Salts of (E)-N-((ls,4s)-4-(dimethylamino)-l,4-diphenylcyclohexyl)-N-m ethyIcinna

The invention relates to physiologically acceptable salts of (E)-N-((l s,4s)-4-(dimethylamino)- l ,4- diphenylcyclohexyl)-N-methylcinnamamide, solid forms of these salts, pharmaceutical compositions and medicaments comprising these salts, the use of these salts as well as to a process for the preparation thereof.

BACKGROUND OF THE INVENTION

Pharmacologically active drugs may exist in different solid forms. For example, a drug may exist in form of different salts that in turn may each exist in different crystalline forms. The different salts as well as the different crystalline forms of each salt have different physical and chemical properties. Different salts may additionally have different pharmacokinetic properties such as AUC and C _max . When developing a particular salt of a pharmacologically active drug, several additional factors need to be taken into account such as synthetic accessibility, polymorphism, physical and chemical properties, toxicological evaluation, commercial availability, costs of counter ion, weight of counter ion, stoichiometry between drug and counter ion, analytical development efforts, and the like.

Different physical properties can cause different crystalline forms of the same drug to have largely different processing and storage performance. Such physical properties include, for example, thermodynamic stability, crystal morphology [form, shape, structure, particle size, particle size distribution, degree of crystallinity, color], ripple behavior, flowability, density, bulk density, powder density, apparent density, vibrated density, depletability, emptyability, hardness, deformability, grindability, compressibility, compactability, brittleness, elasticity, caloric properties [particularly melting point], solubility [particularly equilibrium solubility, pH dependence of solubility], dissolution [particularly dissolution rate, intrinsic dissolution rate], reconstitutability, hygroscopic ity, tackiness, adhesiveness, tendency to electrostatic charging, and the like.

One particular drug that is of great interest for use in treating pain is (E)-N-(( l s,4s)-4-(dirnethylamino)-l ,4- diphenylcyclohexyl)-N-methylcinnamamide, which is known from WO 2009/1 18168 Al . The compound has poor solubility in water and high affinity against the μ-opioid-receptor and the ORL 1 -receptor.

The forms of (E)-N-(4-(dimethylamino)-l,4-diphenylcyclohexyl)-N-methyIcin namamide that are known so far are not satisfactory in every respect and there is a demand for advantageous forms.

It is an object of the invention to provide forms of (E)-N-((ls,4s)-4-(dimethylamino)-l ,4-diphenylcyclohexyl)-N- methylcinnamamide that have advantages compared to the forms of the prior art.

This object has been achieved by the present invention. It has surprisingly been found that salts of (E)-N- (( l s,4s)-4-(dimethylamino)- l ,4-diphenylcyclohexyl)-N-methylcinnamamide can be prepared which have advantageous properties. These inventive salts and their solid forms are described herein. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the DVS (dynamic vapor sorption) isotherm plot according to Example 1(a).

Figure 2 shows the XRPD analysis according to Example 1 (b).

Figure 3 shows the XRPD analysis of SMI according to Example 1 (c).

Figure 4 shows the XRPD analysis of SM2 according to Example 1(c).

Figure 5 shows the DVS isotherm plot of SM2 according to Example 1(c).

Figure 6 shows the XRPD analysis of SM2 according to Example 1(d).

Figure 7 shows the DVS isotherm plot of SM2 according to Example 1 (d).

Figure 8 shows the XRPD analysis of the hemi-L-tartrate salt according to Example 1(d).

Figure 9 shows the DSC isotherm plot of the hemi-L-tartrate salt according to Example 1(d).

Figure 10 shows the XRPD analysis of 2(a)-2 according to Example 2(a).

Figure 1 1 shows a comparison of the XRPD analysis of hemi-D-tartrate, hemi-meso-tartrate, hemi-L-tartrate according to Example 2(a).

Figure 12 shows the XRPD analysis of the crystalline form 3-2 according to Example 3.

Figure 13 shows the DVS isotherm plot of Example 4.

Figure 14 shows the XRPD analysis of Example 4.

Figure 15 shows the DVS isotherm plot of Example 5(a).

Figure 16 shows the XRPD analysis of SM5 according to Example 5(b).

Figure 17 shows the DVS isotherm plot of Example 6.

Figure 18 shows the XRPD analysis of Example 6.

Figure 19 shows the XRPD analysis of Example 7(a). Figure 20 shows the DVS isotherm plot of Example 7(a).

Figure 21 shows the XRPD analysis of SM3 of Example 7(b).

Figure 22 shows equilibrium solubilities of various salts at pHl .3- 1.4 (Example 10).

Figure 23 shows equilibrium solubilities of various salts at pH4.5-4.7 (Example 10).

Figure 24 shows equilibrium solubilities of various salts at pH6.8-7.0 (Example 10).

Figure 25 shows equilibrium solubilities of various salts at pH7.4-7.5 (Example 10).

Figure 26 shows dissolution plots for the hemi-L-tartrate salt in aqueous, FaSSIF and FeSSIF media (Example 10(b)).

Figure 27 shows dissolution plots in aqueous media for the free base (Example 10(b)).

Figure 28 shows the results of in vivo release in dogs: hemi-L-tartrate 60 mg (free base) tablet (Example 10(d)).

Figure 29 shows the results of in vivo release in dogs: free base SD 60 mg IR tablet (Example 10(d)).

Figure 30 shows the results of in vivo release in dogs: 60 mg free base IR tablet (Example 10(d)).

Figure 31 shows the results of in vivo release in dogs: hemi-succinate 60 mg (free base) tablet (Example 10(d)).

Figure 32 shows the results of in vivo release in dogs: release of free base from SEDDS capsules (Example 10(d)).

Figure 33 shows the results of in vivo release in dogs: comparison of mean plasma exposures to free base in different formulations (0-24 h) (Example 10(d)).

Figure 34 shows the results of in vivo release in dogs: log scaled comparison of mean plasma exposures to free base in different formulations (0-24 h) (Example 10(d)).

Figure 35 shows the results of in vivo release in dogs: detailed comparison of mean plasma exposures to free base in different formulations (0-2.5 h) (Example 10(d)).

Figure 36 shows the results of in vivo release in dogs: C _max of different formulations (Example 10(e)). Figure 37 shows the results of in vivo release in dogs: AUC ₀ .6 h of different formulations (Example 10(e)). Figure 38 shows the results of in vivo release in dogs: AUC ₀ -24 h of different formulations (Example 10(e)).

Figure 39 shows the dissolution rate of different salts (15 mg base/tablet) at pH 4.5 (phosphate buffer) according to Example 1 1(a).

Figure 40 shows the dissolution rate of different salts (15 mg base/tablet) at pH 6.8 (phosphate buffer) according to Example 1 1(a).

Figure 41 shows the dissolution rate of different salts (60 mg base/tablet) at pH 4.5 (acetate buffer) according to Example 1 1(b).

Figure 42 shows the dissolution rate of different salts (60 mg base/tablet) at pH 6.8 (phosphate buffer) according to Example 1 1(b).

Figure 43 shows the dissolution rate of different salts (60 mg base/tablet) at pH 6.5 (FaSSIF) according to Example 1 1 (b).

DETAILED DESCRIPTION

A first aspect of the invention relates to salts of (E)-N-(( l s,4s)-4-(dimethylamino)- l ,4-diphenylcyclohexyl)-N- methylcinnamamide and multicarboxylic acids.

The salt according to the invention comprises the pharmacologically active ingredient (E)-N-(( l s,4s)-4- (dimethylamino)-l,4-diphenylcyclohexyl)-N-methylcinnamamide (C30H ₃₄ N2O, CAS RN: 1 189794-24-8), which has the following structure:

and which may be also referred to as "N-(4-(dimethylamino)- l ,4-diphenylcyclohexyl)-N-methylcinnamide, (cis)-", as "(E)-N-(( l s,4s)-4-(dimethylamino)-l ,4-diphenylcyclohexyl)-N-methylcinnamamide (cis)", as "(E)-N- (4-dimethylamino- l ,4-diphenyl-cyclohexyl)-N-methyl-3-phenyl-acrylamide (more polar diastereomer)", or as "2-propenamide, N-[cis-4-(dimethylamino)-l ,4-diphenylcyclohexyl]-N-methyl-3-phenyl-, (2E)-" respectively.

(E)-N-((l s,4s)-4-(dimethylamino)- l ,4-diphenylcycIohexyI)-N-methyIcinnamamide is one of two possible stereoisomers of (E)-N-(4-(dimethylamino)-l ,4-diphenylcyclohexyl)-N-methylcinnamamide. Preferably, the diastereomeric excess of (E)-N-(( 1 s,4s)-4-(dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide within the salt according to the invention is at least 90%de, more preferably at least 95%de, still more preferably at least 96%de, yet more preferably at least 97%de, even more preferably at least 98%de, most preferably at least 99%de, and in particular at least 99.5%de.

The salt according to the invention also comprises a multicarboxylic acid.

The present invention encompasses any forms of these salts such as co-crystals or other complexes and types of complexes, respectively, such as "co-amorphic forms", particularly also possible solvates.

For the purpose of the specification, a multicarboxylic acid comprises at least two carboxylic groups (-C0 ₂ H) which idenpendently of one another may be protonated.

Preferably, the multicarboxylic acid is aliphatic and may be saturated or unsaturated. Preferably, the multicarboxylic acid comprises two or three carboxylic groups, particularly preferably two carboxylic groups so that the multicarboxylic acid preferably is a dicarboxylic acid which may be saturated or unsaturated. In a preferred embodiment, the multicarboxylic acid is a dicarboxylic acid that comprises hydroxyl groups so that the multiocarboxylic acid is a hydroxy dicarboxylic acid, e.g. a monohydroxy dicarboxylic acid or a dihydroxy dicarboxylic acid.

Preferably, the multicarboxylic acid is selected from the group consisting of saturated aliphatic dicarboxylic acids, unsaturated aliphatic dicarboxylic acids, saturated aliphatic monohydroxy dicarboxylic acids and saturated aliphatic dihydroxy dicarboxylic acids.

Saturated aliphatic dicarboxylic acids according to the invention include but are not limited to oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, decanedioic acid, undecanedioic acid, and dodecanedioic acid.

Unsaturated aliphatic dicarboxylic acids according to the invention include but are not limited to maleic acid, fumaric acid, glutaconic acid, traumatic acid, and muconic acid.

Saturated aliphatic monohydroxy dicarboxylic acids include but are not limited to malic acid.

Saturated aliphatic dihydroxy dicarboxylic acids include but are not limited to tartaric acid, particularly L-tartaric acid, D-tartaric acid, and meso-tartaric acid.

Preferably, the multicarboxylic acid is a saturated dicarboxylic acid.

Preferably, the dicarboxylic acid is an aliphatic C ₄ -dicarboxylic acid.

Preferably, the multicarboxylic acid is selected from the group consisting of oxalic acid, glutaric acid, succinic acid, fumaric acid, maleic acid, malic acid and tartaric acid, whereas the latter is preferably selected from L- tartaric acid, D-tartaric acid, and meso-tartaric acid. In a particularly preferred embodiment, the multicarboxylic acid is succinic acid or L-tartaric acid.

When the multicarboxylic acid according to the invention is chiral (e.g. malic acid or D- or L-tartaric acid), its enantiomeric excess within the salt according to the invention is preferably at least 90%ee, more preferably at least 95%ee, still more preferably at least 96%ee, yet more preferably at least 97%ee, even more preferably at least 98%ee, most preferably at least 99%ee, and in particular at least 99.5%ee.

Salts are typically regarded as ionic compounds that result from the neutralization reaction of an acid and a base. Salts are composed of related numbers of cations and anions so that the product is electrically neutral. The salt according to the invention can be regarded as an acid addition salt, whereas the multicarboxylic acid is added at the (E)-N-((ls,4s)-4-(dimethylamino)- l ,4-diphenylcyclohexyl)-N-methylcinnamamide. The salt according to the invention is composed of (E)-N-((l s,4s)-4-(dimethylamino)- l ,4-diphenylcyclohexyl)-N-methylcinnamamide and the multicaroxylic acid. Preferably, the salt according to the invention consists of (E)-N-(( l s,4s)-4- (dimethylamino)-l ,4-diphenylcyclohexyl)-N-methylcinnamamide and the multicaroxylic acid, i.e. is not a ternary or even higher salt.

Usually, at ambient conditions (standard temperature and pressure) the non-dissolved salt according to the invention preferably is in solid state of matter, but it may principally also be a molten salt or consitute an ionic liquid.

The salts according to the invention can be prepared by conventional methods that are known to the skilled person. For example, a solution of (E)-N-(( l s,4s)-4-(dimethylamino)- l ,4-diphenylcyclohexyl)-N-methyl- cinnamamide in a suitable solvent can be combined with a solution of the multicarboxylic acid in a suitable solvent and the solvent(s) can be subsequently evaporated to dryness.

The (E)-N-((ls,4s)-4-(dimethylamino)-l ,4-diphenylcyclohexyl)-N-methylcinnamamide and the multicarboxylic acid in the salt according to the invention may be present in different stoichiometric ratios. Preferably, the stoichiometric ratio of (E)-N-(( l s,4s)-4-(dimethylamino)-l,4-diphenylcyclohexyl)-N-methylcinn amamide : multicarboxylic acid is about 1 : 1 or about 2 : 1 or about 1 : 0.5 (hemi salt).

It has been surprisingly found that Q-dicarboxylic acids tend to form hemi salts with (E)-N-(( l s,4s)-4- (dimethylamino)- l ,4-diphenylcyclohexyl)-N-methylcinnamamide, i.e. the stoichiometric ratio of these salts is about 2 : 1 (hemi salt). For example, succinic acid forms a hemi succinate ( 1 :0.5), fumaric acid forms a hemi fumarate (1 :0.5), L-tartaric acid forms a hemi-L-tartrate (1 :0.5), meso-tartaric acid forms a hemi-meso-tartrate (1 :0.5), D-tartaric acid forms a hemi-D-tartrate ( 1 :0.5), and malic acid forms a hemi-L-malate ( 1 :0.5). This is particulary advantageous, because per salt molecule, the contribution of the weight of the multicarboxylic acid to the overall weight of the salt is only 50% or 40% or 30% or 20% or 10% or 5%. In consequence, the increase of molecular weight relative to the equivalent weight of the free base of (E)-N-(( l s,4s)-4-(dimethylamino)- l ,4- diphenylcyclohexyl)-N-methylcinnamamide is moderate. In contrast, carboxylic acids of different chain length tend to form salts in different stoichiometries- For example, malonic acid forms a 1 : 1 malonate, caproic acid forms a 1 : 1 hexanoate, palmitic acid forms a 1 : 1 palmitate, and stearic acid forms a 1 : 1 stearate. It appears that oxalic acid also forms a 1 : 1 oxalate.

The salt according to the invention is preferably selected from the group consisting of

• (E)-N-(( 1 s,4s)-4-(dimethylamino)- [ ,4-diphenylcyclohexyl)-N-methylc innamamide hemi-L-tartrate;

• (E)-N-(( 1 s,4s)-4-(dimethylamino)- i ,4-diphenylcyclohexyl)-N-methylci innamamide hemi-D-tartrate;

• (E)-N-(( 1 s,4s)-4-(dimethy lamino)- 1 ,4-diphenylcyclohexyl)-N-methylci innamamide hemi-meso-tartrate;

• (E)-N-(( 1 s,4s)-4-(dimethy lamino)- 1 ,4-diphenylcyclohexyl)-N-methylci innamamide (2S,3S)-dibenzoyl tartrate;

• (E)-N-(( 1 s,4s)-4-(dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylci innamamide glutamate;

• (E)-N-(( l s,4s)-4-(dimethylamino)-l ,4-diphenylcyclohexyl)-N-methylci innamamide hemi-L-malate;

• (E)-N-(( 1 s,4s)-4-(dimethy lamino)- 1 ,4-diphenylcyclohexyl)-N-methylci innamamide citrate;

• (E)-N-(( 1 s,4s)-4-(dimethy lamino)- 1 ,4-diphenylcyclohexyl)-N-methylci innamamide hemi-succinate;

• (E)-N-(( 1 s,4s)-4-(dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylci innamamide hemi-fumarate;

• (E)-N-(( 1 s,4s)-4-(dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylci innamamide malonate;

• (E)-N-(( 1 s,4s)-4-(dimethylamino)- ^' ,4-diphenylcyclohexyl)-N-methyIci innamamide hemi-maleate;

• (E)-N-(( 1 s,4s)-4-(dimethylamino)- ,4-diphenylcyclohexyl)-N-methylci innamamide oxalate; and

• (E)-N-((l s,4s)-4-(dimethylamino)- ,4-diphenylcyclohexyl)-N-methylci innamamide sebacate.

Particularly preferred are the salts se !ected from the sub-group consisting of

• (E)-N-(( 1 s,4s)-4-(dimethylamino)- l ,4-diphenylcyclohexyl)-N-methylcinnamamide hemi-L-tartrate;

• (E)-N-(( 1 s,4s)-4-(dimethy lam ino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide hemi-L-malate;

• (E)-N-(( 1 s,4s)-4-(dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide hemi-succinate;

• (E)-N-(( ls,4s)-4-(dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide hemi-fumarate;

• (E)-N-(( 1 s,4s)-4-(dimethyIamino)- l,4-diphenylcyclohexyl)-N-methylcinnamamide hemi-malonate; and

• (E)-N-(( ls,4s)-4-(dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide oxalate.

Preferred salts also include but are not limited to salts selected from the group consisting of (E)-N-((l s,4s)-4- (dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide hydrochloride, (E)-N-(( 1 s,4s)-4-(dimethyl- amino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide hydrobromide, (E)-N-(( 1 s,4s)-4-(dimethylamino)- 1 ,4- diphenylcyclohexyl)-N-methylcinnamamide mucate, (E)-N-(( 1 s,4s)-4-(dimethylamino)- 1 ,4-diphenylcyclo- hexyl)-N-methylcinnamamide L-lysinate, (E)-N-((l s,4s)-4-(dimethylamino)-l,4-diphenylcyclohexyl)-N-methyl- cinnamamide cinnamate, (E)-N-((l s,4s)-4-(dimethylamino)- l,4-diphenylcyclohexyl)-N-methylcinnamamide embonate ( 1 :2), (E)-N-(( 1 s,4s)-4-(dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide camsilate, (E)-N-((l s,4s)-4-(dimethylamino)-l ,4-diphenylcyclohexyl)-N-methylcinnamamide esilate, (E)-N-(( ls,4s)-4- (dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide mesilate, (E)-N-(( 1 s,4s)-4-(dimethy lamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide hexanoate, (E)-N-(( 1 s,4s)-4-(dimethylamino)- 1 ,4-diphenyl- cyclohexyl)-N-methylcinnamamide stearate, (E)-N-((l s,4s)-4-(dimethylamino)- l ,4-diphenylcyclohexyl)-N- methylcinnamamide tosilate, (E)-N-((l s,4s)-4-(dimethylamino)- l ,4-diphenylcyclohexyl)-N-methylcinnamamide palmitate, (E)-N-(( 1 s,4s)-4-(dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide capsilate, (E)-N- (( 1 s,4s)-4-(dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide glyphosate, (E)-N-(( 1 s,4s)-4- (dimethy lamino)- 1 ,4-diphenylcyclohexy l)-N-methy lcinnamamide acesulfamate, (E)-N-(( 1 s,4s)-4-(dimethy 1- amino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide acetate, (E)-N-(( 1 s,4s)-4-(dimethylamino)- 1 ,4- dipheny lcyclohexyl)-N-methy lcinnamamide saccharinate, (E)-N-(( 1 s,4s)-4-(dimethylamino)- 1 ,4-diphenylcyclo- hexyl)-N-methylcinnamamide octanoate, (E)-N-((l s,4s)-4-(dimethylamino)- l ,4-diphenylcyclohexyl)-N-methyl- cinnamamide nicotinate, (E)-N-(( 1 s,4s)-4-(dimethy lamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide formiate, (E)-N-(( l s,4s)-4-(dimethylamino)-l ,4-diphenylcyclohexyl)-N-methylcinnamamide hippurate, (E)-N- (( 1 s,4s)-4-(dimethy lamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide gentisate, (E)-N-(( ls,4s)-4- (dimethylamino)- l ,4-diphenylcyclohexyl)-N-methy lcinnamamide sulfate, (E)-N-(( I s,4s)-4-(dimethy lamino)- 1 ,4- diphenylcyclohexyl)-N-methylcinnamamide nitrate, (E)-N-(( ls,4s)-4-(dimethylamino)- l ,4-diphenylcyclohexyl)- N-methylcinnamamide phosphate, (E)-N-(( 1 s,4s)-4-(dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnam- amide orotate, (E)-N-((ls,4s)-4-(dimethylamino)-l ,4-diphenylcyclohexyl)-N-methylcinnamamide l -hydroxy-2- naphthoate, (E)-N-(( l s,4s)-4-(dimethylamino)-l ,4-diphenylcyclohexyl)-N-methylcinnamamide napadisilate and (E)-N-(( l s,4s)-4-(dimethylamino)-l ,4-diphenylcyclohexyl)-N-methylcinnamamide lactate.

It has been unexpectedly found that when considering factors that are relevant for the development of a new active pharmaceutical ingredient, particularly synthetic accessibility, polymorphism, physical and chemical properties, toxicological evaluation, commercial availability, costs of counter ion, weight of counter ion, stoichiometry between drug and counter ion, and analytical development efforts, that certain salts of (E)-N- ((ls,4s)-4-(dimethylamino)-l ,4-diphenylcyclohexyl)-N-methylcinnamamide have advantages compared to other salts.

Another aspect of the invention relates to a solid form of the salt according to the invention as described above. All preferred embodiments of the salt according to the invention also apply to the solid form according to the invention and are thus not repeated hereinafter.

Preferably, the solid form according to the invention is crystalline or amorphous. When the solid form according to the invention is crystalline, its degree of crystallinity is preferably at least 50%, more preferably at least 60%, still more preferably at least 70%, yet more preferably at least 80%, even more preferably at least 90%, most preferably at least 95%, and in particular at least 99%.

In a preferred embodiment, the solid form according to the invention is amorphous. 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) melt 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, preferably to an amorphous form that is obtainable by any of the above methods or combinations thereof.

Preferably, the solid form according to the invention is an ansolvate or a solvate. When the solid form according to the invention is a solvate, the solvent is not particularly limited. Conventional solvents include 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 is water. In another preferred embodiment, the solvent is an organic solvent selected from the group consisting of methanol, ethanol, n-propanol, iso-propanol, dimethyl formamide and dimethyl sulfoxid. In still another preferred embodiment, the solvent is an organic solvent selected from the group consisting of the C4 to C6 alcohols such as 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; chlorinated hydrocarbons such as dichloromethane and chloroform; and mixtures thereof. In a preferred embodiment, the solvent does neither contain water nor any solvent selected from the group consisting of methanol, ethanol, n- propanol, iso-propanol, dimethyl formamide and dimethyl sulfoxide.

In a preferred embodiment, the salt according to the invention is (E)-N-((l s,4s)-4-(dimethylamino)- l ,4- diphenylcyclohexyl)-N-methylcinnamamide hemi-L-tartrate, which is preferably present in at least partially crystalline form.

The crystalline hemi-L-tartrate according to the invention can be obtained by bringing together (E)-N-(( l s,4s)-4- (dimethyIamino)- l ,4-diphenylcyclohexyI)-N-methylcinnamamide and L-tartaric acid in the desired stoichiometric ratio, optionally in a suitable solvent and subsequently evaporating the solvent to dryness at room temperature.

Preferably, the solid form of (E)-N-((l s,4s)-4-(dimethylamino)-l ,4-diphenylcyclohexyl)-N-methylcinnamamide hemi-L-tartrate has X PD diffraction peaks (measured with Cu a radiation) at 25°C at 18.1±0.2 °2Theta, 18.5±0.2 °2Theta, and 19.2±0.2 °2Theta. Preferably, the solid form of (E)-N-((ls,4s)-4-(dimethyIamino)- l,4- diphenylcyclohexyl)-N-methylcinnamamide hemi-L-tartrate additionally has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 1 1.4±0.2 °2Theta and/or 19.9±0.2 °2Theta. It has been unexpectedly found that when considering factors that are relevant for the development of a new active pharmaceutical ingredient, particularly synthetic accessibility, polymorphism, physical and chemical properties, toxicological evaluation, commercial availability, costs of counter ion, weight of counter ion, stoichiometry between drug and counter ion, and analytical development efforts, the crystalline hemi-L-tartrate of (E)-N-(( l s,4s)-4-(dimethylamino)-l,4-diphenylcyclohexyl)-N-methylcinn amamide has advantages compared to other salts. In particular, for the hemi-L-tartrate reproducible XRPD; single event in DSC with high melting point (~200°C) and low weight loss in TGA can be observerd making the hemi-L-tartrate a promising candidate for drug development. Further, the hemi-salt exhibits an advantageous ratio between (E)-N-(( l s,4s)-4- (dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide and the L-tartrate.

In a preferred embodiment, the salt according to the invention is (E)-N-((ls,4s)-4-(dimethylamino)- l ,4- diphenylcyclohexyl)-N-methylcinnamamide hemi-D-tartrate, which is preferably present in at least partially crystalline form.

The crystalline hemi-D-tartrate according to the invention can be obtained by bringing together (E)-N-((ls,4s)-4- (dimethylamino)- l,4-diphenylcyclohexyl)-N-methylcinnamamide and D-tartaric acid in the desired stoichiometric ratio, optionally in a suitable solvent and subsequently evaporating the solvent to dryness at room temperature.

Preferably, the solid form of (E)-N-(( Is,4s)-4-(dimethylamino)- l,4-diphenylcyclohexyl)-N-methylcinnamamide hemi-D-tartrate has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 12.7±0.2 °2Theta, 18. 0.2 °2Theta, and 18.5±0.2 °2Theta. Preferably, the solid form of (E)-N-((l s,4s)-4-(dimethylamino)-l ,4- diphenylcyclohexyl)-N-methylcinnamamide hemi-D-tartrate additionally has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 19.2±0.2 °2Theta and/or 19.9±0.2 °2Theta.

It has been unexpectedly found that when considering factors that are relevant for the development of a new active pharmaceutical ingredient, particularly synthetic accessibility, polymorphism, physical and chemical properties, toxicological evaluation, commercial availability, costs of counter ion, weight of counter ion, stoichiometry between drug and counter ion, and analytical development efforts, the crystalline hemi-D-tartrate of (E)-N-((ls,4s)-4-(dimethylamino)- l ,4-diphenylcyclohexyl)-N-methylcinnamamide has advantages compared to other salts.

In a preferred embodiment, the salt according to the invention is (E)-N-(( l s,4s)-4-(dimethylamino)-l ,4- diphenylcyclohexyl)-N-methylcinnamamide hemi-meso-tartrate, which is preferably present in at least partially crystalline form.

The crystalline hemi-meso-tartrate according to the invention can be obtained by bringing together (E)-N- ((ls,4s)-4-(dimethylamino)- l,4-diphenylcyclohexyl)-N-methylcinnamamide and meso-tartaric acid in the desired stoichiometric ratio, optionally in a suitable solvent and subsequently evaporating the solvent to dryness at room temperature. Preferably, the solid form of (E)-N-((l s,4s)-4-(dimethylamino)- l ,4-diphenylcyclohexyl)-N-methylcinnamamide hemi-meso-tartrate has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 17.9±0.2 °2Theta, 18.3±0.2 °2Theta, and 19.6±0.2 °2Theta. Preferably, the solid form of (E)-N-(( l s,4s)-4-(dimethylamino)-l ,4- diphenylcyclohexyl)-N-methylcinnamamide hemi-meso-tartrate additionally has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 1 1.9±0.2 °2Theta and/or 21 .1 ±0.2 °2Theta.

It has been unexpectedly found that when considering factors that are relevant for the development of a new active pharmaceutical ingredient, particularly synthetic accessibility, polymorphism, physical and chemical properties, toxicological evaluation, commercial availability, costs of counter ion, weight of counter ion, stoichiometry between drug and counter ion, and analytical development efforts, the crystalline hemi-meso- tartrate of (E)-N-((l s,4s)-4-(dimethylamino)-l,4-diphenylcyclohexyl)-N-methylcinn amamide has advantages compared to other salts.

In a preferred embodiment, the salt according to the invention is (E)-N-(( ls,4s)-4-(dimethylamino)- l ,4- diphenylcyclohexyl)-N-methylcinnamamide hemi-L-malate, which is preferably present in at least partially crystalline form.

The crystalline hemi-L-malate according to the invention can be obtained by bringing together (E)-N-(( l s,4s)-4- (dimethylamino)-l ,4-diphenylcyclohexyl)-N-methylcinnamamide and L-malic acid in the desired stoichiometric ratio, optionally in a suitable solvent and subsequently evaporating the solvent to dryness at room temperature.

It has been unexpectedly found that when considering factors that are relevant for the development of a new active pharmaceutical ingredient, particularly synthetic accessibility, polymorphism, physical and chemical properties, toxicological evaluation, commercial availability, costs of counter ion, weight of counter ion, stoichiometry between drug and counter ion, and analytical development efforts, the crystalline hemi-L-malate of (E)-N-((ls,4s)-4-(dimethylamino)-l ,4-diphenylcyclohexyl)-N-methylcinnamamide has advantages compared to other salts. In particular, for the hemi-L-malate reproducible XPRD analysis, single event in DSC with high melting point (> 200°C) and no weight loss in TGA can be observed, making the hemi-L-malate a promising candidate for drug development.

In a preferred embodiment, the salt according to the invention is (E)-N-((l s,4s)-4-(dimethylamino)- l ,4- diphenylcyclohexyl)-N-methylcinnarnamide hemi-succinate, which is preferably present in at least partially crystalline form.

The crystalline hemi-succinate according to the invention can be obtained by bringing together (E)-N-(( l s,4s)-4- (dimethylamino)-l ,4-diphenylcyclohexyl)-N-methylcinnamamide and succinic acid in the desired stoichiometric ratio, optionally in a suitable solvent and subsequently evaporating the solvent to dryness at room temperature.

Preferably, the solid form of (E)-N-(( I s,4s)-4-(dimethylamino)- I ,4-diphenylcyclohexyl)-N-methylcinnamamide hemi-succinate has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 12.5±0.2 °2Theta, 18.3±0.2 °2Theta, and 28. U0.2 °2Theta. Preferably, the solid form of (E)-N-(( l s,4s)-4-(dimethylamino)- l ,4- diphenylcyclohexyl)-N-methylcinnamamide hemi-succinate additionally has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 19.2±0.2 °2Theta and/or 20.8±0.2 °2Theta and/or 21.0±0.2 °2Theta.

It has been unexpectedly found that when considering factors that are relevant for the development of a new active pharmaceutical ingredient, particularly synthetic accessibility, polymorphism, physical and chemical properties, toxicological evaluation, commercial availability, costs of counter ion, weight of counter ion, stoichiometry between drug and counter ion, and analytical development efforts, the crystalline hemi-succinate of (E)-N-(( l s,4s)-4-(dimethylamino)- l,4-diphenylcyclohexyl)-N-methylcinnamamide has advantages compared to other salts. In particular, for the hemi-succinate reproducible XPRD analysis, single event in DSC with high melting point (> 200°C) and low to some weight loss in TGA can be observed, making the hemi-succinate a promising candidate for drug development.

In a preferred embodiment, the salt according to the invention is (E)-N-(( l s,4s)-4-(dimethylamino)-l ,4- diphenylcyclohexyl)-N-methylcinnamamide hemi-fumarate, which is preferably present in at least partially crystalline form.

The crystalline hemi-fumarate according to the invention can be obtained by bringing together (E)-N-(( ls,4s)-4- (dimethylamino)- l ,4-diphenylcyclohexyl)-N-methylcinnamamide and fumaric acid in the desired stoichiometric ratio, optionally in a suitable solvent and subsequently evaporating the solvent to dryness at room temperature.

It has been unexpectedly found that when considering factors that are relevant for the development of a new active pharmaceutical ingredient, particularly synthetic accessibility, polymorphism, physical and chemical properties, toxicological evaluation, commercial availability, costs of counter ion, weight of counter ion, stoichiometry between drug and counter ion, and analytical development efforts, the crystalline hemi-fumarate of (E)-N-((ls,4s)-4-(dimethylamino)-l ,4-diphenylcyclohexyl)-N-methylcinnamamide has advantages compared to other salts. In particular, for the hemi-fumarate reproducible XPRD analysis, single event in DSC with high melting point (> 200°C) and low weight loss in TGA can be observed, making the hemi-fumarate a promising candidate for drug development.

In a preferred embodiment, the salt according to the invention is (E)-N-(( ls,4s)-4-(dimethylamino)- l ,4- diphenylcyclohexyl)-N-methylcinnamamide hemi-maleate, which is preferably present in at least partially crystalline form.

The crystalline hemi-maleate according to the invention can be obtained by bringing together (E)-N-(( l s,4s)-4- (dimethylamino)-l ,4-diphenylcyclohexyl)-N-methylcinnamamide and maleic acid in the desired stoichiometric ratio, optionally in a suitable solvent and subsequently evaporating the solvent to dryness at room temperature.

It has been unexpectedly found that when considering factors that are relevant for the development of a new active pharmaceutical ingredient, particularly synthetic accessibility, polymorphism, physical and chemical properties, toxicological evaluation, commercial availability, costs of counter ion, weight of counter ion, stoichiometry between drug and counter ion, and analytical development efforts, the crystalline hemi-maleate of (E)-N-(( ls,4s)-4-(dimethylamino)-l ,4-diphenylcyclohexyl)-N-methylcinnamamide has advantages compared to other salts.

In a preferred embodiment, the salt according to the invention is (E)-N-(( l s,4s)-4-(dimethylamino)- l ,4- diphenylcyclohexyl)-N-methylcinnarnamide oxalate, which is preferably present in at least partially crystalline form.

The crystalline oxalate according to the invention can be obtained by bringing together (E)-N-(( ls,4s)-4- (dimethylamino)- l,4-diphenylcyclohexyl)-N-methylcinnamamide and oxalic acid in the desired stoichiometric ratio, optionally in a suitable solvent and subsequently evaporating the solvent to dryness at room temperature.

Preferably, the solid form of (E)-N-((ls,4s)-4-(dimethylamino)- l ,4-diphenylcyclohexyl)-N-methylcinnamamide oxalate has XRPD diffraction peaks (measured with CuKct radiation) at 25°C at 1 1.3±0.2 °2Theta, 18.4±0.2 °2Theta, and 20.8±0.2 °2Theta. Preferably, the solid form of (E)-N-(( l s,4s)-4-(dimethylamino)- l ,4- diphenylcyclohexyl)-N-methylcinnamamide oxalate additionally has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 1 1.9±0.2 °2Theta and/or 28.2±0.2 °2Theta.

It has been unexpectedly found that when considering factors that are relevant for the development of a new active pharmaceutical ingredient, particularly synthetic accessibility, polymorphism, physical and chemical properties, toxicological evaluation, commercial availability, costs of counter ion, weight of counter ion, stoichiometry between drug and counter ion, and analytical development efforts, the crystalline oxalate of (E)-N- ((ls,4s)-4-(dimethylamino)- l ,4-diphenylcyclohexyl)-N-methylcinnamamide has advantages compared to other salts. In particular, for the crystalline oxalate reproducible XPRD analysis, single event in DSC with high melting point (> 200°C) and no weight loss in TGA can be observed, making the crystalline oxalate a promising candidate for drug development.

In a preferred embodiment, the solid form is

• (E)-N-(( 1 s,4s)-4-(dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide hemi-L-tartrate and has XRPD diffraction peaks (measured with Cu _a radiation) at 25°C at 18.1±0.2 °2Theta, 18.5±0.2 °2Theta, and 19.2±0.2 °2Theta;

• (E)-N-(( 1 s,4s)-4-(dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide hemi-D-tartrate and has XRPD diffraction peaks (measured with CuKa radiation) at 18.1±0.2 °2Theta, 18.5±0.2 °2Theta, and 19.2±0.2 °2Theta;

• (E)-N-(( 1 s,4s)-4-(dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide hemi-meso- tartrate and has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 17.9±0.2 °2Theta, 18.3±0.2 °2Theta, and 19.6±0.2 °2Theta;

• (E)-N-(( 1 s,4s)-4-(dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide hemi-succinate and has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 12.5±0.2 °2Theta, 18.3±0.2 °2Theta, and 28.1±0.2 °2Theta; or • (E)-N-((l s,4s)-4-(dimethylamino)-l ,4-diphenylcyclohexyl)-N-methyleinnamamide oxalate and has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 1 1.3±0.2 °2Theta, 18.4±0.2 °2Theta, and 20.8±0.2 °2Theta.

In another preferred embodiment, the solid form is

• (E)-N-(( l s,4s)-4-(dimethylamino)- l,4-diphenylcyclohexyl)-N-methylcinnamamide hemi-L-tartrate and has XRPD diffraction peaks (measured with CuK _a radiation) at 25°C at 18.1±0.2 °2Theta, 18.5±0.2 °2Theta, and 19.2±0.2 °2Theta;

• (E)-N-(( 1 s,4s)-4-(dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide hemi-D-tartrate and has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 12.7±0.2 °2Theta, 18.1±0.2 °2Theta, and 18.5±0.2 °2Theta;

• (E)-N-(( 1 s,4s)-4-(dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide hemi-meso- tartrate and has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 17.9±0.2 °2Theta, 18.3±0.2 °2Theta, and 19.6±0.2 °2Theta;

• (E)-N-(( 1 s,4s)-4-(dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide hemi-succinate and has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 12.5±0.2 °2Theta, 18.3±0.2 °2Theta, and 28.1±0.2 °2Theta; or

• (E)-N-(( 1 s,4s)-4-(dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide oxalate and has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 1 1.3±0.2 °2Theta, 18.4±0.2 °2Theta, and 20.8±0.2 °2Theta.

In still another preferred embodiment, the solid form is

• (E)-N-(( l s,4s)-4-(dimethylamino)-l ,4-diphenylcyclohexyl)-N-methylcinnamamide hemi-L-tartrate and additionally has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 1 1.4±0.2 °2Theta and/or 19.9±0.2 °2Theta and/or 21 .2±0.2 °2Theta and/or 28.0±0.2 °2Theta;

• (E)-N-((l s,4s)-4-(dimethylamino)-l ,4-diphenylcyclohexyl)-N-methylcinnamamide hemi-D-tartrate and additionally has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 1 1.4±0.2 °2Theta and/or 19.9±0.2 °2Theta;

• (E)-N-(( 1 s,4s)-4-(dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide hemi-meso- tartrate and additionally has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 1 1.0±0.2 °2Theta and/or 1 1.9±0.2 °2Theta and/or 21.1±0.2 °2Theta;

• (E)-N-(( l s,4s)-4-(dimethylamino)- l,4-diphenylcyclohexyI)-N-methylcinnamamide hemi-succinate and additionally has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 1 1.0±0.2 °2Theta and/or 11.7±0.2 °2Theta and/or 20.8±0.2 °2Theta and/or 21.0±0.2 °2Theta and/or 28.1±0.2 °2Theta; or

• (E)-N-((ls,4s)-4-(dimethylamino)- l ,4-diphenylcyclohexyl)-N-methylcinnamamide oxalate and

additionally has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 1 1.9±0.2 °2Theta and/or 28.2±0.2 °2Theta.

In yet another preferred embodiment, the solid form is • (E)-N-((ls,4s)-4-(dimethylamino)- l ,4-diphenylcyclohexyl)-N-methylcinnamamide hemi-L-tartrate and additionally has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 1 1.4±0.2 °2Theta and/or 19.9±0.2 °2Theta and/or 21.2±0.2 °2Theta and/or 28.0±0.2 °2Theta;

• (E)-N-((l s,4s)-4-(dimethylamino)- l ,4-diphenylcyclohexyl)-N-methylcinnamamide hemi-D-tartrate and additionally has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 19.2±0.2 °2Theta and/or I 9.9±0.2 °2Theta;

• (E)-N-(( 1 s,4s)-4-(dimethy lamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide hemi-meso- tartrate and additionally has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 1 1.0±0.2 °2Theta and/or 1 1.9±0.2 °2Theta and or 21.1 ±0.2 °2Theta;

• (E)-N-(( 1 s,4s)-4-(dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide hemi-succinate and additionally has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 1 1.0±0.2 °2Theta and/or 1 1.7±0.2 °2Theta and/or 20.8±0.2 °2Theta and/or 21.0±0.2 °2Theta and/or 28. ±0.2 °2Theta; or

• (E)-N-(( 1 s,4s)-4-(dimethylamino)- 1 ,4-diphenylcyclohexyl)-N-methylcinnamamide oxalate and

additionally has XRPD diffraction peaks (measured with CuKa radiation) at 25°C at 1 1.9±0.2 °2Theta and/or 28.2±0.2 °2Theta.

Another aspect of the invention relates to a pharmaceutical composition comprising the salt according to the invention or a solid form according to the invention as described above. All preferred embodiments of the salt according to the invention or the solid form according to the invention also apply to the pharmaceutical composition according to the invention and are thus not repeated hereinafter.

The pharmaceutical composition may optionally contain one or more suitable additives and/or adjuvants such as described below.

In some preferred embodiments, the pharmaceutical composition comprises between about 0.001% by weight and about 40% by weight of one or more of the salts according to the invention described herein. In some preferred embodiments, the pharmaceutical composition comprises between about 0.001%) by weight and about 20% by weight of one or more of the salts according to the invention described herein. In some preferred embodiments, the pharmaceutical composition comprises between about 0.001 % by weight and about 10% by weight of one or more of the salts according to the invention described herein. In some preferred embodiments, the pharmaceutical composition comprises between about 0.001% by weight and about 5% by weight of one or more of the salts according to the invention described herein. In some preferred embodiments, the pharmaceutical composition comprises between about 0.001% by weight and about 1% by weight of one or more of the salts according to the invention described herein. In some preferred embodiments, the pharmaceutical composition comprises between about 0.01% by weight and about 1% by weight of one or more of the salts according to the invention described herein. In some preferred embodiments, the pharmaceutical composition comprises between about 0.01% by weight and about 1 % by weight of one or more of the salts according to the invention described herein.

Preferably said pharmaceutical composition may be used for the treatment of pain. Another aspect of the invention relates to a pharmaceutical dosage form comprising the pharmaceutical composition according to the invention as described above. AH preferred embodiments of the pharmaceutical composition according to the invention also apply to the pharmaceutical dosage form according to the invention and are thus not repeated hereinafter.

In a preferred embodiment, the pharmaceutical dosage form is a solid drug form. The pharmaceutical dosage form is preferably manufactured for oral administration. However, other forms of administration are also possible, e.g. for buccal, sublingual, transmucosal, rectal, intralumbal, intraperitoneal, transdermal, intravenous, intramuscular, intragluteal, intracutaneous and subcutaneous application.

Depending on the configuration, the pharmaceutical 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, intradermal ly, intramuscularly, intranasally, buccally or locally.

Preparations suitable for oral administration are those in the form of tablets, chewable tablets, lozenges, capsules, granules, drops, liquids or syrups, and those suitable for parenteral, topical and inhalatory administration are solutions, suspensions, easily reconstituted dry preparations and sprays. A further possibility is suppositories for rectal administration. The application in a depot in dissolved form, a patch or a plaster, possibly with the addition of agents promoting skin penetration, are examples of suitable percutaneous forms of application.

Examples of adjuvants and additives for oral forms of application are disintegrants, lubricants, binders, fillers, mould release agents, possibly solvents, flavourings, sugar, in particular carriers, diluents, colouring agents, antioxidants etc.

Waxes or fatty acid esters, amongst others, can be used for suppositories and carrier substances, preservatives, suspension aids etc. can be used for parenteral forms of application.

Adjuvants can be, for example: water, ethanol, 2-propanol, glycerine, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, saccharose, dextrose, molasses, starch, modified starch, gelatine, sorbitol, inositol, mannitol, microcrystalline cellulose, methyl cellulose, carboxymethyl-cellulose, cellulose acetate, shellac, cetyl alcohol, polyvinylpyrrolidone, paraffins, waxes, natural and synthetic rubbers, acacia gum, alginates, dextran, saturated and unsaturated fatty acids, stearic acid, magnesium stearate, zinc stearate, glyceryl stearate, sodium lauryl sulphate, edible oils, sesame oil, coconut oil, peanut oil, soybean oil, lecithin, sodium lactate, polyoxyethylene and propylene fatty acid esters, sorbitane fatty acid esters, sorbic acid, benzoic acid, citric acid, ascorbic acid, tannic acid, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, magnesium oxide, zinc oxide, silicon dioxide, titanium oxide, titanium dioxide, magnesium sulphate, zinc sulphate, calcium sulphate, potash, calcium phosphate, dicalcium phosphate, potassium bromide, potassium iodide, talc, kaolin, pectin, crosspovidon, agar and bentonite. The production of these pharmaceutical dosage forms and pharmaceutical compositions is conducted using means, devices, methods and processes that are well known in the art of pharmaceutical technology, as described, for example, in "Remington's Pharmaceutical Sciences", A.R. Gennaro, 17th ed., Mack Publishing Company, Easton, Pa. (1985), in particular in part 8, chapters 76 to 93.

Thus, for example, for a solid formulation such as a tablet, the active substance of the drug can be granulated with a pharmaceutical carrier substance, e.g. conventional tablet constituents such as cornstarch, lactose, saccharose, sorbitol, talc, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable rubbers, and pharmaceutical diluents such as water, for example, in order to form a solid composition that contains the active substance in a homogenous dispersion. Homogenous dispersion is understood here to mean that the active substances are uniformly dispersed throughout the composition, so that this can be readily divided into identically effective standard dosage forms such as tablets, capsules, lozenges. The solid composition is then divided into standard dosage forms. The tablets or pills can also be coated or otherwise compounded to prepare a slow release dosage form. Suitable coating agents include polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and/or cellulose acetate, for example.

In one embodiment of the present invention the salt according to the invention as described herein is present in immediate release form.

In another embodiment of the present invention the salt according to the invention as described herein is at least partially present in controlled-release form. In particular, the active ingredient can be released slowly from preparations that can be applied orally, rectally or percutaneously.

The pharmaceutical dosage form can preferably be manufactured for administration once daily, twice daily (bid), or three times daily. Preferably, the pharmaceutical dosage form is for administration once daily or twice daily.

The term controlled release as used herein refers to any type of release other than immediate release such as delayed release, sustained release, slow release, extended release and the like. These terms are well known to any person skilled in the art as are the means, devices, methods and processes for obtaining such type of release.

In another embodiment of the present invention

• the pharmaceutical dosage form is manufactured for oral administration; and/or

• the pharmaceutical dosage form is a solid and/or compressed and/or film-coated drug form; and/or

• the pharmaceutical dosage form releases the salt according to the invention as described herein slowly from a matrix; and/or

• the pharmaceutical dosage form contains the salt according to the invention in a quantity of 0.001 to 99.999% by wt, more preferred 0.1 to 99.9% by wt., still more preferred 1.0 to 99.0% by wt., even more preferred 2.5 to 80% by wt., most preferred 5.0 to 50% by wt. and in particular 7.5 to 40% by wt., based on the total weight of the pharmaceutical dosage form; and/or • the pharmaceutical dosage form contains a pharmaceutically compatible carrier and/or pharmaceutically compatible adjuvants; and/or

• the pharmaceutical dosage form has a total mass in the range of 25 to 2000 mg, more preferred 50 to 1800 mg, still more preferred 60 to 1600 mg, more preferred 70 to 1400 mg, most preferred 80 to 1200 mg and in particular 100 to 1000 mg; and/or

• the pharmaceutical dosage form is selected from the group comprising tablets, capsules, pellets and granules.

The pharmaceutical dosage form can be provided as a simple tablet and as a coated tablet (e.g. as film-coated tablet or lozenge). The tablets are usually round and biconvex, but oblong forms are also possible. Granules, spheres, pellets or microcapsules, which are contained in sachets or capsules or are compressed to form disintegrating tablets, are also possible.

In yet another one of its aspects, the present invention relates to the use of the salt according to the invention as described herein for the production of a pharmaceutical dosage form. Preferably said pharmaceutical dosage form is suitable for the treatment of pain.

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 salt according to the invention as described herein to a patient.

EXAMPLES

The following examples further illustrate the invention but are not to be construed as limiting its scope.

In the following, unless expressly stated otherwise, "drug" refers to "(E)-N-(( l s,4s)-4-(dimethylamino)- l ,4- diphenylcyclohexyl)-N-methylcinnamamide". "SM" refers to "solid material".

Analytical methods:

XRPD-analysis:

XRPD (i.e. x-ray powder diffractogram(s)) were recorded by means of a transmission diffractometer equipped with a curved germanium monochromator ( 1 1 1) and a linear PSD detector, CuK ₀ irradiation ( 1.540598 nm). XRPD pattern were analysed be means of Peak Finding using STOE Software "WinXPOW FIT", Version 2.09 (26-Jul-2006), STOE & Cie GmbH. The following parameters were set: Peak Search Parameters: Estimated Halfwidth: 0.15; Significance Level: 2.5, Intensity Limit: 50; Remove Spikes: Yes. XRPD (i.e. x-ray powder diffractograms) analyses were carried out in transmission geometry with a STOE StadiP or a Panaiytical X'Pert Pro X-ray powder diffractometer in reflection geometry, monochromatised CuK _a 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 20 values have an error rate of ±0.2° in 20. 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 (± 5 K)). In general, a baseline correction of the measured diffractograms was done using e.g. the program WinXPow (STOE).

Some XRPD pattern refer to arbitrary internal reference numbers without technical meaning (e.g. 136, 177 and 1005 in " 136 L-tartrate 1 :0.5" or " 177 Oxalate" or " 1005 meso-tartrate 1 :0.5").

Calculated XRPD:

X-ray powder diffractogram (XRPD) may be calculated from a single crystal diffractogram (SCXRD) measured using ΜοΚ _α radiation having a wavelength of 0.71073 A at 100 K (± 5 K). Due to the fact that the SCXRD was determined at 100 K (± 5 K), the peak positions determined by a XRPD measured at 298 (± 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 20.

SCXRD (Single Crystal X-ray Diffraction)-analysis:

SCXRD analysis of crystalline forms was carried out with a Bruker D8-goniometer with SMART APEX CCD area detector at 100 K (± 5 K) using MoK _a radiation (wavelength of 0.71073 A, Incoatec microsource, multilayer optics).

DVS-analysis:

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. DSC-analysis:

Differential Scanning Calorimetry (DSC): device reference Mettler Toledo DSC82 1 or Mettler Toledo DSC823. Unless otherwise specified, the samples were weighed in a pierced aluminium crucible. The measurement took place in a nitrogen flow in a temperature range from -50°C up to 350°C with a heating rate of 10°C/min. The temperatures specified in relation to DSC analyses are, unless otherwise specified, the temperatures of the peak onset.

In the following table, "ΔΗ" means "specific heat", "T _onset " means the "onset temperature", and "T _peak " means the "peak temperature" of a thermal event. The values for ΔΗ, T _onset and T _peak 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 ΔΗ, T _onset and T _peak are listed for each event.

TG-analysis:

Thermogravimetry analytical experiments were recorded with a Mettler Toledo TGA/DSC 1 (open aluminium oxide crucible nitrogen atmosphere, heating rate 10°C/min, 25 up to 350°C). Results of the measurements are discussed below.

Estimated solubility:

About 10 mg of the compound are weighed into a 20mL vial. Solvent is added in 50 μί steps until a clear solution is obtained. After each addition step, it is checked if the compound is dissolved or not. If the compound is not dissolved, the suspension is exposed to ultrasound in an ultrasonic bath for about 10 sec. If after such treatment still no clear solution is obtained, additional solvent is added. The procedure is repeated until a maximum amount of about 10 mL solvent has been added.

Example 1 : (E)-N-((ls.4sV4-(dimethylamino)-1.4-diphenylcvclohexylVN-met hylcinnamamide hemi-L-tartrate All experiments of Example 1 describe the production of polymorph A. Example 1(a): Procedure:

501.69 mg free base and 170.46 mg ( 1 eq) L-(+)-tartaric acid were homogenized in a glass vial after which 20 mL 2-propanol were added. The white suspension was vortexed in a PLS-synthesizer at 30°C and 400 rpm.

Work-up:

After 18 h, the suspension was filtered after 1 h at 22°C (solid material SMI, G4-glass filter funnel). The solid SM I was sucked dry and dried for 3.5 h at 40°C (ca. 3 mbar). Analytics are summarized in the table here below.

Table 1 :

The DVS isotherm plot is shown in Figure 1.

Example I (b):

Procedure:

5.00 g free base and 856.40 mg (0.5 eq) L-(+)-tartaric acid were homogenized in a 250 mL round bottom flask. Afterwards, 200 mL 2-propanol were added. The white suspension was rotated using a rotavapor at 280 rpm and 30°C water bath temperature.

Work-up:

After 20 h, the suspension was filtered after 30 min at 22°C (G4-glass filter funnel). The solid SM I was sucked dry and dried for 18 h at 40°C (vaccum of ca. 3 mbar was applied).

Yield: 5.85 g (99.82% of theoretical yield) of white solid SM I , was dried further to give solid SM3.

Analytics are summarized in the table here below.

Table 2:

Drying of solid SMI :

5.80 g SMI were weighed in a tared receptacle and dried for 1 h at 70°C and 2 mbar to give solid SM3. Retained: 5.79 g (weight loss: 1 1.75 mg, 0.2%) SM3.

Drying of solid SM3 :

The flour-like solid SM3 is ground in an agate mortar for ca. 5 min and then dried again. 5.78 g SM3 were weighed in a tared receptacle and dried for 1 h at 70°C and 2 mbar to give solid SM4. Retained: 5.78 g SM4 (no further weight loss).

Yield: 5.79 g (98.8% of theoretical yield), white, flour-like SM3. Analytics are summarized in the table here below.

Table 3 :

Figure 2 shows the XRPD analysis of SM3.

Example 1 (c) : amorphous material Procedure:

In a 100 mL one necked flask, 503.10 mg drug-hemi L-tartrate were dissolved in 500 mL DCM (dichloro- methane). The solvent was evaporated using a rotavapor (ca. 790 mbar, ca. 150 rpm).

After a few minutes, because of the evaporation heat, the flask has cooled down so that a solid precipitates. The flask was vented. After the flask had reached room temperature, the solid dissolved again. Afterwards, evaporation of the solvent was proceeded in a water bath (22°C) at 850 mbar. After 20.5 h, the solid S I was retrieved as a white powder from the flask and analyzed.

Analytics are summarized in the table here below.

Table 4:

202.76 mg S I were stored in a desiccator (75% r.h.) for 4 days giving solid SM2.

The solubility of SM2 in water and ethanol was estimated, the results of which are summarized in the table here below.

Table 5:

Analytics are summarized in the table here below.

Table 6:

After 4 days in the desiccator at 75% r.h., the substance was still amorphous. Figure 3 shows the XRPD of SMI . Figure 4 shows the XRPD of SM2.

Figure 5 shows the DVS - Dynamic Vapour Sorption of SM2. According to DVS, the amorphous material is significantly more hygroscopic than the crystalline material.

Example 1(d): Procedure:

In a 1 L vessel of the Opti Max reactor, 6.93 g L-(+)-tartaric acid were dissolved in 138 mL of deionized water. 250 mL of acetone were addded and the solution was stirred at 750 rpm at 20°C using a propeller with a diameter of 4.5 cm. Then, a suspension of 0.1 g of free base in 200 mL acetone were added slowly and continuously to the reactor. 50 mL acetone were used to complete the transfer of the suspension. The mixture was stirred until no further change in particle size could be observed within 5 min. The solid was separated by filtration (G4 glass filter funnel) and sucked dry for approx. 30 min. After isolation and before drying the yield of the solid (SMI) was not determined.

The analytics are summarized in below table.

Table 7:

The solid (SMI) was dried for 18 h at 45°C and <100 mbar.

Yield: 40.3 lg white solid; residual solvent: ca. 5600 ppm acetone; SM2: dried solid.

Analytics are summarized in the table here below (residual solvent acetone with more than 5600 ppm acetone).

Table 8:

250 mg of the retained sample were dried again in the vacuum drying oven for 19 h at 45°C and <10 mbar giving SM3 (residual solvent 5864.9ppm acetone).

Figure 6 shows the XRPD analysis of S 2.

Figure 7 shows the DVS - Dynamic Vapour Sorption of SM2. a) Powder diffraction data

The XRPD peaks are summarized in the table here below.

Table 9:

D / Angstrom 2Theta / deg I(rel) D / Angstrom 2Theta / deg I(rel)

16.2496 5.43 4 3.1860 27.98 16

14.2308 6.21 3 3.1278 28.51 6

9.5000 9.30 2 3.0806 28.96 3

8.3 1 10 10.64 4 3.0373 29.38 2

7.9973 1 1.05 6 2.9726 30.04 2

7.81 19 1 1.32 20 2.9068 30.73 4

7.7403 1 1.42 21 2.8343 3 1.54 5

7.5041 1 1.78 10 2.7965 3 1.98 5

6.9588 12.71 18 2.7561 32.46 2

6.2012 14.27 3 2.7128 32.99 2

6.0213 14.70 2 2.6677 33.57 5

5.7644 15.36 2 2.6087 34.35 2

5.3341 16.61 12 2.5735 34.83 3

.9109 18.05 100 2.5216 35.57 2

.7959 18.49 3 1 2.5062 35.80 3

.6135 19.22 25 2.4482 36.68 3

.4659 19.86 22 2.4040 37.38 3

.3634 20.34 3 2.3816 37.74 6

.2367 20.95 17 2.3569 38.15 3

.1874 21.20 18 2.3275 38.65 2

.8932 22.82 5 2.2868 39.37 2 3.8129 23.3 1 8 2.2381 40.26 2

3.7237 23.88 3 2.1895 41.20 4

3.6817 24.15 5 2.0561 44.00 2

3.5825 24.83 5 2.0368 44.44 3

3.5022 25.41 3 1.9995 45.32 2

3.3769 26.37 2 1.9583 46.33 2

3.3 155 26.87 5 1.9374 46.86 2

3.2527 27.40 10 1.8451 49.35 1 b) Single crystal data

Table 10:

The atomic coordinates ( x 10 ^A 4) and equivalent isotropic displacement parameters ( ^A 2 x 10 ^A 3) are summarized in the table here below. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

Table 1 1 :

C(4) 471(12) 10912(12) 9594(6) 28(2)

0(8) 6600(8) 6185(8) 6079(4) 27(2)

N(3) 7578(8) 7931(8) 5965(5) 22(1)

N(4) 9026(9) 6781(9) 8674(4) 22(2)

C(35) 6386(9) 7540(10) 6069(6) 22(2)

C(36) 9341(9) 6807(10) 5917(5) 21(1)

C(37) 10056(11) 7630(11) 6349(5) 21(2)

C(38) 9466(12) 7907(11) 7290(5) 24(2)

C(39) 9865(9) 6369(11) 7748(5) 22(1)

C(40) 9286(12) 5404(11) 9203(6) 23(2)

C(41) 9442(12) 7804(11) 9109(6) 26(2)

C(42) 9065(11) 5575(11) 7339(5) 21(2)

C(43) 9693(12) 5294(10) 6392(5) 21(2)

C(44) 11674(9) 5277(11) 7716(6) 23(2)

C(45) 12301(11) 3634(11) 7736(6) 23(2)

C(46) 13941(11) 2653(12) 7723(6) 28(2)

C(47) 14946(11) 3300(12) 7646(6) 27(2)

C(48) 14353(12) 4896(11) 7616(6) 30(2)

C(49) 12724(11) 5889(12) 7647(6) 27(2)

C(50) 10070(11) 6398(11) 4976(5) 21(2)

C(51) 11169(11) 6848(12) 4558(6) 24(2)

C(52) 11840(12) 6408(12) 3725(6) 25(2)

C(53) 11398(11) 5560(11) 3277(6) 24(2)

C(54) 10296(12) 5090(12) 3686(6) 25(2)

C(55) 9647(11) 5519(11) 4518(6) 23(2)

C(56) 7204(12) 9544(10) 5714(7) 27(2)

C(57) 4724(9) 8859(11) 6228(6) 22(2)

C(58) 3593(9) 8811(11) 5878(6) 25(2)

C(59) 1896(9) 10011(10) 6025(5) 23(2)

C(60) 1052(10) 10520(11) 5346(6) 25(2)

C(61) -541(10) 11646(11) 5473(6) 28(2)

C(62) -1311(10) 12288(11) 6267(5) 26(2)

C(63) -523(10) 11774(11) 6952(6) 25(2)

C(64) 1084(10) 10685(10) 6815(5) 22(2)

0(7) -1012(9) 13086(8) 12618(5) 32(2)

N(l) -1929(8) 11277(8) 12686(5) 23(1)

N(2) -3520(9) 12432(9) 10024(4) 22(1)

C(5) -768(9) 11707(10) 12596(6) 22(2)

C(6) -3682(9) 12414(10) 12772(5) 23(1)

C(7) -4027(12) 13906(11) 12279(5) 21(2)

C(8) -3489(12) 13649(11) 11334(5) 22(2)

C(9) -4305(9) 12889(11) 10960(5) 23(1)

C(10) -4055(12) 11482(12) 9609(6) 28(2)

C(ll) -3683(13) 13793(12) 9508(7) 32(2)

C(12) -3896(12) 11323(11) 11420(5) 23(2)

C(13) -4449(12) 11612(12) 12370(5) 23(2)

CO 4) -6117(9) 13975(11) 10995(6) 23(2)

C(15) -7186(11) 13372(12) 11106(6) 26(2)

C(16) -8837(12) 14379(12) 11159(7) 31(2)

C(17) -9376(11) 15977(12) 11095(6) 29(2)

C(18) -8340(12) 16581(12) 10959(6) 28(2)

C(19) -6692(12) 15582(11) 10919(6) 28(2)

C(20) -4397(11) 12842(12) 13705(5) 23(2)

C(21) -3934(12) 13693(11) 14149(6) 27(2)

C(22) -4572(12) 14130(12) 14991(6) 28(2)

C(23) -5676(12) 13714(12) 15405(6) 30(2)

C(24) -6152(12) 12857(12) 14978(6) 29(2)

C(25) -5519(12) 12425(12) 14136(6) 26(2)

C(26) -1532(13) 9664(10) 12949(7) 30(2) C(27) 887(10) 10414(11) 12487(7) 29(2)

C(28) 1992(10) 10429(11) 12869(6) 27(2)

C(29) 3681(9) 9218(11) 12775(5) 25(2)

C(30) 4494(10) 8789(11) 13465(6) 30(2)

C(31) 6067(10) 7675(11) 13375(6) 29(2)

C(32) 6904(11) 7011(12) 12592(6) 31(2)

C(33) 6126(10) 7429(11) 11902(6) 25(2)

C(34) 4531(10) 8533(11) 11992(6) 28(2)

The bond lengths [A] and angles [deg] are summarized in the table here below.

Table 12:

Distance ΓΑ1 C(44)-C(45) 1.407(12)

0(2)-C(l) 1.275(11) C(45)-C(46) 1.403(12)

0(3)-C(2) 1.419(11) C(45)-H(45) 0.9500

0(3)-H(3) 0.8400 C(46)-C(47) 1.373(13)

0(4)-C(3) 1.421(10) C(46)-H(46) 0.9500

0(4)-H(4A) 0.8400 C(47)-C(48) 1.369(13)

0(5)-C(4) 1.259(12) C(47)-H(47) 0.9500

0(6)-C(4) 1.265(11) C(48)-C(49) 1.392(12)

C(l)-C(2) 1.566(13) C(48)-H(48) 0.9500

C(2)-C(3) 1.515(11) C(49)-H(49) 0.9500

C(2)-H(2A) 10000 C(50)-C(51) 1.390(12)

C(3)-C(4) 1.517(13) C(50)-C(55) 1.397(12)

C(3)-H(3A) 10000 C(51)-C(52) 1.378(12)

0(8)-C(35) 1.227(9) C(51)-H(51) 0.9500

N(3)-C(35) 1.358(9) C(52)-C(53) 1.376(12)

N(3)-C(56) 1.475(9) C(52)-H(52) 0.9500

N(3)-C(36) 1.512(9) C(53)-C(54) 1.400(12)

N(4)-C(40) 1.481(11) C(53)-H(53) 0.9500

N(4)-C(4I) 1.483(10) C(54)-C(55) 1.371(12)

N(4)-C(39) 1.541(9) C(54)-H(54) 0.9500

N(4)-H(4) 0.9300 C(55)-H(55) 0.9500

C(35)-C(57) 1.486(10) C(56)-H(56A) 0.9800

C(36)-C(43) 1.529(11) C(56)-H(56B) 0.9800

C(36)-C(37) 1.536(11) C(56)-H(56C) 0.9800

C(36)-C(50) 1.543(10) C(57)-C(58) 1.337(10)

C(37)-C(38) 1.513(11) C(57)-H(57) 0.9500

C(37)-H(37A) 0.9900 C(58)-C(59) 1.473(10)

C(37)-H(37B) 0.9900 C(58)-H(58) 0.9500

C(38)-C(39) 1.529(12) C(59)-C(64) 1.384(10)

C(38)-H(38A) 0.9900 C(59)-C(60) 1.405(10)

C(38)-H(38B) 0.9900 C(60)-C(61) 1.383(10)

C(39)-C(44) 1.545(10) C(60)-H(60) 0.9500

C(39)-C(42) 1.560(12) C(61)-C(62) 1.375(10)

C(40)-H(40A) 0.9800 C(61)-H(61) 0.9500

C(40)-H(40B) 0.9800 C(62)-C(63) 1.385(10)

C(40)-H(40C) 0.9800 C(62)-H(62) 0.9500

C(41)-H(41A) 0.9800 C(63)-C(64) 1.384(10)

C(41)-H(41B) 0.9800 C(63)-H(63) 0.9500

C(41)-H(41C) 0.9800 C(64)-H(64) 0.9500

C(42)-C(43) 1.526(11) 0(7)-C(5) 1.242(9)

C(42)-H(42A) 0.9900 N(l)-C(5) 1.357(9)

C(42)-H(42B) 0.9900 (l)-C(26) 1.475(9)

C(43)-H(43A) 0.9900 N(l)-C(6) 1.502(9)

C(43)-H(43B) 0.9900 N(2)-C(ll) 1.475(11)

C(44)-C(49) 1.387(12) N(2)-C(10) 1.487(11) N(2)-C(9) 1.548(9) C(31)-H(31) 0.9500

N(2)-H(2) 0.9300 C(32)-C(33) 1.385(10)

C(5)-C(27) 1.473(10) C(32)-H(32) 0.9500

C(6)-C(7) 1.527(12) C(33)-C(34) 1.380(10)

C(6)-C(20) 1.529(10) C(33)-H(33) 0.9500

C(6)-C(13) 1.535(11) C(34)-H(34) 0.9500

C(7)-C(8) 1.514(11) C(2)-0(3)-H(3) 109.5

C(7)-H(7A) 0.9900 C(3)-0(4)-H(4A) 109.5

C(7)-H(7B) 0.9900 0(l)-C(l)-0(2) 128.4(10)

C(8)-C(9) 1.517(12) 0(1)-C(1)-C(2) 117.5(8)

C(8)-H(8A) 0.9900 0(2)-C(l)-C(2) 114.1(8)

C(8)-H(8B) 0.9900 0(3)-C(2)-C(3) 111.5(8)

C(9)-C(14) 1.545(10) 0(3)-C(2)-C(l) 109.8(7)

C(9)-C(12) 1.552(12) C(3)-C(2)-C(l) 109.7(7)

C(10)-H(10A) 0.9800 0(3)-C(2)-H(2A) 108.6

C(10)-H(10B) 0.9800 C(3)-C(2)-H(2A) 108.6

C(10)-H(10C) 0.9800 C(1)-C(2)-H(2A) 108.6

C(11)-H(11A) 0.9800 0(4)-C(3)-C(2) 109.7(7)

C(11)-H(11B) 0.9800 0(4)-C(3)-C(4) 107.4(7)

C(11)-H(11C) 0.9800 C(2)-C(3)-C(4) 112.2(7)

C(12)-C(13) 1.525(11) 0(4)-C(3)-H(3A) 109.2

C(12)-H(12A) 0.9900 C(2)-C(3)-H(3A) 109.2

C(12)-H(12B) 0.9900 C(4)-C(3)-H(3A) 109.2

C(13)-H(13A) 0.9900 0(5)-C(4)-0(6) 123.3(10)

C(13)-H(13B) 0.9900 0(5)-C(4)-C(3) 118.9(8)

C(14)-C(19) 1.387(12) 0(6)-C(4)-C(3) 117.8(8)

C(14)-C(15) 1.395(12) C(35)-N(3)-C(56) 118.1(7)

C(15)-C(16) 1.407(12) C(35)-N(3)-C(36) 126.4(7)

C(15)-H(15) 0.9500 C(56)-N(3)-C(36) 114.5(6)

C(16)-C(17) 1.381(13) C(40)-N(4)-C(41) 107.8(7)

C(16)-H(16) 0.9500 C(40)-N(4)-C(39) 114.7(7)

C(17)-C(18) 1.365(13) C(41)-N(4)-C(39) 113.6(7)

C(17)-H(17) 0.9500 C(40)-N(4)-H(4) 106.8

C(18)-C(19) 1.406(13) C(41)-N(4)-H(4) 106.8

C(18)-H(18) 0.9500 C(39)-N(4)-H(4) 106.8

C(19)-H(19) 0.9500 0(8)-C(35)-N(3) 124.3(7)

C(20)-C(21) 1.388(12) 0(8)-C(35)-C(57) 119.0(7)

C(20)-C(25) 1.395(12) N(3)-C(35)-C(57) 116.7(7)

C(21)-C(22) 1.387(12) N(3)-C(36)-C(43) 113.7(7)

C(21)-H(21) 0.9500 N(3)-C(36)-C(37) 107.6(7)

C(22)-C(23) 1.369(13) C(43)-C(36)-C(37) 105.9(7)

C(22)-H(22) 0.9500 N(3)-C(36)-C(50) 107.2(6)

C(23)-C(24) 1.385(13) C(43)-C(36)-C(50) 109.5(7)

C(23)-H(23) 0.9500 C(37)-C(36)-C(50) 113.1(7)

C(24)-C(25) 1.385(12) C(38)-C(37)-C(36) 113.8(7)

C(24)-H(24) 0.9500 C(38)-C(37)-H(37A) 108.8

C(25)-H(25) 0.9500 C(36)-C(37)-H(37A) 108.8

C(26)-H(26A) 0.9800 C(38)-C(37)-H(37B) 108.8

C(26)-H(26B) 0.9800 C(36)-C(37)-H(37B) 108.8

C(26)-H(26C) 0.9800 H(37A)-C(37)-H(37B) 107.7

C(27)-C(28) 1.330(10) C(37)-C(38)-C(39) 112.0(7)

C(27)-H(27) 0.9500 C(37)-C(38)-H(38A) 109.2

C(28)-C(29) 1.472(10) C(39)-C(38)-H(38A) 109.2

C(28)-H(28) 0.9500 C(37)-C(38)-H(38B) 109.2

C(29)-C(34) 1.384(10) C(39)-C(38)-H(38B) 109.2

C(29)-C(30) 1.404(10) H(38A)-C(38)-H(38B) 107.9

C(30)-C(31) 1.368(10) C(38)-C(39)-N(4) 108.1(7)

C(30)-H(30) 0.9500 C(38)-C(39)-C(44) 113.9(7)

C(31)-C(32) 1.377(11) N(4)-C(39)-C(44) 109.5(7) C(38)-C(39)-C(42) 105.8(7) C(53)-C(54)-H(54) 120.3

N(4)-C(39)-C(42) 107.0(7) C(54)-C(55)-C(50) 121.8(8)

C(44)-C(39)-C(42) 112.3(7) C(54)-C(55)-H(55) 119.1

N(4)-C(40)-H(40A) 109.5 C(50)-C(55)-H(55) 119.1

N(4)-C(40)-H(40B) 109.5 N(3)-C(56)-H(56A) 109.5

H(40A)-C(40)-H(40B) 109.5 N(3)-C(56)-H(56B) 109.5

N(4)-C(40)-H(40C) 109.5 H(56A)-C(56)-H(56B) 109.5

H(40A)-C(40)-H(40C) 109.5 N(3)-C(56)-H(56C) 109.5

H(40B)-C(40)-H(40C) 109.5 H(56A)-C(56)-H(56C) 109.5

N(4)-C(41)-H(41A) 109.5 H(56B)-C(56)-H(56C) 109.5

N(4)-C(41)-H(41B) 109.5 C(58)-C(57)-C(35) 119.9(8)

H(41A)-C(41)-H(41B) 109.5 C(58)-C(57)-H(57) 120.0

N(4)-C(41)-H(41C) 109.5 C(35)-C(57)-H(57) 120.0

H(41A)-C(41)-H(41C) 109.5 C(57)-C(58)-C(59) 124.6(9)

H(41B)-C(41)-H(41C) 109.5 C(57)-C(58)-H(58) 117.7

C(43)-C(42)-C(39) 110.6(7) C(59)-C(58)-H(58) 117.7

C(43)-C(42)-H(42A) 109.5 C(64)-C(59)-C(60) 117.8(7)

C(39)-C(42)-H(42A) 109.5 C(64)-C(59)-C(58) 122.3(8)

C(43)-C(42)-H(42B) 109.5 C(60)-C(59)-C(58) 119.9(8)

C(39)-C(42)-H(42B) 109.5 C(61)-C(60)-C(59) 120.6(8)

H(42A)-C(42)-H(42B) 108.1 C(61)-C(60)-H(60) 119.7

C(42)-C(43)-C(36) 113.4(7) C(59)-C(60)-H(60) 119.7

C(42)-C(43)-H(43A) 108.9 C(62)-C(61)-C(60) 120.0(8)

C(36)-C(43)-H(43A) 108.9 C(62)-C(61)-H(61) 120.0

C(42)-C(43)-H(43B) 108.9 C(60)-C(6I)-H(61) 120.0

C(36)-C(43)-H(43B) 108.9 C(61)-C(62)-C(63) 120.6(8)

H(43A)-C(43)-H(43B) 107.7 C(61)-C(62)-H(62) 119.7

C(49)-C(44)-C(45) 118.4(8) C(63)-C(62)-H(62) 119.7

C(49)-C(44)-C(39) 120.9(8) C(64)-C(63)-C(62) 118.8(8)

C(45)-C(44)-C(39) 120.7(8) C(64)-C(63)-H(63) 120.6

C(46)-C(45)-C(44) 120.4(8) C(62)-C(63)-H(63) 120.6

C(46)-C(45)-H(45) 119.8 C(63)-C(64)-C(59) 122.0(8)

C(44)-C(45)-H(45) 119.8 C(63)-C(64)-H(64) 119.0

C(47)-C(46)-C(45) 119.6(9) C(59)-C(64)-H(64) 119.0

C(47)-C(46)-H(46) 120.2 C(5)-N(l)-C(26) 118.2(7)

C(45)-C(46)-H(46) 120.2 C(5)-N(l)-C(6) 124.3(7)

C(48)-C(47)-C(46) 120.6(9) C(26)-N(l)-C(6) 115.3(7)

C(48)-C(47)-H(47) 119.7 C(ll)-N(2)-C(10) 109.9(7)

C(46)-C(47)-H(47) 119.7 C(ll)-N(2)-C(9) 113.2(7)

C(47)-C(48)-C(49) 120.6(9) C(10)-N(2)-C(9) 114.2(7)

C(47)-C(48)-H(48) 119.7 C(ll)-N(2)-H(2) 106.3

C(49)-C(48)-H(48) 119.7 C(10)-N(2)-H(2) 106.3

C(44)-C(49)-C(48) 120.5(9) C(9)-N(2)-H(2) 106.3

C(44)-C(49)-H(49) 119.8 0(7)-C(5)-N(l) 124.7(8)

C(48)-C(49)-H(49) 119.8 0(7)-C(5)-C(27) 119.2(7)

C(51)-C(50)-C(55) 117.8(7) N(l)-C(5)-C(27) 116.1(7)

C(51)-C(50)-C(36) 122.5(8) N(l)-C(6)-C(7) 112.8(7)

C(55)-C(50)-C(36) 119.7(8) N(l)-C(6)-C(20) 109.5(7)

C(52)-C(51)-C(50) 120.8(8) C(7)-C(6)-C(20) 109.9(7)

C(52)-C(51)-H(51) 119.6 N(l)-C(6)-C(13) 107.2(7)

C(50)-C(51)-H(51) 119.6 C(7)-C(6)-C(13) 105.5(7)

C(53)-C(52)-C(51) 120.9(9) C(20)-C(6)-C(13) 111.8(7)

C(53)-C(52)-H(52) 119.6 C(8)-C(7)-C(6) 115.0(7)

C(51)-C(52)-H(52) 119.6 C(8)-C(7)-H(7A) 108.5

C(52)-C(53)-C(54) 119.2(8) C(6)-C(7)-H(7A) 108.5

C(52)-C(53)-H(53) 120.4 C(8)-C(7)-H(7B) 108.5

C(54)-C(53)-H(53) 120.4 C(6)-C(7)-H(7B) 108.5

C(55)-C(54)-C(53) 119.5(8) H(7A)-C(7)-H(7B) 107.5

C(55)-C(54)-H(54) 120.3 C(7)-C(8)-C(9) 111.2(7) C(7)-C(8)-H(8A) 109.4 C(18)-C(19)-H(19) 120.1

C(9)-C(8)-H(8A) 109.4 C(21)-C(20)-C(25) 117.8(7)

C(7)-C(8)-H(8B) 109.4 C(21)-C(20)-C(6) 119.4(8)

C(9)-C(8)-H(8B) 109.4 C(25)-C(20)-C(6) 122.7(8)

H(8A)-C(8)-H(8B) 108.0 C(22)-C(21)-C(20) 121.3(9)

C(8)-C(9)-C(14) 113.5(8) C(22)-C(21)-H(21) 119.3

C(8)-C(9)-N(2) 108.4(7) C(20)-C(21)-H(21) 119.3

C(14)-C(9)-N(2) 108.2(6) C(23)-C(22)-C(21) 120.1(9)

C(8)-C(9)-C(12) 106.4(7) C(23)-C(22)-H(22) 119.9

C(14)-C(9)-C(12) 113.6(7) C(21)-C(22)-H(22) 119.9

N(2)-C(9)-C(12) 106.3(7) C(22)-C(23)-C(24) 119.7(9)

N(2)-C(I0)-H(10A) 109.5 C(22)-C(23)-H(23) 120.1

N(2)-C(10)-H(10B) 109.5 C(24)-C(23)-H(23) 120.1

H(10A)-C(10)-H(10B) 109.5 C(25)-C(24)-C(23) 120.2(9)

N(2)-C(10)-H(10C) 109.5 C(25)-C(24)-H(24) 119.9

H(10A)-C(10)-H(10C) 109.5 C(23)-C(24)-H(24) 119.9

H(10B)-C(10)-H(10C) 109.5 C(24)-C(25)-C(20) 120.8(9)

N(2)-C(11)-H(11A) 109.5 C(24)-C(25)-H(25) 119.6

N(2)-C(11)-H(11B) 109.5 C(20)-C(25)-H(25) 119.6

H(11A)-C(11)-H(11B) 109.5 N(1)-C(26)-H(26A) 109.5

N(2)-C(11)-H(11C) 109.5 N(1)-C(26)-H(26B) 109.5

H(11A)-C(11)-H(11C) 109.5 H(26A)-C(26)-H(26B) 109.5

H(11B)-C(11)-H(11C) 109.5 N(1)-C(26)-H(26C) 109.5

C(13)-C(12)-C(9) 111.2(7) H(26A)-C(26)-H(26C) 109.5

C(13)-C(12)-H(12A) 109.4 H(26B)-C(26)-H(26C) 109.5

C(9)-C(12)-H(12A) 109.4 C(28)-C(27)-C(5) 122.5(9)

C(13)-C(12)-H(12B) 109.4 C(28)-C(27)-H(27) 118.7

C(9)-C(12)-H(12B) 109.4 C(5)-C(27)-H(27) 118.7

H(12A)-C(12)-H(12B) 108.0 C(27)-C(28)-C(29) 126.2(9)

C(12)-C(13)-C(6) 113.4(7) C(27)-C(28)-H(28) 116.9

C(12)-C(13)-H(13A) 108.9 C(29)-C(28)-H(28) 116.9

C(6)-C(13)-H(13A) 108.9 C(34)-C(29)-C(30) 118.2(8)

C(12)-C(13)-H(13B) 108.9 C(34)-C(29)-C(28) 120.6(8)

C(6)-C(13)-H(13B) 108.9 C(30)-C(29)-C(28) 121.1(8)

H(13A)-C(13)-H(13B) 107.7 C(31)-C(30)-C(29) 121.0(9)

C(19)-C(14)-C(15) 119.3(8) C(31)-C(30)-H(30) 119.5

C(19)-C(14)-C(9) 119.4(8) C(29)-C(30)-H(30) 119.5

C(15)-C(14)-C(9) 121.3(8) C(30)-C(31)-C(32) 120.1(9)

C(14)-C(15)-C(16) 120.7(9) C(30)-C(31)-H(31) 119.9

C(14)-C(15)-H(15) 119.7 C(32)-C(31)-H(31) 119.9

C(16)-C(15)-H(15) 119.7 C(31)-C(32)-C(33) 119.6(9)

C(17)-C(16)-C(15) 118.6(9) C(31)-C(32)-H(32) 120.2

C(17)-C(16)-H(16) 120.7 C(33)-C(32)-H(32) 120.2

C(15)-C(16)-H(16) 120.7 C(34)-C(33)-C(32) 120.4(9)

C(18)-C(17)-C(16) 121.4(9) C(34)-C(33)-H(33) 119.8

C(18)-C(17)-H(17) 119.3 C(32)-C(33)-H(33) 119.8

C(16)-C(17)-H(17) 119.3 C(33)-C(34)-C(29) 120.5(8)

C(17)-C(18)-C(1 ) 120.2(9) C(33)-C(34)-H(34) 119.7

C(17)-C(18)-H(18) 119.9 C(29)-C(34)-H(34) 119.7

C(19)-C(18)-H(18) 119.9

C(14)-C(19)-C(18) 119.8(9)

C(14)-C(19)-H(19) 120.1

The hydrogen coordinates ( x 10 ^Λ 4) and isotropic parameters ( ^Λ 2 x 10 ^Λ 3) are summarized table here below.

Table 13: Atom X y z U(eq) H(63) -1076 12162 7507 30

H(3) 4001 8640 8067 47 H(64) 1647 10392 7277 27

H(4A) 3493 10980 9055 53 H(2) -2432 11799 10021 26

H(2A) 3002 7890 9484 30 H(7A) -5191 14628 12394 25

H(3A) 2243 10082 10333 30 H(7B) -3494 14434 12493 25

H(4) 7935 7345 8667 26 H(8A) -2318 12966 11209 27

H(37A) 11234 6982 6248 25 H(8B) -3741 14671 11069 27

H(37B) 9795 8654 6085 25 H(10A) -3808 10507 9911 41

H(38A) 8294 8595 7394 28 H(IOB) -3500 11229 9023 41

H(38B) 9959 8458 7521 28 H(10C) -5210 12085 9618 41

H(40A) 10387 4879 9311 34 H(11A) -4767 14362 9377 47

H(40B) 9098 4668 8909 34 H(11B) -2909 13425 8983 47

H(40C) 8545 5756 9741 34 H(11C) -3481 14497 9823 47

H(41A) 8887 8004 9696 39 H(12A) -4420 10791 11202 28

H(41B) 9115 8803 8822 39 H(12B) -2727 10622 11301 28

H(41C) 10598 7279 9099 39 H(13A) -4192 10592 12640 28

H(42A) 9295 4559 7607 25 H(13B) -5624 12276 12485 28

H(42B) 7893 6259 7436 25 H(15) -6796 12269 11147 31

H(43A) 9205 4746 6154 25 H(16) -9565 13969 11238 37

H(43B) 10862 4594 6302 25 H(17) -10490 16671 11147 35

H(45) 11611 3186 7759 27 H(18) -8733 17679 10891 34

H(46) 14353 1548 7767 34 H(1 ) -5975 16007 10840 33

H(47) 16062 2634 7614 32 H(21) -3165 13983 13870 33

H(48) 15059 5329 7574 35 H(22) -4243 14718 15282 33

H(49) 12329 6994 7621 33 H(23) -6113 14013 15982 37

H(51) 11462 7467 4851 29 H(24) -6915 12565 15264 35

H(52) 12619 6695 3456 30 H(25) -5854 11838 13848 31

H(53) 11836 5296 2697 29 H(26A) -1487 9052 12472 45

H(54) 10001 4479 3390 30 H(26B) -2352 9701 13415 45

H(55) 8888 5210 4790 27 H(26C) -491 9167 13134 45

H(56A) 6218 10022 5473 40 H(27) 1177 9537 12130 35

H(56B) 8084 9510 5291 40 H(28) 1659 11303 13238 33

H(56C) 7060 10170 6209 40 H(30) 3942 9281 14003 36

H(57) 4466 9735 6578 27 H(31) 6584 7358 13855 34

H(58) 3905 7943 5509 30 H(32) 8008 6270 12525 37

H(60) 1581 10087 4795 30 H(33) 6694 6953 11363 30

H(61) -1104 11977 5011 33 H(34) 4014 8825 11513 33

H(62) -2393 13091 6347 31

The anisotropic displacement parameters ( ^Λ 2 x 10 ^Λ 3) £ re summarized in the table here below. The anisotropic displacement factor exponent takes the form: -2 pi ^A 2 [ h ^A 2 a* ^A 2 Ul 1 + ... + 2 h k a* b* U12 ]

Table 14:

Atom (Ull) (U22) (U33) (U23) (13) (U12)

0(1) 30(3) 46(4) 28(2) 0(3) -9(2) -6(3)

0(2) 21(3) 36(3) 32(3) 3(3) -5(2) -9(3)

0(3) 23(3) 40(3) 28(2) -2(2) -7(2) -11(2)

0(4) 31(3) 34(3) 51(3) -4(3) -7(3) -22(3)

0(5) 33(3) 38(3) 42(3) 11(2) -11(3) -15(3)

0(6) 18(3) 32(3) 30(3) 2(2) -7(2) -11(2)

C(l) 24(2) 32(4) 27(3) -3(3) -6(2) -9(3)

C(2) 24(2) 27(3) 26(3) 1(3) -4(2) -14(2)

C(3) 23(2) 26(3) 29(3) -1(2) -4(2) -14(2)

C(4) 24(2) 28(4) 33(4) 1(3) -4(3) -14(2)

0(8) 20(3) 27(2) 38(3) 2(3) -9(3) -12(2) N(3) 18(2) 24(3) 25(3) 3(3) -7(2) -11(2)

N(4) 18(3) 25(3) 25(2) -1(2) -4(2) -12(3)

C(35) 18(2) 27(3) 21(4) 3(3) -7(3) -10(2)

C(36) 17(2) 24(3) 26(2) 0(2) -7(2) -11(2)

C(37) 18(3) 22(3) 24(2) 0(2) -7(3) -9(3)

C(38) 25(4) 24(3) 23(2) -1(2) -7(3) -12(2)

C(39) 24(2) 23(3) 21(2) 0(2) -7(3) -11(2)

C(40) 17(4) 26(3) 22(3) 1(3) -3(3) -9(3)

C(41) 28(4) 29(4) 24(3) -4(3) -5(3) -14(3)

C(42) 17(3) 20(3) 24(2) 0(2) -5(3) -7(3)

C(43) 19(4) 23(3) 22(2) 0(2) -7(3) -9(3)

C(44) 22(2) 26(3) 19(4) -2(3) -6(2) -11(2)

C(45) 21(3) 27(3) 20(4) -1(3) -9(3) -9(2)

C(46) 23(3) 30(3) 27(4) 0(3) -7(3) -9(2)

C(47) 20(3) 37(3) 18(4) 3(3) -5(3) -10(2)

C(48) 25(3) 38(3) 29(4) 4(3) -9(3) -16(3)

C(49) 25(3) 32(3) 27(4) 1(3) -7(3) -14(2)

C(50) 20(3) 20(4) 25(2) 0(2) -7(2) -9(3)

C(51) 20(4) 27(4) 27(3) -2(3) -6(3) -12(3)

C(52) 18(4) 30(4) 27(3) -1(3) -6(3) -11(3)

C(53) 22(4) 24(4) 23(3) 0(3) -8(3) -7(3)

C(54) 24(4) 24(4) 29(3) -3(3) -12(3) -9(3)

C(55) 19(4) 22(4) 29(3) 0(3) -7(3) -10(3)

C(56) 23(4) 24(3) 34(4) 5(3) -9(3) -11(2)

C(57) 19(2) 23(3) 26(4) 1(3) -5(3) -12(2)

C(58) 21(2) 24(4) 30(4) 0(3) -10(2) -9(2)

C(59) 20(2) 21(4) 28(3) 2(3) -7(2) -10(2)

C(60) 20(3) 28(4) 27(3) 1(3) -7(2) -11(2)

C(61) 22(3) 29(4) 31(3) 6(3) -10(3) -10(2)

C(62) 17(3) 27(4) 36(3) 0(3) -8(2) -11(3)

C(63) 22(3) 21(4) 30(3) 2(3) -5(2) -9(2)

C(64) 21(3) 24(4) 25(3) 3(3) -8(2) -12(2)

0(7) 31(3) 27(2) 43(3) 0(3) -14(3) -17(2)

N(l) 22(2) 24(3) 27(3) 1(3) -8(2) -12(2)

N(2) 17(3) 24(3) 22(2) 0(2) -8(2) -6(3)

C(5) 21(2) 26(3) 23(4) -3(3) -6(3) -12(2)

C(6) 19(2) 26(3) 28(2) 1(2) -9(2) -13(2)

C(7) 18(4) 23(3) 24(2) -2(2) -5(3) -11(2)

C(8) 22(3) 21(4) 24(2) -2(2) -4(3) -9(3)

C(9) 23(2) 25(3) 24(2) -2(2) -3(3) -13(2)

C(10) 26(4) 31(4) 27(4) -3(3) -7(3) -13(3)

C(ll) 30(4) 31(4) 33(4) 5(3) -3(3) -15(3)

C(12) 23(4) 24(3) 25(2) 0(2) -7(3) -12(3)

C(13) 23(3) 26(4) 27(2) 1(2) -7(3) -14(3)

C(14) 22(2) 26(3) 19(4) 0(3) -5(2) -10(2)

C(15) 26(3) 29(3) 27(4) -3(3) -9(3) -14(2)

C(16) 25(3) 37(3) 32(4) 0(3) -3(3) -17(3)

C(17) 25(3) 36(3) 24(4) 4(3) -8(3) -11(3)

C(18) 28(3) 28(3) 24(4) 3(3) -7(3) -10(2)

C(19) 27(3) 28(3) 29(4) 1(3) -8(3) -13(2)

C(20) 16(3) 27(4) 27(2) 3(2) -10(2) -9(3)

C(21) 25(4) 27(4) 30(3) -1(3) -10(3) -10(3)

C(22) 21(4) 27(4) 31(3) -1(3) -11(3) -7(3)

C(23) 30(4) 31(4) 29(3) 1(3) -9(3) -12(3)

C(24) 29(4) 30(4) 29(3) 3(3) -7(3) -15(3)

C(25) 26(4) 27(4) 27(3) 4(3) -8(3) -12(3)

C(26) 27(4) 25(3) 39(4) 5(3) -9(3) -13(3)

C(27) 23(2) 28(3) 38(4) -3(3) -6(3) -14(2)

C(28) 22(2) 29(4) 32(4) 0(3) -6(2) -13(2) C(29) 24(2) 25(4) 31(3) 2(3) -7(2) -14(2)

C(30) 26(3) 32(4) 34(3) 2(3) - 10(2) -14(2)

C(3 1 ) 24(3) 32(4) 34(3) 2(3) -9(3) - 15(3)

C(32) 28(3) 30(4) 37(3) 0(3) - 13(2) - 13(3)

C(33) 22(3) 25(4) 34(3) -2(3) -8(2) - 15(2)

C(34) 22(3) 30(4) 33(3) - 1(3) -7(2) - 13(2)

Solid State Characteristics hemi L-tartrate (Hemi-L-Tartrate Salt) Figure 8 shows the Powder Diffraction pattern of the hemi-L-tartrate salt.

Figure 9 shows the DSC of the hemi-L-tartrate salt (specimen holder aluminum standard 40μί (method: 1.00 s, 30.0-260.0°C, 10.00 K/min, N2 50.0 mL/min, perforated lid)).

One predominant polymorph with defined stoichiometric ratio of drug to counter ion ( 1 :0.5).

It can be concluded from the above experimental data that reproducible XRPD; single event in DSC with high melting point (~200°C) and low weight loss in TGA were observerd making the hemi-L-tartrate a promising candidate for drug development. Further, the hemi-salt exhibits an advantageous ratio between (E)-N-(( ls,4s)-4- (dimethylamino)- l ,4-diphenylcyclohexyl)-N-methylcinnamamide and the L-tartrate.

Example 2: (E)-N-(( 1 s.4s)-4-(dimethylamino)- 1.4-diphenylcvclohexyl)-N-methylcinnamamide hemi-D-tartrate

Example 2(a):

Procedure:

In each case, 4 mL of the respective solvent were added to 100 mg of free base and 17.1 1 mg (0.5 eq) of D- tartaric acid in a vial (exact quantity: see table below). The resulting mixtures were vortexed at 500 rpm and 30°C for ca. 24 h (16:50). If a solution was obtained, the solvent was evaporated to yield the solid product. If a suspension was obtained, the solid was filtered off. The composition of the mixtures are summarized in the table here below:

Table 15:

Work-up: After 22 h, the mixtures were subjected to a work-up after 2 h at 20°C. Mixture 2(a)- 1 was left without cover in the fume hood to defume. The suspensions were filtered (G4 glass filter funnel, solid SM I) and the solids were sucked dry. After 3 days at room temperature, the solids SMI were dried for 3 h at 40°C and 0 mbar. The filtrates were leaft in the fume hood to evaporate (SM2).

Yield:

2(a)-l : not determined, white SM I .

2(a)-2: 107.99 mg (91.59% of theoretical value), white SM I .

2(a)-3 : 1 12.36 mg (96.16% of theoretical value), white SM I .

2(a)-4: 44.18 mg (37.79% of theoretical value), white SMI .

Analytics are summarized in the table here below.

Table 16:

Conclusion:

2(a)- 1, 2(a)-2, and 2(a)-3 gave hemi-D-tartrate. The powder diffraction analyses coincided with those of the hemi-L-tartrate.

Figure 10 shows the XRPD analysis of 2(a)-2. Figure 1 1 shows a comparison of the XRPD analysis of L-tartrate, D-tartrate and meso-tartrate. The tartrate show the same XRPD pattern, whereas the meso-tartrate shows a different XRPD pattern.

The XRPD peaks are summarized in the table here below.

Table 17:

Example 3 : (E)-N-(Y 1 s.4s)-4-(dimethylamino)- 1.4-diphenylcvclohexyl N-methylcinnamamide hemi-meso- tartrate

Meso-tartrate (1 :0.5) was synthesized as described here below. Procedure:

In each case, 4 mL of the respective solvent (see table) were added to ca. 100 mg of free base and ca. 19.16 mg (0.5 eq) of meso-tartaric acid mono hydrate in a 8 mL vial (exact quantity: see table below). The resulting mixtures were vortexed at 500 rpm and 30°C.

Table 18:

Work-up: After 22 h, the resulting mixtures were subjected to a work-up after 2 h at 20°C. Sample 3- 1 was left without cover in the fume hood to defume. The suspensions were filtered (G4 glass filter funnel, solid SM I ) and the solids were sucked dry. After 3 h at room temperature, the solids SMI were dried for 3 h at 40°C and 0 mbar.

Yield:

3-1 : not determined, residue after evaporation, white solid SMI .

3-2: 1 10.52 mg (94.87% of theoretical value), white SMI .

3-3 : 1 1 1.57 mg (95.63% of theoretical value), white SM I .

3-4: 94.16 g (80.74% of theoretical value), white SMI .

Analytics are summarized in the table here below.

Table 19:

All experiments gave the hemi-meso-tartrate.

Figure 12 shows the XRPD of the crystalline form 3-2. The XRPD peaks are summarized in the table here below.

Table 20:

D / Angstrom 2Theta / deg I(rel) D / Angstrom 2Theta / deg l(rel)

8.3441 10.59 6 3.2622 27.32 5

8.0359 1 1.00 25 3.2137 27.74 9

7.41 12 1 1.93 30 3.1940 27.91 10

6.9169 12.79 27 3.1692 28.13 18

5.3828 16.45 10 3.0373 29.38 6

4.9405 17.94 40 3.01 10 29.65 5 4.8381 18.32 100 2.8484 3 1 .38 4

4.7301 18.74 6 2.8159 3 1 .75 4

4.5267 19.60 38 2.7746 32.24 6

4.3832 20.24 5 2.6950 33.22 4

4.3229 20.53 6 2.6587 33.68 3

4.2065 21.10 3 1 2.5601 35.02 3

4.1640 21.32 12 2.3343 38.54 6

4.0433 21.97 5 2.3094 38.97 5

3.9099 22.72 7 2.2284 40.45 3

3.7863 23.48 5 2.1299 42.40 3

3.6396 24.44 10 2.021 1 44.81 3

3.4639 25.70 4

Example 4: (E)-N-((ls.4s)-4-(dimethylamino)-L4-diphenylcyclo^ hemi-L-malate

Procedure:

In a vial, 10 mL 2-propanol were added to 499.18 mg free base and 152.76 mg (1 eq.) L-(-)-malic acid. The suspension was vortexed for 17 h at 30°C and 400 rpm. After 17 h, the suspension was filtered after additional 2 h at 22-23°C (G4 glass filter funnel, solid SMI ), sucked dry and dried at 40°C and ca. 3 mbar.

Yield: 529.45 mg (92.0%) white SM I .

Analytics are summarized in the table here below.

Table 21 :

Figure 13 shows the DVS analysis of Example 4. a) Powder diffraction data

The XRPD peaks are summarized in below table.

Table 22:

D / Angstrom 2Theta / deg I(rel)

7.979184 1 1 .0798 13.70

7.553428 1 1.7064 13.52

6.994930 12.6448 30.59

5.367367 16.5026 22.86

4.871569 18.1957 100.00

4.562510 19.4399 21.95

4.483629 19.7853 23.15

4.229182 20.9888 29.20

3.190970 27.9383 21.79 2.846052 31.4065 13.70

2.686414 33.3256 7.3 1

2.357476 38.1429 8.77

Figure 14 shows the X PD analysis of of Example 4.

It can be concluded from the above experimental data that reproducible XPRD analysis, single event in DSC with high melting point (> 200°C) and no weight loss in TGA were observed, making the hemi-L-malate a promising candidate for drug development.

Example 5 : (E)-N-(( 1 s.4s)-4-(dimethylamino)- 1.4-diphenylcvclohexyl)-N-methylcinnamamide hemi-succinate

Under the given conditions, the hemi-succinate always gave the same crystalline form.

All experiments describe the production of polymorph A.

Example 5 (a)

Procedure:

501 .4 mg free base and 136.46 mg ( 1 eq.) of succinic acid were homogenized and 20 mL ethyl acetate were added to the mixture. The suspension was vortexed using a PLS-Synthesizer (30°C, 400 rpm). After addition of sovent, an almost clear solution was obtained. After ca. 2 min a white solid precipitated.

Work-up:

After 18 h, the suspension was filtered after 1 h at 22°C (SM I, G4 glass filter funnel), the sojid was sucked dry and then dried for 3.5 h at 40°C and ca. 3 mbar.

Yield: 525.72 mg (92.4% of theoretical value) white solid.

Although 1 eq. of succinic acid was added, only the hemi-succinate could be obtained. Analytics are summarized in the table here below.

Table 23 :

Figure 15 shows the DVS - Dynamic Vapour Sorption - of Example 5(a). Example 5(b)

Procedure:

In a 250 tnL round bottom flask, 5.20450 g free base and 703.09 mg (0.5 eq.) succinic acid were homogenized. Then, 200 mL ethyl acetate was added. The resulting suspension was rotated at 280 rpm in a water bath (30°C).

Work-up:

After 20 h, the suspension is filtered after 30 min at 22°C (SM I , G4 glass filter funnel), the solid is sucked dry and then dried for 18 h at 40°C and ca. 3 mbar.

Drying of SMI :

5.47 g SMI were weighed into a tared receptacle (47.73 g) and dried for 1 h at 70°C and 2 mbar. The retained weight was 5.46 g (weight loss 5.6 mg, 0.1%) SM4.

5.30 g SM4 were weighed into a tared receptacle and dried for 1 h at 70°C and 2 mbar. Retained weight: 5.30 g SM5 (no further weight loss).

Yield:

5.54 g (93.9% of theoretical value) white SMI is further dried;

5.46 g (92.4% of theoretical value) white fine crystalline SM4, no analytics, is further dried;

5.30 g (89.8 % of theoretical value) white fine crystalline SM5.

Analytics are summarized in the table here below.

Table 24:

Figure 16 shows the XRPD of SM5. a) Powder diffraction data

The XRPD peaks are summarized in the table here below.

Table 25:

D / Angstrom 2Theta / deg I(rel) D / Angstrom 2Theta / deg I(rel)

16.9400 5.21 4 3.6965 24.06 6 8.4223 10.50 15 3.5816 24.84 4

8.0213 11.02 17 3.5331 25.19 4

7.8325 11.29 13 3.2917 27.07 4

7.5767 11.67 15 3.2080 27.79 11

7.3312 12.06 10 3.1756 28.08 21

7.0736 12.50 19 3.0530 29.23 5

5.3908 16.43 12 2.8809 31.02 6

4.8446 18.30 100 2.8502 31.36 6

4.6206 19.19 16 2.8215 31.69 5

4.4649 19.87 13 2.6975 33.18 5

4.3858 20.23 7 2.4474 36.69 3

4.3209 20.54 10 2.3664 37.99 6

4.2580 20.84 23 2.3409 38.42 4

4.2271 21.00 21 2.2522 40.00 3

4.0461 21.95 4 2.2073 40.85 3

3.9484 22.50 6 2.0583 43.96 3

3.8161 23.29 8 2.0238 44.74 3

Single crystal data

The atomic coordinates ( x 10 ^Λ 4) and equivalent isotropic displacement parameters ( ^Λ 2 x 10 ^Λ 3) are summarized in the table here below. U(eq) is defined as one third of the trace of the orthogonal ized Uij tensor.

Table 26:

Atom X y z U(eq)

0(2) 3895(5) 12339(4) 5477(3) 44(1)

C(l) 3708(6) 12651(6) 4792(4) 30(1)

C(2) 4581(8) 14385(6) 4631(3) 43(2)

0(3) 4619(4) 11005(4) 1710(2) 38(1)

N(l) 1933(5) 10203(5) 1635(3) 30(1)

N(2) 1629(5) 8721(5) 4280(3) 29(1)

C(3) 3517(7) 11321(6) 1733(3) 32(1)

C(4) 1285(6) 8446(6) 1557(3) 27(1)

C(5) -226(6) 7797(6) 2009(3) 28(1)

C(6) 94(6) 8369(6) 2936(3) 29(1)

C(7) 1194(6) 7882(6) 3379(3) 26(1)

C(8) 214(6) 8264(7) 4753(3) 34(1)

C(9) 2838(7) 8506(7) 4770(4) 37(2)

C(10) 2740(6) 8521(6) 2945(3) 29(1)

C(ll) 2408(6) 7988(6) 2010(3) 27(1)

C(12) 442(6) 6062(6) 3354(3) 28(1)

C(13) 1359(7) 5320(6) 3419(3) 31(1)

C(14) 658(7) 3689(6) 3395(3) 31(1)

C(15) -986(7) 2777(7) 3301(3) 36(2)

C(16) -1918(7) 3480(7) 3237(3) 39(2)

C(17) -1236(6) 5096(6) 3263(3) 32(1)

C(18) 978(6) 7771(6) 634(3) 27(1)

C(19) 2259(6) 8205(6) 145(3) 30(1)

C(20) 2042(7) 7600(6) -676(4) 33(1)

C(21) 503(7) 6496(7) -1066(4) 37(2)

C(22) -779(7) 6034(6) -599(4) 32(1)

C(23) -551(6) 6648(6) 231(3) 30(1)

C(24) 744(6) 10699(7) 1403(4) 37(2)

C(25) 3875(6) 13002(6) 1889(3) 32(1)

C(26) 4986(6) 14099(6) 1505(3) 33(1) C(27) 5510(6) 15819(6) 1647(3) 28(1)

C(28) 5823(6) 16642(6) 970(4) 30(1)

C(29) 6320(6) 18278(7) 1099(4) 36(2)

C(30) 6513(6) 19054(6) 1885(4) 30(1)

C(31) 6201(6) 18234(7) 2565(4) 33(1)

C(32) 5661(6) 16603(6) 2439(4) 30(1)

Bond lengths [A] and angles [deg] are summarized in the table here below.

Table 27: distance ΓΑ1 C(16)-C(17) 1.376(8)

0(1)-C(1) 1.277(6) C(16)-H(16) 0.9500

0(2)-C(l) 1.214(6) C(17)-H(17) 0.9500

C(l)-C(2) 1.541(8) C(18)-C(19) 1.401(7)

C(2)-C(2)#l 1.479(11) C(18)-C(23) 1.413(7)

C(2)-H(2A) 0.9900 C(19)-C(20) 1.359(7)

C(2)-H(2B) 0.9900 C(19)-H(19) 0.9500

0(3)-C(3) 1.232(6) C(20)-C(21) 1.408(8)

N(l)-C(3) 1.366(7) C(20)-H(20) 0.9500

N(l)-C(24) 1.484(7) C(21)-C(22) 1.377(7)

N(l)-C(4) 1.499(7) C(21)-H(21) 0.9500

N(2)-C(8) 1.481(6) C(22)-C(23) 1.373(7)

N(2)-C(9) 1.489(7) C(22)-H(22) 0.9500

N(2)-C(7) 1.527(6) C(23)-H(23) 0.9500

N(2)-H(2N) 0.98(6) C(24)-H(24A) 0.9800

C(3)-C(25) 1.487(8) C(24)-H(24B) 0.9800

C(4)-C(18) 1.521(7) C(24)-H(24C) 0.9800

C(4)-C(5) 1.528(7) C(25)-C(26) 1.331(7)

C(4)-C(ll) 1.539(7) C(25)-H(25) 0,9500

C(5)-C(6) 1.508(7) C(26)-C(27) 1.483(8)

C(5)-H(5A) 0.9900 C(26)-H(26) 0.9500

C(5)-H(5B) 0.9900 C(27)-C(32) 1.380(7)

C(6)-C(7) 1.532(7) C(27)-C(28) 1.391(7)

C(6)-H(6A) 0.9900 C(28)-C(29) 1.410(8)

C(6)-H(6B) 0.9900 C(28)-H(28) 0.9500

C(7)-C(10) 1.538(7) C(29)-C(30) 1.361(7)

C(7)-C(12) 1.552(7) C(29)-H(29) 0.9500

C(8)-H(8A) 0.9800 C(30)-C(31) 1.394(8)

C(8)-H(8B) 0.9800 C(30)-H(30) 0.9500

C(8)-H(8C) 0.9800 C(31)-C(32) 1.397(8)

C(9)-H(9A) 0.9800 C(31)-H(31) 0.9500

C(9)-H(9B) 0.9800 C(32)-H(32) 0.9500

C(9)-H(9C) 0.9800 0(2)-C(l)-0(l) 127.1(5)

C(10)-C(ll) 1.515(7) 0(2)-C(l)-C(2) 119.9(5)

C(10)-H(10A) 0.9900 0(1)-C(1)-C(2) 113.0(5)

C(10)-H(10B) 0.9900 C(2)#l-C(2)-C(l) 116.6(6)

C(11)-H(11A) 0.9900 C(2)#1-C(2)-H(2A) 108.1

C(11)-H(11B) 0.9900 C(1)-C(2)-H(2A) 108.1

C(12)-C(13) 1.385(7) C(2)#1-C(2)-H(2B) 108.1

C(12)-C(17) 1.410(7) C(1)-C(2)-H(2B) 108.1

C(13)-C(14) 1.388(7) H(2A)-C(2)-H(2B) 107.3

C(13)-H(13) 0.9500 C(3)-N(l)-C(24) 118.0(4)

C(14)-C(15) 1.378(8) C(3)-N(l)-C(4) 125.7(4)

C(14)-H(14) 0.9500 C(24)-N(l)-C(4) 114.9(4)

C(15)-C(16) 1.366(8) C(8)-N(2)-C(9) 108.1(4)

C(15)-H(15) 0.9500 C(8)-N(2)-C(7) 112.7(4) C(9)-N(2)-C(7) 114.8(4) C(12)-C(13)-H(13) 119.3

C(8)-N(2)-H(2N) 100(3) C(14)-C(13)-H(13) 119.3

C(9)-N(2)-H(2N) 116(3) C(15)-C(14)-C(13) 119.8(5)

C(7)-N(2)-H(2N) 105(3) C(15)-C(14)-H(14) 120.1

0(3)-C(3)-N(l) 123.9(5) C(13)-C(14)-H(14) 120.1

0(3)-C(3)-C(25) 120.0(5) C(16)-C(15)-C(14) 119.9(5)

N(l)-C(3)-C(25) 116.0(5) C(16)-C(15)-H(15) 120.0

N(l)-C(4)-C(18) 108.3(4) C(14)-C(15)-H(15) 120.0

N(l)-C(4)-C(5) 106.7(4) C(15)-C(16)-C(17) 120.8(6)

C(18)-C(4)-C(5) 113.4(4) C(15)-C(16)-H(16) 119.6

N(l)-C(4)-C(ll) 113.2(4) C(17)-C(16)-H(16) 119.6

C(18)-C(4 C(11) 110.2(4) C(16)-C(17)-C(12) 120.7(5)

C(5)-C(4)-C(ll) 105.2(4) C(16)-C(17)-H(17) 119.7

C(6)-C(5)-C(4) 113.5(4) C(12)-C(17)-H(17) 119.7

C(6)-C(5)-H(5A) 108.9 C(19)-C(18)-C(23) 116.3(5)

C(4)-C(5)-H(5A) 108.9 C(19)-C(18)-C(4) 120.0(5)

C(6)-C(5)-H(5B) 108.9 C(23)-C(18)-C(4) 123.6(5)

C(4)-C(5)-H(5B) 108.9 C(20)-C(19)-C(18) 121.9(5)

H(5A)-C(5)-H(5B) 107.7 C(20)-C(19)-H(19) 119.0

C(5)-C(6)-C(7) 113.0(4) C(18)-C(19)-H(19) 119.0

C(5)-C(6)-H(6A) 109.0 C(19)-C(20)-C(21) 120.6(5)

C(7)-C(6)-H(6A) 109.0 C(19)-C(20)-H(20) 119.7

C(5)-C(6)-H(6B) 109.0 C(21)-C(20)-H(20) 119.7

C(7)-C(6)-H(6B) 109.0 C(22)-C(21)-C(20) 118.9(6)

H(6A)-C(6)-H(6B) 107.8 C(22)-C(21)-H(21) 120.6

N(2)-C(7)-C(6) 108.3(4) C(20)-C(21)-H(21) 120.6

N(2)-C(7)-C(10) 107.7(4) C(23)-C(22)-C(21) 120.2(6)

C(6)-C(7)-C(10) 106.7(4) C(23)-C(22)-H(22) 119.9

N(2)-C(7)-C(12) 110.3(4) C(21)-C(22)-H(22) 119.9

C(6)-C(7)-C(12) 113.4(4) C(22)-C(23)-C(18) 122.1(5)

C(10)-C(7)-C(12) 110.3(4) C(22)-C(23)-H(23) 119.0

N(2)-C(8)-H(8A) 109.5 C(18)-C(23)-H(23) 119.0

N(2)-C(8)-H(8B) 109.5 N(1)-C(24)-H(24A) 109.5

H(8A)-C(8)-H(8B) 109.5 N(1)-C(24)-H(24B) 109.5

N(2)-C(8)-H(8C) 109.5 H(24A)-C(24)-H(24B) 109.5

H(8A)-C(8)-H(8C) 109.5 N(1)-C(24)-H(24C) 109.5

H(8B)-C(8)-H(8C) 109.5 H(24A)-C(24)-H(24C) 109.5

N(2)-C(9)-H(9A) 109.5 H(24B)-C(24)-H(24C) 109.5

N(2)-C(9)-H(9B) 109.5 C(26)-C(25)-C(3) 121.2(5)

H(9A)-C(9)-H(9B) 109.5 C(26)-C(25)-H(25) 119.4

N(2)-C(9)-H(9C) 109.5 C(3)-C(25)-H(25) 119.4

H(9A)-C(9)-H(9C) 109.5 C(25)-C(26)-C(27) 126.0(5)

H(9B)-C(9)-H(9C) 109.5 C(25)-C(26)-H(26) 117.0

C(ll)-C(10)-C(7) 112.1(4) C(27)-C(26)-H(26) 117.0

C(11)-C(10)-H(10A) 109.2 C(32)-C(27)-C(28) 119.8(5)

C(7)-C(10)-H(10A) 109.2 C(32)-C(27)-C(26) 120.8(5)

C(11)-C(10)-H(10B) 109.2 C(28)-C(27)-C(26) 119.4(5)

C(7)-C(10)-H(10B) 109.2 C(27)-C(28)-C(29) 119.8(5)

H(10A)-C(10)-H(10B) 107.9 C(27)-C(28)-H(28) 120.1

C(10)-C(ll)-C(4) 115.3(4) C(29)-C(28)-H(28) 120.1

C(10)-C(11)-H(11A) 108.5 C(30)-C(29)-C(28) 120.1(5)

C(4)-C(11)-H(11A) 108.5 C(30)-C(29)-H(29) 120.0

C(10)-C(11)-H(11B) 108.5 C(28)-C(29)-H(29) 120.0

C(4)-C(11)-H(11B) 108.5 C(29)-C(30)-C(31) 120.3(5)

H(11A)-C(11)-H(11B) 107.5 C(29)-C(30)-H(30) 119.8

C(13)-C(12)-C(17) 117.4(5) C(31)-C(30)-H(30) 119.8

C(13)-C(12)-C(7) 122.5(5) C(30)-C(31)-C(32) 119.9(5)

C(17)-C(12)-C(7) 120.1(5) C(30)-C(31)-H(31) 120.1

C(12)-C(13)-C(14) 121.5(5) C(32)-C(31)-H(31) 120.1 C(31 )-C(32)-H(32) 120.0

Symmetry transformations used to generate equivalent atoms: # 1 -x+l ,-y+3,-z+ l . The hydrogen coordinates ( x 10 ^Λ 4) and isotropic displacement parameters ( ^Λ 2 x 10 ^Λ 3) are summarized in the table here below.

Table 28:

The anisotropic displacement parameters ( ^Λ 2 x 10 ^A 3) are summarized in the table here below. The anisotropic displacement factor exponent takes the form: -2 pi ^A 2 [ h ^A 2 a* ^A 2 Ul 1 + ... + 2 h k a* b* U12 ]

Table 29:

It can be concluded from the above experimental data that reproducible XPRD analysis, single event in DSC with high melting point (> 200°C) and low to some weight loss in TGA were observed, making the hemi- succinate a promising candidate for drug development.

Example 6: (E)-N-(( l s,4s)-4-(dimethylamino)- 1.4-diphenylcvclohexyl)-N-methylcinnamamide hemi fumarate

Procedure: 499.74 mg free base and 133.12 mg (1 eq.) fumaric acid were homogenized. 20 mL 2-ptopanol were added to the resultant mixture. The suspension was vortexed at 30°C and 400 rpm. After addition of solvent, a white suspension was obtained. After ca. 2 min, the suspension was more clear with coarse suspended crystals.

Work-up:

After 18h, the suspension was filtered after 1 h at 22°C (SMI , G4-glass filter funnel), the solid was sucked dry and then dried for 3.5 h at 40°C and ca. 3 mbar.

Yield:

569.88 mg ( 100.71% of theoretical value) white solid. Analytics are summarized in the table here below.

Table 30:

Figure 17 shows the DVS - Dynamic Vapour Sorption - of Example 6. a) Powder diffraction data

The XRPD peaks are summarized in below table.

Table 3 1 :

Figure 18 shows the XRPD analysis of of Example 6. It can be concluded from the above experimental data that reproducible XPRD analysis, single event in DSC with high melting point (> 200°C) and low weight loss in TGA can be observed, making the hemi-fumarate a promising candidate for drug development.

Example 7: (E N- ds^s ^' l^-Cdimethylaminol-l ^-diphenylcvclohexyn-N-methylcinnamamide oxalate

Example 7 (a)

Procedure:

499.85 mg free base and 142.96 mg (1 eq.) oxalic acid dehydrate were homogenized. 15 mL ethyl acetate were added to the resultant mixture. The white suspension was vortexed at 30°C and 400 rpm.

Work-up:

After 18h, the suspension was filtered after 1 h at 22°C (SM I, G4-glass filter funnel), the solid was sucked dry and then dried for 3.5 h at 40°C and ca. 3 mbar.

Yield:

577.14 mg (95.80% of theoretical value) white solid.

Analytics are summarized in the table here below.

Table 32:

Figure 19 shows the XRPD of Example 7 (a).

Figure 20 shows the results of the DVS - Dynamic Vapour Sorption - of Example 7 (a).

Example 7 (b):

Procedure:

In a 250 mL round bottom flask, 4.79925 g free base and 1.38 mg (1 eq.) oxalic acid dihydrate were homogenized. 140 mL of ethyl acetate were added to the resultant mixture. The white suspension was rotated at 280 rpm in a water bath (30°C).

Work-up: After 17 h, the suspension is filtered after 30 min at 22°C (SM I , G4-glass filter funnel), the solid is sucked dry and then dried for 21 h at 40°C and ca. 3mbar.

Drying of SM I :

5.69 g SM I are weighed into a tared receptacle and dried for 1 h at 70°C and 2 mbar giving 5.68 g (weight loss 13.15 mg, 0.23%) SM2.

Drying of SM2:

Since the weight loss of 0.23% is too low (acc. to TG -1.94%), the flour-like solid is groung in an agate mortar for 5 min and then dried again. 5.62 g SM2 are weighed into a tared receptacle and dried for 1 h at 70°C and 2 mbar giving 5.62 g SM3 (no further weight loss).

Yield:

5.76 g (99.6 % theoretical value.) white SMI is further dried;

5.62 g (97.2 % theoretical value) white flour-like SM2, no analytics, is further dried;

5.62 g (97.2 % theoretical value) white flour-like SM3.

Analytics are summarized in the table here below.

Table 33 :

Figure 21 shows the XRPD analysis of SM3.

The XRPD data are summarized in the table here below.

Table 34:

D / Angstrom 2Theta / deg I(rel) D / Angstrom 2Theta / deg I(rel)

15.4299 5.72 1 3.6535 24.34 4

8.4016 10.52 7 3.6207 24.57 3

7.8145 1 1.3 1 14 3.2024 27.84 10

7.4150 1 1.93 22 3.1643 28. 18 13

6.0028 14.75 2 3.0942 28.83 5

5.5778 15.88 6 3.0465 29.29 7

4.8292 18.36 100 3.0012 29.74 2

4.7177 18.79 1 1 2.8948 30.86 2

4.6072 19.25 10 2.8379 31.50 3 4.5266 19.60 13 2.7884 32.07 3

4.4725 19.83 6 2.6690 33.55 2

4.2651 20.81 25 2.4148 37.20 2

4.1775 21.25 7 2.3645 38.03 5

4.0636 2 1 .85 3 2.1345 42.3 1 1

3.8772 22.92 3 2.0958 43.13 2

3.7763 23.54 5 2.0356 44.47 1

3.7092 23.97 3

It can be concluded from the above experimental data that reproducible XPRD analysis, single event in DSC with high melting point (> 200°C) and no weight loss in TGA were observed, are making the crystalline oxalate a promising candidate for drug development.

Example 8: evaluation of drug salt options

The evaluation of drug salt options are summarized in the table below.

Table 35:

3 better than 2 better than I

Salts of the free base having each one of the following counter ions were prepared: succinate, fumarate, embonate, citrate, oxalate, camsilate, L-malate, esilate, mesilate, maolate, hexanoate, tosilate, palmitate (hexadecanoate), stearate (octadecanoate), L-tartrate, mucate, cinnamate, hydrochloride, hydrobromide, capsilate, glyphosate, acesulfamate, acetate, sebacate, saccharinate, octanoate, nicotinate, S-glutamate, formiate, hippurate, gentisate, sulfate, phosphate, nitrate, orolate, l -hydroxy-2-naphtholate, napadisilate, lactate or (2S,3S)-dibenzoyl tartrate. The resultant salts had one or more crystalline forms.

Selected characteristic data of selected salts of (E)-N-(( l s,4s)-4-(dimethylamino)- l ,4-diphenylcyclohexyl)-N- methylcinnamamide are summarized in the table here below (for sake of conciseness, the name of the drug has been omitted).

Table 36: analytical characterization of material from 20 mg scale. salt component Analytical data and conclusions

(from solid state point of view) succinate XRPD: 103 succinate 1:0.5

NMR: 1 : 0.5; hemi-succinate

DSC: To = 201 -202 °C; Tp = 203 - 204 °C; 114-118 J/g

TG: mass loss: 0-1.2 %

fumarate XRPD: 104 fumarate 1:0.5

NMR: 1 : 0.5; hemi-fumarate

DSC: To = 211 -214°C;Tp = 213-215°C; 102 -108 J/g

TG: mass loss: < 0.5 %

embonate XRPD: 170 embonate 1:2

NMR: 1 : 2; bis-embonate

DSC: To = 225 - 230 °C; Tp = 229 - 233 °C; 77 -92 J/g

TG: mass loss: < 0.1 %

citrate XRPD: 111 citrate

NMR: 1 : 1.2

DSC: To= 117°C; Tp= 136 °C; 55 J/g

To = 145 °C; Tp = 154 °C; 28 J/g

TG: mass loss: 1 - 2 %

oxalate XRPD: 177 oxalate

NMR: salt formation, no info on stoichiometry

DSC: To = 218 -220 °C;Tp = 219-221 °C; 125 -139 J/g

TG: mass loss: < 0.1 %

camsilate XRPD: 284 camsilate

NMR: 1 : 1;

DSC: To = 207 - 212 °C; Tp = 211 - 215 °C; 57 - 62 J/g

TG: mass loss: < 0.1 %

L-malate XRPD: 147 L-malate

NMR: 1 : 0.5, hemi-malate

DSC: To = 196 - 199 °C; Tp = 201 - 203 °C; 82 - 84 J/g

TG: mass loss: < 0.1 %

esilate XRPD: 353 esilate

NMR: 1 : 1

DSC: To = 213 - 224 °C; Tp = 216 - 225 °C; 72 - 73 J/g

TG: mass loss: < 0.3 %

mesilate XRPD: 358 mesilate

NMR: 1 : 1; mesilate

DSC: To= 193-210 °C;Tp = 200 -215 °C; 55 - 67 J/g

TG: mass loss: < 0.4 %

malonate XRPD: 359 malonate

NMR: 1 : 1,

DSC: To = 130 - 159°C; Tp = 163 - 164°C; 205 J/g

TG: mass loss: no weight loss

(decomposition during/after melting; ~ 19 %) hexanoate XRPD: 381 hexanoate

(caproate) NMR: 1 : 1, hexanoate

DSC: To= 130 - 132 °C;Tp= 133 - 134 °C; 96 - 98 J/g

TG: mass loss: < 0.5 %

tosilate XRPD: 334 tosilate

(para-toluene NMR: 1 : 1, tosilate

sulfonate) DSC: To = 200 - 202 °C; Tp = 203 - 204 °C; 64 - 70 J/g

TG: mass loss: < 0.3 %

palmitate XRPD: several different pattern and free base

(hexadecanoate) NMR: 1 : 1, palmitate (Bl, B3, B4) or free base (B2)

DSC: several events, low melting point (< 80°C)

TG: mass loss: between 0.5 and 0.9 % stearate XRPD: 394 stearate

(octadecanoate) NMR: 1 : 1, stearate

DSC: To = 56 - 59 °C;Tp = 61 -65 °C; 61 - 85 (65) J/g (To = 67 °C; Tp = 67 °C; 14 J/g)

TG: mass loss: < 0.4 %

L-tartrate XRPD: 136 L-tartrate 1:0.5

NMR: 1 : 0.5; hemi-L-tartrate DSC: To = 213 - 215 °C; Tp = 216 - 218 °C; 100 - 120 J/g

TG: mass loss: < 0.1 %

mucate Salt could not be reproduced in 20 mg scale

cinnamate XRPD: several XYGroups

NMR: 1 : 1 ; cinnamate

DSC: several events

TG: mass loss: up to 5.5%

hydrochloride No experiments performed

Table 37: more detailed physico-chemical characterization of material from 500 mg scale.

Evaluation of drug salt options concerning the solid state perspective is summarized in the table here below.

Table 38: free base HCl salt hemi- hemi-L- mesilate salt oxalate salt succinate salt tartrate salt

yield/% (100) 94.5 89.8 98.8 88.1 97.2

NMR 1 :0 1 : 1 1 :0.5 1 :0.5 1 : 1 n.a.

produced be produced be produced

Example 9: stability of various salts under stress conditions

Samples of various salts of the drug were prepared and stored as solutions in various solvents as well as in solid form.

Table 39:

The preparation was realized according to the procedures described above. HCI and mesilate salts were prepared as is described in the following.

HCl-salt

Procedure:

20 mL of 2-propanol, was added to a 50 mL round bottom flask containing 4.34 g SMI and 1 .20 g SM2. The suspension was heated to 60°C giving an not stirrable suspension. Additional 15 mL of 2-propanol were added and the suspension was stirred for 1.25 h at 60°C. Then, the suspension was leaft to cool down slowly in a water bath (after 1.75 h at 30°C). The suspension was then stirred over night ( 17 h) at 19°C.

Work-up:

The suspension was stirred for 1.5 h in an ice bath. After 1 .5 h, the white suspension was filtered (G4-glass filter funnel) and the white SMI was left over night ( 17 h) at room temperature. The next day, SM I was dried for 16 h at 70°C and 0 mbar.

Only SMI was kept for further use, SM2 was discarded. Yield:

5.24 g (94.5% of theoretical value), white fine crystalline SM I . Analytics are summarized in the table here below.

Table 40:

Mesilate SM5

Procedure:

In a PLS-vial, 5.00 g free base (SM I ) were suspended in 200 mL acetone (weak suspension). 740 ( 1 eq., 7 x 100 μί + 1 x 40 μί) methane sulfonic acid were added (observation: at first, almost dissolved, after a few seconds precipitate). The suspension is rotated at 280 rpm in a water bath at 30°C.

Work-up:

After 17 h, the suspension was filtered after 30 min at room temperature (G4-glass filter funnel, SMI ), the solid was sucked dry and then dried for 21 h at 40°C and ca. 3 mbar. The filtrate SM2 was kept.

Drying of SMI :

5.521 g SMI were weighed into a tared receptacle and dried for 1 h at 70°C and 2 mbar. Retained weight: 5.516 g (weight loss 5 mg, 0.09%) SM3.

Drying of SM3 :

Since the weight loss of 0.09% was too low (lit.: TG -0.78%), the white fine crystalline solid was ground in an agate mortar for ca. 5 min and then dried again. 5.374 g SM3 were weighed into a tared receptacle (62.465 g) and dried for 1 h at 70°C and 2 mbar. Retained weight: 5.374 g SM4 (no further weight loss).

Yield- white fine crystalline SMI .

5.639 g (92.4% of theoretical value) white SM I , was dried further;

451.3 mg (7.4% of theoretical value) white SM2, no analytics;

5.516 g (90.4% of theoretical value) white fine crystalline SM3, no analytics, was dried further;

5.374 g (88.1 % of theoretical value) white fine crystalline SM4, was handed over as SM5. Analytics are summarized in the table here below.

Table 41:

Test protocol a) In solution

Table 42:

b) In solid state

Table 43:

The experimental results are summarized in the table here below.

Table 44: pH neutral hydrochloride hemi succinate hemi L-tartrate oxalate mesilate time

Oh >99 ca.99 >99 >99 >99

3h >99 ca.99 >99 >99 >99

Id >99 ca.99 >99 >99 >99

3d >99 ca.99 >99 >99 >99

7d >99 ca.99 >99 >99 >99 degree of decomposition t _en< j - - decomposition product [m/z ^' - - - pH acidic hydrochloride hemi succinate hemi L-tartrate oxalate mesilate time

Oh >99 98.5 >99 >99 >99

3h 64.0 57.2 60.3 48.4 43.5

Id 0.2 0.7 0.6 0 0

3d 0 0 0 0 0

7d 0 0 0 0 0 degree of decomposition t _cnd >99 >99 >99 >99 > 99 decomposition product [m/z ^' 162/296/278 162/ 296/ 278 162/ 296/ 278 162/ 296/278 162/296/278 pH. alkaline hydrochloride hemi succinate hemi L-tartrate oxalate mesilate time

Oh >99 ca.99 >99 >99 >99

3h >99 ca.99 >99 >99 > 99

Id >99 ca.99 >99 >99 >99

3d >99 ca.99 >99 >99 >99

7d >99 ca.99 >99 >99 >99 degree of decomposition t _end - decomposition product [m/z] - - - - -

Oxidation H ₂ 0 ₂ hydrochloride hemi succinate hemi L-tartrate oxalate mesilate time

Oh >99 ca.99 >99 >99 >99

3h >99 98.8 >99 >99 >99

Id >99 95.3 >99 >99 >99

3d 98.2 93.2 98.3 >99 >99

7d 96.8 87.3 97.8 >99 >99 degree of decomposition t _end ca.3% ca.12% ca.3% - - decomposition product [m/z] 455/394 455/ 394 455 - -

Oxidation. Cu(II) hydrochloride hemi succinate hemi L-tartrate oxalate mesilate time

Oh >99 ca.99 >99 >99 >99

3h >99 ca.99 >99 >99 >99

Id >99 ca.99 >99 >99 >99

3d >99 ca.99 >99 >99 >99

7d >99 ca.99 >99 >99 >99 degree of decomposition t _e „ _d - - - decomposition product [m/z] - - - - -

Oxidation F(III) hydrochloride hemi succinate hemi L-tartrate oxalate mesilate time

Oh >99 ca.99 >99 >99 >99

3h >99 ca.99 >99 >99 >99

Id >99 98.7 >99 >99 >99

3d >99 98.2 >99 >99 >99

7d 97.4 97.0 98.7 >99 >99 degree of decomposition t _end ca.3% ca.2% < 1% - - decomposition product [m/z] 162 162 162 - - light 72h solid hydrochloride hemi succinate hemi L-tartrate oxalate mesilate type of glass

clear glass >99 ca.99 >99 >99 >99 clear glass + aluminium foild >99 ca.99 >99 >99 >99 degree of decomposition t _end - - - - - decomposition product [m/z] - - - - - light 72h in solution hydrochloride hemi succinate hemi L-tartrate oxalate mesilate type of glass

clear glass >99 92 A 98.4 96.7 ca.99 clear glass + aluminium foild >99 96.3 >99 >99 >99 degree of decomposition t _end - ca.4% ca.1% ca.3% < 1% decomposition product [m/z] - 162/278 162/278 diverse 162/278 temperature hydrochloride hemi succinate hemi L-tartrate oxalate mesilate \ time

Oh > 99 ca. 99 > 99 > 99 > 99

7d > 99 · ca. 99 > 99 > 99 > 99

21 d(t _end ) > 99 ca. 99 > 99 > 99 > 99

degree of decomposition t _mi - - - - - decomposition product [m/z] - - - - -

Example 10: equilibrium solubilities of various salts a) Equilibrium solubilities of various salts were investigated. The thermodynamic solubility was determined similar to BCS-Classification.

Table 45:

Table 46:

The concentration of drug (free base) after 24 h at 25°C agitation was measured (solubility testing similar to BSC-classification soubility testing procedure). Two different batches of the free base were investigated twice, independently from each other. After 24 h, the initial solid form often was not present any more in the pecipitate. It was observed that (i) in less acidic media with the same buffer anion less drug stays in solution (see phosphate buffers); (ii) in acetate buffer more drug is soluble than in phosphate buffers or chloride containing media; and (iii) when compared to free base, no clear top candidate salt could be identified regarding solubility improvement over all tested buffer systems.

No reliable equilbrium solubilities of the free base could be obtained under the given conditions due to precipitation events and decomposition observed in both batches of the free base.

Figure 22 shows the equilibrium solubilities of various salts at pH 1.3-1.4. Figure 23 shows the equilibrium solubilities of various salts at pH 4.5-4.7. Figure 24 shows the equilibrium solubilities of various salts at pH 6.8-7.0. Figure 25 shows the equilibrium solubilities of various salts at pH 7.4-7.5. b) GI Dissolution was investigated (Sirius Analytical) by determining the dissolution profiles of small tablets of compressed drug material.

Results:

The dissolution kinetics are worse for free base and hydrochloride salt than for other salts. Furthermore, the dissolution kinetics seem to be retarded by FaSSIF and FeSSIF components.

The experimental results are displayed in Figure 26 and Figure 27.

Example 1 1 : evaluation of pharmacokinetic parameters in dogs a) Experimental design rationale

Dogs are the animals of choice because

• in vitro dissolution tests can neither simulate nor predict the real behavior of formulations of very poorly soluble drugs such as drug in the human GI tract

• the anatomy of the Gl tract of dogs is closest to that of humans than that of other species used for preclinical investigations

• the gastric pH of fasted dogs is high (pH 4-8) compared to humans (pH 1-2) but can be "humanised" by pretreatment with pentagastrin

• information on the in vivo performance of clinically relevant formulations and doses is valuable for choosing the optimal human formulation for development b) Experimental design: Dogs, dosing, sampling

• 4 male beagle dogs per group

• only 4 dogs / formulation; weak statistical power, but sufficient to observe gross differences

• dogs were fasted overnight, and were pretreated intramuscular with 6 pg/kg pentagastrin before dosing to assure they had an acidic„human" gastric content; they were fed 3 hours after dosing.

• various formulations of 60 mg drug/dog were administered as in capsules by gavage followed by a small volume of rinsing water

• blood samples were collected in heparinised tubes 0, 0.17, 0.25, 0.5, 0.75, 1.0, 1.33, 1.67, 2.0, 2.5, 3.5, 6, 14 and 48 hours after administration

• plasma samples were prepared and frozen for delivery

• bioanalysis was performed at GRT using a validated HPLC-MS/ MS method c) Formulations

Table 47:

SEDDS: Self-emulsifying drug delivery system

The formulations were filled manually into capsules to the desired weight to assure the delivery of 60 mg drug. d) Evaluation

The plasma concentrations of individual dogs were normalised linearly to 1.0 mg drug base/kg body weight.

The pharmacokinetic parameters were calculated with WinNonLin and the PK parameters were compared between the different formulations. Statistical analysis was done by one-way ANOVA (p = 0.05) using GraphPad Prism 5.03.

The log scaled individual exposures to different formulations (normalized to 1 mg drug/kg) are displayed in Figure 28 to Figure 32.

The mean exposures (normalized to 1 mg drug/kg) are displayed in Figure 33 to Figure 35. e) Results

The extents of plasma exposures (AUC, C _max ) from solid formulations vary strongly. The drug succinate formulation performed best, although no significant difference of PK values between formulations could be shown.

C _max and AUCo-6 h> as well as AUCo-24 h (all normalized to 1 mg drug/kg) from different formulations are displayed in Figure 36 to Figure 38.

Example 12: manufacture of tablets containing different salts Example 11(a)

Tablets were prepared containing free base, hemi-tartrate, hydrochloride, mesilate, hemi-succinate and oxalate (in all cases 15 mg base/tablet).

Figure 39 shows the dissolution rate of different salts ( 15 mg base/tablet) at pH 4.5 (phosphate buffer). Figure 40 shows the dissolution rate of different salts ( 15 mg base/tablet) at pH 6.8 (phosphate buffer). Example 11(b)

Tablets were prepared containing free base, hemi-tartrate, hydrochloride, mesilate, hemi-succinate and oxalate (in all cases 60 mg base/tablet).

Figure 41 shows the dissolution rate of different salts (60 mg base/tablet) at pH 4.5 (acetate buffer). Figure 42 shows the dissolution rate of different salts (60 mg base/tablet) at pH 6.8 (phosphate buffer). Figure 43 shows the dissolution rate of different salts (60 mg base/tablet) at pH 6.5 (FaSSIF).