WO2018007842A1 - Pimavanserin salts useful for the production of a pharmaceutical preparation - Google Patents

Abstract

The object of the present invention relates to the formula (1) 1-(4-fluorobenzyl)-1-(1- methylpiperidin-4-yl)-3-[4-(2-methylpropoxy)benzyl]carbamide (pimavanserin) besylate, cyclamate, tosylate, benzoate and mandelate salts, as well as to their amorphous and crystalline forms, their hydrates and solvates, to the production of these salts, and to pharmaceutical preparations containing these, as well as to the therapeutic use of these salts.

Description

Pimavanserin salts useful for the production of a pharmaceutical preparation

The object of the invention

The object of the present invention relates to the formula 1 l-(4-fluorobenzyl)-l-(l- methylpiperidin-4-yl)-3-[4-(2-methylpropoxy)benzyl]carbamide (pimavanserin)

1 besylate, cyclamate, tosylate, benzoate and mandelate salts, as well as to their amorphous and crystalline forms, their hydrates and solvates.

More specifically the object of the present invention relates to the formula 2 benzene sulphonic acid salt (besylate) of pimavanserin

2 to the formula 3 cyclohexyl sulphamic acid salt (cyclamate) monohydrate

3

to its formula 4 /?-toluenesulphonic acid salt (tosylate)

to its formula 5 /?-toluenesulphonic acid salt (tosylate) monohydrate

to its formula 6 benzoic acid salt (benzoate) monohydrate

6

to its formula 7 D-(-)-mandelic acid salt

and to its formula 8 L-(+)- mandelic acid salt

8

The state of the art

It is known that l-(4-fluorobenzyl)-l-(l-methylpiperidin-4-yl)-3-[4-(2- methylpropoxy)benzyl]carbamide (pimavanserin) of formula 1 is a pharmaceutical active substance with a selective serotonin inverse agonist effect mechanism for the treatment of the psychosis associated with Parkinson's and Alzheimer's disease.

The structure of the formula 1 pimavanserin was first disclosed in international patent application with publication number WO 2004064738, which described its production, as well as its salt formed with tartaric acid.

International patent applications with publication numbers WO 2006036874, WO 2006037043, WO 2007133802, WO 2008144326 disclose the production of the pimavanserin base and several of its salts and characterise these with their physical characteristics as follows. Patent application number WO 2006036874 discloses the production of the pimavanserin base, and of its citrate, fumarate ("form A" and "form B"), maleate, malate, phosphate, succinate, sulphate, and edisylate salts. The salts are characterised by x-ray powder diffraction data.

Patent application number WO 2007133802 describes the production of the "Form A" and "Form C" crystalline forms of the pimavanserin base and its hemitartrate salt, and methods for their purification. It also discloses the advantageous characteristics of the pharmaceutical preparations containing pimavanserin.

Patent application number WO 2008144326 discloses the production of the pimavanserin base and of its hemitartrate salt. In addition to the amorphous form of the pimavanserin base, it discloses the production of its "Form Y" crystalline form, supplemented with the information that the "Form Y" crystalline base is thermodynamically stable. In addition to the amorphous form of the pimavanserin hemitartrate salt, it discloses the production of the "A", "B", "C", "D", "E" and "F" crystalline forms, with the additional information in paragraph 0077 that among the hemitartrate salts, "Form C" is the most stable. The numerical results of the stability test of the crystalline "Form C" are also given in the application in paragraph number 0217. The above crystalline forms are characterised by x-ray powder diffraction data. The structures of two contaminants are also disclosed in the application and give a limit for their amounts. Brief description of the invention

There is a continuous demand in the pharmaceuticals industry to be able to produce pure, morphologically homogenous and stable active substances. This is a basic condition of being able to simultaneously satisfy pharmaceutical formulation, quality assurance and registration authority demands. It is well known that in the case of various salts, polymorphs, hydrates, and solvates differences occur in important attributes such as solubility, chemical stability, polymorphic stability, dissolution rate, bioavailability, filterability, ability to dry, and form tablets. Furthermore from the point of view of the cost-effectiveness of production, it is extremely important to produce the product with a procedure that may also be realised on the industrial scale, that is easy to reproduce and results in a morphologically homogenous, contaminant-free, sufficiently stable form.

The aim when creating the pimavanserin salts according to the invention was to produce a highly pure form of pimavanserin salt with homogenous crystal structure, the polymorphic, chemical stability, and physical-chemical properties of which are more preferable than the known forms and that may be reproducibly produced at industrial scales, and especially that are more stable, among the previously produced pimavanserin forms, than the Y crystalline form of the pimavanserin base, and that are more stable and have lower hygroscopicity than the pimavanserin hemitartrate salt crystalline "Form C", which proved to be the most stable.

During our work it was surprising to find that the set objective may be achieved with the production of the pimavanserin besylate (1: 1) "Form I", the pimavanserin cyclamate (1: 1) monohydrate, the pimavanserin tosylate (1: 1) "Form I", the pimavanserin tosylate (1: 1) monohydrate, the pimavanserin benzoate (1: 1) monohydrate, the pimavanserin D-(-)-mandelate (1: 1) "Form I" and the pimavanserin L-(+)-mandelate (1: 1) "Form I" salts.

The salts according to the invention are also suitable for purification by pimavanserin salt formation.

The object of the invention are the pimavanserin besylate, cyclamate, tosylate, benzoate and mandelate salts, as well as their amorphous and crystalline forms, hydrates and solvates. The pimavanserin salt according to the object of the invention is preferably

- the "Form I" crystalline pimavanserin besylate salt (1: 1), the characteristic x-ray powder diffraction peaks of which are the following: 2Θ (±0.2 °2Θ): 4.06; 16.44; 18.19; 21.86,

- the crystalline pimavanserin cyclamate salt (1: 1) monohydrate, the characteristic x-ray powder diffraction peaks of which are the following: 2Θ (±0.2 °2Θ): 3.95; 7.90; 17.39; 18.73; 20.85, - the "Form I" crystalline pimavanserin tosylate salt (1: 1), the characteristic x-ray powder diffraction peaks of which are the following: 2Θ (±0.2 °2Θ): 4.00; 8.02; 16.43; 21.76,

- the crystalline pimavanserin tosylate salt (1: 1) monohydrate, the characteristic x-ray powder diffraction peaks of which are the following: 2Θ (±0.2 °2Θ): 4.25; 8.51; 16.58; 17.65; 21.99,

- the crystalline pimavanserin benzoate salt (1: 1) monohydrate, the characteristic x-ray powder diffraction peaks of which are the following: 2Θ (±0.2 °2Θ): 4.23; 8.46; 10.46; 17.96; 22.22,

- the "Form I" crystalline pimavanserin D-(-)-mandelate salt (1:1), the characteristic x-ray powder diffraction peaks of which are the following: 2Θ (±0.2 °2Θ): 6.94; 7.75; 18.99,

- the "Form I" crystalline pimavanserin L-(+)-mandelate salt (1:1), the characteristic x-ray powder diffraction peaks of which are the following: 2Θ (±0.2 °2Θ): 6.94; 7.75; 18.99.

The object of the invention also relates to a method for the production of the pimavanserin besylate, cyclamate, tosylate, benzoate and mandelate salts, as well as of their amorphous and crystalline forms, their hydrates and solvates, in such a way that the pimavanserin base is reacted with an inorganic or organic acid in water, or in an organic solvent or in a mixture of an organic solvent and water, then the pimavanserin salt formed is isolated.

The object of the invention also relates to a pharmaceutical preparation that contains a pimavanserin salt according to the above. The object of the invention also relates to the use of a pimavanserin salt according to the above in the treatment or prevention of any of the following neurodegenerative diseases: Parkinson's disease, including the treatment of hallucinations and delusions associated with the psychosis occurring in Parkinson's disease, Huntington's disease, Alzheimer's disease, Spinocerebellar atrophy, Tourette syndrome, Friedreich's ataxia, Machado-Joseph disease, Lewy body dementia, dystonia, progressive supranuclear palsy and frontotemporal dementia.

Detailed description of the invention We repeated the methods disclosed in international patent application number WO 2008144326 for the production of the homogenous crystalline "Form Y" of the pimavanserin base. The base produced in this way has a high degree of purity and on the basis of the x-ray powder diffraction measurement results it corresponds to the homogenous "Form Y" crystalline pimavanserin base according to the application.

We repeated the methods disclosed in international patent application number WO 2008144326 for the production of the homogenous "Form C" pimavanserin hemitartrate salt (2: 1). Proceeding according to example 38, the hemitartrate salt obtained was not the homogenous crystalline "Form C", therefore the salt was suspended in methyl ethyl ketone (MEK) according to that described in example 44. The salt produced in this way has a high degree of purity and on the basis of the x- ray powder diffraction measurement results it corresponds to the homogenous "Form C" crystalline pimavanserin hemitartrate salt according to the application.

When examining our novel salts the "Form Y" crystalline pimavanserin base and the "Form C" crystalline hemitartrate salt characterised in international patent application number WO 2008144326 were viewed as references. The compounds used as references are samples with high chemical purity and have a well-characterised composition, and their x-ray powder diffraction data agree with the data appearing in international patent application number WO 2008144326. The following salts were also produced during our salt-formation experiments: pimavanserin ascorbinate, lactate, hydrochloride and acetate. However, these were not found to be suitable from the point of view of production of medicines. Following this it was especially surprising that the pimavanserin besylate salt (1 : 1) "Form I", the pimavanserin cyclamate salt (1 : 1) monohydrate, the pimavanserin tosylate salt (1 : 1) "Form I", the pimavanserin tosylate salt (1: 1) monohydrate, the pimavanserin benzoate salt (1: 1) monohydrate, the pimavanserin D-(-)-mandelate salt (1: 1) "Form Γ' and the pimavanserin L-(+)-mandelate salt (1: 1) "Form I" according to the object of the invention are polymorphic ally and chemically stable, and may be produced in a reproducible and upscalable way.

The x-ray powder diffraction data given in the present application were obtained under the following measuring conditions:

Device: PANalytical Empyrean x-ray powder diffractometer

Measurement alignment: Transmission

X-ray tube

Type: Empyrean long fine focussing, high resolution tube

Anode: Cu

Wavelength: Ka (1.541874 A)

Focus: line focus

Source-side optical elements

Divergence slit: Fixed slit 1/2 °

Mirror: Focussing elliptical mirror

Soller slit: 0.04 rad

Diffusion inhibitor slit: Fixed slit 1/2 °

Diffracted side optical elements

Diffusion inhibitor slit: Programmable slit in fixed mode:

Soller slit: 0.04 rad Sample table

Type: Reflection-transmission, with rotatable sample holders

Sample rotation speed: 1 rotation/second

Direct beam catcher

("beam knife"): Transmission Detector

Type: PIXcel 3D 1 x 1 area detector

Operation mode: Scanning line detector (ID) operation mode

Active detector window

size: 3.3473°

Sample preparation: samples placed between two Mylar sheets, without pulverising Measurement conditions

Temperature: room temperature

Accelerating voltage: 45 kV

Anode heating current: 40 mA

Scanning method: continuous (Θ/Θ) scanning

Measurement range: 2.0000 - 34.9964° 2Θ

Step gap: 0.0131° 2Θ

Step duration: 109.650 seconds

No of measurement cycles: 1

Measurement duration: -20 minutes The new salt forms were also studied using thermoanalytical methods (TGA: thermogravimentric analysis and DSC: differential scanning calorimetry). On the basis of the TGA thermograms the amounts of the volatile components emitted from the materials due to the effect of heat were determined, which, in the case of hydrates, may be associated with the crystalline water content of the form. DSC may be suitable for the precise determination of the melting point of the substances (as long as the substances have a well defined melting point). The thermoanalytical testing of the samples was performed under the following measurement conditions (the end temperatures associated with the measurements were determined by the thermal properties of the currently tested sample):

The measurement conditions of the thermogravimetric analysis (TGA) were the following:

Device: TA Instruments Discovery TGA

thermogravimetric analyser Atmosphere: flowing N₂: 25 mL/min (furnace)

10 mL/min (balance)

Sampling frequency: 0.5 seconds/point

30 °C - end

Temperature program: 10 °C/min

temperature

Crucible: Platinum 100

The measurement conditions of the differential scanning calorimetry (DSC) were the following:

Device: TA Instruments Discovery DSC

differential scanning calorimeter

Atmosphere: flowing N₂ (50 mL/min)

Sampling frequency: 0.1 seconds/point

30 °C - end

Temperature program: 10 °C/min

temperature

Crucible: Standard Al sealed The propensity for the substance to take on water, its hygroscopicity, may have great significance from the point of view of pharmaceutical development. The hygroscopicity may influence formulatability, stability and the constancy of the composition of the preparation as well.

The hygroscopicity was examined with a DVS device, by recording the water sorption isotherms, under the following measurement conditions:

SMS DVS Advantage DVSA1-STD dynamic vapour sorption

Device:

analyser Atmosphere: nitrogen

Carrier gas flow rate: 200 mL/min

Solvent: water

Temperature: 25 °C

regulation: Control without feedback ("Open Loop")

Step size: 5% RH

Stability criterion: 0.002%/min

Stabilisation time base: 5 min

Operation mode: DMDT Minimum stabilisation time: 30 min

Maximum duration of one

360 min step:

Data saving frequency: 1 min

Measurement range: 0% RH→ 95% RH

The figures in the application are the following:

Figure 1: The x-ray powder diffractogram of the pimavanserin besylate salt (1: 1) "Form I" Figure 2: The water sorption isotherm of the pimavanserin besylate salt (1: 1) "Form I" at 25 °C Figure 3: The x-ray powder diffractogram of the pimavanserin cyclamate salt (1: 1) monohydrate Figure 4: The water sorption isotherm of the pimavanserin cyclamate salt (1: 1) monohydrate at 25 °C

Figure 5: The x-ray powder diffractogram of the pimavanserin tosylate salt (1: 1) "Form I" Figure 6: The water sorption isotherm of the pimavanserin tosylate salt (1: 1) "Form I" at 25 °C Figure 7: The x-ray powder diffractogram of the pimavanserin tosylate salt (1: 1) monohydrate Figure 8: The water sorption isotherm of the pimavanserin tosylate salt (1: 1) monohydrate at 25 °C

Figure 9: The x-ray powder diffractogram of the pimavanserin benzoate salt (1: 1) monohydrate Figure 10: The water sorption isotherm of the pimavanserin benzoate salt (1: 1) monohydrate at 25 Figure 11: The x-ray powder diffractogram of the pimavanserin D-(-)-mandelate salt (1: 1) "Form I" (The x-ray powder diffractogram of the pimavanserin L-(+)-mandelate salt (1: 1) "Form I" is identical to this)

Figure 12: The water sorption isotherm of the pimavanserin D-(-)-mandelate salt (1: 1) "Form I" at 25 °C (The water sorption isotherm of the pimavanserin L-(+)-mandelate salt (1: 1) "Form I" at 25 °C is identical to this.)

Figure 13: The water sorption isotherm of the pimavanserin tartrate salt (2: 1) "Form C" at 25 °C Figure 14: Comparison of the water sorption isotherms of the pimavanserin besylate salt (1: 1) "Form I" and the pimavanserin tartrate salt (2: 1) "Form C" (25 °C)

Figure 15: Comparison of the water sorption isotherms of the pimavanserin cyclamate salt (1: 1) monohydrate and the pimavanserin tartrate salt (2: 1) "Form C" (25 °C)

Figure 16: Comparison of the water sorption isotherms of the pimavanserin tosylate salt (1: 1) "Form I" and the pimavanserin tartrate salt (2: 1) "Form C" (25 °C)

Figure 17: Comparison of the water sorption isotherms of the pimavanserin tosylate salt (1: 1) monohydrate and the pimavanserin tartrate salt (2: 1) "Form C" (25 °C): In the interest of better depicting hygroscopicity, the mass measured at 25% RH was viewed as the initial value.

Figure 18: Comparison of the water sorption isotherms of the pimavanserin benzoate salt (1: 1) monohydrate and the pimavanserin tartrate salt (2: 1) "Form C" (25 °C)

Figure 19: Comparison of the water sorption isotherms of the pimavanserin D-(-)-mandelate salt (1: 1) "Form I" and the pimavanserin tartrate salt (2: 1) "Form C" (25 °C) (The water sorption isotherm of the pimavanserin L-(+)-mandelate salt (1: 1) "Form I" at 25 °C is identical to that of the D-(-)-mandelate salt.)

In the x-ray powder diffracto grams shown in figures 1, 3, 5, 7, 9 and 11 the measured intensity can be seen (in counts per second (cps)) as a function of the 2 theta (°) angle value.

The equilibrium moisture content of the individual samples can be seen on the sorption curves in figures 2, 4, 6, 8, 10 and 12 to 19 as a function of relative humidity.

The object of the invention is the crystalline pimavanserin besylate salt (1: 1) "Form I", the characteristic x-ray powder diffractogram of which can be seen in figure 1, and the 1% or greater intensity signals are summarised in table 1. The characteristic x-ray powder diffractogram peaks of the pimavanserin besylate salt (1: 1) "Form I" are the following: 2Θ (±0.2 °2Θ): 4.06; 8.14; 13.78; 16.44; 18.19; 21.86; 26.58, and the even more characteristic x-ray powder diffraction peaks are the following: 2Θ (±0.2 °2Θ): 4.06; 16.44; 18.19; 21.86. Table 1

The positions of the x-ray powder diffraction peaks characteristic of the formula 2 pimavanserin besylate salt (1: 1) "Form I" and relative intensities (> 1%)

Relative intensity

Peak 2Θ (°) d (A)

(%)

1 4.06 21.75 53

2 8.14 10.87 5

3 10.70 8.27 2

4 12.22 7.24 2

5 13.15 6.73 2

6 13.31 6.65 8

7 13.78 6.43 7

8 14.52 6.10 8

9 14.65 6.05 2

10 14.74 6.01 1

11 15.50 5.72 4

12 15.67 5.65 1

13 16.06 5.52 6

14 16.44 5.39 69

15 16.68 5.31 17

16 16.94 5.23 18

17 17.83 4.97 13

18 18.00 4.93 17

19 18.19 4.88 46

20 18.37 4.83 10

21 18.60 4.77 19 Relative intensity

Peak 2Θ (°) d (A)

(%)

22 18.76 4.73 29

23 19.46 4.56 2

24 19.82 4.48 4

25 20.45 4.34 2

26 21.03 4.23 8

27 21.12 4.21 9

28 21.52 4.13 16

29 21.86 4.07 100

30 22.34 3.98 16

31 22.67 3.92 5

32 23.00 3.87 4

33 23.25 3.83 4

34 23.50 3.79 2

35 23.82 3.74 8

36 24.19 3.68 2

37 24.48 3.64 6

38 24.78 3.59 1

39 25.11 3.55 1

40 25.59 3.48 3

41 25.64 3.47 1

42 25.85 3.45 6

43 25.94 3.44 4

44 26.12 3.41 1

45 26.39 3.38 5

46 26.58 3.35 21 Relative intensity

Peak 2Θ (°) d (A)

(%)

47 26.82 3.32 5

48 27.15 3.28 1

49 27.24 3.27 1

50 27.88 3.20 10

51 28.14 3.17 6

52 28.49 3.13 3

53 28.84 3.10 3

54 29.35 3.04 2

55 29.57 3.02 1

56 29.82 3.00 2

57 30.01 2.98 2

58 30.25 2.96 1

59 30.49 2.93 1

60 31.30 2.86 2

61 31.99 2.80 1

62 32.20 2.78 3

63 32.54 2.75 2

64 32.73 2.74 1

65 33.01 2.71 1

66 33.92 2.64 1

67 34.17 2.62 1

68 34.45 2.60 4

The water sorption isotherm of the pimavanserin besylate salt (1:1) "Form I" at 25 °C is shown in figure 2. It is clearly visible that the substance does not display hygroscopicity. The maximum water sorption in the 0-95% RH range is under 0.04%, therefore, taking measurement uncertainty into consideration, it cannot be demonstrated in practice.

The object of the invention is the crystalline pimavanserin cyclamate salt (1: 1) monohydrate, the characteristic x-ray powder diffractogram of which can be seen in figure 3, and the 1% or greater intensity signals are summarised in table 2. The characteristic x-ray powder diffractogram peaks of the pimavanserin cyclamate salt (1: 1) monohydrate are the following: 2Θ (±0.2 °2Θ): 3.95; 7.90; 13.82; 17.39; 18.73; 20.13; 20.85; 23.06; 25.82, and the even more characteristic x-ray powder diffraction peaks are the following: 2Θ (±0.2 °2Θ): 3.95; 7.90; 17.39; 18.73; 20.85.

Table 2

The positions of the x-ray powder diffraction peaks characteristic of the formula 3 pimavanserin cyclamate salt (1: 1) monohydrate and relative intensities (> 1%)

Relative intensity

Peak 2Θ (°) d (A)

( )

1 3.95 22.40 84

2 7.90 11.19 9

3 9.52 9.29 2

4 10.57 8.37 1

5 11.09 7.98 2

6 11.74 7.54 2

7 12.86 6.88 7

8 13.03 6.79 21

9 13.53 6.55 8

10 13.82 6.41 21

11 14.72 6.02 6

12 15.02 5.90 9

13 15.11 5.86 12

14 15.49 5.72 3 Relative intensity

Peak 2Θ (°) d (A)

(%)

15 15.68 5.65 4

16 15.85 5.59 3

17 16.34 5.42 13

18 17.39 5.10 76

19 17.71 5.01 5

20 17.84 4.97 11

21 18.73 4.74 100

22 19.13 4.64 27

23 19.74 4.50 8

24 19.86 4.47 15

25 20.13 4.41 78

26 20.85 4.26 93

27 21.05 4.22 6

28 21.80 4.08 37

29 22.26 3.99 9

30 22.57 3.94 2

31 23.06 3.86 32

32 23.61 3.77 6

33 23.84 3.73 18

34 24.26 3.67 20

35 24.74 3.60 2

36 24.95 3.57 18

37 25.82 3.45 69

38 26.24 3.40 2

39 26.47 3.37 7 Relative intensity

Peak 2Θ (°) d (A)

(%)

40 27.27 3.27 4

41 27.55 3.24 2

42 27.86 3.20 6

43 28.06 3.18 2

44 28.87 3.09 2

45 29.08 3.07 4

46 29.29 3.05 6

47 29.76 3.00 8

48 29.97 2.98 4

49 30.51 2.93 7

50 30.96 2.89 5

51 31.32 2.86 1

52 31.65 2.83 5

53 32.10 2.79 5

54 32.52 2.75 1

55 32.98 2.72 1

56 33.27 2.69 1

57 33.72 2.66 3

58 34.43 2.60 1

During the thermogravimetric (TG) testing of the pimavanserin cyclamate salt (1: 1) monohydrate a 2.8% mass loss was determined up to a temperature of 140 °C, which corresponds well to the theoretical drop in mass (2.9%) associated with the loss of moisture of the monohydrate, which also confirms the presumed monohydrate structure.

The water sorption isotherm of the pimavanserin cyclamate salt (1:1) monohydrate at 25 °C is shown in figure 4. It is clearly visible that the substance does not display hygroscopicity. The maximum water sorption in the 0-95% RH range is around 0.3%, therefore, exceptionally low. The results also show that even in extreme dry conditions the substance only slightly gives up its crystal water at a temperature of 25 °C: the change in mass is around 0.2%, and the theoretical drop in mass associated with the loss of water of the monohydrate would be 2.9%.

The object of the invention is the crystalline pimavanserin tosylate salt (1: 1) "Form I", the characteristic x-ray powder diffractogram of which can be seen in figure 5, and the 1% or greater intensity signals are summarised in the following table 3. The characteristic x-ray powder diffractogram peaks of the pimavanserin tosylate salt (1:1) "Form I" are the following: 2Θ (±0.2 °2Θ): 4.00; 8.02; 13.71; 16.43; 18.15; 21.76; 22.23; 25.84, and the even more characteristic x-ray powder diffraction peaks are the following: 2Θ (±0.2 °2Θ): 4.00; 8.02; 16.43; 21.76.

Table 3

The positions of the x-ray powder diffraction peaks characteristic of the formula 4 pimavanserin tosylate salt (1: 1) "Form I" and relative intensities (> 1%)

Relative intensity

Peak 2Θ (°) d (A)

( )

1 4.00 22.07 69

2 8.02 11.03 7

3 12.04 7.35 1

4 13.09 6.76 4

5 13.22 6.70 7

6 13.71 6.46 12

7 14.42 6.14 6

8 14.53 6.09 7

9 15.39 5.76 6

10 15.99 5.54 2

11 16.43 5.40 100

12 16.61 5.34 7

13 16.92 5.24 11 Relative intensity

Peak 2Θ (°) d (A)

(%)

14 17.83 4.98 37

15 18.15 4.89 39

16 18.30 4.85 12

17 18.48 4.80 18

18 18.71 4.74 32

19 19.25 4.61 3

20 19.45 4.56 2

21 19.66 4.52 7

22 20.15 4.41 3

23 20.81 4.27 7

24 21.05 4.22 16

25 21.46 4.14 22

26 21.76 4.08 96

27 22.23 4.00 34

28 22.59 3.94 2

29 22.87 3.89 11

30 23.07 3.86 7

31 23.39 3.80 6

32 23.67 3.76 7

33 24.12 3.69 3

34 24.34 3.66 7

35 24.61 3.62 4

36 25.09 3.55 3

37 25.44 3.50 2

38 25.84 3.45 16 Relative intensity

Peak 2Θ (°) d (A)

(%)

39 26.00 3.43 6

40 26.38 3.38 16

41 26.49 3.37 17

42 26.63 3.35 6

43 26.90 3.31 2

44 27.03 3.30 3

45 27.62 3.23 10

46 27.95 3.19 4

47 28.18 3.17 4

48 28.32 3.15 5

49 28.52 3.13 1

50 28.78 3.10 1

51 29.11 3.07 4

52 29.32 3.05 5

53 29.54 3.02 1

54 29.67 3.01 1

55 29.91 2.99 1

56 30.16 2.96 1

57 31.06 2.88 1

58 31.33 2.86 2

59 31.86 2.81 1

60 32.12 2.79 6

61 32.55 2.75 3

62 32.95 2.72 1

63 33.22 2.70 1 Relative intensity

Peak 2Θ (°) d (A)

(%)

64 33.48 2.68 1

65 33.65 2.66 1

66 33.91 2.64 2

67 34.16 2.62 2

68 34.29 2.62 4

69 34.77 2.58 3

The water sorption isotherm of the pimavanserin tosylate salt (1: 1) "Form I" at 25 °C is shown in figure 6. It is clearly visible that the substance does not display hygroscopicity. The maximum water sorption in the 0-95% RH range is under 0.025%, therefore, taking measurement uncertainty into consideration, it cannot be demonstrated in practice.

The object of the invention is the crystalline pimavanserin tosylate salt (1: 1) monohydrate, the characteristic x-ray powder diffractogram of which can be seen in figure 7, and the 1% or greater intensity signals are summarised in table 4. The characteristic x-ray powder diffractogram peaks of the pimavanserin tosylate salt (1: 1) monohydrate are the following: 2Θ (±0.2 °2Θ): 4.25; 8.51; 13.39; 14.59; 16.58; 17.65; 20.42; 21.99; 24.24, and the even more characteristic x-ray powder diffraction peaks are the following: 2Θ (±0.2 °2Θ): 4.25; 8.51; 16.58; 17.65; 21.99.

Table 4

The positions of the x-ray powder diffraction peaks characteristic of the formula 5 pimavanserin tosylate salt (1: 1) monohydrate and relative intensities (> 1%)

Relative intensity

Peak 2Θ (°) d (A)

( )

1 4.25 20.78 100

2 8.51 10.39 17

3 9.30 9.51 1

4 10.67 8.29 2 Relative intensity

Peak 2Θ (°) d (A)

(%)

5 11.45 7.73 10

6 11.87 7.45 2

7 12.02 7.36 4

8 12.65 7.00 4

9 12.79 6.92 2

10 13.39 6.61 25

11 13.52 6.55 4

12 13.94 6.35 5

13 14.59 6.07 15

14 15.25 5.81 9

15 15.59 5.68 5

16 15.76 5.62 17

17 16.04 5.53 16

18 16.58 5.35 82

19 17.08 5.19 6

20 17.18 5.16 1

21 17.65 5.03 96

22 17.92 4.95 8

23 18.07 4.91 3

24 18.67 4.75 14

25 18.99 4.67 5

26 19.20 4.62 29

27 19.69 4.51 26

28 19.88 4.47 6

29 20.06 4.43 9 Relative intensity

Peak 2Θ (°) d (A)

(%)

30 20.42 4.35 37

31 20.55 4.32 15

32 20.94 4.24 20

33 21.38 4.16 7

34 21.46 4.14 5

35 21.99 4.04 54

36 22.84 3.89 5

37 23.02 3.86 11

38 23.15 3.84 20

39 23.80 3.74 4

40 23.91 3.72 6

41 24.24 3.67 38

42 24.45 3.64 18

43 24.60 3.62 9

44 25.05 3.55 8

45 25.33 3.52 14

46 25.50 3.49 3

47 25.65 3.47 6

48 25.73 3.46 4

49 25.92 3.44 1

50 26.35 3.38 5

51 26.57 3.35 3

52 26.78 3.33 3

53 27.24 3.27 17

54 27.47 3.25 9 Relative intensity

Peak 2Θ (°) d (A)

(%)

55 27.83 3.21 4

56 28.17 3.17 3

57 28.28 3.16 6

58 28.47 3.14 6

59 29.15 3.06 5

60 29.43 3.03 8

61 29.74 3.00 1

62 30.14 2.96 1

63 30.31 2.95 3

64 30.52 2.93 2

65 30.88 2.90 20

66 31.30 2.86 7

67 31.49 2.84 4

68 31.57 2.83 3

69 31.71 2.82 4

70 32.07 2.79 1

71 32.43 2.76 2

72 33.03 2.71 2

73 33.43 2.68 1

74 33.55 2.67 1

75 34.06 2.63 2

76 34.58 2.59 2

77 34.76 2.58 2

During the thermogravimetric (TG) testing of the pimavanserin tosylate salt (1: 1) monohydrate a 2.7% mass loss was determined up to a temperature of 120 °C, which corresponds well to the theoretical drop in mass (2.9%) associated with the loss of moisture of the monohydrate, which also confirms the presumed monohydrate structure.

The water sorption isotherm of the pimavanserin tosylate salt (1:1) monohydrate at 25 °C is shown in figure 8. It is clearly visible that the substance gives up its water of crystallization under dry conditions (under 10% RH), presumably completely (drop in mass is around 2.6%, which corresponds well to the value determined during TG testing). The substance is able to regain its crystal water as the ambient humidity content increases (in other words the process is reversible). The salt form does not display hygroscopicity in the 15-95% RH range: the maximum surplus water sorption (as compared to the crystal water) is just around 0.2%.

The object of the invention is the crystalline pimavanserin benzoate salt (1: 1) monohydrate, the characteristic x-ray powder diffractogram of which can be seen in figure 9, and the 1% or greater intensity signals are summarised in table 5. The characteristic x-ray powder diffractogram peaks of the pimavanserin benzoate salt (1: 1) monohydrate are the following: 2Θ (±0.2 °2Θ): 4.23; 8.46; 10.46; 14.41; 16.44; 17.96; 18.51; 22.22; 26.15, and the even more characteristic x-ray powder diffraction peaks are the following: 2Θ (±0.2 °2Θ): 4.23; 8.46; 10.46; 17.96; 22.22.

Table 5

The positions of the x-ray powder diffraction peaks characteristic of the formula 6 pimavanserin benzoate salt (1: 1) monohydrate and relative intensities (> 1%)

Relative intensity

Peak 2Θ (°) d (A)

(%)

1 4.23 20.91 100

2 8.46 10.45 13

3 10.46 8.46 27

4 11.64 7.60 5

5 11.78 7.51 2

6 12.70 6.97 3 Relative intensity

Peak 2Θ (°) d (A)

(%)

7 12.84 6.90 7

8 14.07 6.30 5

9 14.41 6.15 22

10 15.14 5.85 4

11 15.43 5.74 20

12 16.44 5.39 36

13 16.60 5.34 18

14 16.99 5.22 4

15 17.22 5.15 2

16 17.96 4.94 83

17 18.51 4.79 36

18 18.87 4.70 2

19 19.21 4.62 27

20 19.53 4.55 8

21 19.81 4.48 2

22 20.06 4.43 2

23 20.80 4.27 7

24 21.05 4.22 23

25 21.21 4.19 30

26 21.74 4.09 9

27 21.83 4.07 6

28 22.22 4.00 79

29 22.83 3.90 7

30 23.41 3.80 11

31 23.58 3.77 12 Relative intensity

Peak 2Θ (°) d (A)

(%)

32 23.72 3.75 4

33 23.95 3.72 6

34 24.40 3.65 3

35 25.14 3.54 2

36 25.29 3.52 3

37 25.64 3.47 7

38 25.86 3.45 1

39 26.15 3.41 24

40 26.49 3.37 15

41 26.72 3.34 5

42 27.15 3.28 11

43 27.45 3.25 20

44 27.93 3.20 2

45 28.09 3.18 2

46 28.24 3.16 2

47 28.74 3.11 15

48 29.07 3.07 1

49 29.20 3.06 1

50 29.95 2.98 3

51 30.08 2.97 4

52 30.18 2.96 3

53 30.43 2.94 1

54 30.52 2.93 1

55 30.80 2.90 10

56 31.05 2.88 3 Relative intensity

Peak 2Θ (°) d (A)

(%)

57 31.30 2.86 2

58 31.45 2.84 2

59 31.62 2.83 4

60 31.73 2.82 7

61 32.44 2.76 2

62 33.56 2.67 2

63 34.02 2.64 2

64 34.36 2.61 1

65 34.73 2.58 3

During the thermogravimetric (TG) testing of the pimavanserin benzoate salt (1: 1) monohydrate a 3.2% mass loss was determined up to a temperature of 120 °C, which corresponds to the theoretical drop in mass associated with the loss of moisture of the monohydrate, which also confirms the presumed monohydrate structure.

The water sorption isotherm of the pimavanserin benzoate salt (1:1) monohydrate at 25 °C is shown in figure 10. It is clearly visible that the substance does not display hygroscopicity. The maximum water sorption in the 0-95% RH range is under 0.04%, therefore, taking measurement uncertainty into consideration, it cannot be demonstrated in practice.

The object of the invention is the crystalline pimavanserin D-(-)-mandelate salt (1: 1) "Form I", and the pimavanserin L-(+)-mandelate salt (1: 1) "Form I". The x-ray powder diffractograms of the pimavanserin D-(-)- and L-(+)-mandelate salts (1: 1) "Form I" are identical, the x-ray powder diffraction peaks are equally characteristic of both forms. The characteristic x-ray powder diffractograms of the crystalline pimavanserin D-(-)- and L-(+)-mandelate salts (1: 1) "Form I" can be seen in in figure 11, and the 1% or greater intensity signals are summarised in table 6. The characteristic x-ray powder diffractogram peaks of the pimavanserin D-(-)- and L-(+)-mandelate salts (1:1) "Form I" are the following: 2Θ (±0.2 °2Θ): 6.94; 7.75; 17.82; 18.99; 20.73; 24.96, and the even more characteristic x-ray powder diffraction peaks are the following: 2Θ (±0.2 °2Θ): 6.94; 7.75; 18.99. Table 6

The positions of the x-ray powder diffraction peaks characteristic of the formula 7 pimavanserin

D-(-)-mandelate salt (1: 1) "Form I" and relative intensities (> 1%) The x-ray powder diffraction data characteristic of the formula 8 pimavanserin L-(+)-mandelate salt (1: 1) "Form I" are identical

Relative intensity

Peak 2Θ (°) d (A)

(%)

1 6.94 12.74 59

2 7.75 11.41 21

3 11.49 7.70 13

4 11.58 7.64 3

5 11.70 7.57 8

6 11.84 7.48 10

7 11.98 7.39 9

8 12.96 6.83 16

9 13.05 6.78 3

10 13.91 6.37 2

11 14.01 6.32 1

12 14.74 6.01 8

13 15.22 5.82 8

14 15.54 5.70 21

15 15.76 5.62 12

16 16.06 5.52 8

17 16.22 5.47 12

18 16.37 5.42 18

19 16.51 5.37 15

20 16.84 5.27 17 Relative intensity

Peak 2Θ (°) d (A)

(%)

21 17.03 5.21 13

22 17.18 5.16 19

23 17.82 4.98 52

24 18.99 4.67 100

25 19.35 4.59 13

26 19.51 4.55 6

27 19.89 4.46 21

28 20.06 4.43 8

29 20.27 4.38 20

30 20.35 4.37 27

31 20.52 4.33 33

32 20.73 4.28 54

33 21.71 4.09 4

34 21.97 4.05 5

35 22.63 3.93 17

36 23.04 3.86 9

37 23.23 3.83 12

38 23.54 3.78 33

39 24.10 3.69 26

40 24.69 3.61 1

41 24.96 3.57 41

42 25.50 3.49 3

43 25.65 3.47 6

44 25.99 3.43 4

45 26.13 3.41 10 Relative intensity

Peak 2Θ (°) d (A)

(%)

46 26.35 3.38 9

47 26.54 3.36 6

48 27.40 3.25 5

49 27.82 3.21 7

50 28.05 3.18 15

51 28.71 3.11 1

52 29.01 3.08 1

53 29.22 3.06 5

54 29.45 3.03 6

55 29.62 3.02 5

56 29.80 3.00 8

57 30.69 2.91 4

58 31.38 2.85 6

59 31.73 2.82 13

60 32.04 2.79 10

61 32.53 2.75 8

62 32.81 2.73 1

63 33.12 2.70 1

64 33.36 2.69 2

65 34.12 2.63 7

The water sorption isotherm of the pimavanserin D-(-)-mandelate salt (1: 1) "Form I" at 25 °C is shown in figure 12. The water sorption isotherm of the pimavanserin L-(+)-mandelate salt (1: 1) "Form I" at 25 °C is identical to this. It is clearly visible that the substance does not display hygroscopicity under 90% RH: maximum water sorption is 0.2%. However, above 90% RH it becomes strongly hygroscopic: water sorption at 95% RH is 21.2%, the substance deliquesces. The hygroscopicity of the salt forms according to our invention

The sorption characteristics of the novel pimavanserin salts presented in the invention were compared with the "Form C" pimavanserin hemitartrate salt (2: 1) disclosed in patent application number WO 2008144326 and given as the most stable form, its water sorption isotherm recorded at 25 °C is presented in figure 13.

It can be clearly seen in figure 13 that the pimavanserin tartrate salt (2: 1) "Form C" becomes highly hygroscopic in environments with a high humidity, above 90% relative humidity (RH). Of the novel salt forms according to our invention, this is only characteristic of the D-(-)- and L-(+)- mandelate salts shown in figure 19. According to the measurement results among the novel pimavanserin salt forms the besylate salt shown in figure 14 and the tosylate salt "Form I" shown in figure 16, as well as the benzoate monohydrate form shown in figure 18 have lower hygroscopicity throughout the entire tested range than the pimavanserin tartrate salt (2: 1) "Form C" crystalline form. In figure 19 it can be seen that the hygroscopicity of the pimavanserin D-(-)- and L-(+)-mandelate salts "Form I" is lower up to 90% RH. The D-(-)- and L-(+)-mandelate salts deliquesce in environments more humid than this. The pimavanserin cyclamate salt monohydrate visible in figure 15 gives up a part of its crystal water (-0.2%) under completely dry conditions, while the tosylate salt monohydrate shown in figure 17 is able to give up all of its crystal water (-2.6%), but in the 15-95% RH range these salt forms display a lower water sorption tendency than the originator's pimavanserin hemitartrate salt (2: 1) "Form C". The lower hygroscopicity experienced is preferable from the points of view of stability and preparation formulation as well. Overall then it can be said that in the humidity range of 15 to 85% RH, which is relevant from the point of view of the pharmaceutical industry environment (crystallization, grinding, formulation, storage), all of the seven examined salts display a preferably lower level of hygroscopicity than the reference "Form C" pimavanserin hemitartrate salt (2: 1). On the basis of the toxicological data in the literature it may be determined that the 14.8 mg of benzenesulphonic acid, the 16.1 mg of /?-toluenesulphonic acid, the 16.8 mg of cyclohexylsulphamic acid, the 11.4 mg of benzoic acid or 14.2 mg of D-(-)-, or L-(+)-mandelic acid to be consumed with the daily 40 mg pimavanserin dose is under the permitted daily amount, therefore there are no toxicity concerns in connection with the salts according to the present application.

The stability of the salt forms according to the invention

The forced stability test essentially provides a model of accelerated mode for the degradations taking place in the pharmaceutical preparation during storage. The results of this predict whether the novel pimavanserin salts according to the invention will be stable in pharmaceutical preparations. This preferable characteristic of the pimavanserin salts of the present invention is very important from the point of view of the formulation of the pharmaceutical preparation, its storage and the minimising of the damaging effects on the human body.

Forced stability tests were carried out on the pimavanserin cyclamate (1 : 1) monohydrate, pimavanserin tosylate (1 : 1) "Form I" and pimavanserin benzoate (1 : 1) monohydrate salt forms forming the object of the present invention. The references used were the crystalline "Form Y" pimavanserin base and the crystalline "Form C" hemitartrate salt (2: 1).

Method description of the forced stability tests

a. / Tests performed on solutions (0.5 mg/mL pimavanserin base or salt)

1./ Hydrolysis in water, 80 °C, 24 hours

2.1 Hydrolysis in 0.05 M hydrochloric acid, 80 °C, 24 hours

3.1 Hydrolysis in 0.05 M sodium hydroxide solution, 80 °C, 24 hours

A.I Oxidation in 5% hydrogen peroxide, room temperature, 24 hours

b. / Solid sample test (storage without packaging)

5. / Heat load in solid state, 100 °C, 24 hours

6. / Photostability test, according to ICH CPMP/ICH/279/95 (Q1B) (1.2 million Luxh, 200 Wh/m²)

The amounts of the main decomposition products were determined using a gradient UHPLC method, and the presumed structures using MS precise mass detecting. LC-MS measurement conditions: UHPLC system, YMC Triart C₁₈ column, 0.1 M ammonium- acetate / acetonitrile gradient method, assessment: at 225 nm. The measurement results are summarised in the following table 7. Table 7

The amounts of the main decomposition products formed during the forced stability tests performed on the pimavanserin base and salts, determined using a UHPLC-MS method

It was surprising to experience, and this is clearly shown in table 7, that on the basis of the amount of the main decomposition product the pimavanserin salts according to the present invention subjected to the forced stability test were shown to be more stable than or similarly stable to the "Form Y" pimavanserin base. Under numerous test conditions, especially under oxidative conditions, the pimavanserin cyclamate salt (1: 1) monohydrate and the pimavanserin tosylate salt (1: 1) "Form I" were shown to be significantly more stable than the "Form C" crystalline form of the pimavanserin hemitartrate salt (2: 1) is, which, according to patent application number WO 2008144326, is the most stable of the polymorphs of the hemitartrate salt.

Under oxidative conditions all four novel salts tested proved to be significantly more stable than the "Form Y" pimavanserin base (85% decomposition product), and the pimavanserin cyclamate (1: 1) monohydrate and the pimavanserin tosylate (1:1) "Form I" salts display an order of magnitude less decomposition as compared to the "Form C" crystalline form of the pimavanserin hemitartrate (2: 1) salt (0.2-0.3% vs. 3% decomposition product).

Under thermal stress conditions the pimavanserin besylate (1:1) "Form I", the pimavanserin cyclamate (1: 1) monohydrate and the pimavanserin tosylate (1: 1) "Form I" salts proved to be more stable than the "Form Y" pimavanserin base. In the case of these novel salts decomposition was practically not detected during the test.

All the four tested novel salts proved to be more stable on the effect of light irradiation as compared to the "Form Y" pimavanserin base, which suffered mild decomposition (0.88% decomposition product). It was surprising to find that the pimavanserin besylate (1: 1) "Form Γ', the pimavanserin cyclamate (1: 1) monohydrate and the pimavanserin tosylate (1: 1) "Form I" salts displayed less decomposition than the mildly decomposing "Form C" crystalline form of pimavanserin hemitartrate (2: 1).

During water hydrolysis, considering all contaminants together, the pimavanserin cyclamate (1: 1) monohydrate, the pimavanserin tosylate (1: 1) "Form I" and the pimavanserin benzoate (1: 1) monohydrate salts displayed a lower degree of decomposition as compared to both reference compounds.

When testing acidic and alkaline hydrolysis, considering all contaminants together, the pimavanserin cyclamate (1: 1) monohydrate, the pimavanserin tosylate (1: 1) "Form I" and the pimavanserin benzoate (1: 1) monohydrate salts proved to be significantly more stable than the "Form C" crystalline form of the pimavanserin hemitartrate (2: 1) salt, and proved to be slightly more stable than the "Form Y" pimavanserin base. The object of the invention also relates to a pharmaceutical preparation containing a therapeutically effective amount of any of the pimavanserin salts according to the invention and, optionally, one or more excipients used in the production of medical preparations, furthermore, a method for the production of a pharmaceutical preparation, in such a way that any pimavanserin salt according to the invention or a mixture of these is mixed with an appropriate amount of pharmaceutically acceptable carrier, solid or liquid diluents and, optionally, other excipients, and the mixture is then placed in a galenic formulation.

The novel salts of pimavanserin according to the present invention are produced by reacting the amorphous, or crystalline, anhydrous, hydrate or solvate form of the pimavanserin base with the desired organic or inorganic acid in water, or in a suitable organic solvent, or solvent mixture, then the salt formed is isolated.

The reaction may be performed in water, or organic solvents, such as in 1-6 carbon atom aliphatic alcohols, in 1-5 carbon atom straight chain or cyclic ethers, in 1-6 carbon atom esters, in open chain asymmetric or symmetric ketones, and in dipolar aprotic solvents, in addition mixtures of the listed solvents, and mixtures and blends of the listed solvents also containing water may be used.

In order to carry out the reaction 1-4 carbon atom ether, ester or alcohol, an open chain ketone or a dipolar aprotic solvent may be preferably used, diisopropyl ether, ethyl acetate, acetonitrile, methanol, 2-propanol or a mixture of these, and mixtures and blends of the listed solvents also containing water may be especially preferably used.

An amount of 0.9-2.0 mol equivalents, preferably an amount of 1.0-1.2 mol equivalents of the acid serving for forming the salt calculated for the amount of pimavanserin is used.

Preferably, the process involves that the organic acid is used as a solution, suspension or in solid form, and the salt formation reaction is carried out at a temperature between 0 °C and the boiling point of the solvent or at the boiling point of the solvent. Any method used in the pharmaceutical industry may be used for isolating the salt that serves for separating the solid phase and the liquid phase, for example, it may be filtered under atmospheric conditions, or by using vacuum filtering, or even under pressure, and a centrifuge may even be used. If the salt precipitates at the temperature of addition of the acid or when cooled, after the required crystallization time, the product is filtered, washed and dried. If the salt does not precipitate, the solvent is evaporated in a vacuum, and the residue material is crystallized by adding a suitable solvent or solvent mixture, then finally the crystalline material is filtered, washed and dried.

The new salts according to the invention may be recrystallized in order to achieve the appropriate pharmaceutical active substance quality. The recrystallization is performed by dissolving the product obtained according to the above in a polar aprotic solvent, or in a mixture of a polar aprotic solvent and an alcohol with 1 to 6 carbon atoms, preferably the dissolving is performed in ethyl acetate, acetonitrile or in a mixture of acetonitrile and methanol at boiling point, then by cooling the solution the desired salt is precipitated, or it is crystalized by adding an ether-type solvent, preferably diisopropyl ether.

The novel salts of pimavanserin according to the present invention are produced by dissolving or suspending the pimavanserin base in a polar aprotic, straight carbon chain alcohol, nitrile or ester- type solvent, preferably in acetonitrile, 2-propanol or ethyl acetate at a temperature between 0 °C and the boiling point of the solvent, preferably at 20 to 50 °C, then 0.9-1.5 mol equivalents, preferably 1.0-1.2 mol equivalents, most preferably 1.0 mol equivalent of inorganic or organic acid calculated for the amount of pimavanserin base is added on its own or in the form of a solution or suspension,

- benzene sulphonic acid in the case of the production of the pimavanserin besylate ( 1 : 1 ) salt "Form I",

- cyclohexyl sulphamic acid in the case of the production of the pimavanserin cyclamate (1: 1) salt monohydrate form,

- /?-toluenesulphonic acid in the case of the production of the pimavanserin tosylate (1: 1) salt "Form I" and its monohydrate form,

- benzoic acid in the case of the production of the pimavanserin benzoate (1: 1) salt monohydrate form, - and D-(-)- or L-(+)-mandelic acid in the case of the production of the pimavanserin D-(-)- and L-(+)-mandelate salts (1: 1) "Form I", while stirring. The reaction mixture is stirred for 1 to 24 hours, preferably for 2 to 4 hours at a temperature between 0 °C and the boiling point of the solvent, preferably at a temperature between 20 and 50 °C. In the case of the monohydrate forms the water required for the formation of the salt is provided in the reagents, the solvents or as added water, or it is provided by the humidity in the air. If the salt precipitates at the temperature of addition of the acid or when cooled, after the required crystallization time, the product is filtered, washed and dried. If the salt does not precipitate, the solvent is evaporated in a vacuum, and the residue material is crystallized by adding a suitable solvent or solvent mixture, then finally the crystalline material is filtered, washed and dried at an appropriate temperature.

The advantage of the pimavanserin salts according to the invention is that they are high-purity substances with a homogenous morphology, a homogenous and preferable crystalline structure and have preferable and reproducible characteristics from the point of view of dissolution rate, bioavailability and processing - filtering, drying and tableting.

A further advantage of the pimavanserin salts according to the invention is that their polymorphic and chemical stability, and their physical-chemical characteristics are more preferable than those of the known forms, furthermore their production is reproducible and they may be produced on the industrial scale.

The pimavanserin salts according to the invention are especially preferable from the point of view of that they are more stable under the majority of conditions than the Y crystalline form of the pimavanserin base of the previously produced pimavanserin forms and the most stable "Form C" crystalline form of the pimavanserin hemitartrate (2: 1) salt.

The pimavanserin salts according to the invention are also especially preferable from the point of view of that they are less hygroscopic than the a pimavanserin hemitartrate salt (2: 1) "Form C" form in the humidity range of 15-85% RH relevant from the point of view of the pharmaceutical industry environment (crystallization, grinding, formulation, storage).

The invention is illustrated through the following examples without limiting the invention to these examples. Example 1

The production of formula 2 l-(4-fluorobenzyl)-l-(l-methylpiperidin-4-yl)-3-[4-(2- methylpropoxy)benzyl]carbamide benzenesulfonate salt (1:1) (pimavanserin besylate) "Form I"

10.0 g (23.40 mmol) of pimavanserin is dissolved in 200 ml of ethyl acetate at 40-42 °C, then while stirring a solution of 3.71 g (23.40 mmol; 1.0 equiv.) of benzenesulphonic acid prepared in 40 ml of ethyl acetate is added to it drop by drop at 40-42 °C. The reaction mixture is stirred for 1 hour at 40-42 °C, then it is left to cool to room temperature and then stirred for 4 hours, then cooled to 10-12 °C. The precipitated solid material is filtered, washed on the filter with ethyl acetate, then dried for 4 hours in a drying cabinet at 40-42 °C and at a pressure of 15-20 mbar. In this way 13.46 g (98.2%) of a white solid product is obtained. 10 g of the raw product besylate salt is dissolved in 180 ml of acetonitrile at boiling point, then the solution is filtered and left to cool to room temperature, and then stirred for 2 hours and then cooled to 10-12 °C. The precipitated solid material is filtered, then dried for 4 hours in a drying cabinet at 40-42 °C at a pressure of 15-20 mbar. In this way 9.16 g of a white solid product is obtained.

Mp.: 218 °C (onset).

IR (cm^"1, KBr): 3373; 3012; 2958; 2874; 2696; 1640; 1536; 1511; 1234; 1162; 615

*H NMR (DMSO-ifc, 600 MHz): 9.14 (br, 1H); 7.62 (m, 2H); 7.33 (m, 3H); 7.24 (dd, Jl=8.7 Hz, J2=5.6 Hz, 2H); 7.14 (t, J1=J2=8.7 Hz, 2H); 7.11 (d, J=8.7 Hz, 2H); 7.01 (br t, J1=J2=5.8 Hz, 1H); 6.84 (d, J=8.7 Hz, 2H); 4.40 (br s, 2H); 4.19 (br d, J=5.8 Hz, 2H); 4.19 (m, 1H); 3.70 (d, J=6.6 Hz, 2H); 3.36 (br, 2H); 2.99 (br m, 2H); 2.71 (br s, 3H); 1.99 (m, 1H); 1.84 (br m,2H); 1.66 (br m, 2H); 0.97 (d, J=6.7 Hz, 6H).

¹³C NMR (DMSO-ifc, 150 MHz): 161.21 (d, J=242 Hz); 157.68; 157.52; 148.19; 136.44 (br d, J~2 Hz); 133.00; 128.80; 128.52 (d, J=8.1 Hz); 128.43; 127.94; 125.57; 115.16 (d, J=21.2 Hz); 114.26; 73.92; 53.40 (br); 49,99 (br); 44.65 (br); 43.29 (br); 42.69 (br); 27.91; 27.42 (br); 19.28.

Element analysis calculated for the formula C3iH₄oFN₃05S (M=585.74):

C 63.57%; H 6.88%; N 7.17%; S 5.47%

Measured: C 63.46%; H 6.95%; N 7.17%; S 5.43%. Example 2

The production of the formula 3 l-(4-fluorobenzyl)-l-(l-methylpiperidin-4-yl)-3-[4-(2- methylpropoxy)benzyl]carbamide cyclohexyl sulphamate salt (1:1) (pimavanserin cyclamate) monohydrate 10.0 g (23.40 mmol) of pimavanserin is dissolved in 200 ml of ethyl acetate (0.3% water) at 40- 42 °C, then while stirring a suspension of 4.19 g (23.40 mmol; 1.0 equiv.) of cyclohexyl sulphamic acid made in 40 ml of ethyl acetate is added to it at 40-42 °C. After combining the substances a clear solution is obtained. The reaction mixture is stirred for 1 hour at 40-42 °C, then it is left to cool to room temperature and then stirred for 4 hours and then cooled to 10- 12 °C. The precipitated solid material is filtered, washed on the filter with ethyl acetate, then dried for 4 hours in a drying cabinet at 40-42 °C at a pressure of 15-20 mbar. In this way 13.70 g (93.7%) of a white solid product is obtained.

The product is monohydrate.

IR (cm^"1, KBr): 3544; 3468; 3377; 3232; 2932; 2856; 2730; 1625; 1512; 1221; 1170; 1031 ^lH NMR (DMSO-ifc, 600 MHz): 7.25 (dd, Jl=8.7 Hz, J2=5.6 Hz, 2H); 7.14 (t, J1=J2=8.7 Hz, 2H); 7.10 (d, J=8.6 Hz, 2H); 6.98 (br t, J1=J2=5.8 Hz, 1H); 6.83 (d, J=8.6 Hz, 2H); 4.43 (br s, 2H); 4.20 (m, 1H); 4.19 (d, J=5.8 Hz, 2H); 3.70 (d, J=6.5 Hz, 2H); 3.31 (br m, 2H); 2.94 (br m, 2H); 2.89 (m, 1H); 2.67 (br s, 3H); 1.99 (m, 1H); 1.90 (br m, 4H); 1.64 (br m, 2H); 1.61 (m, 2H); 1.49 (m, 1H); 1.16 (m, 2H); 1.04 (br m, 3H); 0.97 (d, J=6.7 Hz, 6H).

¹³C NMR (DMSO-ifc, 150 MHz): 161.19 (d, J=242 Hz); 157.66; 157,56; 136.60 (br d, J-2.5 Hz); 133.04; 128.53 (d, J=8.2 Hz); 128,39; 115.10 (d, J=21.4 Hz); 114,25; 73.92; 53,40 (br); 52.39 (br); 50.08 (br); 44.49 (br); 43.28 (br); 42.81 (br); 33.70 (br); 27.92; 27.32 (br); 25.73; 24.96 (br); 19.28. Element analysis calculated for the formula C₃iH₄9FN₄06S (M=624.81):

C 59.59%; H 7.90%; N 8.97%; S 5.13%

Measured: C 59.64%; H 7.90%; N 8.93%; S 5.21%.

Water content on the basis of Karl Fischer titration: 2.9% (calculated value: 2.9%)

Example 3

The production of the formula 4 l-(4-fluorobenzyl)-l-(l-methylpiperidin-4-yl)-3-[4-(2- methylpropoxy)benzyl]carbamide /?-toluenesulphonate salt (1:1) (pimavanserin tosylate) "Form I"

10.0 g (23.40 mmol) of pimavanserin is dissolved in 200 ml of ethyl acetate at 40-42 °C, then while stirring a solution of 4.45 g (23.40 mmol; 1.0 equiv.) of p-toluenesulphonic acid monohydrate prepared in 40 ml of ethyl acetate is added to it drop by drop at 40-42 °C.

The reaction mixture is stirred for 1 hour at 40-42 °C, then it is left to cool to room temperature and then stirred for 4 hours, then cooled to 10-12 °C. The precipitated solid material is filtered, washed on the filter with ethyl acetate, then dried for 4 hours in a drying cabinet at 40-42 °C and at a pressure of 15-20 mbar. In this way 13.74 g (97.9%) of a white solid product is obtained. Mp.: 210 °C (onset).

IR (cm ¹, KBr): 3363; 2961; 2696; 1642; 1535; 1511; 1233; 1162; 1030; 1009; 812; 684

*H NMR (DMSO-ifc, 600 MHz): 9.12 (br, 1H); 7.49 (d, J=8.1 Hz, 2H); 7.24 (dd, Jl=8.7 Hz, J2=5.2 Hz, 2H); 7.14 (t, J1=J2=8.7 Hz, 2H); 7.12 (d, 2H); 7.11 (d, 2H); 7.00 (br t, J1=J2=5.6 Hz, 1H); 6.83 (d, J=8.6 Hz, 2H); 4.40 (br s, 2H); 4.19 (d, J=5.6 Hz, 2H); 4.19 (br m, 1H); 3.70 (d, J=6.5 Hz, 2H); 3.37 (br, 2H); 2.98 (br, 2H); 2.71 (br s, 3H); 2.29 (s, 3H); 1.99 (m, 1H); 1.83 (br m, 2H); 1.67 (br m, 2H); 0.97 (d, J=6.7 Hz, 6H).

¹³C NMR (DMSO-ifc, 150 MHz): 161.21 (d, J=242 Hz); 157.67; 157.51; 145.60; 138.03; 136.44 (br); 132.99; 128.51 (d, J=8.1 Hz); 128.42; 128.35; 125.68; 115.16 (d, J=21.3 Hz); 114.26; 73.92; 53.43 (br); 49.96 (br); 44.66 (br); 43.29 (br); 42.72(br); 27.91; 27.45 (br); 20.99; 19.26.

Element analysis calculated for the formula C32H₄2FN₃05S (M=599.76):

C 64.08%; H 7.06%; N 7.01%; S 5.35%

Measured: C 64.03%; H 7.08%; N 7.03%; S 5.31%. Example 4

The production of the formula 5 l-(4-fluorobenzyl)-l-(l-methylpiperidin-4-yl)-3-[4-(2- methylpropoxy)benzyl]carbamide ?-toluenesulphonate salt (1:1) (pimavanserin tosylate) monohydrate

10 g of the pimavanserin tosylate described in example 3 is dissolved in 90 ml of aqueous acetonitrile (5% water) at boiling point, then filtered, and the solvent is left to cool to room temperature, it is stirred for 2 hours and then cooled to 10-12 °C. The precipitated solid material is filtered, then dried for 4 hours in a drying cabinet at 40-42 °C and at a pressure of 15-20 mbar.

In this way 9.16 g (91.6%) of a white solid product is obtained.

IR (cm^"1, KBr): 3569; 3497; 3360; 3037; 2962; 2759; 1643; 1530; 1510; 1224; 1168

lH NMR (DMSO-ifc, 600 MHz): 9.09 (br, 1H); 7.48 (d, J=8.0 Hz, 2H); 7.24 (dd, Jl=8.8 Hz, J2=5.8

Hz, 2H); 7.15 (t, J1=J2=8.8 Hz, 2H); 7.12 (d, J=8.0 Hz, 2H); 7.10 (d, J=8.5 Hz, 2H); 7.00 (br t,

J1=J2=5.7 Hz, 1H); 6.83 (d, J=8.5 Hz, 2H); 4.40 (br s, 2H); 4.19 (br d, J=5.7 Hz, 2H); 4.19 (br m,

1H); 3.70 (d, J=6.6 Hz, 2H); 3.37 (br m, 2H); 2.97 (br m, 2H); 2.71 (br s, 3H); 2.29 (s, 3H); 1.99

(m, 1H); 1.82 (br m, 2H); 1.68 (br m, 2H); 0.97 (d, J=6.6 Hz, 6H).

1³C NMR (DMSO-ifc, 150 MHz): 161.22 (d, J=242 Hz); 157.68; 157.50; 145.72; 137.95; 136.41

(br); 132.98; 128.51 (d, J=8.1 Hz); 128.42; 128.32; 125.68; 115.25 (d, J=21.4 Hz); 114.26; 73.92;

53.44 (br); 49.97 (br); 44.71 (br); 43.28 (br); 42.70 (br); 27.91; 27.46 (br); 20.99; 19.28.

Element analysis calculated for the formula C₃₂H₄₄FN₃06S (M=617.78):

C 62.22%; H 7.18%; N 6.80%; S 5.19% Measured: C 62.30%; H 7.18%; N 6.69%; S 5.08%.

Water content on the basis of Karl Fischer titration: 2.9 % (calculated value: 2.9 %)

Example 5

The production of the formula 6 l-(4-fluorobenzyl)-l-(l-methylpiperidin-4-yl)-3-[4-(2- methylpropoxy)benzyl]carbamide benzoate salt (1:1) (pimavanserin benzoate) monohydrate

10.0 g (23.40 mmol) of pimavanserin is dissolved in 200 ml of ethyl acetate (0.3% water) at 40- 42 °C, then while stirring a solution made with 2.86 g (23.40 mmol; 1.0 equiv.) of benzoic acid in 40 ml of ethyl acetate is added to it at 40-42 °C. After addition of the acid a clear solution is obtained. The reaction mixture is stirred for 1 hour at 40-42 °C, then it is left to cool to room temperature. The reaction mixture is evaporated to 40 ml and 60 ml of diisopropyl ether is added to it, in this way the product precipitates, it is stirred for 4 hours at room temperature, then cooled to 10-12 °C. The precipitated solid material is filtered, washed with diisopropyl ether on the filter, then dried for 4 hours in a drying cabinet at 40-42 °C at a pressure of 15-20 mbar. In this way 9.6 g (72.3%) of a white solid product is obtained.

The product is monohydrate.

IR (cm^"1, KBr): 3511; 3310; 3048; 2963; 2679; 2504; 1644; 1625; 1531; 1510; 1241 ; 727 ^lH NMR (DMSO-ifc, 600 MHz): 7.95 (~d, 2H); 7.58 (~t, 1H); 7.47 (~t, 2H); 7.23 (dd, Jl=8.8 Hz, J2=5.7 Hz, 2H); 7.11 (d, J=8.6 Hz, 2H); 7.09 (t, J1=J2=8.8 Hz, 2H); 6.91 (br t, J1=J2=5.8 Hz, 1H); 6.84 (d, J=8.6 Hz, 2H); 4.41 (br s, 2H); 4.19 (br d,J=5.8 Hz, 2H); 3.97 (m, 1H); 3.70 (d, J=6.5 Hz, 2H); 2.83 (m, 2H); 2.20 (s, 3H); 2.07 (m, 2H); 1.99 (m, 1H); 1.63 (m, 2H); 1.46 (br m, 2H); 0.97 (d, J=6.7 Hz, 6H).

¹³C NMR (DMSO-ifc, 150 MHz): 168.14; 161.07 (d, J=242 Hz); 157.72; 157.64; 137.18 (d, J=2.8 Hz); 133.25; 132.59; 132.37; 129.42; 128.54 (d, J=8.1 Hz); 128.54; 128.35; 114.96 (d, J=21.2 Hz); 114.25; 73.92; 54.61; 52.04; 45.26; 44.14; 43.30; 29.51; 27.92; 19.28.

Element analysis calculated for the formula C32H₄2FN₃05 (M=567.702):

C 67.70%; H 7.46%; N 7.40%

Measured: C 67.73%; H 7.42%; N 7.44%.

Water content on the basis of Karl Fischer titration: 3.2 % (calculated value: 3.2%)

Example 6

The production of the formula 7 l-(4-fluorobenzyl)-l-(l-methylpiperidin-4-yl)-3-[4-(2- methylpropoxy)benzyl]carbamide D-(-)-mandelate salt (1:1) (pimavanserin D-(-)- mandelate) "Form I" 10.0 g (23.40 mmol) of pimavanserin is dissolved in 200 ml of ethyl acetate at 40-42 °C, then while stirring a solution of 3.71 g (23.40 mmol; 1.0 equiv.) of D-(-)-mandelic acid made in 40 ml of ethyl acetate is added to it drop by drop at 40-42 °C. The reaction mixture is stirred for 1 hour at 40-42 °C, then is left to cool to room temperature. The reaction mixture is evaporated to 40 ml and 10 ml of diisopropyl ether is added to it, in this way the product precipitates, it is stirred for 4 hours at room temperature, then cooled to 10-12 °C. The precipitated solid material is filtered, washed with diisopropyl ether on the filter, then dried for 4 hours in a drying cabinet at 40-42 °C at a pressure of 15-20 mbar. In this way 8.81 g (65.0%) of a white solid product is obtained. Mp.: 112 °C (onset).

IR (cm ¹, KBr): 3396; 3066; 2957; 1618; 1510; 1243; 1042

*H NMR (DMSO-ifc, 600 MHz): 7.40 (~d, 2H); 7.29 (~t, 2H); 7.22 (m, 1H); 7.21 (dd, Jl=8.8 Hz, J2=5.6 Hz, 2H); 7.11 (t, J1=J2=8.8 Hz, 2H); 7.10 (d, J=8.7 Hz, 2H); 6.92 (br t, J1=J2=5.7 Hz, 1H); 6.83 (d, J=8.7 Hz, 2H); 4.81 (s, 1H); 4.37 (d, J~16 Hz, 1H); 4.35 (d, J~16 Hz, 1H); 4.18 (br d, J=5.7 Hz, 2H); 4.04 (br m, 1H); 3.70 (d, J=6.5 Hz, 2H); 2.96 (m, 2H); 2.35 (m, 2H); 2.34 (s, 3H); 1.99 (m, 1H); 1.68 (m, 2H); 1.48 (m, 2H); 0.97 (d, J=6.7 Hz, 6H).

¹³C NMR (DMSO-ifc, 150 MHz): 174.96; 161.11 (d, J=242 Hz); 157.65; 142.07; 136.98 (d, J=2.2 Hz); 133.16; 128.53 (d, J=7.9 Hz); 128.36; 127.99; 127.13; 126.67; 115.01 (d, J=21.5 Hz); 114.25; 73.92; 73.12; 54.00 (br); 51.23 (br); 44.17 (br); 43.29 (br); 28.57 (br); 27.92; 19.29.

Element analysis calculated for the formula C33H₄2FN₃05 (M=579.713):

C 68.37%; H 7.30%; N 7.25%

Measured: C 68.00%; H 7.19%; N 7.14%.

Example 7

The production of the formula 8 l-(4-fluorobenzyl)-l-(l-methylpiperidin-4-yl)-3-[4-(2- methylpropoxy)benzyl]carbamide L-(+)-mandelate salt (1:1) (pimavanserin L-(+)- mandelate) "Form I"

10.0 g (23.40 mmol) of pimavanserin is dissolved in 200 ml of ethyl acetate at 40-42 °C, then while stirring a solution of 3.71 g (23.40 mmol; 1.0 equiv.) of L-(+)-mandelic acid made in 40 ml of ethyl acetate is added to it drop by drop at 40-42 °C. The reaction mixture is stirred for 1 hour at 40-42 °C, then is left to cool to room temperature. The reaction mixture is evaporated to 40 ml and 10 ml of diisopropyl ether is added to it, in this way the product precipitates, it is stirred for 4 hours at room temperature, then cooled to 10-12 °C. The precipitated solid material is filtered, washed with diisopropyl ether on the filter, then dried for 4 hours in a drying cabinet at 40-42 °C at a pressure of 15-20 mbar. In this way 8.81 g (65.0%) of a white solid product is obtained. Mp.: 112 °C (onset).

IR (cm^"1, KBr): 3397; 3066; 2957; 1618; 1510; 1243; 1042

*H NMR (DMSO-ifc, 600 MHz): 7.39 (~d, 2H); 7.29 (~t, 2H); 7.22 (m, IH); 7.21 (dd, Jl=8.7 Hz, J2=5.6 Hz, 2H); 7.11 (t, J1=J2=8.7 Hz, 2H); 7.10 (d, J=8.6 Hz, 2H); 6.92 (br t, J1=J2=5.8 Hz, IH); 6.83 (d, J=8.6 Hz, 2H); 4.81 (s, IH); 4.38 (d, J~16 Hz, IH); 4.35 (d, J~16Hz, IH); 4.18 (br d, J=5.8Hz, 2H); 4.03 (br m, IH); 3.70 (d, J=6.6Hz, 2H); 2.95 (m, 2H); 2.32 (m, 2H); 2.32 (s, 3H); 1.99 (m, IH); 1.67 (m, 2H); 1.48 (m, 2H); 0.97 (d, J=6.7 Hz, 6H).

¹³C NMR (DMSO-ifc, 150 MHz): 174.90; 161.10 (d, J=241 Hz); 157.64; 142.03; 137.00 (d, J=2.5 Hz); 133,16; 128,52 (d, J=8.2 Hz); 128.36; 127.99; 127.14; 126.67; 115.01 (d, J=21.1 Hz); 114.25; 73.92; 73.10; 54.06 (br); 51.30 (br); 44.27 (br); 44.17 (br); 43.29 (br); 28.67 (br); 27.91; 19.28. Element analysis calculated for the formula C33H₄2FN₃05 (M=579.713):

C 68.37%; H 7.30%; N 7.25%

Measured: C 68.31%; H 7.29%; N 7.24%.

Claims

Claims

1. Pimavanserin besylate, cyclamate, tosylate, benzoate and mandelate salts, as well as their amorphous and crystalline form, their hydrates and solvates.

2. The crystalline pimavanserin besylate salt (1 : 1) "Form I" according to claim 1 , the characteristic x-ray powder diffraction peaks of which are the following: 2Θ (±0.2 °2Θ): 4.06; 16.44; 18.19; 21.86.

3. The crystalline pimavanserin cyclamate salt (1 : 1) monohydrate according to claim 1, the characteristic x-ray powder diffraction peaks of which are the following: 2Θ (±0.2 °2Θ): 3.95; 7.90; 17.39; 18.73; 20.85.

4. The crystalline pimavanserin tosylate salt (1 : 1) "Form I" according to claim 1, the characteristic x-ray powder diffraction peaks of which are the following: 2Θ (±0.2 °2Θ): 4.00; 8.02; 16.43; 21.76.

5. The crystalline pimavanserin tosylate salt (1 : 1) monohydrate according to claim 1, the characteristic x-ray powder diffraction peaks of which are the following: 2Θ (±0.2 °2Θ): 4.25; 8.51 ; 16.58; 17.65; 21.99.

6. The crystalline pimavanserin benzoate salt (1 : 1) monohydrate according to claim 1, the characteristic x-ray powder diffraction peaks of which are the following: 2Θ (±0.2 °2Θ): 4.23; 8.46; 10.46; 17.96; 22.22.

7. The crystalline pimavanserin D-(-)-mandelate salt (1 : 1) "Form l" according to claim 1 , the characteristic x-ray powder diffraction peaks of which are the following: 2Θ (±0.2 °2Θ): 6.94; 7.75; 18.99.

8. The crystalline pimavanserin L-(+)-mandelate salt (1 : 1) "Form l" according to claim 1, the characteristic x-ray powder diffraction peaks of which are the following: 2Θ (±0.2 °2Θ): 6.94; 7.75;

18.99.

9. Method for the production of the pimavanserin salt according to any of claims 1 to 8, characterised by that the pimavanserin base is reacted with an inorganic or organic acid in water, or in an organic solvent or in a mixture of an organic solvent and water, then the pimavanserin salt formed is isolated.

10. Pharmaceutical preparation that contains a pimavanserin salt according to any of claims 1 to 8.

11. The use of a pimavanserin salt according to any of claims 1 to 8 in the treatment or prevention of the following neurodegenerative diseases: Parkinson's disease, including the treatment of hallucinations and delusions associated with the psychosis occurring in Parkinson's disease, Huntington's disease, Alzheimer's disease, Spinocerebellar atrophy, Tourette syndrome, Friedreich's ataxia, Machado-Joseph disease, Lewy body dementia, dystonia, progressive supranuclear palsy and frontotemporal dementia.