Crystalline forms of 1,6-Bis [3-(3-carboxymethylphenyl)-4-(2-alpha-D-mannopyranosyl-oxy)-phenyl] hexane

Abstract

The novel crystalline and polymorphic forms of 1,6-Bis [3-(3-carboxymethylphenyl)-4-(2-α-D-mannopyranosyloxy)-phenyl] hexane have advantageous properties and can be used in pharmaceutical and dermatological compositions.

1 . A polymorph of the compound of formula (I) 
     
       
         
         
             
             
         
       
     
     selected from the group of polymorphs FORM 1, FORM 2, FORM 3, FORM 4, FORM 5 and FORM 6. 
   
   
       2 . (canceled) 
   
   
       3 . A crystalline polymorph according to  claim 1  which consists of FORM 1 and is further characterized in that it provides an X-ray powder diffraction pattern for this crystalline form which shows the following diffraction angles (2Theta) based on cupric K α1 : at approximately 4.8° (strong peak). 
   
   
       4 . A crystalline polymorph according to  claim 1  which consists of FORM 2 and is further characterized in that it provides an X-ray powder diffraction pattern for this crystalline form which shows the following diffraction angles (2Theta) based on cupric K α1 :
 at approximately 5.3° (strong peak),   at approximately 5.6° (strong peak),   at approximately 17.4° (strong peak), and   at approximately 15.1° (medium peak).   
   
   
       5 . A crystalline polymorph according to  claim 1  which consists of FORM 3 and is further characterized in that it provides an X-ray powder diffraction pattern for this crystalline form which shows the following diffraction angles (2Theta) based on cupric K α1 :
 at approximately 5.3° (strong peak),   at approximately 5.6° (strong peak),   at approximately 4.2° (medium peak),   at approximately 4.3° (medium peak), and   at approximately 4.8° (medium peak).   
   
   
       6 . A crystalline polymorph according to  claim 1  which consists of FORM 4 and is further characterized in that it provides an X-ray powder diffraction pattern for this crystalline form which shows the following diffraction angles (2Theta) based on cupric K α1 :
 at approximately 16.8° (strong peak),   at approximately 26.5° (strong peak),   at approximately 19.7° (stronger medium peak), and   at approximately 21.5° (stronger medium peak)   
   
   
       7 . A crystalline polymorph according to  claim 1  which consists of FORM 5 and is further characterized in that it provides an X-ray powder diffraction pattern for this crystalline form which shows the following diffraction angles (2Theta) based on cupric K α1 :
 at approximately 5.2° (strong peak),   at approximately 5.6° (strong peak),   at approximately 21.4° (strong peak),   at approximately 16.5° (stronger medium peak),   at approximately 18.7° (stronger medium peak),   at approximately 20.0° (stronger medium peak), and   at approximately 20.6° (stronger medium peak).   
   
   
       8 . A crystalline polymorph according to  claim 1  which consists of FORM 6 and is further characterized in that it provides an X-ray powder diffraction pattern for this amorphous form which shows a broad peak at the diffraction angles (2Theta) of approximately 19.6°. 
   
   
       9 .- 13 . (canceled) 
   
   
       14 . A crystalline polymorph according to  claim 1  which provides an X-ray powder diffraction pattern substantially in accordance with  FIG. 1 . 
   
   
       15 . A crystalline polymorph according to  claim 1  which provides an X-ray powder diffraction pattern substantially in accordance with  FIG. 2 . 
   
   
       16 . A crystalline polymorph according to  claim 1 , which provides an X-ray powder diffraction pattern substantially in accordance with  FIG. 3 . 
   
   
       17 . A crystalline polymorph according to  claim 1 , which provides an X-ray powder diffraction pattern substantially in accordance with  FIG. 4 . 
   
   
       18 . A crystalline polymorph according to  claim 1 , which provides an X-ray powder diffraction pattern substantially in accordance with  FIG. 5 . 
   
   
       19 . An amorphous polymorph according to  claim 1 , which provides an X-ray powder diffraction pattern substantially in accordance with  FIG. 6 . 
   
   
       20 .- 22 . (canceled) 
   
   
       23 . Use of a polymorph of the compound of formula (I) according to  claim 1  for the preparation of a pharmaceutical composition. 
   
   
       24 . A pharmaceutical composition comprising a polymorph according to  claim 1  and at least one further pharmaceutically acceptable component. 
   
   
       25 . A pharmaceutical composition according to  claim 24  for the treatment, diagnosis and/or prophylaxis of inflammatory diseases or conditions. 
   
   
       26 . A pharmaceutical composition comprising a polymorph according to  claim 1 , at least one further active pharmaceutical ingredient and at least one further pharmaceutically acceptable component. 
   
   
       27 . A pharmaceutical composition according to  claim 26  for the treatment, diagnosis and/or prophylaxis of inflammatory diseases or conditions. 
   
   
       28 .- 29 . (canceled) 
   
   
       30 . A process for the preparation of a polymorph according to  claim 1  characterized in that the following process steps are applied:
 a) Add compound of formula (I) to a mixture of water and a lower alcohol (e.g. ethanol or isopropyl alcohol) in a reactor.   b) Heat the mixture to a temperature of about 10° C. under its atmospheric boiling point and stir until dissolution.   c) Cool the reaction mixture to a temperature between 0° C. and 25° C. and stir the reaction mixture between 0° C. and 25° C. for 30 minutes up to 20 hours.   d) Filter the suspension.   e) Wash the filter cake with a mixture of water and a lower alcohol (e.g. ethanol or isopropyl alcohol) previously cooled to a temperature between 0° C. and 25° C.   f) Suspend the wet filter cake obtained from the filtration in a mixture of water and a lower alcohol (e.g. ethanol or isopropyl alcohol) in a reactor.   g) Heat the mixture to a temperature of about 10° C. under its atmospheric boiling point and stir until dissolution.   h) Transfer the reaction mixture from the reactor into another reactor, through a filter with a maximum porosity of 1 μm.   i) Wash the filtration line with a mixture of water and a lower alcohol (e.g. ethanol or isopropyl alcohol) previously heated to a temperature of about 10° C. under its atmospheric boiling point.   j) Concentrate the mixture, under vacuum.   k) Set the solution's Karl Fischer at a value between 30% and 60%, by addition of water.   l) Cool the reaction mixture to a temperature between 0° C. and 25° C. and stir the reaction mixture between 0° C. and 25° C. for 30 minutes up to 20 hours.   m) Filter the suspension.   n) Wash the filter cake with a mixture of water and a lower alcohol (e.g. ethanol or isopropyl alcohol) previously cooled to a temperature between 0° C. and 25° C.   o) Add the filter cake from step 14 above into a reactor charged with water.   p) Add (in relation to the amount of compound of formula (I)) at least 2 molar equivalents of a 1M aqueous solution of sodium hydroxide, prepared by dissolution of pure sodium hydroxide in water and stir the mixture until total dissolution.   q) Add an adsorbent agent (1 to 10 molar equivalents) to reaction mixture.   r) Stir the reaction mixture until a purity higher than or equal to 99.0% is reached (in process control of purity by HPLC).   s) Filter the reaction mixture, from the reactor into another reactor, R 2 , through a filter, F 1 , with a maximum porosity of 1 μm.   t) Wash the filter cake with water, passing the washings through F 1  to R 2 .   u) Charge a mixture of water and a lower alcohol (e.g. ethanol or isopropyl alcohol) into R 2 , through F 1 .   v) Add (in relation to the amount of sodium hydroxide in step 16) an equimolar amount of a 1M solution of hydrochloric acid, prepared by dissolution of hydrochloric acid in water, through F 1 .   w) Cool the reaction mixture to a temperature between 0° C. and 25° C. and stir the reaction mixture between 0° C. and 25° C. for 30 minutes up to 20 hours.   x) Filter the suspension.   y) Wash the filter cake with a mixture of water and a lower alcohol (e.g. ethanol or isopropyl alcohol), previously filtered through F 1 .   z) Dry the product, under vacuum, at a temperature of about 50° C., until water content, by Karl Fischer, is less than 1.5%.   
   
   
       31 . A process for the preparation of a polymorph according to  claim 1  characterized in that the following process steps are applied:
 a) Add compound of formula (I) to a mixture of water and a lower alcohol (e.g. ethanol or isopropyl alcohol) in a reactor.   b) Heat the mixture to a temperature of about 10° C. under its atmospheric boiling point and stir until dissolution.   c) Cool the reaction mixture to a temperature between 0° C. and 25° C. and stir the reaction mixture between 0° C. and 25° C. for 30 minutes up to 20 hours.   d) Filter the suspension.   e) Wash the filter cake with a mixture of water and a lower alcohol (e.g. ethanol or isopropyl alcohol) previously cooled to a temperature between 0° C. and 25° C.,   f) Suspend the wet filter cake obtained from the filtration in a mixture of water and a lower alcohol (e.g. ethanol or isopropyl alcohol) in a reactor.   g) Heat the mixture to a temperature of about 10° C. under its atmospheric boiling point and stir until dissolution.   h) Transfer the reaction mixture from the reactor into another reactor, through a filter with a maximum porosity of 1 μm.   i) Wash the filtration line with a mixture of water and a lower alcohol (e.g. ethanol or isopropyl alcohol) previously heated to a temperature of about 10° C. under its atmospheric boiling point.   j) Concentrate the mixture, under vacuum.   k) Set the solution's Karl Fischer at a value between 30% and 60%, by addition of water.   l) Cool the reaction mixture to a temperature between 0° C. and 25° C. and stir the reaction mixture between 0° C. and 25° C. for 30 minutes up to 20 hours.   m) Filter the suspension.   n) Wash the filter cake with a mixture of water and a lower alcohol (e.g. ethanol or isopropyl alcohol) previously cooled to a temperature between 0° C. and 25° C.   o) Dry the product, under vacuum, at a temperature of about 40° C. to 60° C., until water content, by Karl Fischer, is less than 3%.   
   
   
       32 . (canceled)