Hydrobromide salt of pridopidine

Abstract

This invention relates to a new salt of Pridopidine, a drug substance currently in development for the treatment of Huntington's disease. More specifically the invention provides the pharmaceutically acceptable hydrobromide salt, pharmaceutical compositions comprising this salt, and uses of this salt as a drug substance.

Claims

1. A hydrobromide salt of 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine (Pridopidine) having an X-ray powder diffraction pattern with reflections corresponding to the d-spacing values 6.0, 3.8, 3.6 and 4.0.

2. The hydrobromide salt of claim 1 provided in an anhydrous form which is in a substantially crystalline form.

3. A pharmaceutical composition comprising a therapeutically effective amount of the hydrobromide salt according to claim 1, together with one or more adjuvants, excipients, carriers and/or diluents.

4. The pharmaceutical composition of claim 3 wherein the therapeutically effective amount of 4-(3-methanesulfonyl-phenyl)-1-propyl-piperdine (Pridopidine) is from 1 mg to 500 mg.

5. The pharmaceutical composition of claim 3 wherein the therapeutically effective amount of 4-(3-methanesulfonyl-phenyl)-1-propyl-piperdine (Pridopidine) is from 10 mg to 100 mg.

6. The pharmaceutical composition of claim 3 wherein the therapeutically effective amount of 4-(3-methanesulfonyl-phenyl)-1-propyl-piperdine (Pridopidine) is 45 mg.

7. The pharmaceutical composition of claim 3 wherein the therapeutically effective amount of 4-(3-methanesulfonyl-phenyl)-1-propyl-piperdine (Pridopidine) is 67.5 mg.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The present invention is further illustrated by reference to the accompanying drawing, in which:

(2) FIG. 1 shows a characteristic X-ray powder diffraction pattern of crystalline Pridopidine hydrobromide;

(3) FIG. 2 shows a characteristic DSC thermogram of crystalline Pridopidine hydrobromide;

(4) FIG. 3 shows a characteristic FT-IR spectrum of crystalline Pridopidine hydrobromide;

(5) FIG. 4 shows a characteristic TGA thermogram of crystalline Pridopidine hydrobromide;

(6) FIG. 5 shows a characteristic dynamic vapour sorption (DVS) profile of crystalline Pridopidine hydrobromide in the relative humidity range 0-95%. Size 8.6650 mg, Method adsorption 0-95% 2 cycles 25. Instrument TGA Q5000 V3.10 Build 258.

(7) FIG. 6 shows a characteristic dynamic vapour sorption (DVS) moisture sorption and desorption kinetics plot of crystalline pridopidine hydrobromide in the relative humidity range 0-95%. Size 11.4530 mg, Method adsorption 0-95% 2 cycles 25. Instrument TGA Q5000 V3.5 Build 252.

(8) FIG. 7 shows a characteristic dynamic vapour sorption (DVS) moisture sorption and desorption kinetics plot of crystalline pridopidine hydrochloride in the relative humidity range 0-95%. Size 9.9530 mg, Method adsorption 0-95% 2 cycles 25. Instrument TGA 05000 V3.5 Build 252.

(9) FIG. 8 shows a characteristic dynamic vapour sorption (DVS) profile of crystalline pridopidine hydrochloride in the relative humidity range 0-95%. 11.4530 mg, Method adsorption 0-95% 2 cycles 25. Instrument TGA Q5000 V3.5 Build 252.

(10) FIG. 9 shows a characteristic dynamic vapour sorption (DVS) isotherm with smaller steps in the mid eighties relative humidity range for crystalline pridopidine hydrochloride in the relative humidity range 0-95%. 5.7650 mg, Method adsorption 80-90-80%. Instrument TGA Q5000 V3.5 Build 252.

EXAMPLE 1

Preparation of Pridopidine HBr

(11) In order to prepare 33 g of pridopidine HBr, 28.5 g of free base was dissolved in 150 ml 99% ethanol at room temperature. 1.5 equivalents of hydrobromic acid 48% were added. Precipitation occurred spontaneously, and the suspension was left in refrigerator for 2.5 hours. Then the crystals were filtered, followed by washing with 99% ethanol and ether. The crystals were dried over night under vacuum at 40° C.: m.p. 196° C. The results of a CHN analysis are presented in Table 2, below.

(12) NMR .sup.1H NMR (DMSO-d.sub.6): 0.93 (3H, t), 1.68-1.80 (2H, m), 1.99-2.10 (4H, m) 2.97-3.14 (5H, m), 3.24 (3H, s), 3.57-3.65 (2H, d), 7.60-7.68 (2H, m), 7.78-7.86 (2H, m) and 9.41 ppm (1H, bs).

(13) TABLE-US-00002 TABLE 2 Elemental analysis Result Elemental analysis W/W % (n=2) Element C H N Theoretical content 49.72 6.68 3.87 Anhydrous Pridopidine HBr Measured 49.95 6.66 3.81

Example

Analytical Methods

(14) X-Ray Powder Diffraction

(15) X-ray powder diffraction (XRPD) experiments were conducted using a Bruker D8 Advance diffractometer configured as listed below:

(16) TABLE-US-00003 Goniometer Theta-theta Geometry Bragg-Brentano geometry Primary slit 1.0 mm and 2.5° soller slit Secondary collimator 1.0 mm and 2.5° Soller slit Detector slit 0.1 mm Monochromator Ni-filter Detector Scintillation counter Scan range 3-30°, 2 Theta Scan speed 5 s/step, 0.020° 2 theta/step Radiation CuK.sub.α (λ = 1.5418) Generator 40 kV, 40 mA Sample stage 9 position, spinning mode

(17) The sample was placed on a zero back ground silicon single crystal sample holder in a thin film of vaseline. The diffractograms were acquired using Bruker “XRD Commander”, ver. 2.6.1, and was evaluated using “Bruker Evaluation”, ver. 11,0,0,3.

(18) Following this procedure the d-spacing's shown in Table 1, and the diffractogram shown in FIG. 1, were obtained. FIG. 1 has an X-ray powder diffraction pattern with reflections corresponding to the following d-spacing values: 10.8, 7.6, 6.9, 6.0, 5.7, 5.4, 5.3, 5.2, 4.7, 4.6, 4.3, 4.2, 4.0, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1.

(19) Differential Scanning Calorimetry

(20) Differential scanning calorimetry (DSC) experiments were conducted on a Mettler Toledo DSC 821e Differential Scanning calorimeter, using Mettler-Toledo StarE ver. 9.2 software package. The sample (approx. 3 mg) was heated in a pinholed aluminium pan from 30° C. to 300° C. at 10° C./min. The DSC was continuously purged with dry nitrogen, and was routinely calibrated with indium and zinc.

(21) Following this procedure the DSC thermogram shown in FIG. 2 was obtained. FIG. 2 shows an endotherm with an onset of about 196° C., as obtained with DSC.

(22) Thermo Gravimetric Analysis

(23) Thermo gravimetric analysis (TGA) experiments were conducted on a Mettler Toledo TGA/SDTA 851e. The sample (approx. 10 mg) was heated in an open Al crucible from 30° C. to 300° C. at 10° C./min. The TGA was continuously purged with dry nitrogen, and was routinely calibrated with Indium and aluminum. Data was evaluated using Mettler-Toledo StarE ver. 9.2 software package.

(24) Following this procedure the TGA thermogram shown in FIG. 4 was obtained. The TGA thermogram in FIG. 4 shows a minor loss of mass below 130° C., a minor loss of mass at approximately 140° C. and 180° C. and a major loss of mass above approximately 230° C.

(25) Fourier Transform Infrared Spectroscopy

(26) Fourier Transform infrared spectroscopy (FTIR) experiments were conducted on a Perkin-Elmer Spectrum One FTIR instrument equipped with an attenuated total reflection (ATR) unit Goldengate supplied from Specac. The system was controlled using Spectrum Ver. 5.0.1 software. The samples (approx. 1-2 mg) were placed directly on the diamond surface of the ATR unit and the anvil pressed firmly against the sample. Samples were analysed in the wave number region 4000-600 cm-1. The instrument was routinely calibrated against internal polystyrene filters.

(27) Following this procedure the FT-IR spectrum of crystalline pridopidine hydrobromide shown in FIG. 3 was obtained. The IR spectrum in FIG. 3 has absorptions at about 2950 cm.sup.−1, 2700-2500 cm.sup.−1, 1550 cm.sup.−1, 1450 cm.sup.−1, 1300 cm.sup.−1, 1150 cm.sup.−1, 1100 cm.sup.−1, 950 cm.sup.−1, 900 cm.sup.−1, 850 cm.sup.−1, 750 cm.sup.−1, and 650 cm.sup.−1.

(28) Karl Fischer Titration

(29) Water determinations using Karl Fischer (KF) titrations were performed using Metrohm KF 756 KF Coulometer equipped with a generator electrode without diaphragm. The titrator was equipped with a Metrohm 832 KF Thermoprep oven. The sample was weighed off in small HPLC glass vials, sealed and introduced into the oven (130° C.). Here a needle was used to puncture the rubber septum of the HPLC vial and a dry carrier gas (N2) was used to carry the released water via heated tubing to the titration chamber.

(30) Prior to sample titration, a series of blanks were titrated to determine the blank level. Results were automatically corrected for the blank value. The instrument was routinely controlled by using solid standards with certified water content.

(31) Dynamic Vapour Sorption Measurements

(32) Dynamic vapour sorption (DVS) measurements were conducted using a Q5000 SA from TA instruments.

(33) Experiments were conducted in two sorption/desorption cycles between 0% RH and 95% RH. Prior to the first sorption cycle the sample was equilibrated at 20% RH and the initial weight recorded. Samples were analyzed in an aluminium pan. Humidity was brought down to 0% RH and the sample dried until the weight had stabilized within a given limit. The temperature was held constant at 25° C. Maximum step time was 720 min. Gas flow was 200 cm.sup.3/min.

(34) Following this procedure the DVS profile shown in FIG. 5 was obtained. The DVS profile in FIG. 5 has a dynamic vapour sorption (DVS) profile which shows that between 0 and 95% relative humidity, the salt gradually gained approximately 0.15% weight, which is lost during desorption.

(35) CHN Measurements

(36) CHN measurements were performed at Mikroanalytisk Laboratorium, Kemisk Institut, University of Copenhagen, using a Flash EA 1112 analyzer.

(37) Approximately two milligrams of compound was weighed into a small tin beaker and inserted into the combustion chamber. The resulting gasses were collected on a column and analyzed via gas chromatography. Analyses were performed in duplicate.