NZ623344B2 - Polymorphic form of pridopidine hydrochloride - Google Patents

Abstract

Disclosed is a new crystalline form of the dopaminergic stabilizer Pridopidine (4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine hydrochloride salt), characterized by an X-ray powder diffraction pattern with reflections corresponding to the d-spacing values 8.9, 7.7, 6.7, 6.1, 5.1, 4.9, 4.3, 4.1, and 3.6, and by a DSC thermogram having an endotherm with an onset of about 210°C. The new polymorph is suitable for the treatment of Huntington's disease. d 3.6, and by a DSC thermogram having an endotherm with an onset of about 210°C. The new polymorph is suitable for the treatment of Huntington's disease.

Description

POLYMORPHIC FORM OF PRIDOPIDINE HYDROCHLORIDE TECHNICAL FIELD This invention relates to a new crystalline form of Pridopidine, a drug substance currently in development for the ent of Huntington's disease. More specifically the invention provides polymorphic Form II of the Pridopidine hloride salt, a process for the preparation this polymorphic form, pharmaceutical compositions comprising polymorphic Form II, and methods of uses of this polymorphic form.

BACKGROUND ART Polymorphism in al science is the ability of a solid material to exist in more than one crystal form with each form having different orientations and/or conformations of the molecules in the crystal lattice. Polymorphism is important in the pment of pharmaceutical ingredients, because each polymorph exhibits a unique set of ochemical properties, due to the differences in structural arrangements in the ls. Thus, solubility and dissolution rate may vary between polymorphs, leading to potential differences in bioavailability. Furthermore, ical properties such as flowability and compactability, which affect the processing properties of a compound, may be different. Stability and shelf life of a compound may also depend on the chosen polymorph. For these reasons it is valuable to screen for the existence of different polymorphic forms and to characterize discovered forms.

Having different polymorphic forms to choose from provides new opportunities to' improve the mance of a pharmaceutical product.

The polymorphic outcome of a chemical synthesis is determined by the crystallization conditions such as choice of solvent(s), rate of solvent addition, temperature, stirring rate, level of super—saturation, and level of impurities. Hence, different crystallization processes may give rise to different polymorphs. Polymorphs also have ent stabilities and may neously convert from one form to another. rphs can be distinguished from each other by a variety of techniques. Polymorphs exhibit distinct spectroscopic properties and can be identified W0 20131034622 using infrared spectroscopy, raman spectroscopy, and 13C—NMR spectroscopy. Due to the fact that each crystal form cts X—rays in different ways, X—ray powder diffractometry (XRPD) can also be used for identification. Furthermore, thermal methods such as ential ng calorimetry (DSC) and thermogravimetric analysis (TGA) can provide information unique to a particular polymorph.

Pridopidine, i.e. ethanesuIfonyi—phenyI)-1~propyl—piperidine, is a drug substance currently in clinical development for the treatment of Huntington's disease.

The hydrochloride salt of 4—(3-methanesuifonyi-phenyI)—1—propyl—piperidine and a method for its synthesis is described in WO 01/46145. in an 1O alternative method for the synthesis of 4—(3-methanesuifonyl-phenyl)-1—propy|— piperidine is described. When following these routes of synthesis a crystalline phase results with a melting point of 199°C. This crystalline phase is designated Form l.

Pridopidine hydrochloride Form l crystallises in the hombic space group PnaZ1, with the e ters a = 105A, b = 23.1A, c = 6.9A, a = 90°C, [3 = 90°C, V = 90°C, and cell volume 1682 A3. Form 1 is characterised by an X—ray powder diffractogram having the characteristic d-spacing's shown in Table 1, below, or a diffractogram ntially as depicted in Fig. ‘i; a DSC thermogram substantially as shown in Fig. 2, having an endotherm with an onset of about 199°C; an IR spectrum substantially as depicted in Fig. 3; and a TGA thermogram substantially as depicted in Fig. 4.

Table 1 unannnnana The dynamic vapour sorption (DVS) profile shows that Form | is non- hygroscopic below 80% RH, but deliquescent in excess of 80% RH (Fig. 5). TGA shows Form | to be a non-soivated form (Fig. 4). Form l is highly soluble in aqueous liquids with solubility in water of above 200 mg/ml.

The particle size — and shape distributions for Form i was investigated using image analysis and presented in Table 2 below. The D50 is 21 um, and the D10 and D90 are 9 and 42 pm, respectively. The aspect ratio (AR) is obtained by dividing the longest ion of the particles with the shortest one. Since the AR50 is 3.1 the particles are needle shaped.

Table 2 The bulk density and tapped density of Form l are 0.212 g/ml i2.2%, and 0.264 g/ml i1.’l%, respectively.

A polymorph screening was performed on idine hydrochloride, including various methods of crystallization such as slurrying in organic solvents, solvent evaporation, cooling llization, crash cooling, and anti solvent addition. A wide selection of solvents was employed in order to increase the chance of finding new polymorphic forms. However, no forms besides the known Form I were discovered in the screening.

SUMMARY OF THE lNVENTlON In one aspect of the present invention there is provided 4-(3—methanesulfonyl— phenyl)—1-propy|—piperidine hydrochloride salt in a crystalline form, wherein the crystalline form is crystalline Form ll characterized by an X-ray powder diffraction pattern with tions corresponding to the d-spacing values 6.1 and 4.9, or 8.9 and 4.1, or a solvate f.

The discovery of new polymorphic forms of a drug substance provides new opportunities to improve the mance characteristics of the drug. Crucial parameters such as melting point, copicity and crystallinity are of paramount importance in the selection of the most suitable form of the drug. in addition, bulk properties such as particle size and shape can affect the manufacturing of a drug product.

Prodopidine is being developed as a hydrochloride salt, and the t invention is directed to the crystalline Form ll of the hydrochloride salt. This crystalline form was not ered during the development of the synthesises described in WO 01/46145 and , above, and it was not found in a polymorph screening wo 2013/034622 which, as described above, was designed to facilitate crystallization of new solid forms.

Thus, the existence of Form II was not obvious.

According to the present invention a new polymorph of the 4-(3- methanesulfonyI-phenyl)propy|—piperidine hydrochloride salt is identified, and a s for its preparation is provided. in another aspect pharmaceutical compositions comprising a therapeutically effective amount of the 4-(3-methanesulfonyl-phenyl)-1—propyl-piperidine hydrochloride salt according to the invention, together with one or more nts, excipients, carriers and/or ts.

Viewed from another aspect the ion relates to the 4—(3— methanesulfonyl~phenyl)-1~propyl-piperidine hydrochloride of the invention for use as a medicament. in a further aspect the invention provides a method of treatment, prevention or alleviation of a dopamine mediated disorder, which method comprises the step of administering to such a living animal body in need thereof, a therapeutically effective amount of the ethanesulfonyl—phenyl)—1-propyl-piperidine hydrochloride salt of the invention.

Other objects of the invention will be apparent to the person skilled in the art from the following detailed description and examples.

DETAILED DISCLOSURE OF THE INVENTION Pridopidine is a dopaminergic stabilizer currently in development for the treatment of Huntington's disease. The drug substance is a weak base in the form of a ry amine with a calculated pKa value of 8.9. 0/\/o 4-(3-methanesulfonyl-phenyl)propyl-piperidine; Pridopidine A new crystalline form of Pridopidine hydrochloride, Form II, was discovered during DSC analysis of Form I. For some Form | batches, the DSC thermogram showed an extra endotherm with an onset of about 210°C, following the Form I melting erm at around 199°C (Fig. 6). This indicated the existence of a new crystalline phase. In order to isolate this crystal phase, a sample of Form I was heated to 203°C, followed by cooling. XRPD of the resulting solid phase showed that a new solid form had been formed, and this form has been designated Form II.

Accordingly, in its first aspect the invention provides a new crystalline form, Form ll, of 4—(3—methanesulfonyl-phenyl)~1~propyI-piperidine hydrochloride salt, or a solvate thereof.

In a preferred embodiment the crystalline Form II is provided in an anhydrous form.

In another preferred ment the crystalline Form II is provided in an anhydrous form and non-solvated form.

The crystalline Form II of the ion is characterised by a powder X-ray diffractogram having the d-spacing's shown in Table 3, below, or a diffractogram substantially as depicted in Fig. 7.

Table 3 mannannn Therefore, in a third preferred ment, the lline 4-(3- esulfonyl-phenyl)-1—propyl~piperidine hydrochloride salt of the invention is characterized by having an X-ray powder diffraction pattern with reflections corresponding to the d-spacing values 6.1 and 4.9.

In a more preferred embodiment, the crystalline Form II of the invention is characterized by having an X-ray powder diffraction pattern with reflections corresponding to the d-spacing values 8.9 and 4.1.

In a third more red embodiment, the crystalline Form II of the invention may be characterized by having an X-ray powder diffraction pattern with reflections corresponding to the d-spacing values 8.9, 7.7, 6.7, 6.1, 5.1, 4.9, 4.3, 4.1 and 3.6.

In a third preferred embodiment, the crystalline Form ll of the invention may be terized by having a DSC thermogram substantially as shown in Fig. 8. in a fourth preferred embodiment, the crystalline Form ll of the invention may be characterized by having an endotherm with an onset of about 210°C, as ed with DSC.

In a fifth preferred embodiment, the crystalline Form ll of the invention may be characterized by having an IR spectrum substantially as depicted in Fig. 9.

In a sixth red embodiment, the crystalline Form ll of the invention may be characterized by having a TGA gram substantially as depicted in Fig. 10.

Form ll crystallises in the monoclinic space group P21/c, with the lattice parameters a = 12.2A, b = 13.5A, c = 10.2A, a = 90°C, [3 = , y = 90°C, and cell volume 1685A3. The dynamic vapour sorption (DVS) e shows that Form II is non- hygroscopic below 80% RH, but deliquescent in excess of 80% RH (Fig. 11). TGA shows Form ll to be a non-solvated form (Fig. 10), and Karl Fisher is confirmed the anhydrous nature of the salt. The solubility of Form II at room temperature could not be determined, as Form ll transforms rapidly to Form I when exposed to solvent.

Only one polymorphic form is thermodynamically stable at a given temperature. Therefore it is of interest to determine which polymorph is the most stable one at ambient temperature, and how the stability relationship between the polymorph is ed by a change in temperature. The stability at ambient temperature was determined by exposing both forms to solvent to form a slurry. When exposed to solvent, Form ll rapidly transformed into Form l, and from this it is concluded that Form l is the stable form at ambient temp.

The relative thermodynamic stability of the forms as a function of temperature was igated based on thermal data. According to the heat of fusion rule proposed by Burger & Ramberger (Burger A and Ramberger R: On the polymorphism of pharmaceuticals and other molecular crystals; l. Mikrochim. Acta. ll 1979 259—271), the polymorphs are enantiotropically related, as Form ll has a higher melting point and a lower heat of fusion than Form |. Form I has a melting point of 199°C and a heat of fusion of 34.8 KJ/mol, while Form II has a melting point of 210°C and a heat of fusion of 32.0 KJ/mol, as determined by DSC.

In a seventh red embodiment, the crystalline 4-(3-methanesulfonyl- phenyl)—1-pr0pyl-piperidine hydrochloride salt of the invention is characterized by WO 2013034622 having a DSC thermogram substantially as shown in Fig. 8, and by having an endotherm with an onset of about 210°C.

When two forms are otropically d it is of interest to determine the transition temperature (Ti) in order to be able to control the outcome of synthesis and pharmaceutical processing. Lian Yu (Yu L: inferring thermodynamic ity relationship of polymorphs from melting data; J. Pharm. Sci. 1995 84 966—974) has proposed a model where T: can be calculated based on melting points and heats of fusion. ng this method, a Ti of 127°C was obtained. In order to confirm this finding experimentally, a seeding experiment was carried out, where mixtures of the two forms were slurried in an organic solvent for 4 hours at various temperatures.

Following slurrying, the identity of the ing solid phase was ined by XRPD. At temperatures below 125°C, the polymorphic outcome was Form I, and above 130°C the outcome was Form ll. Hence, the study indicates that Form | and II are otropically related, with Form i being the most stable form at room temperature, and Form i being the most stable form at temperatures above 127°C.

The particle size — and shape distributions for Form ll was investigated using image analysis and presented in Table 4 below. The D50 is 170 um, and the D10 and D90 are 49 and 363 pm, respectively. The aspect ratio (AR) is obtained by dividing the longest dimension of the particles with the shortest dimension. Since the ARso for Form ii is 1.6 compared to 3.1 for Form l, the Form ll crystals are less needle shaped than the Form l crystals. This may be an advantage in terms of pharmaceutical processing, where needle shaped particles are known to affect the flow and compression properties of the powder.

Table 4 The bulk density and tapped density of Form II are 0.382 g/ml 10.3%, and 0.486 g/ml i1.1%, respectively, which is much higher than the densities of Form i (see Table 2). This may have implication for instance during formulation of capsules, where smaller hard gelatin capsules could be used to administrate the same amount of Form ll compared to Form I.

Methods of Preparation Form II of pripopidine hydrochloride is thermodynamically stable above 127°C, and hence it should be possible to e Form ll be re-crystallization of Form | at elevated temperature. However, attempt to prepare Form II by re-crystallization of Form l at temperatures above 127°C without addition of seed crystals of Form II were unsuccessful. in order to successfully prepare Form II is was necessary to produce Form II seed crystals by heating solid Form l to 203°C to allow melting of Form l and re- crystallization to Form ll, followed by cooling. This was done in a TGA oven. Seed crystals prepared in this way were used to prepare Form ll. Form l was dissolved in -chlorobenzene at 165°C to form a clear solution. The Form ll seed crystals were added and the seeded on was left to crystallise at 165°C. The formed suspension was filtered at 150°C and the crystals were dried under vacuum.

Biological activity WO 01/46145, WO 01/46146, , WO 2008/127188 and WO 2008/155357 all be substituted 4-phenyl-N-alkyl- piperazines and 4—phenyl-N-alkyl—piperidines, reported to be modulators of dopamine neurotransmission, and to be useful in treatment of ms of various ers of the central nervous system. The 4—(3-methanesulfonyl-phenyl)-1~propyl-piperidine hloride salt of the invention is considered useful for the same medical indications as described in these publications, and these publications therefore are incorporated by reference. ogical indications contemplated according to these ations include the treatment of Huntington‘s disease and other movement disorders, as well as movement ers induced by drugs.

Therefore, in a preferred embodiment, the invention relates to the use of the 4-(3—methanesulfonyl-phenyl)propyl-piperidine hydrochloride salt of the ion for use as a medicament for the treatment of Huntington's disease.

Pharmaceutical Compositions Viewed from another aspect the invention provides 4-(3-methanesulfonyl- phenyl)—1-propyl-piperidine hydrochloride salt, or a solvate thereof, in a crystalline form (Form II), for use as medicaments. Therefore, in another aspect, the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of the compound of the invention.

While a compound of the invention for use in y may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically able salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical aries.

Pharmaceutical compositions of the invention may in particular be formulated as described in WO 45.

Further details on techniques for formulation and administration may be found in the latest edition of Remington’s Pharmaceutical Sciences (Maack Publishing 00., Easton, PA).

The dose administered must of course be carefully adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the result desired, and the exact dosage should of course be determined by the practitioner.

The actual dosage depends on the nature and severity of the disease being treated, and is within the discretion of the ian, and may be varied by titration of the dosage to the particular circumstances of this invention to e the desired therapeutic effect. However, it is presently contemplated that pharmaceutical compositions containing of from about 1 to about 500 mg of active ingredient per individual dose, preferably of from about 10 to about 100 mg, most preferred of from about 25 to about 50 mg, are suitable for therapeutic treatments. The daily dose will preferably be administered in individual dosages 1 to 4 times daily.

Methods of Therapy in another aspect the invention provides a method for the treatment, tion or alleviation of a dopamine ed er of a living animal body, ing a human, which method comprises the step of administering to such a living wo 2013/034622 animal body in need f a therapeutically effective amount of the 4-(3- methanesulfonyl-phenyl)—1-propyl-piperidine hydrochloride salt of the invention. in a preferred embodiment the dopamine mediated disorder is Huntington's disease.

BRIEF DESCRIPTION OF THE DRAWINGS The present invention is further illustrated by reference to the anying drawing, in which: Fig. 1 shows a characteristic X—ray powder diffraction pattern of crystalline Pridopidine hydrochloride Form I; Fig. 2 shows a teristic DSC thermogram of crystalline Pridopidine hydrochloride Form I; Fig. 3 shows a characteristic FT-IR spectrum of crystalline Pridopidine hydrochloride Form I; Fig. 4 shows a characteristic TGA thermogram of crystalline Pridopidine hydrochloride Form i; Fig. 5 shows a characteristic dynamic vapour on (DVS) profile of crystalline Pridopidine hydrochloride Form l in the relative humidity range 0-95%; Fig. 6 shows a DSC thermogram of lline Pridopidine hydrochloride Form l, where endotherms characteristic of both Form | (199°C) and Form ll ) are present; Fig. 7 shows a characteristic X—ray powder ction pattern of crystalline Pridopidine hydrochloride Form ll; Fig. 8 shows a characteristic DSC thermogram of crystalline Pridopidine hydrochloride Form ll; Fig. 9 shows a characteristic FT-IR spectrum of crystalline Pridopidine hydrochloride Form ll; Fig. 10 shows a characteristic TGA thermogram of lline Pridopidine 3O hydrochloride Form II; and Fig. 11 shows a characteristic dynamic vapour sorption (DVS) profile of crystalline Pridopidine hydrochloride Form ll in the relative humidity range 0-95%.

W0 34622 EXAMPLES The invention is further illustrated with reference to the following examples, which are not intended to be in any way limiting to the scope of the invention as claimed.

Example 1 Preparation of Pridopidine Form II In order to prepare Form ll on a larger (gram) scale is was necessary to first e Form ll seed crystals in mg scale. This was done by g solid Form l to to 203°C to allow melting of Form l and subsequent re-crystallization to Form ll, followed by cooling. This took place in a TGA oven. In this way approximately 10 mg of Form II was prepared.

To prepare Form ll, 15 g of Pridopidine Form l was dissolved in 375 ml 1,2—dl- chlorobenzene under heating to reflux at approximately 180°C. A clear on was formed at around 165°C. The solution was transferred to an oil bath of 165°C and seed ls of Pridopidine Form ll were added. Stirring was started as soon as the seed crystals d to grow. Over 30 minutes the temperature was lowered to 150°C. After another 30 minutes, the suspension was filtered at 150°C, followed by washing with heptane. The crystals were dried under vacuum: mp. 210°C. The results of a CHN analysis are presented in Table 5, below.

NMR 1H NMR (DMSO-de): 0.93 (3H, t), 1.73—1.79 (2H, m),2.00—2.13 (4H, m), 2.96-3.06 (5H, m), 3.23 (3H, s),3.54-3.57 (2H, m), 7.61-7.67 (2H, m), 7.79-7.84 (2H, m),10.52 (1H, bs) Table 5 Theoretical content 56.68 7.61 4.41 Anhydrous Pridopidine wo 2013/034622 Example 2 rph screening of Pridopidine A polymorph screening was performed on Pridopidine to see if solid forms alternative to Form I could be formed by various methods of crystallization using various solvents. The following solvents and solvent mixtures were d.

Ethanol Ethanol:water 90:10 Acetone:water 90:10 Dimethyl ide (DMSO) NN-dimethylacetamide (DMA) N-methylpyrrolidone (NMP) 1-butanol 2-propanol Toluene Tetrahydrofuran (TH F) Acetonitrile Acetonitrile:water 90:10 Ethyl acetate In the following a description of each experiment is given.

Slurrying in solvents A starting amount of the Pridopidine was added to small, clear Eppendorf plastic vials. The appropriate t/solvent mixture was added and the vial put on a rotamixer overnight. If a clear solution could be observed in that time, more compound was added and the vial put back on the rotamixer. This was continued until a solution ning solid Pridopidine could be observed in all vials. Total equilibration time was 7 days. The dried precipitate was examined by XRPD. t evaporation The supernatants generated during the slurry experiments were covered with pierced parafilm and left at room temperature in the dark. High boiling solvents were evaporated in a vacuum oven at 40°C. Dried precipitates were analyzed by XRPD.

Cooling crystallization Saturated solutions of idine were prepared in good solvents at 50°C using a water bath. The solutions were covered and left in the refrigerator for a week.

Dried precipitates were analyzed by XRPD.

Crash cooling Saturated ons of Pridopidine were prepared in good solvent at 50°C using a water bath. The solutions were crash cooled by placing them in a dry ice-salt mixture for a few minutes. if precipitation did not occur instantly, the solutions were kept in the freezer until the next day. The supernatant was removed and the dried material was analyzed by XRPD.

Non-solvent precipitation Saturated solutions of Pridopidine were prepared in good solvents at 50°C using a water bath. To these solutions, cold (room temp.) non—solvents were added drop wise until the solution volume had been doubled. The supernatant was removed and the dried material was ed by XRPD.

Compression Pridopidine powder was filled into the die of a hydraulic lR-press. The die was placed in the press and the powder was compressed for 24 hours at 10 T. The compressed al was analyzed by XRPD.

XRPD analyses showed that all of the formed material was Form l.

Example 3 ical methods X-ray powder ction X—ray powder diffraction (XRPD) experiments were conducted using a Bru ker D8 Advance diffractometer configured as listed below: Goniometer Theta-theta ry 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 romator Ni—filter Detector llation counter Scan range 3-30°, 2 Theta Scan speed 5 s/step, 0.020° 2 theta/step Radiation CuK Generator 40 kV, 40 mA Sample stage 9 position, spinning mode The sample was placed on a zero back ground silicon single crystal sample holder in a thin film of vaseline. The diffractograms were ed using Bruker “XRD Commander“, ver. 2.6.1, and was evaluated using “Bruker Evaluation“, ver. 11,0,0,3.

Following this ure the ing's shown in Table 3, and the diffractogram shown in Fig. 7 were obtained.

Differential Scanning Calorimetry Differential scanning calorimetry (DSC) experiments were conducted on a Mettler Toledo DSC 821s Differential Scanning Calorimeter, using Mettler-Toledo StarE ver. 9.2 software e. 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.

Following this procedure the DSC thermogram shown in Fig. 8 was obtained.

Thermo Gravimetric Analysis 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.

Following this procedure the TGA thermogram shown in Fig. 10 was obtained.

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

Following this procedure the FT-lR spectrum of crystalline pridopidine hydrochloride Form || shown in Fig. 9 was obtained.

Karl Fischer Titration Water determinations using Karl Fischer (KF) ions were performed using Metrohm KF 756 KF Coulometer equipped with a generator electrode without diaphragm. The titrator was equipped with a Metrohm 832 KF prep 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.

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 lled by using solid standards with certified water content.

Dynamic Vapour on Measurements Dynamic vapour sorption (DVS) ements were conducted using a 05000 SA from TA instruments.

Experiments were conducted in two on/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 ed. 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 nt at 25°C. Maximum step time was 720 min. Gas flow was 2000m3/min.

Following this procedure the DVS profiles shown in Fig. 11 were obtained.

CHN measurements CHN measurements were performed at Mikroanalytisk Laboratorium, 1O Kemisk lnstitut, University of Copenhagen, using a Flash EA 1112 analyzer. imately 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. es were performed in ate.

Image analysis Microscopic analysis was carried out using a Zeiss Axiolab microscope (Carl Zeiss, Gottingen, Germany). Photomicrographs were captured using a ix digital camera and Deltapix software version 1.6 (Maaloev, Denmark). A 5x magnification ive (1.626 ,um/pixei) was used without immersion oil and a 40x magnification objective (0.208 pm/pixel) was used with liquid paraffin as immersion oil. The particle size was inated using Motic Image Plus 2.0 software (Motic Group Inc, China), calibrated to pictures of reference scales taken with the used objectives. The particle size distribution and the aspect ratio distribution were calculated using Matlab version 2009b (Mathworks Inc., USA).

Bulk density and tapped density Density determinations were performed as described in Ph. Eur. 2.9.34. The method was modified as the sample amount placed in the 250 ml volumetric glass 3O cylinder was 50.0 g and 2500 taps were run at 100 taps/min. The measurements were done in triplicate.

Claims (15)

1. 4-(3-Methanesulfonyl-phenyl)propyl-piperidine hydrochloride salt in a crystalline form, wherein the crystalline form is crystalline Form ll characterized by an X—ray powder diffraction pattern with tions corresponding to the d-spacing values 6.1 and 4.9, or 8.9 and 4.1, or a e thereof.

2. The ethanesuIfonyl-phenyl)—1-propyl—piperidine hydrochloride salt according to claim 1, wherein the crystalline form is anhydrous.

3. The 4—(3—methanesulfonyl-phenyl)propyl-piperidine hydrochloride salt in crystalline form according to claim 1, characterized by an X—ray powder diffraction pattern with reflections corresponding to the d-spacing values 6.1 and 4.9, and 8.9 and 4.1.

4. A pharmaceutical composition comprising a therapeutically effective amount of the 4-(3-methanesulfonyl-phenyl)propyl-piperidine hydrochloride salt, or e thereof, according to any one of claims 1-3, together with one or more nts, excipients, rs and/or diluents.

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

6. The pharmaceutical composition of claim 4, wherein the therapeutically effective amount of 4-(3-methanesulfonyl-phenyl)propyl-piperidine is from 10 mg to 100 mg.

7. The pharmaceutical composition of claim 4, wherein the therapeutically effective amount of 4-(3-methanesulfonyl-phenyl)propyI-piperidine is from 25 mg to 50 mg.

8. The 4—(3-methanesulfonyl—phenyl)propyl-piperidine hydrochloride salt according to any one of claims 1-3, for use as a medicament.

9. Use of the ethanesulfonyl-phenyl)-1—propyl-piperidine hydrochloride salt according to any one of claims 1—3, in the manufacture of a medicament.

10. Use of the 4—(3—methanesulfonyl-phenyl)—1-propyl—piperidine hydrochloride salt according to any one of claims 1-3, in the manufacture of a ment for the ation of a symptom, the treatment, or the prevention, of a dopamine mediated disorder.

11. Use of the ethanesulfonyl—phenyl)—1-propy|—piperidine hydrochloride salt according to any one of claims 1-3, in the manufacture of a medicament for the alleviation of a symptom, or the treatment, of Huntington’s disease.

12. The 4-(3-methanesulfonyl-phenyl)—1-propyl-piperidine hydrochloride salt according to claim 1, substantially as herein described with reference to any one of the Examples and/or Figures thereof.

13. The ethanesu|fonyl—phenyl)-1~propyl-piperidine hydrochloride salt according to any one of claims 1 to 3 or 8, substantially as herein described.

14. The pharmaceutical composition according to any one of claims 4 to 7, substantially as herein described.

15. The use according to any one of claims 9 to 11, substantially as herein descnbed.