Crystalline forms

Abstract

There is provided EtO 2 C—CH 2 —(R)Cgl-Aze-Pab-OH, or a pharmaceutically-acceptable salt thereof, in a form which is substantially crystalline. It has been found that crystalline forms of EtO 2 C—CH 2 —(R)Cgl-Aze-Pab-OH have a high chemical and solid state stability when compared to amorphous forms of the compound.

1 . A substantially crystalline form of EtO 2 C—CH 2 —(R)Cgl-Aze-Pab-OH, or a pharmaceutically-acceptable salt thereof.  
     
     
         2 . A stable form of EtO 2 C—CH 2 —(R)Cgl-Aze-Pab-OH, or a pharmaceutically-acceptable salt thereof.  
     
     
         3 . EtO 2 C—CH 2 —(R)Cgl-Aze-Pab-OH, or a pharmaceutically-acceptable salt thereof, in a form which has a high stability.  
     
     
         4 . A compound as claimed in  claim 1 , which is not in the form of a salt, and which is in the form of an anhydrate.  
     
     
         5 . A compound as claimed in  claim 1  that contains no more than 2% (w/w) water.  
     
     
         6 . A compound as claimed in  claim 4  characterised by a differential scanning calorimetry curve, at a heating rate of 5° C./min in a closed cup with a pinhole under flowing nitrogen, exhibiting an endotherm with an extrapolated onset temperature of about 150° C., a peak temperature of about 151° C., and an associated heat of about 113 J/gram, followed by an exotherm in the region 190-280° C.; and/or a X-ray powder diffraction pattern characterized by peaks with d-values at 12.0, 10.0, 8.2, 7.2, 6.0, 5.5, 5.0, 4.92, 4.85, 4.80, 4.42, 4.22, 4.11, 4.06, 3.99, 3.78, 3.72, 3.62, 3.34, 3.11, 3.10 and 3.03 Å.  
     
     
         7 . A compound as claimed in  claim 4  characterised by a differential scanning calorimetry curve, at a heating rate of 5° C./min in a closed cup with a pinhole under flowing nitrogen, exhibiting an endotherm with an extrapolated onset temperature of about 169° C., a peak temperature of about 170° C., and an associated heat of about 142 J/gram, followed by an exotherm in the region 180-280° C.; and/or a X-ray powder diffraction pattern characterized by peaks with d-values at 12.0, 11.1, 8.8, 7.2, 6.8, 6.6, 6.5, 6.4, 6.0, 5.8, 5.6, 5.3, 5.2, 4.75, 4.52, 4.39, 4.31, 4.29, 4.25, 4.06, 4.00, 3.82, 3.73, 3.71, 3.69, 3.66, 3.59, 3.55, 3.41, 3.37, 3.34, 3.29, 3.25, 3.22, 3.10, 3.03, 3.00, 2.91, 2.78, 2.73, 2.62, 2.51, 2.46, 2.40, 2.38, 2.34, 2.29, 2.26 Å.  
     
     
         8 . A compound as claimed in  claim 1  which is not in the form of a salt, and which is in the form of a monohydrate.  
     
     
         9 . A compound as claimed in  claim 8 , characterised by a differential scanning calorimetry curve, at a heating rate of 5° C./min in a closed cup with a pinhole under flowing nitrogen, exhibiting an endotherm with an extrapolated onset temperature of about 94° C., a peak temperature of about 109° C., and an associated heat of about 171 J/gram, followed by an exotherm in the region 170-290° C.; and/or a X-ray powder diffraction pattern characterized by peaks with d-values at 16.4, 13.7, 9.4, 8.2, 7.1, 6.2, 5.5, 5.1, 4.98, 4.75, 4.68, 4.57, 4.48, 4.27, 4.21, 4.11, 4.04, 3.93, 3.89, 3.83, 3.68, 3.52, 3.47, 3.34, 3.26, 3.02, 2.61 and 2.42 Å.  
     
     
         10 . A compound as claimed in  claim 1  which is in the form of a hydrobromide salt.  
     
     
         11 . A compound as claimed in  claim 10 , characterised by a differential scanning calorimetry curve, at a heating rate of 5° C./min in a closed cup with a pinhole under flowing nitrogen, exhibiting an endotherm with an extrapolated onset temperature of about 166° C., a peak temperature of about 167° C., and an associated heat of about 69 J/gram, followed by an exotherm in the region 170-220° C.; and/or a X-ray powder diffraction pattern characterized by peaks with d-values at 12.0, 10.1 9.5, 6.0, 5.7, 5.6, 5.2, 5.1, 4.95, 4,74, 4.57, 4.41, 4.35, 4.17, 4.07, 4.03, 3.92, 3.82, 3.72, 3.69, 3.62, 3.51, 3.48, 3.38, 3.25, 3.06, 2.92, 2.86, 2.71, 2.53 and 2.33 Å.  
     
     
         12 . A compound as claimed in  claim 1  which is in the form of a methanesulphonate salt.  
     
     
         13 . A compound as claimed in  claim 12 , characterised by a differential scanning calorimetry curve, at a heating rate of 5° C./min in a closed cup with a pinhole under flowing nitrogen, exhibiting an endotherm with an extrapolated onset temperature of about 134° C., a peak temperature of about 137° C, and an associated heat of about 93 J/gram, followed by an exotherm in the region 140-220° C.; and/or a X-ray powder diffraction pattern characterized by peaks with d-values at 12.0, 11.7, 10.4, 10.2, 8.3, 7.8, 6.0, 5.6, 5.5, 5.2, 5.1, 5.0, 4.98, 4.90, 4.75, 4.63, 4.54, 4.46, 4.15, 4.06, 3.92, 3.84, 3.74, 3.65, 3.56, 3.47, 3.39, 3.22, 3.12, 2.95, 2.88, 2.76, 2.74, 2.69, 2.65, 2.54, 2.52, 2.49, 2.27, 2.21, 2.04 and 2.02 Å.  
     
     
         14 . A process for the production of a compound as claimed in  claim 1 , which comprises crystallising EtO 2 C—CH 2 —(R)Cgl-Aze-Pab-OH, or a pharmaceutically acceptable salt thereof.  
     
     
         15 . A process as claimed in  claim 14 , which comprises crystallising EtO 2 C—CH 2 —(R)Cgl-Aze-Pab-OH, or the salt, from a solvent.  
     
     
         16 . A process as claimed in  claim 15 , wherein the solvent is selected from the group: acetates, lower alkyl alcohols, aliphatic and aromatic hydrocarbons, dialkyl ethers, dialkyl ketones, acetonitrile, aqueous solvents, or mixtures thereof.  
     
     
         17 . A process as claimed in  claim 16  wherein the solvent is selected from the group: C 1-6  alkyl acetates, linear or branched C 1-6  alkyl alcohols, C 6-12  aliphatic hydrocarbons, C 6-10  aromatic hydrocarbons, di-C 1-6  alkyl ethers, di-C 1-6  alkyl ketones, acetonitrile, water, or mixtures thereof.  
     
     
         18 . A process as claimed in  claim 17  wherein the solvent is selected from the group: ethyl acetate, butyl acetate, ethanol, isopropanol, isooctane, n-heptane, toluene, di-isopropyl ether, acetone, methyl isobutyl ketone, acetonitrile, water, or mixtures thereof.  
     
     
         19 . A process for the production of a compound as claimed  claim 4 , which comprises a process as defined above, in which the solvent is substantially free of water.  
     
     
         20 . A process for the production of a compound as claimed in  claim 4 , which comprises a process as defined above, in which the solvent contains water.  
     
     
         21 . A process for the production of a compound as claimed in  claim 8 , which comprises a process as defined above, in which the solvent contains water.  
     
     
         22 . A process for the conversion of one crystalline form of a compound as claimed in  claim 1  to another which comprises recrystallising a compound as claimed in  claim 1  from an appropriate solvent system.  
     
     
         23 . A compound obtainable by a process according to  claim 14 .  
     
     
         24 . A compound as claimed in  claim 1  for use as a pharmaceutical.  
     
     
         25 . A compound as claimed in  claim 1  for use as a prodrug.  
     
     
         26 . A pharmaceutical formulation including a compound as defined in  claim 1  in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.  
     
     
         27 . The use of compound as defined in  claim 1  for the manufacture of a medicament for the treatment of a condition where inhibition of thrombin is required or desired.  
     
     
         28 . A method of treatment of a condition where inhibition of thrombin is required or desired which method comprises administering a therapeutically effective amount of a compound according to  claim 1  to a patient in need of such treatment.