


H1.4
23.3 mg E
2-Propanol
30 (7 d)
H



24.2 mg C

20 (2 h)


H1.5
22.8 mg E
2-Propanol
30 (7 d)
A + H



23.4 mg L

20 (2 h)









I) Crystalline Form I

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.
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 10° 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
45 mg or 78 mg crystalline form C were stored in a vacuum oven at reduced pressure (10 mbar) at 25° C. for 24 h, at 41° C. for 24 h or at 65° C. for 72 h. In all cases crystalline form C transformed into crystalline form J.
K) Crystalline Form K
Example K1
39.6 mg of crystalline form C were stored in a vacuum oven at reduced pressure (5 to 10 mbar) at 50° C. for 16 h. It was found that crystalline form C had transformed into crystalline form K.
Example K2
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 16 h. It was found that crystalline form C had transformed into crystalline form K.
L) Crystalline form L
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.
















Crystalline form of
Amount


Reaction


Ex.
starting material
[mg]
Solvent/amount
T [° C.]
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

Example Q1
Compound (1) (6.6 g) was charged to a 250 mL flask and suspended in toluene p.a. (1.25 moles; 132.00 mL; 115.00 g) and vigorously stirred with a magnetic stir bar for 3 h 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
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 Form Q into Amorphous Material.
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.
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).
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.
According to XRPD-analyses SM1 is a poorly crystalline material, SM2 amorphous.
Example S1
Chemical Stability of Crystalline Forms of Compound (1)
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.
The results of this stability study are listed below in table 12:













TABLE 12





Ex-
Initial


Rel. humidity
Resulting
Content cmpd (1)


No.
solid form
Storage [d]
T[° C.]
% r.H.
solid form
[%]





















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









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






crystalline




1
2



Example
form
Tstorage
humidity
excipients
0 month
month
months
3 months


























S2-1A
A
50° C.
dry
Microcrystalline
HPMC
L-HPC LH21
magnesium
99.64
99.59
99.59
99.62


S2-1B
B


cellulose
6 mPas

stearate
99.75
95.74
91.45
87.34


S2-2A
A
40° C.
75% rel. hum.
Microcrystalline
HPMC
L-HPC LH21
magnesium
90.64
99.61
99.60
99.66


S2-2B
B


cellulose
6 mPas

stearate
99.69
99.53
98.57
99.39


S2-3A
A
50° C.
dry
Lactose
PVP25
Crospovidone
Talcum
99.66
99.58
99.54
99.56


S2-3B
B


monohydrate



99.57
95.82
91.04
85.33


S2-4A
A
40° C.
75% rel. hum.
Lactose
PVP25
Crospovidone
Talcum
99.66
99.93
99.72
99.86


S2-4B
B


monohydrate



99.57
99.22
99.05
96.87









Example X1
Analysis—XRPD (X-Ray Powder Diffraction) or PXRD (Powder X-Ray Diffraction)
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 CuK 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)).
In general a baseline correction of the measured diffractograms was done using the program WinXPow (STOE).
Crystalline Form A
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.









TABLE 14





d value
2θ
rel. I


[Å]
[°]
[%]

















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









Crystalline Form B

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
2θ
rel. I


[Å]
[°]
[%]

















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

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
2θ
rel. I


[Å]
[°]
[%]

















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

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
2θ
rel. I


[Å]
[°]
[%]

















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

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
2θ
rel. I


[Å]
[°]
[%]

















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

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
2θ
rel. I


[Å]
[°]
[%]

















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

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
2θ
rel. I


[Å]
[°]
[%]

















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

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.









TABLE 21





d value
2θ
rel. I


[Å]
[°]
[%]

















17.3
5.1
4


12.4
7.1
32


11.9
7.4
10


11.0
8.0
79


8.8
10.1
5


8.5
10.4
23


7.8
11.4
4


7.5
11.8
8


7.3
12.1
4


7.1
12.4
12


6.8
13.0
12


6.4
13.8
9


6.2
14.3
12


6.1
14.5
5


6.0
14.9
7


5.7
15.5
9


5.5
16.0
5


5.5
16.0
6


5.3
16.8
15


5.2
17.1
19


5.1
17.3
40


5.1
17.5
27


5.0
17.7
60


4.9
18.1
73


4.9
18.2
100


4.7
18.8
44


4.6
19.2
66


4.6
19.4
19


4.5
19.7
74


4.4
19.9
6


4.4
20.2
15


4.3
20.7
44


4.2
20.9
26


4.2
21.1
8


4.2
21.2
8


4.1
21.5
9


4.0
22.3
6


3.9
22.8
20


3.8
23.3
6


3.7
23.7
8


3.7
24.3
6


3.6
24.6
6


3.6
24.9
4


3.5
25.4
4


3.5
25.7
9


3.4
26.1
4


3.3
26.7
8


3.3
27.0
10


3.3
27.2
14


3.2
27.6
15


3.2
28.1
18


3.2
28.3
27


3.1
28.9
7


3.1
29.1
5


3.0
29.3
7


3.0
29.9
3


2.9
30.4
8


2.9
30.9
4


2.9
31.3
5


2.8
31.7
3


2.8
32.3
5


2.7
32.9
7


2.7
33.4
7


2.6
34.6
2


2.6
35.1
3


2.5
35.9
5


2.4
37.0
8


2.4
37.5
6


2.3
38.3
3


2.3
38.8
5


2.2
40.4
3


2.2
40.7
4


2.2
41.1
2


2.2
41.5
3


2.1
42.5
5


2.0
45.9
3


1.9
47.6
3


1.8
49.3
3









Crystalline Form I

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
2θ
rel. I


[Å]
[°]
[%]

















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

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
2θ
rel. I


[Å]
[°]
[%]

















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

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
2θ
rel. I


[Å]
[°]
[%]

















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

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.









TABLE 25





d value
2θ
rel. I


[Å]
[°]
[%]

















11.4
7.7
28


10.9
8.1
100


8.3
10.7
5


7.9
11.2
4


7.4
12.0
66


6.2
14.4
9


6.0
14.9
16


5.6
15.7
9


5.4
16.4
35


5.3
16.8
13


5.2
17.1
91


4.9
18.0
20


4.9
18.2
4


4.7
18.7
7


4.6
19.3
7


4.4
20.1
68


4.3
20.4
8


4.3
20.6
4


4.2
21.2
39


4.1
21.5
15


4.1
21.9
39


3.9
22.5
8


3.9
23.1
8


3.8
23.3
9


3.7
24.0
9


3.7
24.3
41


3.6
25.0
2


3.4
25.8
21


3.4
26.3
5


3.3
26.8
11


3.3
27.0
5


3.3
27.3
6


3.2
27.5
10


3.2
27.8
4


3.2
28.0
4


3.1
28.5
17


3.1
29.0
14


3.0
30.2
3


2.9
30.6
1


2.9
31.0
4


2.9
31.3
5


2.8
31.6
2


2.8
32.0
3


2.7
33.0
3


2.7
33.8
4


2.6
34.4
3


2.6
34.9
2


2.5
35.8
7


2.4
36.7
2


2.4
37.5
2


2.4
38.0
3


2.3
38.7
3


2.3
39.1
3


2.3
40.0
3


2.2
40.8
3


2.2
41.1
3


2.2
41.9
3


2.1
42.5
2


2.1
43.8
2


2.0
44.7
3


2.0
45.3
3


2.0
45.8
2


1.9
48.5
3


1.9
49.0
2


1.8
49.6
3









Crystalline Form Q

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
2θ
rel. I


[Å]
[°]
[%]

















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

X-ray powder diffractogram (XRPD) may be calculated from a single crystal diffractogram (SCXRD) measured using MoK radiation having a wavelength of 0.71073 Å 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 (Single Crystal X-Ray Diffraction)
Polymorph A (Measure at Low Temperature)
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
C33H34FN3O


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{circumflex over ( )}3


Z
  4


Density (calculated)
1.277 Mg/m{circumflex over ( )}3


Absorption coefficient
0.082 mm{circumflex over ( )}−1


F(000)
 1080


Crystal size
0.45 × 0.21 × 0.08 mm


Theta range for data
1.82 to 28.30 deg.


collection


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{circumflex over ( )}2


Data/restraints/parameters
6534/0/346


Goodness-of-fit on F{circumflex over ( )}2
  1.000


Final R indices
R1 = 0.0497, wR2 = 0.1281


[I > 2sigma(I)]


R indices (all data)
R1 = 0.0643, wR2 = 0.1405


Largest diff. peak and hole
.496 and −.260 e · A{circumflex over ( )}−3
















TABLE 28







Atomic coordinates (×10{circumflex over ( )}4) and equivalent isotropic


displacement parameters ({circumflex over ( )}2 × 10{circumflex over ( )}3). U(eq) is defined


as one third of the trace of the orthogonalized Uij tensor.












x
y
z
U(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(8)—H(8B)
.9900


O(1)—C(10)
1.2307(17)
C(9)—C(22)
1.506(2)


N(1)—C(6)
1.4639(19)
C(9)—C(29)
1.5408(19)


N(1)—C(5)
1.4685(19)
C(10)—C(11)
1.4938(19)


N(1)—C(4)
1.4991(18)
C(11)—C(12)
1.332(2)


N(2)—C(10)
1.3785(18)
C(11)—H(11)
.9500


N(2)—C(19)
1.4855(18)
C(12)—C(13)
1.466(2)


N(2)—C(9)
1.5091(17)
C(12)—H(12)
.9500


N(3)—C(23)
1.3802(18)
C(13)—C(14)
1.396(2)


N(3)—C(22)
1.3856(18)
C(13)—C(18)
1.403(2)


N(3)—H(3N)
.8663
C(14)—C(15)
1.391(2)


C(1)—C(33)
1.375(2)
C(14)—H(14)
.9500


C(1)—C(2)
1.378(2)
C(15)—C(16)
1.386(3)


C(2)—C(3)
1.398(2)
C(15)—H(15)
.9500


C(2)—H(2)
.9500
C(16)—C(17)
1.389(3)


C(3)—C(31)
1.405(2)
C(16)—H(16)
.9500


C(3)—C(4)
1.542(2)
C(17)—C(18)
1.388(2)


C(4)—C(7)
1.5436(19)
C(17)—H(17)
.9500


C(4)—C(30)
1.5447(19)
C(18)—H(18)
.9500


C(5)—H(5A)
.9800
C(19)—C(20)
1.531(2)


C(5)—H(5B)
.9800
C(19)—H(19A)
.9900


C(5)—H(5C)
.9800
C(19)—H(19B)
.9900


C(6)—H(6A)
.9800
C(20)—C(21)
1.503(2)


C(6)—H(6B)
.9800
C(20)—H(20A)
.9900


C(6)—H(6C)
.9800
C(20)—H(20B)
.9900


C(7)—C(8)
1.523(2)
C(21)—C(22)
1.371(2)


C(7)—H(7A)
.9900
C(21)—C(24)
1.432(2)


C(7)—H(7B)
.9900
C(23)—C(28)
1.393(2)


C(8)—C(9)
1.5518(19)
C(23)—C(24)
1.415(2)


C(8)—H(8A)
.9900
C(24)—C(25)
1.403(2)


C(25)—C(26)
1.385(2)
N(1)—C(4)—C(3)
111.21(11)


C(25)—H(25)
.9500
C(7)—C(4)—C(3)
112.67(12)


C(26)—C(27)
1.401(2)
N(1)—C(4)—C(30)
110.43(11)


C(26)—H(26)
.9500
C(7)—C(4)—C(30)
105.39(11)


C(27)—C(28)
1.388(2)
C(3)—C(4)—C(30)
110.44(11)


C(27)—H(27)
.9500
N(1)—C(5)—H(5A)
109.5


C(28)—H(28)
.9500
N(1)—C(5)—H(5B)
109.5


C(29)—C(30)
1.533(2)
H(5A)—C(5)—H(5B)
109.5


C(29)—H(29A)
.9900
N(1)—C(5)—H(5C)
109.5


C(29)—H(29B)
.9900
H(5A)—C(5)—H(5C)
109.5


C(30)—H(30A)
.9900
H(5B)—C(5)—H(5C)
109.5


C(30)—H(30B)
.9900
N(1)—C(6)—H(6A)
109.5


C(31)—C(32)
1.389(2)
N(1)—C(6)—H(6B)
109.5


C(31)—H(31)
.9500
H(6A)—C(6)—H(6B)
109.5


C(32)—C(33)
1.388(2)
N(1)—C(6)—H(6C)
109.5


C(32)—H(32)
.9500
H(6A)—C(6)—H(6C)
109.5


C(33)—H(33)
.9500
H(6B)—C(6)—H(6C)
109.5




C(8)—C(7)—C(4)
114.44(12)


C(6)—N(1)—C(5)
107.70(12)
C(8)—C(7)—H(7A)
108.7


C(6)—N(1)—C(4)
114.92(11)
C(4)—C(7)—H(7A)
108.7


C(5)—N(1)—C(4)
113.68(12)
C(8)—C(7)—H(7B)
108.7


C(10)—N(2)—C(19)
117.99(11)
C(4)—C(7)—H(7B)
108.7


C(10)—N(2)—C(9)
121.96(11)
H(7A)—C(7)—H(7B)
107.6


C(19)—N(2)—C(9)
112.14(11)
C(7)—C(8)—C(9)
112.98(12)


C(23)—N(3)—C(22)
108.75(12)
C(7)—C(8)—H(8A)
109.0


C(23)—N(3)—H(3N)
120.3
C(9)—C(8)—H(8A)
109.0


C(22)—N(3)—H(3N)
130.5
C(7)—C(8)—H(8B)
109.0


F(1)—C(1)—C(33)
118.92(14)
C(9)—C(8)—H(8B)
109.0


F(1)—C(1)—C(2)
117.24(14)
H(8A)—C(8)—H(8B)
107.8


C(33)—C(1)—C(2)
123.80(14)
C(22)—C(9)—N(2)
105.22(11)


C(1)—C(2)—C(3)
119.46(14)
C(22)—C(9)—C(29)
112.91(12)


C(1)—C(2)—H(2)
120.3
N(2)—C(9)—C(29)
115.53(11)


C(3)—C(2)—H(2)
120.3
C(22)—C(9)—C(8)
109.16(11)


C(2)—C(3)—C(31)
117.55(13)
N(2)—C(9)—C(8)
109.87(11)


C(2)—C(3)—C(4)
121.08(13)
C(29)—C(9)—C(8)
104.10(11)


C(31)—C(3)—C(4)
121.32(13)
O(1)—C(10)—N(2)
123.67(13)


N(1)—C(4)—C(7)
106.48(11)
O(1)—C(10)—C(11)
118.88(13)


N(2)—C(10)—C(11)
117.37(12)
C(22)—C(21)—C(24)
106.88(13)


C(12)—C(11)—C(10)
118.96(13)
C(22)—C(21)—C(20)
122.57(14)


C(12)—C(11)—H(11)
120.5
C(24)—C(21)—C(20)
130.55(13)


C(10)—C(11)—H(11)
120.5
C(21)—C(22)—N(3)
109.70(13)


C(11)—C(12)—C(13)
126.15(14)
C(21)—C(22)—C(9)
125.74(13)


C(11)—C(12)—H(12)
116.9
N(3)—C(22)—C(9)
124.51(12)


C(13)—C(12)—H(12)
116.9
N(3)—C(23)—C(28)
130.03(13)


C(14)—C(13)—C(18)
118.60(14)
N(3)—C(23)—C(24)
107.51(13)


C(14)—C(13)—C(12)
118.72(14)
C(28)—C(23)—C(24)
122.45(14)


C(18)—C(13)—C(12)
122.58(13)
C(25)—C(24)—C(23)
118.81(14)


C(15)—C(14)—C(13)
120.71(16)
C(25)—C(24)—C(21)
134.01(14)


C(15)—C(14)—H(14)
119.6
C(23)—C(24)—C(21)
107.16(13)


C(13)—C(14)—H(14)
119.6
C(26)—C(25)—C(24)
118.90(14)


C(16)—C(15)—C(14)
120.09(16)
C(26)—C(25)—H(25)
120.5


C(16)—C(15)—H(15)
120.0
C(24)—C(25)—H(25)
120.5


C(14)—C(15)—H(15)
120.0
C(25)—C(26)—C(27)
121.20(14)


C(17)—C(16)—C(15)
119.86(16)
C(25)—C(26)—H(26)
119.4


C(17)—C(16)—H(16)
120.1
C(27)—C(26)—H(26)
119.4


C(15)—C(16)—H(16)
120.1
C(28)—C(27)—C(26)
121.30(15)


C(18)—C(17)—C(16)
120.27(16)
C(28)—C(27)—H(27)
119.4


C(18)—C(17)—H(17)
119.9
C(26)—C(27)—H(27)
119.4


C(16)—C(17)—H(17)
119.9
C(27)—C(28)—C(23)
117.31(14)


C(17)—C(18)—C(13)
120.45(15)
C(27)—C(28)—H(28)
121.3


C(17)—C(18)—H(18)
119.8
C(23)—C(28)—H(28)
121.3


C(13)—C(18)—H(18)
119.8
C(30)—C(29)—C(9)
113.19(11)


N(2)—C(19)—C(20)
110.87(12)
C(30)—C(29)—H(29A)
108.9


N(2)—C(19)—H(19A)
109.5
C(9)—C(29)—H(29A)
108.9


C(20)—C(19)—H(19A)
109.5
C(30)—C(29)—H(29B)
108.9


N(2)—C(19)—H(19B)
109.5
C(9)—C(29)—H(29B)
108.9


C(20)—C(19)—H(19B)
109.5
H(29A)—C(29)—H(29B)
107.8


H(19A)—C(19)—H(19B)
108.1
C(29)—C(30)—C(4)
111.40(11)


C(21)—C(20)—C(19)
109.17(12)
C(29)—C(30)—H(30A)
109.3


C(21)—C(20)—H(20A)
109.8
C(4)—C(30)—H(30A)
109.3


C(19)—C(20)—H(20A)
109.8
C(29)—C(30)—H(30B)
109.3


C(21)—C(20)—H(20B)
109.8
C(4)—C(30)—H(30B)
109.3


C(19)—C(20)—H(20B)
109.8
H(30A)—C(30)—H(30B)
108.0


H(20A)—C(20)—H(20B)
108.3
C(32)—C(31)—C(3)
121.30(14)


C(32)—C(31)—H(31)
119.4
C(31)—C(32)—H(32)
119.6


C(3)—C(31)—H(31)
119.4
C(1)—C(33)—C(32)
117.00(14)


C(33)—C(32)—C(31)
120.89(14)
C(1)—C(33)—H(33)
121.5


C(33)—C(32)—H(32)
119.6
C(32)—C(33)—H(33)
121.5
















TABLE 30







Hydrogen coordinates (×10{circumflex over ( )}4) and isotropic


displacement parameters ({circumflex over ( )}2 × 10{circumflex over ( )}3).












x
y
z
U(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({circumflex over ( )}2 × 10{circumflex over ( )}3).


The anisotropic displacement factor exponent takes the form:


−2 pi{circumflex over ( )}2 [h{circumflex over ( )}2 a*{circumflex over ( )}2 U11 + . . . + 2 h k a* b* U12]














U11
U22
U33
U23
U13
U12



















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)
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
C33H34FN3O


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{circumflex over ( )}3


Z
  4


Density (calculated)
1.255 Mg/m{circumflex over ( )}3


Absorption coefficient
0.081 mm{circumflex over ( )}−1


F(000)
 1080


Crystal size
0.45 × 0.21 × 0.08 mm


Theta range for data
1.80 to 28.27 deg.


collection


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{circumflex over ( )}2


Data/restraints/parameters
6654/0/346


Goodness-of-fit on F{circumflex over ( )}2
  0.946


Final R indices
R1 = 0.0625, wR2 = 0.1445


[I > 2sigma(I)]


R indices (all data)
R1 = 0.1004, wR2 = 0.1600


Largest diff. peak and hole
0.323 and −0.319 e · A{circumflex over ( )}−3
















TABLE 33







Atomic coordinates (×10{circumflex over ( )}4) and equivalent isotropic


displacement parameters ({circumflex over ( )}2 × 10{circumflex over ( )}3). U(eq) is defined


as one third of the trace of the orthogonalized Uij tensor.












x
y
z
U(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(3)—C(4)
1.537(3)


O(1)—C(10)
1.2214(18)
C(4)—C(7)
1.537(2)


N(1)—C(6)
1.455(2)
C(4)—C(30)
1.540(2)


N(1)—C(5)
1.472(2)
C(5)—H(5A)
.9700


N(1)—C(4)
1.502(2)
C(5)—H(5B)
.9700


N(2)—C(10)
1.379(2)
C(5)—H(5C)
.9700


N(2)—C(19)
1.479(2)
C(6)—H(6A)
.9700


N(2)—C(9)
1.512(2)
C(6)—H(6B)
.9700


N(3)—C(22)
1.383(2)
C(6)—H(6C)
.9700


N(3)—C(23)
1.385(2)
C(7)—C(8)
1.515(3)


N(3)—H(3N)
.8609
C(7)—H(7A)
.9800


C(1)—C(33)
1.355(3)
C(7)—H(7B)
.9800


C(1)—C(2)
1.377(3)
C(8)—C(9)
1.556(2)


C(2)—C(3)
1.391(3)
C(8)—H(8A)
.9800


C(2)—H(2)
.9400
C(8)—H(8B)
.9800


C(3)—C(31)
1.396(2)
C(9)—C(22)
1.502(3)


C(9)—C(29)
1.538(2)
C(29)—H(29B)
.9800


C(10)—C(11)
1.490(2)
C(30)—H(30A)
.9800


C(11)—C(12)
1.316(2)
C(30)—H(30B)
.9800


C(11)—H(11)
.9400
C(31)—C(32)
1.384(3)


C(12)—C(13)
1.469(3)
C(31)—H(31)
.9400


C(12)—H(12)
.9400
C(32)—C(33)
1.385(3)


C(13)—C(18)
1.383(3)
C(32)—H(32)
.9400


C(13)—C(14)
1.387(3)
C(33)—H(33)
.9400


C(14)—C(15)
1.387(3)


C(14)—H(14)
.9400
C(6)—N(1)—C(5)
108.11(16)


C(15)—C(16)
1.357(3)
C(6)—N(1)—C(4)
115.41(14)


C(15)—H(15)
.9400
C(5)—N(1)—C(4)
113.77(16)


C(16)—C(17)
1.381(3)
C(10)—N(2)—C(19)
118.05(15)


C(16)—H(16)
.9400
C(10)—N(2)—C(9)
121.32(13)


C(17)—C(18)
1.383(3)
C(19)—N(2)—C(9)
112.20(14)


C(17)—H(17)
.9400
C(22)—N(3)—C(23)
108.89(15)


C(18)—H(18)
.9400
C(22)—N(3)—H(3N)
132.3


C(19)—C(20)
1.521(3)
C(23)—N(3)—H(3N)
118.4


C(19)—H(19A)
.9800
C(33)—C(1)—F(1)
119.36(19)


C(19)—H(19B)
.9800
C(33)—C(1)—C(2)
123.77(19)


C(20)—C(21)
1.497(3)
F(1)—C(1)—C(2)
116.85(17)


C(20)—H(20A)
.9800
C(1)—C(2)—C(3)
119.68(18)


C(20)—H(20B)
.9800
C(1)—C(2)—H(2)
120.2


C(21)—C(22)
1.372(2)
C(3)—C(2)—H(2)
120.2


C(21)—C(24)
1.425(3)
C(2)—C(3)—C(31)
117.03(17)


C(23)—C(28)
1.387(3)
C(2)—C(3)—C(4)
121.23(16)


C(23)—C(24)
1.408(3)
C(31)—C(3)—C(4)
121.69(16)


C(24)—C(25)
1.406(3)
N(1)—C(4)—C(7)
106.69(14)


C(25)—C(26)
1.378(3)
N(1)—C(4)—C(3)
111.08(15)


C(25)—H(25)
.9400
C(7)—C(4)—C(3)
113.06(15)


C(26)—C(27)
1.392(3)
N(1)—C(4)—C(30)
110.08(15)


C(26)—H(26)
.9400
C(7)—C(4)—C(30)
105.17(15)


C(27)—C(28)
1.383(3)
C(3)—C(4)—C(30)
110.54(14)


C(27)—H(27)
.9400
N(1)—C(5)—H(5A)
109.5


C(28)—H(28)
.9400
N(1)—C(5)—H(5B)
109.5


C(29)—C(30)
1.527(3)
H(5A)—C(5)—H(5B)
109.5


C(29)—H(29A)
.9800
N(1)—C(5)—H(5C)
109.5


H(5A)—C(5)—H(5C)
109.5
C(14)—C(13)—C(12)
118.64(18)


H(5B)—C(5)—H(5C)
109.5
C(15)—C(14)—C(13)
120.3(2)


N(1)—C(6)—H(6A)
109.5
C(15)—C(14)—H(14)
119.9


N(1)—C(6)—H(6B)
109.5
C(13)—C(14)—H(14)
119.9


H(6A)—C(6)—H(6B)
109.5
C(16)—C(15)—C(14)
120.7(2)


N(1)—C(6)—H(6C)
109.5
C(16)—C(15)—H(15)
119.6


H(6A)—C(6)—H(6C)
109.5
C(14)—C(15)—H(15)
119.6


H(6B)—C(6)—H(6C)
109.5
C(15)—C(16)—C(17)
119.8(2)


C(8)—C(7)—C(4)
114.70(15)
C(15)—C(16)—H(16)
120.1


C(8)—C(7)—H(7A)
108.6
C(17)—C(16)—H(16)
120.1


C(4)—C(7)—H(7A)
108.6
C(16)—C(17)—C(18)
119.9(2)


C(8)—C(7)—H(7B)
108.6
C(16)—C(17)—H(17)
120.0


C(4)—C(7)—H(7B)
108.6
C(18)—C(17)—H(17)
120.0


H(7A)—C(7)—H(7B)
107.6
C(17)—C(18)—C(13)
120.8(2)


C(7)—C(8)—C(9)
113.05(15)
C(17)—C(18)—H(18)
119.6


C(7)—C(8)—H(8A)
109.0
C(13)—C(18)—H(18)
119.6


C(9)—C(8)—H(8A)
109.0
N(2)—C(19)—C(20)
110.73(15)


C(7)—C(8)—H(8B)
109.0
N(2)—C(19)—H(19A)
109.5


C(9)—C(8)—H(8B)
109.0
C(20)—C(19)—H(19A)
109.5


H(8A)—C(8)—H(8B)
107.8
N(2)—C(19)—H(19B)
109.5


C(22)—C(9)—N(2)
105.07(14)
C(20)—C(19)—H(19B)
109.5


C(22)—C(9)—C(29)
113.57(14)
H(19A)—C(19)—H(19B)
108.1


N(2)—C(9)—C(29)
115.57(14)
C(21)—C(20)—C(19)
109.80(16)


C(22)—C(9)—C(8)
108.97(15)
C(21)—C(20)—H(20A)
109.7


N(2)—C(9)—C(8)
109.74(13)
C(19)—C(20)—H(20A)
109.7


C(29)—C(9)—C(8)
103.86(14)
C(21)—C(20)—H(20B)
109.7


O(1)—C(10)—N(2)
123.79(16)
C(19)—C(20)—H(20B)
109.7


O(1)—C(10)—C(11)
118.84(16)
H(20A)—C(20)—H(20B)
108.2


N(2)—C(10)—C(11)
117.30(14)
C(22)—C(21)—C(24)
106.63(16)


C(12)—C(11)—C(10)
120.00(16)
C(22)—C(21)—C(20)
122.25(19)


C(12)—C(11)—H(11)
120.0
C(24)—C(21)—C(20)
131.12(17)


C(10)—C(11)—H(11)
120.0
C(21)—C(22)—N(3)
109.58(17)


C(11)—C(12)—C(13)
126.77(17)
C(21)—C(22)—C(9)
125.71(17)


C(11)—C(12)—H(12)
116.6
N(3)—C(22)—C(9)
124.67(16)


C(13)—C(12)—H(12)
116.6
N(3)—C(23)—C(28)
130.15(17)


C(18)—C(13)—C(14)
118.47(19)
N(3)—C(23)—C(24)
106.96(17)


C(18)—C(13)—C(12)
122.80(17)
C(28)—C(23)—C(24)
122.88(18)


C(25)—C(24)—C(23)
118.18(19)
C(9)—C(29)—H(29B)
108.9


C(25)—C(24)—C(21)
133.87(18)
H(29A)—C(29)—H(29B)
107.8


C(23)—C(24)—C(21)
107.94(16)
C(29)—C(30)—C(4)
111.75(15)


C(26)—C(25)—C(24)
118.92(19)
C(29)—C(30)—H(30A)
109.3


C(26)—C(25)—H(25)
120.5
C(4)—C(30)—H(30A)
109.3


C(24)—C(25)—H(25)
120.5
C(29)—C(30)—H(30B)
109.3


C(25)—C(26)—C(27)
121.6(2)
C(4)—C(30)—H(30B)
109.3


C(25)—C(26)—H(26)
119.2
H(30A)—C(30)—H(30B)
107.9


C(27)—C(26)—H(26)
119.2
C(32)—C(31)—C(3)


C(28)—C(27)—C(26)
120.9(2)
121.78(18)


C(28)—C(27)—H(27)
119.5
C(32)—C(31)—H(31)
119.1


C(26)—C(27)—H(27)
119.5
C(3)—C(31)—H(31)
119.1


C(27)—C(28)—C(23)
117.43(19)
C(31)—C(32)—C(33)


C(27)—C(28)—H(28)
121.3
120.36(19)


C(23)—C(28)—H(28)
121.3
C(31)—C(32)—H(32)
119.8


C(30)—C(29)—C(9)
113.18(14)
C(33)—C(32)—H(32)
119.8


C(30)—C(29)—H(29A)
108.9
C(1)—C(33)—C(32)
117.4(2)


C(9)—C(29)—H(29A)
108.9
C(1)—C(33)—H(33)
121.3


C(30)—C(29)—H(29B)
108.9
C(32)—C(33)—H(33)
121.3
















TABLE 35







Hydrogen coordinates (×10{circumflex over ( )}4) and isotropic


displacement parameters ({circumflex over ( )}2 × 10{circumflex over ( )}3) for ansolvat_ht.












x
y
z
U(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 ({circumflex over ( )}2 × 10{circumflex over ( )}3).


The anisotropic displacement factor exponent takes the form:


−2 pi{circumflex over ( )}2 [h{circumflex over ( )}2 a*{circumflex over ( )}2 U11 + . . . + 2 h k a* b* U12]














U11
U22
U33
U23
U13
U12

















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)
42(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)









Polymorph B

SCXRD (Single Crystal X-Ray Diffraction)

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 37





Crystal data and structure refinement
















Identification code
GM391-063-P1A1


Empirical formula
C33H40FN3O4


Formula weight
 561.68


Temperature
100(2) K


Wavelength
.71073 A


Crystal system
Orthorhombic


Space group
P b c a


Unit cell dimensions
a = 9.6937(12) A alpha = 90 deg.



b = 25.858(3) A beta = 90 deg.



c = 23.491(3) A gamma = 90 deg.


Volume
5888.2(13) A{circumflex over ( )}3


Z
  8


Density (calculated)
1.267 Mg/m{circumflex over ( )}3


Absorption coefficient
0.088 mm{circumflex over ( )}−1


F(000)
 2400


Crystal size
0.31 × 0.08 × 0.02 mm


Theta range for data collection
1.73 to 17.30 deg.


Index ranges
−8 <= h <= 8, −21 <= k <= 21,



−19 <= l <= 19


Reflections collected
17449


Independent reflections
1797 [R(int) = 0.0904]


Absorption correction
None


Refinement method
Full-matrix least-squares on F{circumflex over ( )}2


Data/restraints/parameters
1797/48/172


Goodness-of-fit on F{circumflex over ( )}2
  1.200


Final R indices [I > 2sigma(I)]
R1 = 0.1515, wR2 = 0.3024


R indices (all data)
R1 = 0.1580, wR2 = 0.3055


Largest diff. peak and hole
.840 and −.560 e · A{circumflex over ( )}−3
















TABLE 38







Atomic coordinates (×10{circumflex over ( )}4) and equivalent isotropic


displacement parameters ({circumflex over ( )}2 × 10{circumflex over ( )}3). U(eq) is defined


as one third of the trace of the orthogonalized Uij tensor.












x
y
z
U(eq)

















F(1)
3998(14)
 561(5)
 −65(6)
103(4) 



O(1)
3137(11)
3318(4)
1280(4)
25(3)



N(1)
5513(13)
1742(5)
1773(5)
28(3)



N(2)
5488(14)
3380(5)
1096(5)
27(3)



N(3)
5620(13)
3217(5)
−476(5)
28(3)



C(1)
5090(2) 
 866(8)
 147(9)
68(4)



C(2)
4810(2) 
1264(7)
 499(8)
54(4)



C(3)
5880(19)
1543(7)
 733(7)
39(3)



C(4)
5623(17)
1971(6)
1163(7)
29(3)



C(5)
4444(16)
1347(6)
1830(7)
30(4)



C(6)
6828(17)
1541(6)
2007(7)
36(5)



C(7)
4322(17)
2265(6)
1046(7)
29(3)



C(8)
4417(17)
2636(6)
 550(7)
28(3)



C(9)
5599(17)
3021(6)
 599(7)
26(3)



C(10)
4323(18)
3484(6)
1405(7)
29(3)



C(11)
4500(18)
3800(6)
1921(7)
28(3)



C(12)
3543(17)
4105(6)
2110(7)
27(3)



C(13)
3517(18)
4420(6)
2622(7)
31(3)



C(14)
4506(18)
4318(7)
3040(7)
37(4)



C(15)
4484(19)
4648(7)
3532(7)
44(4)



C(16)
3521(19)
5025(7)
3594(8)
44(4)



C(17)
2600(2) 
5106(7)
3188(7)
40(4)



C(18)
2531(19)
4802(6)
2696(7)
34(4)



C(19)
6546(17)
3776(6)
1108(7)
26(3)



C(20)
6241(17)
4176(6)
 659(6)
27(3)



C(21)
5960(17)
3893(6)
 121(7)
29(3)



C(22)
5736(17)
3387(6)
 87(7)
27(3)



C(23)
5778(17)
3656(6)
−818(7)
31(3)



C(24)
6009(17)
4080(6)
−469(7)
30(3)



C(25)
6149(16)
4570(6)
−706(7)
31(3)



C(26)
6076(17)
4623(7)
−1292(7) 
33(4)



C(27)
5877(17)
4196(6)
−1621(7) 
33(4)



C(28)
5684(17)
3697(6)
−1418(7) 
33(3)



C(29)
6919(16)
2703(6)
 667(7)
28(3)



C(30)
6855(16)
2354(6)
1191(7)
28(3)



C(31)
7205(19)
1368(7)
 588(7)
41(4)



C(32)
7420(2) 
 976(7)
 206(8)
49(4)



C(33)
6380(2) 
 709(8)
 −33(8)
58(4)



O(2)
 526(12)
2738(4)
1134(5)
47(4)



O(3)
4823(11)
2458(4)
2660(4)
34(3)



O(4)
2311(11)
2973(4)
2428(4)
37(3)

















TABLE 39





Bond lengths [A] and angles [deg]


















F(1)—C(1)
 1.41(2)
C(11)—C(12)
1.296(19)


O(1)—C(10)
 1.261(17)
C(11)—H(11)
.9500


N(1)—C(5)
 1.461(18)
C(12)—C(13)
1.45(2)


N(1)—C(6)
 1.484(19)
C(12)—H(12)
.9500


N(1)—C(4)
 1.55(2)
C(13)—C(18)
1.38(2)


N(2)—C(10)
 1.369(19)
C(13)—C(14)
1.40(2)


N(2)—C(19)
 1.448(18)
C(14)—C(15)
1.44(2)


N(2)—C(9)
 1.495(19)
C(14)—H(14)
.9500


N(3)—C(22)
 1.397(18)
C(15)—C(16)
1.36(2)


N(3)—C(23)
 1.399(19)
C(15)—H(15)
.9500


N(3)—H(3)
  .9200
C(16)—C(17)
1.32(2)


C(1)—C(2)
 1.35(2)
C(16)—H(16)
.9500


C(1)—C(33)
 1.38(3)
C(17)—C(18)
1.40(2)


C(2)—C(3)
 1.38(2)
C(17)—H(17)
.9500


C(2)—H(2)
  .9500
C(18)—H(18)
.9500


C(3)—C(31)
 1.40(2)
C(19)—C(20)
1.51(2)


C(3)—C(4)
 1.52(2)
C(19)—H(19A)
.9900


C(4)—C(7)
 1.50(2)
C(19)—H(19B)
.9900


C(4)—C(30)
 1.55(2)
C(20)—C(21)
1.48(2)


C(5)—H(5A)
  .9800
C(20)—H(20A)
.9900


C(5)—H(5B)
  .9800
C(20)—H(20B)
.9900


C(5)—H(5C)
  .9800
C(21)—C(22)
1.328(19)


C(6)—H(6A)
  .9800
C(21)—C(24)
1.47(2)


C(6)—H(6B)
  .9800
C(23)—C(24)
1.39(2)


C(6)—H(6C)
  .9800
C(23)—C(28)
1.42(2)


C(7)—C(8)
 1.51(2)
C(24)—C(25)
1.39(2)


C(7)—H(7A)
  .9900
C(25)—C(26)
1.39(2)


C(7)—H(7B)
  .9900
C(25)—H(25)
.9500


C(8)—C(9)
 1.52(2)
C(26)—C(27)
1.36(2)


C(8)—H(8A)
  .9900
C(26)—H(26)
.9500


C(8)—H(8B)
  .9900
C(27)—C(28)
1.39(2)


C(9)—C(29)
 1.53(2)
C(27)—H(27)
.9500


C(9)—C(22)
 1.54(2)
C(28)—H(28)
.9500


C(10)—C(11)
 1.47(2)
C(29)—C(30)
1.53(2)


C(29)—H(29A)
  .9900
C(7)—C(4)—N(1)
107.7(13)


C(29)—H(29B)
  .9900
C(3)—C(4)—N(1)
110.3(12)


C(30)—H(30A)
  .9900
C(30)—C(4)—N(1)
104.9(12)


C(30)—H(30B)
  .9900
N(1)—C(5)—H(5A)
109.5


C(31)—C(32)
 1.37(2)
N(1)—C(5)—H(5B)
109.5


C(31)—H(31)
  .9500
H(5A)—C(5)—H(5B)
109.5


C(32)—C(33)
 1.35(2)
N(1)—C(5)—H(5C)
109.5


C(32)—H(32)
  .9500
H(5A)—C(5)—H(5C)
109.5


C(33)—H(33)
  .9500
H(5B)—C(5)—H(5C)
109.5


O(2)—H(1W)
  .8500
N(1)—C(6)—H(6A)
109.5


O(2)—H(2W)
  .8499
N(1)—C(6)—H(6B)
109.5


O(3)—H(3W)
  .8499
H(6A)—C(6)—H(6B)
109.5


O(3)—H(4W)
  .8500
N(1)—C(6)—H(6C)
109.5


O(4)—H(5W)
  .8499
H(6A)—C(6)—H(6C)
109.5


O(4)—H(6W)
  .8502
H(6B)—C(6)—H(6C)
109.5




C(4)—C(7)—C(8)
114.3(14)


C(5)—N(1)—C(6)
109.3(12)
C(4)—C(7)—H(7A)
108.7


C(5)—N(1)—C(4)
113.5(12)
C(8)—C(7)—H(7A)
108.7


C(6)—N(1)—C(4)
114.6(12)
C(4)—C(7)—H(7B)
108.7


C(10)—N(2)—C(19)
115.8(13)
C(8)—C(7)—H(7B)
108.7


C(10)—N(2)—C(9)
126.5(13)
H(7A)—C(7)—H(7B)
107.6


C(19)—N(2)—C(9)
113.7(12)
C(7)—C(8)—C(9)
113.7(13)


C(22)—N(3)—C(23)
106.3(13)
C(7)—C(8)—H(8A)
108.8


C(22)—N(3)—H(3)
123.1
C(9)—C(8)—H(8A)
108.8


C(23)—N(3)—H(3)
128.3
C(7)—C(8)—H(8B)
108.8


C(2)—C(1)—C(33)
126(2)
C(9)—C(8)—H(8B)
108.8


C(2)—C(1)—F(1)
120(2)
H(8A)—C(8)—H(8B)
107.7


C(33)—C(1)—F(1)
113.9(19)
N(2)—C(9)—C(8)
114.3(13)


C(1)—C(2)—C(3)
120(2)
N(2)—C(9)—C(29)
108.3(13)


C(1)—C(2)—H(2)
120.1
C(8)—C(9)—C(29)
106.5(12)


C(3)—C(2)—H(2)
120.1
N(2)—C(9)—C(22)
103.6(12)


C(2)—C(3)—C(31)
114.9(16)
C(8)—C(9)—C(22)
114.1(13)


C(2)—C(3)—C(4)
121.7(17)
C(29)—C(9)—C(22)
109.9(13)


C(31)—C(3)—C(4)
123.2(16)
O(1)—C(10)—N(2)
124.2(14)


C(7)—C(4)—C(3)
112.8(14)
O(1)—C(10)—C(11)
119.1(15)


C(7)—C(4)—C(30)
109.3(12)
N(2)—C(10)—C(11)
116.7(15)


C(3)—C(4)—C(30)
111.5(14)
C(12)—C(11)—C(10)
122.5(16)


C(12)—C(11)—H(11)
118.7
C(24)—C(21)—C(20)
129.4(14)


C(10)—C(11)—H(11)
118.7
C(21)—C(22)—N(3)
112.4(14)


C(11)—C(12)—C(13)
129.6(16)
C(21)—C(22)—C(9)
124.9(15)


C(11)—C(12)—H(12)
115.2
N(3)—C(22)—C(9)
122.7(13)


C(13)—C(12)—H(12)
115.2
C(24)—C(23)—N(3)
108.6(14)


C(18)—C(13)—C(14)
121.3(15)
C(24)—C(23)—C(28)
122.8(16)


C(18)—C(13)—C(12)
121.0(15)
N(3)—C(23)—C(28)
128.7(15)


C(14)—C(13)—C(12)
117.6(15)
C(23)—C(24)—C(25)
119.9(15)


C(13)—C(14)—C(15)
116.3(16)
C(23)—C(24)—C(21)
107.0(14)


C(13)—C(14)—H(14)
121.8
C(25)—C(24)—C(21)
132.9(15)


C(15)—C(14)—H(14)
121.8
C(26)—C(25)—C(24)
118.9(16)


C(16)—C(15)—C(14)
121.6(18)
C(26)—C(25)—H(25)
120.6


C(16)—C(15)—H(15)
119.2
C(24)—C(25)—H(25)
120.6


C(14)—C(15)—H(15)
119.2
C(27)—C(26)—C(25)
119.4(16)


C(17)—C(16)—C(15)
119.9(19)
C(27)—C(26)—H(26)
120.3


C(17)—C(16)—H(16)
120.0
C(25)—C(26)—H(26)
120.3


C(15)—C(16)—H(16)
120.0
C(26)—C(27)—C(28)
125.3(16)


C(16)—C(17)—C(18)
122.6(18)
C(26)—C(27)—H(27)
117.3


C(16)—C(17)—H(17)
118.7
C(28)—C(27)—H(27)
117.3


C(18)—C(17)—H(17)
118.7
C(27)—C(28)—C(23)
113.7(16)


C(13)—C(18)—C(17)
118.1(17)
C(27)—C(28)—H(28)
123.2


C(13)—C(18)—H(18)
120.9
C(23)—C(28)—H(28)
123.2


C(17)—C(18)—H(18)
120.9
C(30)—C(29)—C(9)
111.6(13)


N(2)—C(19)—C(20)
109.4(13)
C(30)—C(29)—H(29A)
109.3


N(2)—C(19)—H(19A)
109.8
C(9)—C(29)—H(29A)
109.3


C(20)—C(19)—H(19A)
109.8
C(30)—C(29)—H(29B)
109.3


N(2)—C(19)—H(19B)
109.8
C(9)—C(29)—H(29B)
109.3


C(20)—C(19)—H(19B)
109.8
H(29A)—C(29)—H(29B)
108.0


H(19A)—C(19)—H(19B)
108.2
C(29)—C(30)—C(4)
111.9(13)


C(21)—C(20)—C(19)
107.0(13)
C(29)—C(30)—H(30A)
109.2


C(21)—C(20)—H(20A)
110.3
C(4)—C(30)—H(30A)
109.2


C(19)—C(20)—H(20A)
110.3
C(29)—C(30)—H(30B)
109.2


C(21)—C(20)—H(20B)
110.3
C(4)—C(30)—H(30B)
109.2


C(19)—C(20)—H(20B)
110.3
H(30A)—C(30)—H(30B)
107.9


H(20A)—C(20)—H(20B)
108.6
C(32)—C(31)—C(3)
122.7(18)


C(22)—C(21)—C(24)
105.8(14)
C(32)—C(31)—H(31)
118.7


C(22)—C(21)—C(20)
124.6(15)
C(3)—C(31)—H(31)
118.7


C(33)—C(32)—C(31)
122(2)
C(1)—C(33)—H(33)
123.2


C(33)—C(32)—H(32)
118.9
H(1W)—O(2)—H(2W)
116.5


C(31)—C(32)—H(32)
118.9
H(3W)—O(3)—H(4W)
114.8


C(32)—C(33)—C(1)
114(2)
H(5W)—O(4)—H(6W)
120.8


C(32)—C(33)—H(33)
123.2









Symmetry transformations used to generate equivalent atoms:







TABLE 40







Hydrogen coordinates (×10{circumflex over ( )}4) and isotropic


displacement parameters ({circumflex over ( )}2 × 10{circumflex over ( )}3).














x
y
z
U(eq)

















H(3)
5255
2901
−573
34



H(2)
3885
1351
586
65



H(5A)
4716
1038
1616
45



H(5B)
3571
1481
1678
45



H(5C)
4327
1259
2232
45



H(6A)
6667
1399
2388
55



H(6B)
7503
1822
2030
55



H(6C)
7184
1268
1758
55



H(7A)
4070
2463
1392
35



H(7B)
3571
2015
971
35



H(8A)
3539
2829
519
33



H(8B)
4534
2434
195
33



H(11)
5347
3780
2122
33



H(12)
2739
4125
1880
32



H(14)
5157
4046
3000
45



H(15)
5159
4601
3820
53



H(16)
3509
5231
3929
53



H(17)
1958
5381
3233
48



H(18)
1829
4856
2420
41



H(19A)
7460
3617
1035
32



H(19B)
6569
3941
1488
32



H(20A)
5428
4385
769
33



H(20B)
7040
4410
610
33



H(25)
6291
4864
−470
37



H(26)
6164
4955
−1463
40



H(27)
5870
4243
−2022
40



H(28)
5506
3409
−1659
39



H(29A)
7055
2487
323
33



H(29B)
7718
2939
701
33



H(30A)
6767
2571
1536
34



H(30B)
7727
2156
1221
34



H(31)
7981
1527
762
50



H(32)
8344
889
106
58



H(33)
6513
439
−301
69



H(1W)
316
2664
1476
56



H(2W)
1381
2739
1053
56



H(3W)
4928
2196
2447
41



H(4W)
4046
2608
2630
41



H(5W)
1576
2797
2466
45



H(6W)
2564
3081
2102
45

















TABLE 41







Anisotropic displacement parameters ({circumflex over ( )}2 × 10{circumflex over ( )}3).


The anisotropic displacement factor exponent takes the form:


−2 pi{circumflex over ( )}2 [h{circumflex over ( )}2 a*{circumflex over ( )}2 U11 + . . . + 2 h k a * b * U12]














U11
U22
U33
U23
U13
U12

















F(1)
79(7)
124(8)
106(7)
−52(7)
−5(7)
4(7)









Polymorph C

SCXRD (Single Crystal X-Ray Diffraction)

SCXRD analyses of crystalline form C was carried out with a Bruker D8-goniometer with SMART APEX CCD area detector at 130 K (±5 K) using MoKα radiation (wavelength of 0.71073 Å, Incoatec microsource, multilayer optics).







TABLE 42





Crystal data and structure refinement
















Empirical formula
C35H42FN3O3


Formula weight
 571.72


Temperature
130(2) K


Wavelength
.71073 A


Crystal system
Triclinic


Space group
P-1


Unit cell dimensions
a = 9.0215(12) A alpha = 67.547(3) deg.



b = 13.3823(17) A beta = 81.853(4) deg.



c = 13.7021(19) A gamma = 83.608(4) deg.


Volume
1510.4(3) A{circumflex over ( )}3


Z
  2


Density (calculated)
1.257 Mg/m{circumflex over ( )}3


Absorption coefficient
0.084 mm{circumflex over ( )}−1


F(000)
 612


Crystal size
0.14 × 0.13 × 0.07 mm


Theta range for data
1.83 to 28.47 deg.


collection


Index ranges
−11 <= h <= 12, −17 <= k <= 17,



−17 <= l <= 17


Reflections collected
23406


Independent reflections
7011 [R(int) = 0.0494]


Absorption correction
None


Refinement method
Full-matrix least-squares on F{circumflex over ( )}2


Data/restraints/parameters
7011/0/395


Goodness-of-fit on F{circumflex over ( )}2
  1.052


Final R indices
R1 = 0.0439, wR2 = 0.0852


[I > 2sigma(I)]


R indices (all data)
R1 = 0.0723, wR2 = 0.0898


Largest diff. peak and hole
.277 and −.202 e · A{circumflex over ( )}−3
















TABLE 43







Atomic coordinates (× 10{circumflex over ( )}4) and equivalent isotropic


displacement parameters ({circumflex over ( )}2 × 10{circumflex over ( )}3). U(eq) is defined


as one third of the trace of the orthogonalized Uij tensor.












x
y
z
U(eq)

















F(1)
−3098(1) 
14196(1) 
−739(1)
32(1)



O(1)
 570(1)
8487(1)
4358(1)
46(1)



N(1)
 886(1)
12561(1) 
2348(1)
21(1)



N(2)
1344(1)
9118(1)
2565(1)
21(1)



N(3)
−2295(1) 
8634(1)
1894(1)
23(1)



C(1)
−3032(2) 
13654(1) 
 330(1)
22(1)



C(2)
−1719(2) 
13081(1) 
 654(1)
21(1)



C(3)
−1605(2) 
12513(1) 
1734(1)
20(1)



C(4)
−134(2)
11872(1) 
2124(1)
20(1)



C(5)
1443(2)
13476(1) 
1405(1)
27(1)



C(6)
 236(2)
12982(1) 
3172(1)
28(1)



C(7)
 761(1)
11453(1) 
1298(1)
20(1)



C(8)
 27(2)
10558(1) 
1155(1)
22(1)



C(9)
−176(2)
9560(1)
2203(1)
21(1)



C(10)
1559(2)
8592(1)
3624(1)
27(1)



C(11)
3118(2)
8152(1)
3852(1)
27(1)



C(12)
3357(2)
7256(1)
4687(1)
28(1)



C(13)
4800(2)
6701(1)
5015(1)
26(1)



C(14)
4822(2)
5706(1)
5861(1)
32(1)



C(15)
6161(2)
5141(1)
6172(1)
37(1)



C(16)
7506(2)
5556(1)
5641(1)
39(1)



C(17)
7505(2)
6548(1)
4805(1)
43(1)



C(18)
6168(2)
7110(1)
4500(1)
35(1)



C(19)
2259(2)
8660(1)
1837(1)
24(1)



C(20)
1656(2)
7592(1)
1967(1)
27(1)



C(21)
 −15(2)
7764(1)
1943(1)
22(1)



C(22)
−813(2)
8659(1)
2029(1)
21(1)



C(23)
−2463(2) 
7688(1)
1749(1)
22(1)



C(24)
−1046(2) 
7115(1)
1787(1)
20(1)



C(25)
−928(2)
6105(1)
1688(1)
23(1)



C(26)
−2175(2) 
5710(1)
1532(1)
26(1)



C(27)
−3567(2) 
6298(1)
1479(1)
29(1)



C(28)
−3723(2) 
7287(1)
1589(1)
27(1)



C(29)
−1192(2) 
10002(1) 
2968(1)
22(1)



C(30)
−449(2)
10877(1) 
3150(1)
22(1)



C(31)
−2863(2) 
12573(1) 
2439(1)
26(1)



C(32)
−4174(2) 
13151(1) 
2082(1)
28(1)



C(33)
−4280(2) 
13703(1) 
1011(1)
27(1)



O(2)
3399(1)
1185(1)
3038(1)
34(1)



C(34)
3411(2)
 897(2)
4142(1)
51(1)



O(3)
5196(1)
 178(1)
1887(1)
34(1)



C(35)
5215(2)
 942(1)
 836(1)
41(1)

















TABLE 44





Bond lengths [A] and angles [deg].


















F(1)—C(1)
1.3706(15)
C(11)—H(11)
.9500


O(1)—C(10)
1.2214(16)
C(12)—C(13)
1.4643(19)


N(1)—C(5)
1.4708(17)
C(12)—H(12)
.9500


N(1)—C(6)
1.4711(17)
C(13)—C(18)
1.389(2)


N(1)—C(4)
1.5082(17)
C(13)—C(14)
1.392(2)


N(2)—C(10)
1.3809(18)
C(14)—C(15)
1.382(2)


N(2)—C(19)
1.4747(16)
C(14)—H(14)
.9500


N(2)—C(9)
1.5044(17)
C(15)—C(16)
1.379(2)


N(3)—C(22)
1.3813(17)
C(15)—H(15)
.9500


N(3)—C(23)
1.3815(18)
C(16)—C(17)
1.384(2)


N(3)—H(3N)
.890(15)
C(16)—H(16)
.9500


C(1)—C(2)
1.3694(18)
C(17)—C(18)
1.377(2)


C(1)—C(33)
1.3701(19)
C(17)—H(17)
.9500


C(2)—C(3)
1.3943(18)
C(18)—H(18)
.9500


C(2)—H(2)
.9500
C(19)—C(20)
1.5235(19)


C(3)—C(31)
1.3981(18)
C(19)—H(19A)
.9900


C(3)—C(4)
1.5430(18)
C(19)—H(19B)
.9900


C(4)—C(30)
1.5397(18)
C(20)—C(21)
1.5020(18)


C(4)—C(7)
1.5407(18)
C(20)—H(20A)
.9900


C(5)—H(5A)
.9800
C(20)—H(20B)
.9900


C(5)—H(5B)
.9800
C(21)—C(22)
1.3628(18)


C(5)—H(5C)
.9800
C(21)—C(24)
1.4301(19)


C(6)—H(6A)
.9800
C(23)—C(28)
1.3873(19)


C(6)—H(6B)
.9800
C(23)—C(24)
1.4120(18)


C(6)—H(6C)
.9800
C(24)—C(25)
1.3992(18)


C(7)—C(8)
1.5185(18)
C(25)—C(26)
1.3714(19)


C(7)—H(7A)
.9900
C(25)—H(25)
.9500


C(7)—H(7B)
.9900
C(26)—C(27)
1.4009(19)


C(8)—C(9)
1.5468(18)
C(26)—H(26)
.9500


C(8)—H(8A)
.9900
C(27)—C(28)
1.379(2)


C(8)—H(8B)
.9900
C(27)—H(27)
.9500


C(9)—C(22)
1.5010(19)
C(28)—H(28)
.9500


C(9)—C(29)
1.5405(18)
C(29)—C(30)
1.5255(19)


C(10)—C(11)
1.491(2)
C(29)—H(29A)
.9900


C(11)—C(12)
1.3259(19)
C(29)—H(29B)
.9900


C(30)—H(30A)
.9900
N(1)—C(4)—C(7)
106.77(10)


C(30)—H(30B)
.9900
C(30)—C(4)—C(7)
107.06(11)


C(31)—C(32)
1.3817(19)
N(1)—C(4)—C(3)
111.63(11)


C(31)—H(31)
.9500
C(30)—C(4)—C(3)
111.18(11)


C(32)—C(33)
1.379(2)
C(7)—C(4)—C(3)
112.04(11)


C(32)—H(32)
.9500
N(1)—C(5)—H(5A)
109.5


C(33)—H(33)
.9500
N(1)—C(5)—H(5B)
109.5


O(2)—C(34)
1.4122(18)
H(5A)—C(5)—H(5B)
109.5


O(2)—H(2O)
.959(19)
N(1)—C(5)—H(5C)
109.5


C(34)—H(34A)
.9800
H(5A)—C(5)—H(5C)
109.5


C(34)—H(34B)
.9800
H(5B)—C(5)—H(5C)
109.5


C(34)—H(34C)
.9800
N(1)—C(6)—H(6A)
109.5


O(3)—C(35)
1.4115(18)
N(1)—C(6)—H(6B)
109.5


O(3)—H(3O)
.897(17)
H(6A)—C(6)—H(6B)
109.5


C(35)—H(35A)
.9800
N(1)—C(6)—H(6C)
109.5


C(35)—H(35B)
.9800
H(6A)—C(6)—H(6C)
109.5


C(35)—H(35C)
.9800
H(6B)—C(6)—H(6C)
109.5




C(8)—C(7)—C(4)
113.56(11)


C(5)—N(1)—C(6)
108.13(11)
C(8)—C(7)—H(7A)
108.9


C(5)—N(1)—C(4)
114.35(10)
C(4)—C(7)—H(7A)
108.9


C(6)—N(1)—C(4)
114.17(10)
C(8)—C(7)—H(7B)
108.9


C(10)—N(2)—C(19)
115.06(11)
C(4)—C(7)—H(7B)
108.9


C(10)—N(2)—C(9)
122.53(11)
H(7A)—C(7)—H(7B)
107.7


C(19)—N(2)—C(9)
111.79(10)
C(7)—C(8)—C(9)
111.94(11)


C(22)—N(3)—C(23)
108.44(12)
C(7)—C(8)—H(8A)
109.2


C(22)—N(3)—H(3N)
124.0(10)
C(9)—C(8)—H(8A)
109.2


C(23)—N(3)—H(3N)
127.4(10)
C(7)—C(8)—H(8B)
109.2


C(2)—C(1)—C(33)
123.72(14)
C(9)—C(8)—H(8B)
109.2


C(2)—C(1)—F(1)
117.76(12)
H(8A)—C(8)—H(8B)
107.9


C(33)—C(1)—F(1)
118.52(12)
C(22)—C(9)—N(2)
105.47(10)


C(1)—C(2)—C(3)
119.65(13)
C(22)—C(9)—C(29)
114.07(11)


C(1)—C(2)—H(2)
120.2
N(2)—C(9)—C(29)
113.37(11)


C(3)—C(2)—H(2)
120.2
C(22)—C(9)—C(8)
111.02(11)


C(2)—C(3)—C(31)
117.19(13)
N(2)—C(9)—C(8)
108.77(10)


C(2)—C(3)—C(4)
120.84(12)
C(29)—C(9)—C(8)
104.15(10)


C(31)—C(3)—C(4)
121.96(12)
O(1)—C(10)—N(2)
124.17(14)


N(1)—C(4)—C(30)
107.89(10)
O(1)—C(10)—C(11)
119.73(13)


N(2)—C(10)—C(11)
116.09(12)
C(22)—C(21)—C(24)
107.31(12)


C(12)—C(11)—C(10)
120.45(14)
C(22)—C(21)—C(20)
122.89(12)


C(12)—C(11)—H(11)
119.8
C(24)—C(21)—C(20)
129.73(12)


C(10)—C(11)—H(11)
119.8
C(21)—C(22)—N(3)
109.76(12)


C(11)—C(12)—C(13)
127.74(14)
C(21)—C(22)—C(9)
125.41(12)


C(11)—C(12)—H(12)
116.1
N(3)—C(22)—C(9)
124.79(12)


C(13)—C(12)—H(12)
116.1
N(3)—C(23)—C(28)
130.61(13)


C(18)—C(13)—C(14)
117.84(14)
N(3)—C(23)—C(24)
107.78(12)


C(18)—C(13)—C(12)
122.81(13)
C(28)—C(23)—C(24)
121.61(13)


C(14)—C(13)—C(12)
119.32(14)
C(25)—C(24)—C(23)
118.83(13)


C(15)—C(14)—C(13)
121.03(15)
C(25)—C(24)—C(21)
134.51(13)


C(15)—C(14)—H(14)
119.5
C(23)—C(24)—C(21)
106.66(12)


C(13)—C(14)—H(14)
119.5
C(26)—C(25)—C(24)
119.45(13)


C(16)—C(15)—C(14)
120.18(15)
C(26)—C(25)—H(25)
120.3


C(16)—C(15)—H(15)
119.9
C(24)—C(25)—H(25)
120.3


C(14)—C(15)—H(15)
119.9
C(25)—C(26)—C(27)
120.93(14)


C(15)—C(16)—C(17)
119.52(15)
C(25)—C(26)—H(26)
119.5


C(15)—C(16)—H(16)
120.2
C(27)—C(26)—H(26)
119.5


C(17)—C(16)—H(16)
120.2
C(28)—C(27)—C(26)
120.94(14)


C(18)—C(17)—C(16)
120.07(16)
C(28)—C(27)—H(27)
119.5


C(18)—C(17)—H(17)
120.0
C(26)—C(27)—H(27)
119.5


C(16)—C(17)—H(17)
120.0
C(27)—C(28)—C(23)
118.22(13)


C(17)—C(18)—C(13)
121.35(15)
C(27)—C(28)—H(28)
120.9


C(17)—C(18)—H(18)
119.3
C(23)—C(28)—H(28)
120.9


C(13)—C(18)—H(18)
119.3
C(30)—C(29)—C(9)
111.42(11)


N(2)—C(19)—C(20)
109.67(11)
C(30)—C(29)—H(29A)
109.3


N(2)—C(19)—H(19A)
109.7
C(9)—C(29)—H(29A)
109.3


C(20)—C(19)—H(19A)
109.7
C(30)—C(29)—H(29B)
109.3


N(2)—C(19)—H(19B)
109.7
C(9)—C(29)—H(29B)
109.3


C(20)—C(19)—H(19B)
109.7
H(29A)—C(29)—H(29B)
108.0


H(19A)—C(19)—H(19B)
108.2
C(29)—C(30)—C(4)
112.79(11)


C(21)—C(20)—C(19)
108.06(11)
C(29)—C(30)—H(30A)
109.0


C(21)—C(20)—H(20A)
110.1
C(4)—C(30)—H(30A)
109.0


C(19)—C(20)—H(20A)
110.1
C(29)—C(30)—H(30B)
109.0


C(21)—C(20)—H(20B)
110.1
C(4)—C(30)—H(30B)
109.0


C(19)—C(20)—H(20B)
110.1
H(30A)—C(30)—H(30B)
107.8


H(20A)—C(20)—H(20B)
108.4
C(32)—C(31)—C(3)
121.53(14)


C(32)—C(31)—H(31)
119.2
H(34A)—C(34)—H(34B)
109.5


C(3)—C(31)—H(31)
119.2
O(2)—C(34)—H(34C)
109.5


C(33)—C(32)—C(31)
120.88(13)
H(34A)—C(34)—H(34C)
109.5


C(33)—C(32)—H(32)
119.6
H(34B)—C(34)—H(34C)
109.5


C(31)—C(32)—H(32)
119.6
C(35)—O(3)—H(3O)
105.6(11)


C(1)—C(33)—C(32)
117.02(13)
O(3)—C(35)—H(35A)
109.5


C(1)—C(33)—H(33)
121.5
O(3)—C(35)—H(35B)
109.5


C(32)—C(33)—H(33)
121.5
H(35A)—C(35)—H(35B)
109.5


C(34)—O(2)—H(2O)
110.1(11)
O(3)—C(35)—H(35C)
109.5


O(2)—C(34)—H(34A)
109.5
H(35A)—C(35)—H(35C)
109.5


O(2)—C(34)—H(34B)
109.5
H(35B)—C(35)—H(35C)
109.5









Symmetry transformations used to generate equivalent atoms:







TABLE 45







Hydrogen coordinates (×10{circumflex over ( )}4) and isotropic


displacement parameters ({circumflex over ( )}2 × 10{circumflex over ( )}3).












x
y
z
U(eq)

















H(3N)
−3011(17)
9131(12)
1945(11)
38(5)



H(2)
−889
13070
146
25



H(5A)
591
13955
1090
41



H(5B)
2009
13201
885
41



H(5C)
2097
13880
1614
41



H(6A)
1002
13341
3337
42



H(6B)
−120
12382
3815
42



H(6C)
−607
13504
2915
42



H(7A)
882
12066
605
24



H(7B)
1774
11180
1518
24



H(8A)
653
10335
609
26



H(8B)
−966
10838
899
26



H(11)
3947
8517
3396
32



H(12)
2489
6935
5124
34



H(14)
3901
5411
6229
38



H(15)
6154
4465
6753
45



H(16)
8427
5162
5847
47



H(17)
8428
6843
4441
52



H(18)
6181
7791
3925
42



H(19A)
3316
8537
1996
28



H(19B)
2227
9176
1095
28



H(20A)
2119
7358
1383
33



H(20B)
1898
7023
2649
33



H(25)
9
5698
1730
28



H(26)
−2095
5027
1459
31



H(27)
−4415
6011
1364
35



H(28)
−4668
7683
1556
33



H(29A)
−2153
10307
2671
27



H(29B)
−1414
9401
3657
27



H(30A)
509
10567
3452
26



H(30B)
−1108
11111
3676
26



H(31)
−2814
12208
3181
31



H(32)
−5015
13168
2580
34



H(33)
−5178
14100
758
33



H(2O)
2570(2)
1694(16)
2792(15)
79(7)



H(34A)
4130
1321
4266
77



H(34B)
3705
123
4469
77



H(34C)
2407
1046
4456
77



H(3O)
 4624(19)
 497(14)
2292(14)
57(6)



H(35A)
4195
1084
625
62



H(35B)
5872
655
358
62



H(35C)
5591
1618
796
62

















TABLE 46







Anisotropic displacement parameters ({circumflex over ( )}2 × 10{circumflex over ( )}3).


The anisotropic displacement factor exponent takes the form:


−2 pi{circumflex over ( )}2 [h{circumflex over ( )}2 a*{circumflex over ( )}2 U11 + . . . + 2 h k a * b * U12]














U11
U22
U33
U23
U13
U12



















F(1)
32(1)
29(1)
31(1)
−8(1)
−9(1)
6(1)



O(1)
48(1)
47(1)
24(1)
0(1)
5(1)
19(1)



N(1)
23(1)
20(1)
22(1)
−8(1)
−1(1)
−2(1)



N(2)
22(1)
20(1)
21(1)
−9(1)
−1(1)
1(1)



N(3)
20(1)
20(1)
31(1)
−12(1)
−3(1)
4(1)



C(1)
26(1)
16(1)
26(1)
−7(1)
−6(1)
−2(1)



C(2)
21(1)
18(1)
25(1)
−10(1)
0(1)
−1(1)



C(3)
20(1)
15(1)
26(1)
−10(1)
−1(1)
−2(1)



C(4)
20(1)
20(1)
20(1)
−8(1)
−2(1)
0(1)



C(5)
28(1)
24(1)
29(1)
−9(1)
−1(1)
−7(1)



C(6)
33(1)
27(1)
26(1)
−13(1)
−4(1)
−2(1)



C(7)
19(1)
19(1)
19(1)
−5(1)
−2(1)
2(1)



C(8)
22(1)
22(1)
20(1)
−9(1)
−2(1)
3(1)



C(9)
19(1)
20(1)
22(1)
−9(1)
−1(1)
1(1)



C(10)
35(1)
18(1)
24(1)
−5(1)
−2(1)
3(1)



C(11)
33(1)
24(1)
22(1)
−7(1)
−4(1)
−1(1)



C(12)
33(1)
27(1)
23(1)
−9(1)
−1(1)
1(1)



C(13)
33(1)
26(1)
21(1)
−11(1)
−6(1)
2(1)



C(14)
34(1)
29(1)
28(1)
−8(1)
−3(1)
3(1)



C(15)
45(1)
30(1)
32(1)
−6(1)
−10(1)
5(1)



C(16)
36(1)
44(1)
40(1)
−17(1)
−17(1)
9(1)



C(17)
35(1)
52(1)
39(1)
−10(1)
−7(1)
−6(1)



C(18)
39(1)
34(1)
27(1)
−3(1)
−10(1)
−2(1)



C(19)
19(1)
28(1)
25(1)
−13(1)
0(1)
3(1)



C(20)
25(1)
26(1)
35(1)
−17(1)
−4(1)
5(1)



C(21)
22(1)
20(1)
23(1)
−9(1)
−1(1)
1(1)



C(22)
21(1)
20(1)
21(1)
−7(1)
0(1)
2(1)



C(23)
25(1)
20(1)
20(1)
−8(1)
−1(1)
0(1)



C(24)
21(1)
20(1)
19(1)
−7(1)
−2(1)
1(1)



C(25)
23(1)
19(1)
25(1)
−7(1)
−1(1)
1(1)



C(26)
32(1)
20(1)
26(1)
−9(1)
−2(1)
−2(1)



C(27)
26(1)
32(1)
33(1)
−14(1)
−2(1)
−6(1)



C(28)
21(1)
29(1)
32(1)
−12(1)
−3(1)
2(1)



C(29)
22(1)
20(1)
23(1)
−8(1)
1(1)
0(1)



C(30)
24(1)
20(1)
21(1)
−8(1)
0(1)
2(1)



C(31)
26(1)
23(1)
27(1)
−10(1)
1(1)
−1(1)



C(32)
21(1)
26(1)
38(1)
−15(1)
6(1)
−2(1)



C(33)
18(1)
22(1)
43(1)
−14(1)
−5(1)
2(1)



O(2)
32(1)
40(1)
31(1)
−14(1)
−8(1)
8(1)



C(34)
61(1)
56(1)
40(1)
−19(1)
−24(1)
16(1)



O(3)
32(1)
29(1)
36(1)
−11(1)
0(1)
8(1)



C(35)
40(1)
37(1)
41(1)
−12(1)
5(1)
1(1)










Analysis—FT Raman Spectroscopy

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).
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










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 47







RAMAN peak-list of crystalline form A; spectrum shown in FIG. 2a











No.
cm−1
Intensity















1
98
M



2
128
W



3
170
W



4
189
VW



5
227
VW



6
272
VW



7
310
VW



8
355
VW



9
417
VW



10
461
VW



11
485
VW



12
509
VW



13
543
VW



14
589
VW



15
611
VW



16
620
VW



17
644
VW



18
676
W



19
697
VW



20
725
VW



21
746
VW



22
783
VW



23
801
VW



24
831
VW



25
865
VW



26
893
VW



27
927
VW



28
955
VW



29
978
VW



30
1001
M



31
1012
VW



32
1028
VW



33
1048
VW



34
1074
VW



35
1111
VW



36
1155
VW



37
1175
W



38
1183
W



39
1204
W



40
1244
VW



41
1268
W



42
1294
W



43
1343
VW



44
1368
VW



45
1385
VW



46
1407
VW



47
1447
W



48
1462
W



49
1493
VW



50
1568
W



51
1574
W



52
1584
W



53
1606
VS



54
1650
W



55
2782
VW



56
2834
VW



57
2878
VW



58
2910
W



59
2946
VW



60
2960
VW



61
2980
VW



62
2999
VW



63
3026
VW



64
3062
W



65
3075
W



66
3449
VW

















TABLE 48







RAMAN peak-list of crystalline form B; spectrum shown in FIG. 2b











No
cm−1
Intensity















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 ofcrystalline form D: shown in FIG. 2d.











No
cm−1
Intensity















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

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.
In the following table, “ΔH” means “specific heat”, “Tonset” means the “onset temperature”, and “Tpeak” means the “peak temperature” of a thermal event.
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
46.7
61.2
10


(one sample measured)
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






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
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
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.
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 Form
T [° 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:

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.
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 FIG. 3a).
DVS measurements therefor revealed that crystalline form A is not hygroscopic or just slightly hygroscopic.
Crystalline Form B:
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 FIG. 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:
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 FIG. 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:
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 FIG. 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:
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 FIG. 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.
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:
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:
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:
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:
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), 11.9±0.2 (2Θ), 17.4±0.2 (2Θ), and 27.1±0.2 (2Θ).

2. Crystalline form A according to claim 1, which has one or more Raman peaks selected from the group consisting of 1606±2 cm−1, 1175±2 cm−1, 1568±2 cm−1, 1574±2 cm−1 and 1650±2 cm−1.

3. Crystalline form A according to claim 1, which in DSC analysis exhibits an endothermal event with an onset temperature in the range of 227° C. to 247° C. and/or a peak temperature in the range of 235° C. to 255° C.

4. Crystalline form A according to claim 1, which has X-ray powder diffraction peaks (CuKα radiation) of 8.7±0.2 (2Θ), 11.9±0.2 (2Θ), 17.4±0.2 (2Θ), 18.3±0.2 (2Θ), and 27.1±0.2 (2Θ).

5. Crystalline form A according to claim 1, which has at least one additional X-ray powder diffraction peak (CuKα radiation) selected from 7.7±0.2 (2Θ), 10.0±0.2 (2Θ), 15.3±0.2 (2Θ), 15.8±0.2 (2Θ), 21.9±0.2 (2Θ), and 22.2±0.2 (2Θ).

6. Crystalline form A according to claim 1, which has at least one additional X-ray powder diffraction peak selected from the group consisting of 10.0±0.2 (2Θ), 16.7±0.2 (2Θ), and 26.2±0.2 (2Θ).

7. Crystalline form A according to claim 1, which has one additional X-ray powder diffraction peak at about 17.8±0.2 (2Θ).

8. Crystalline form A according to claim 1, which has additional X-ray powder diffraction peaks at 10.0±0.2 (2Θ), 16.7±0.2 (2Θ), and 26.2±0.2 (2Θ).

9. Crystalline form A according to claim 8, which has at least one additional X-ray powder diffraction peak selected from about 15.3±0.2 (2Θ), and about 21.9±0.2 (2Θ).

10. Crystalline form A according to claim 1, which has additional X-ray powder diffraction peaks at about 18.3±0.2 (2Θ), 15.3±0.2 (2Θ), about 21.9±0.2 (2Θ), and about 16.7±0.2 (2Θ).

11. A pharmaceutical composition comprising at least one Crystalline form A according to claim 1.

12. 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 claim 1, 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 0.3 h 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 by 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.

13. The process according to claim 12, wherein the solid obtained in step (b-1′) is dried at a temperature in the range of 20 to 55° C.

14. The process according to claim 12, wherein the solid obtained in step (b-1′) is dried at 50° C.

15. Crystalline form A according to claim 2, which in DSC analysis exhibits an endothermal event with an onset temperature in the range of 227° C. to 247° C., and/or a peak temperature in the range of 235° C. to 255° C.

16. Crystalline form A according to claim 2, which in DSC analysis exhibits an endothermal event with an onset temperature in the range of 240° C. to 245° C. and/or a peak temperature in the range of 245° C. to 250° C.

17. Crystalline form A according to claim 15, which in DSC analysis exhibits an endothermal event with an onset temperature in the range of 240° C. to 245° C. and/or a peak temperature in the range of 245° C. to 250° C.

18. 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 claim 2, 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 0.3 h 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 by 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.

19. The process according to claim 18, wherein the solid obtained in step (b-1′) is dried at a temperature in the range of 20 to 55° C.

20. The process according to claim 18, wherein the solid obtained in step (b-1′) is dried at 50° C.

21. 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 claim 3, 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 0.3 h 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 by 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.

22. The process according to claim 21, wherein the solid obtained in step (b-1′) is dried at a temperature in the range of 20 to 55° C.

23. The process according to claim 21, wherein the solid obtained in step (b-1′) is dried at 50° C.

24. 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 claim 4, 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 0.3 h 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 by 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.

25. The process according to claim 24, wherein the solid obtained in step (b-1′) is dried at a temperature in the range of 20 to 55° C.

26. The process according to claim 24, wherein the solid obtained in step (b-1′) is dried at 50° C.

27. 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 claim 5, 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 0.3 h 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 by 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.

28. The process according to claim 27, wherein the solid obtained in step (b-1′) is dried at a temperature in the range of 20 to 55° C.

29. The process according to claim 27, wherein the solid obtained in step (b-1′) is dried at 50° C.

30. 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 claim 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 0.3 h 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 by 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.

31. The process according to claim 30, wherein the solid obtained in step (b-1′) is dried at a temperature in the range of 20 to 55° C.

32. The process according to claim 30, wherein the solid obtained in step (b-1′) is dried at 50° C.

33. 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 claim 7, 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 0.3 h 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 by 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.

34. The process according to claim 33, wherein the solid obtained in step (b-1′) is dried at a temperature in the range of 20 to 55° C.

35. The process according to claim 33, wherein the solid obtained in step (b-1′) is dried at 50° C.

36. 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 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 0.3 h 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 by 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.

37. The process according to claim 36, wherein the solid obtained in step (b-1′) is dried at a temperature in the range of 20 to 55° C.

38. The process according to claim 36, wherein the solid obtained in step (b-1′) is dried at 50° C.

39. 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 claim 9, 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 0.3 h 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 by 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.

40. The process according to claim 39, wherein the solid obtained in step (b-1′) is dried at a temperature in the range of 20 to 55° C.

41. The process according to claim 39, wherein the solid obtained in step (b-1′) is dried at 50° C.

42. 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 claim 10, 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 0.3 h 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 by 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.

43. The process according to claim 42, wherein the solid obtained in step (b-1′) is dried at a temperature in the range of 20 to 55° C.

44. The process according to claim 42, wherein the solid obtained in step (b-1′) is dried at 50° C.