i ) the present invention relates to a crystalline form , such as an essentially pure crystalline form , of the compound ( r )- 5 -[ 3 - chloro - 4 -( 2 , 3 - dihydroxy - propoxy )- benz [ z ] ylidene ]- 2 -([ z ]- propylimino )- 3 - o - tolyl - thiazolidin - 4 - one containing from 0 to 2 equivalents of h 2 o per equivalent of ( r )- 5 -[ 3 - chloro - 4 -( 2 , 3 - dihydroxy - propoxy )- benz [ z ] ylidene ]- 2 -([ z ]- propylimino )- 3 - o - tolyl - thiazolidin - 4 - one . ii ) in another embodiment the present invention relates to a crystalline form according to embodiment i ) containing from 0 to 1 equivalents of h 2 o per equivalent of ( r )- 5 -[ 3 - chloro - 4 -( 2 , 3 - dihydroxy - propoxy )- benz [ z ] ylidene ]- 2 -([ z ]- propylimino )- 3 - o - tolyl - thiazolidin - 4 - one . iii ) in another embodiment the present invention relates to a crystalline form according to embodiment i ) containing from 0 to 0 . 5 equivalents of h 2 o per equivalent of ( r )- 5 -[ 3 - chloro - 4 -( 2 , 3 - dihydroxy - propoxy )- benz [ z ] ylidene ]- 2 -([ z ]- propylimino )- 3 - o - tolyl - thiazolidin - 4 - one . iv ) in another embodiment the present invention relates to a crystalline form according to embodiment i ) containing 0 . 5 equivalents of h 2 o per equivalent of ( r )- 5 -[ 3 - chloro - 4 -( 2 , 3 - dihydroxy - propoxy )- benz [ z ] ylidene ]- 2 -([ z ]- propylimino )- 3 - o - tolyl - thiazolidin - 4 - one . v ) in another embodiment the present invention relates to a crystalline form according to embodiment i ), wherein the compound ( r )- 5 -[ 3 - chloro - 4 -( 2 , 3 - dihydroxy - propoxy )- benz [ z ] ylidene ]- 2 -([ z ]- propylimino )- 3 - o - tolyl - thiazolidin - 4 - one is in anhydrous form . vi ) in another embodiment the present invention relates to a crystalline form according to any one of embodiments i ) to iii ) containing from 0 . 1 to 2 equivalents of propionic acid per equivalent of ( r )- 5 -[ 3 - chloro - 4 -( 2 , 3 - dihydroxy - propoxy )- benz [ z ] ylidene ]- 2 -([ z ]- propylimino )- 3 - o - tolyl - thiazolidin - 4 - one . vii ) in another embodiment the present invention relates to a crystalline form according to any one of embodiments i ) to iv ), characterised by the presence of peaks in the x - ray powder diffraction diagram at the following angles of refraction 2θ : 7 . 0 °, 11 . 2 °, and 12 . 6 °. viii ) in another embodiment the present invention relates to a crystalline form according to any one of embodiments i ) to iii ), and v ), characterised by the presence of peaks in the x - ray powder diffraction diagram at the following angles of refraction 2θ : 10 . 5 °, 22 . 2 °, and 23 . 4 °. ix ) in another embodiment the present invention relates to a crystalline form according to any one of embodiments i ) to iii ) and vi ), characterised by the presence of peaks in the x - ray powder diffraction diagram at the following angles of refraction 2θ : 10 . 7 °, 15 . 2 °, and 22 . 4 °. x ) in another embodiment the present invention relates to a crystalline form according to any one of embodiments i ) to iii ), and v ), characterised by the presence of peaks in the x - ray powder diffraction diagram at the following angles of refraction 2θ : 6 . 4 °, 13 . 2 °, and 25 . 3 °. xi ) in another embodiment the present invention relates to a crystalline form according to any one of embodiments i ) to iv ), characterised by the presence of peaks in the x - ray powder diffraction diagram at the following angles of refraction 2θ : 7 . 0 °, 11 . 2 °, 12 . 6 °, 16 . 6 °, 18 . 8 °, 21 . 3 °, 23 . 6 °, and 26 . 0 °. xii ) in another embodiment the present invention relates to a crystalline form according to any one of embodiments i ) to iii ), and v ), characterised by the presence of peaks in the x - ray powder diffraction diagram at the following angles of refraction 2θ : 10 . 5 °, 11 . 1 °, 11 . 4 °, 13 . 6 °, 13 . 9 °, 16 . 3 °, 20 . 8 °, 22 . 2 °, 23 . 4 °, 24 . 1 °, 25 . 7 °, 27 . 7 °, 27 . 9 °, 28 . 7 °, and 29 . 3 °. xiii ) in another embodiment the present invention relates to a crystalline form according to any one of embodiments i ) to iii ) and vi ), characterised by the presence of peaks in the x - ray powder diffraction diagram at the following angles of refraction 2θ : 8 . 5 °, 10 . 7 °, 14 . 7 °, 15 . 2 °, 18 . 0 °, 22 . 4 °, and 23 . 4 °. xiv ) in another embodiment the present invention relates to a crystalline form according to any one of embodiments i ) to iii ), and v ), characterised by the presence of peaks in the x - ray powder diffraction diagram at the following angles of refraction 2θ : 6 . 4 °, 13 . 2 °, 16 . 9 °, 18 . 6 °, 19 . 3 °, 20 . 8 °, and 25 . 3 °. xv ) in another embodiment the present invention relates to a crystalline form according to any one of embodiments i ) to iv ), which essentially shows the x - ray powder diffraction pattern as depicted in fig2 . xvi ) in another embodiment the present invention relates to a crystalline form according to any one of embodiments i ) to iii ), and v ), which essentially shows the x - ray powder diffraction pattern as depicted in fig3 . xvii ) in another embodiment the present invention relates to a crystalline form according to any one of embodiments i ) to iii ) and vi ), which essentially shows the x - ray powder diffraction pattern as depicted in fig4 . xviii ) in another embodiment the present invention relates to a crystalline form according to any one of embodiments i ) to iii ), and v ), which essentially shows the x - ray powder diffraction pattern as depicted in fig5 . xix ) in another embodiment the present invention relates to a crystalline form according to any one of embodiments i ) to iv ), vii ), xi ), and xv ), which has a melting point of about 113 ° c . as determined by differential scanning calorimetry using the method as described herein . xx ) in another embodiment the present invention relates to a crystalline form according to any one of embodiments i ) to iii ), v ), viii ), xii ), and xvi ), which has a melting point of about 133 ° c . as determined by differential scanning calorimetry using the method as described herein . xxi ) in another embodiment the present invention relates to a crystalline form according to any one of embodiments i ) to iii ), v ), x ), xiv ), and xviii ), which has a melting point of about 101 ° c . as determined by differential scanning calorimetry using the method as described herein . xxii ) in another embodiment the present invention relates to the crystalline form a according to any one of embodiments i ) to iv ), vii ), xi ), xv ), and xix ) obtainable by : i ) dissolving amorphous ( r )- 5 -[ 3 - chloro - 4 -( 2 , 3 - dihydroxy - propoxy )- benz [ z ] ylidene ]- 2 -([ z ]- propylimino )- 3 - o - tolyl - thiazolidin - 4 - one ( 251 . 1 g ) in acetonitrile ( 1 . 25 l ) by heating ; ii ) equilibrating the internal temperature at 58 ° c . with paddle stirring at 350 rpm ; iii ) adding deionised water ( 1 . 0 l ) in 250 ml aliquots ( minimum internal temperature = 45 ° c .) yielding a clear solution on mixing ; iv ) allowing the internal temperature to reach 55 ° c . and adding one additional aliquot of water ( 250 ml ) yielding a clear solution on mixing ; v ) allowing the solution temperature to equilibrate at 59 . 5 - 60 ° c . ; vi ) cooling the solution to 12 ° c . over about 2 hours ( cooling rate = 0 . 4 ° c ./ min ); and vii ) stirring the suspension at 12 ° c . for 18 hours . xxiii ) in another embodiment the present invention relates to the crystalline form c according to any one of embodiments i ) to iii ), v ), viii ), xii ), xvi ), and xx ) obtainable by : i ) suspending the crystalline form a of ( r )- 5 -[ 3 - chloro - 4 -( 2 , 3 - dihydroxy - propoxy )- benz [ z ] ylidene ]- 2 -([ z ]- propylimino )- 3 - o - tolyl - thiazolidin - 4 - one ( 20 . 0 g ) in tert - butyl methyl ether ( 100 ml ); ii ) stirring with a mechanical stirrer at room temperature yielding a highly viscous paste that transforms to a thin fluid suspension of distinct yellow colour after stirring for 40 hours ; and iii ) filtering off the solid and drying the same for 4 hours under vaccum at room temperature . xxiv ) in another embodiment the present invention relates to the crystalline form iii according to any one of embodiments i ) to iii ), vi ), ix ), xiii ), and xvii ) obtainable by : i ) adding 1 ml propionic acid to crystalline form a of ( r )- 5 -[ 3 - chloro - 4 -( 2 , 3 - dihydroxy - propoxy )- benz [ z ] ylidene ]- 2 -([ z ]- propylimino )- 3 - o - tolyl - thiazolidin - 4 - one ( 0 . 5 g ); ii ) shaking the sample to completely dissolve all solid ; iii ) keeping the sample overnight at room temperature ; and iv ) filtering off the resulting solid . xxv ) in another embodiment the present invention relates to the crystalline form ii according to any one of embodiments i ) to iii ), v ), x ), xiv ), xviii ), and xxi ) obtainable by : i ) storing crystalline form iii of ( r )- 5 -[ 3 - chloro - 4 -( 2 , 3 - dihydroxy - propoxy )- benz [ z ] ylidene ]- 2 -([ z ]- propylimino )- 3 - o - tolyl - thiazolidin - 4 - one under high vaccum (& lt ; 0 . 1 mbar ) for one week ; and ii ) storing the product open at room temperature and about 40 % relative humidity overnight . the term “ essentially pure ” is understood in the context of the present invention to mean especially that at least 90 , preferably at least 95 , and most preferably at least 99 percent by weight of the crystals of a compound are present in a crystalline form according to the present invention , especially in a single crystalline form of the present invention . when defining the presence of peak in e . g . an x - ray powder diffraction diagram , a common approach is to do this in terms of the s / n ratio ( s = signal , n = noise ). according to this definition , when stating that a peak has to be present in an x - ray powder diffraction diagram , it is understood that the peak in the x - ray powder diffraction diagram is defined by having an s / n ratio ( s = signal , n = noise ) of greater than x ( x being a numerical value greater than 1 ), usually greater than 2 , especially greater than 3 . in the context with stating that the crystalline form essentially shows an x - ray powder diffraction pattern as depicted in fig2 , fig3 , fig4 , and fig5 , respectively , the term “ essentially ” means that at least the major peaks of the diagram depicted in said figures , i . e . those having a relative intensity of more than 10 %, especially more than 20 %, as compared to the most intense peak in the diagram , have to be present . however , the person skilled in the art of x - ray powder diffraction will recognize that relative intensities in x - ray powder diffraction diagrams may be subject to strong intensity variations due to preferred orientation effects . unless used regarding temperatures , the term “ about ” placed before a numerical value “ x ” refers in the current application to an interval extending from x minus 10 % of x to x plus 10 % of x , and preferably to an interval extending from x minus 5 % of x to x plus 5 % of x . in the particular case of temperatures , the term “ about ” placed before a temperature “ y ” refers in the current application to an interval extending from the temperature y minus 10 ° c . to y plus 10 ° c ., and preferably to an interval extending from y minus 5 ° c . to y plus 5 ° c . the crystalline forms of the present invention can be used as medicaments , e . g . in the form of pharmaceutical compositions for enteral or parenteral administration , such as especially oral administration , and are suitable for decreasing the number of circulating lymphocytes and for the prevention and / or treatment of diseases or disorders associated with an activated immune system . the production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art ( see for example remington , the science and practice of pharmacy , 21st edition ( 2005 ), part 5 , “ pharmaceutical manufacturing ” [ published by lippincott williams & amp ; wilkins ]) by bringing the crystalline forms of the present invention , optionally in combination with other therapeutically valuable substances , into a galenical administration form together with suitable , non - toxic , inert , pharmaceutically acceptable solid or liquid carrier materials and , if desired , usual pharmaceutical adjuvants . the crystalline forms of compound may be used as single component or as mixtures with other crystalline forms or the amorphous form of compound . diseases or disorders associated with an activated immune system which can be treated and / or prevented with the crystalline forms of the present invention are described for example in wo 2005 / 054215 . preferred diseases or disorders to be treated and / or prevented with the crystalline forms of the present invention are selected from the group consisting of rejection of transplanted organs such as kidney , liver , heart , lung , pancreas , cornea , and skin ; graft - versus - host diseases brought about by stem cell transplantation ; autoimmune syndromes including rheumatoid arthritis , multiple sclerosis , inflammatory bowel diseases such as crohn &# 39 ; s disease and ulcerative colitis , psoriasis , psoriatic arthritis , thyroiditis such as hashimoto &# 39 ; s thyroiditis , and uveo - retinitis ; atopic diseases such as rhinitis , conjunctivitis , and dermatitis ; asthma ; type i diabetes ; post - infectious autoimmune diseases including rheumatic fever and post - infectious glomerulonephritis ; solid cancers ; and tumor metastasis . particularly preferred diseases or disorders to be treated and / or prevented with the crystalline forms of the present invention are selected from the group consisting of rejection of transplanted organs selected from kidney , liver , heart and lung ; graft - versus - host diseases brought about by stem cell transplantation ; autoimmune syndromes selected from rheumatoid arthritis , multiple sclerosis , psoriasis , psoriatic arthritis , crohn &# 39 ; s disease , and hashimoto &# 39 ; s thyroiditis ; and atopic dermatitis . very preferably the diseases or disorders to be treated and / or prevented with the crystalline forms of the present invention are selected from multiple sclerosis and psoriasis . the present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein or mentioned in wo 2005 / 054215 comprising administering to a subject a pharmaceutically active amount of a crystalline form of the present invention . furthermore , the crystalline forms of the present invention are also useful in combination with one or several immunomodulating agents , for the prevention and / or treatment of the diseases and disorders mentioned herein . according to a preferred embodiment of the invention , said agents are selected from the group consisting of immunosuppressants , corticosteroids , nonsteroidal anti - inflammatory drugs , cytotoxic drugs , adhesion molecule inhibitors , cytokines , cytokine inhibitors , cytokine receptor antagonists and recombinant cytokine receptors . the present invention also relates to the use of the crystalline forms of the present invention for the preparation of a pharmaceutical composition , optionally for use in combination with one or several immunomodulating agents , for the prevention or treatment of the diseases and disorders mentioned herein or mentioned in wo 2005 / 054215 . ( r )- 5 -[ 3 - chloro - 4 -( 2 , 3 - dihydroxy - propoxy )- benz [ z ] ylidene ]- 2 -([ z ]- propylimino )- 3 - o - tolyl - thiazolidin - 4 - one can be prepared for example as described in the published pct application wo 2005 / 054215 ( see in particular example 85 ) or by using the preparation process as disclosed in the published pct application wo 2008 / 062376 . the following examples illustrate the invention in more detail . temperatures are given in degrees celsius . if not stated otherwise , room temperature is in the range of 18 - 25 ° c ., and percentages are given by weight . rrt relative retention times indicating the ratio of the retention times of impurities to the retention time of the active ingredient x - ray powder diffraction patterns for amorphous compound and compound in crystalline forms a , c , and ii ( fig1 - 3 and 5 ) were collected on a bruker axs / siemens d5000 diffractometer using cu kα radiation ( 40 kv , 40 ma ), θ - θ goniometer , automatic divergence and receiving slits , a graphite secondary monochromator and a scintillation counter . the instrument is performance checked using a certified corundum standard ( nist 1976 ). samples run under ambient conditions were prepared as flat plate specimens using powder as received . approximately 35 mg of the sample was gently packed into a cavity cut into polished , zero - background ( 510 ) silicon wafer . the sample was rotated in its own plane during analysis . the data were collected over an angular range of 2 ° to 42 ° 2θ in continuous scan mode using a step size of 0 . 02 ° 2θ and a step time of 1 second . diffraction data are reported using cu kα1 ( λ = 1 . 5406 å ), after the kα2 component has been stripped using the instrument evaluation software ( eva ). the accuracy of the 2θ values as provided herein is in the range of +/− 0 . 1 - 0 . 2 ° as it is generally the case for conventionally recorded x - ray powder diffraction patterns . x - ray powder diffraction analysis method 2 used to produce the x - ray powder diffraction pattern for compound in crystalline form iii ( fig4 ): x - ray powder diffraction patterns were collected on a bruker d8 hts x - ray diffractometer equipped with a gadds histar detector operated with cu kα - radiation in reflection geometry . typically , the x - ray tube was run at 40 kv / 40 ma . the instrument is performance checked using a certified corundum standard ( nist 1976 ). samples run under ambient conditions were prepared as flat plate specimens using powder as received . approximately 3 mg of the sample was gently pressed on a microscopy slide . the data were collected over an angular range of 6 ° to 32 ° 2θ in 2 automatically merged and integrated frames using bruker pilot software with an acquisition time of 180 second per frame . diffraction data are reported without kα2 component stripping and the background signal has not been removed . the accuracy of the 2θ values as provided herein is in the range of +/− 0 . 1 - 0 . 2 °. dsc data were collected on a ta instruments q1000 equipped with a 50 position auto - sampler . the instrument was calibrated for energy and temperature using certified indium . typically 0 . 5 - 3 mg of each sample , in a pin - holed aluminium pan , was heated at 10 ° c . min − 1 , unless stated otherwise , from 25 ° c . to 250 ° c . a nitrogen purge at 30 ml min − 1 was maintained over the sample . onset temperatures are given as peak tangential onset temperatures whereas melting points are reported as peak temperatures . tga data were collected on a ta instruments q500 tga , equipped with a 16 position auto - sampler . the instrument was temperature calibrated using certified alumel . typically 3 - 10 mg of each sample was loaded onto a pre - tared platinum crucible and aluminium dsc pan , and was heated at 10 ° c . min − 1 from room temperature to 350 ° c . a nitrogen purge at 60 ml min − 1 was maintained over the sample . purity analysis was performed on an agilent hp1100 series system equipped with a diode array detector and using chemstation software v9 . samples were protected from light with foil . the autosampler tray was kept at 4 ° c . amorphous compound ( 251 . 1 g ) is dissolved in acetonitrile ( 1 . 25 l ) by heating , and the internal temperature is equilibrated at ca . 58 ° c . with paddle stirring at 350 rpm . deionised water ( 1 . 0 l ) is added in 250 ml aliquots ( minimum internal temperature = 45 ° c .) yielding a clear solution on mixing . the internal temperature is allowed to reach 55 ° c . and one additional aliquot of water ( 250 ml ) is added : the solution gets clear on mixing . the solution temperature is allowed to equilibrate at 59 . 5 - 60 ° c . and the solution is cooled to 12 ° c . over ca . 2 hours ( cooling rate = 0 . 4 ° c ./ min ). the suspension is stirred at 12 ° c . for 18 hours and a sample of the solid product is analysed by xrpd . the product is form a . 1 ): the tga thermogram of form a shows a 1 . 9 % weight loss between ambient and about 60 ° c . ( equivalent to 0 . 5 moles of water per mole of compound ) and a 19 . 6 % weight loss between 225 and 340 ° c . due to decomposition . the first weight loss corresponds to a broad endotherm in the dsc with an onset of about 33 . 6 ° c . a second , sharper endotherm is observed with an onset of about 108 ° c . which corresponds to a melt . amorphous compound is obtainable by the process described for example 85 of the published pct application wo 2005 / 054215 . alternatively , compound in crystalline form a ( 501 mg ) is dissolved in dichloromethane ( 5 ml ). the solution is filtered through a 0 . 45 μm ptfe filter and the solvent is removed by rotary evaporation to yield a pale yellow foam . the solid is dried at 40 ° c . under high vacuum for one day to yield the product : nb - 174 - 6 - 1 ( herein also referred to as “ amorphous compound ”). compound in crystalline form a ( 20 . 0 g ) is suspended in tbme ( 100 ml ) and stirred with a mechanical stirrer at rt . a highly viscous paste is obtained that transforms to a thin fluid suspension of distinct yellow color after stirring for 40 hours . the solid is filtered off and dried for 4 hours under vacuum at rt . the product is identified as form c by xrpd . compound in crystalline form a ( 0 . 5 g ) is dissolved in propionic acid ( 1 ml ). a solid product forms within several hours at room temperature . said solid is isolated by filtration and is compound in crystalline form iii . compound in crystalline form iii is stored under high vacuum (& lt ; 0 . 1 mbar ) for 1 week and then stored open at about 40 % relative humidity and room temperature overnight , yielding the compound in crystalline form ii . sorption isotherms are obtained using a hiden igasorp moisture sorption analyser , controlled by cfrsorp software . the sample temperature is maintained at 25 ° c . by a huber re - circulating water bath . the humidity is controlled by mixing streams of dry and wet nitrogen , with a total flow rate of 250 ml · min − 1 . the relative humidity is measured by a calibrated vaisala rh probe ( dynamic range of 0 - 95 % rh ), located near the sample . the weight change of the sample as a function of % rh is constantly monitored by the microbalance ( accuracy ± 0 . 001 mg ). typically 10 - 20 mg of sample is placed in a tared mesh stainless steel basket under ambient conditions . the sample is loaded and unloaded at 40 % rh and 25 ° c . ( typical room conditions ). a moisture sorption isotherm is performed as outlined below ( 2 scans giving 1 complete cycle ). the standard isotherm is performed at 25 ° c . at 10 % rh intervals over a 0 - 90 % rh range . the software uses a least squares minimisation procedure together with a model of the mass relaxation , to predict an asymptotic value . the measured mass relaxation value must be within 5 % of that predicted by the software , before the next % rh value is selected . the minimum equilibration time is set to 1 hour and the maximum to 4 hours . classification is done according to the european pharmacopea technical guide ( 1999 edition ) ( e . g . slightly hygroscopic : increase in mass is less than 2 % and equal to or greater than 0 . 2 % mass / mass ; hygroscopic : increase in mass is less than 15 % and equal to or greater than 2 % mass / mass ). the mass change between 40 % relative humidity and 80 % relative humidity in the first adsorption scan is considered . capsules containing 10 mg , 20 mg , or 40 mg of compound in crystalline form a or c the intragranular materials are sieved in a high shear mixer e . g . a diosna where they are mixed together during the dry blending step . water is added to the dry blend of intra - granular materials whilst mixing until suitable granules of suitable size are formed during the wet granulation step . the granules are then dried in a fluid bed dryer and milled using a screen of suitable porosity . all the extra - granular materials except magnesium stearate are passed through a 1000 μm screen and mixed with the granules . the magnesium stearate is then sieved together with a given amount of the previous blend and added to the rest of the powder blend . the final mixture is further blended . the powder is then filled in size “ 0 ”, white - opaque hard gelatine capsules . the intragranular materials are sieved in a high shear mixer e . g . a diosna where they are mixed together during the dry blending step . water is added to the dry blend of intra - granular materials whilst mixing until suitable granules of suitable size are formed during the wet granulation step . the granules are then dried in a fluid bed dryer and milled using a screen of suitable porosity . all the extra - granular materials except magnesium stearate are passed through a 1000 μm screen and mixed with the granules . the magnesium stearate is then sieved together with a given amount of the previous blend and added to the rest of the powder blend . the final mixture is further blended . the powder is then transferred on suitable tabletting equipment for compression . the tablets are then coated with opadry ii brown at 4 % w / w gain during coating .
the invention relates to crystalline forms of - 5 -- benzylidene ]- 2 -- propylimino )- 3 - o - tolyl - thiazolidin - 4 - one , processes for the preparation thereof , pharmaceutical compositions containing said crystalline forms , and their use as compounds improving vascular function and as immunomodulating agents , either alone or in combination with other active compounds or therapies .