Stable hydrate of a muscarinic receptor antagonist

Abstract

A stable solid hydrate of a muscarinic receptor antagonist is useful in the treatment of irritable bowel syndrome, diverticular disease, oesophageal achalasia, chronic obstructive airways disease, over active bladder (including symptoms of incontinence, urge and frequency), urinary incontinence, neurogenic urinary urgency or pollakiuria, treatment of bladder functional disorder, urinary leakage, painful or difficult urination caused by neurogenic bladder, spastic or hypertonic bladder, dysfunctional bladder syndrome, gastrointestinal disorders including gastrointestinal hyperactivity, and relaxing effect on intestinal smooth muscle cells.

1 . A stable solid hydrate of darifenacin.  
     
     
         2 . A hydrate according to  claim 1 , possessing a stoichiometry of from about 1:0.6 to 1:1 of darifenacin:water.  
     
     
         3 . A hydrate according to  claim 1 , having the formula (IX):  
       
         
           
           
               
               
           
         
       
     
     
         4 . A hydrate according to  claim 1  characterised by an infra-red spectrum, run using single reflection ATR (attenuated total reflectance), which shows significant absorption bands at ν max.  (cm −1 ): 3625, 3516, 3440, 2948, 2806, 1699, 1622, 1597, 1578, 1488, 1471, 1445, 1378, 1353, 1325, 1312, 1280, 1242, 1196, 1152, 1119, 1102, 1086, 1024, 981, 939, 925, 900.  
     
     
         5 . A hydrate according to  claim 1  which is characterised by a powder X-ray diffraction pattern obtained using copper radiation (λ=0.15405 nm) which shows main peaks at 8.39, 10.519, 13.272, 13.693, 15.908, 16.289, 16.855, 19.637, 21.135, 21.55, 21.722, 23.006, and 26.284 degrees 2θ.  
     
     
         6 . A hydrate according to  claim 1  which is characterised by a differential scanning calorimetry (DSC) trace showing a sharp endotherm at 101° C. at a scan rate of 2° C./min.  
     
     
         7 . A pharmaceutical composition comprising a hydrate according to  claim 1  together with a pharmaceutically acceptable excipient, diluent or carrier.  
     
     
         8 - 10 . (canceled)  
     
     
         11 . A composition according to  claim 7  wherein said composition is suitable for topical transdermal administration.  
     
     
         12 . A composition according to  claim 7  wherein said composition is suitable for buccal administration.  
     
     
         13 . A method of treatment of a mammal to cure or prevent a medical condition for which an antagonist of muscarinic receptors is indicated, which comprises administering to said mammal an effective amount of a compound according to  claim 1 .  
     
     
         14 . A method according to  claim 13  wherein, said medical condition is selected from irritable bowel syndrome, diverticular disease, oesophageal achalasia, chronic obstructive airways disease, over active bladder (including symptoms of incontinence, urge and frequency), urinary incontinence, neurogenic urinary urgency or pollakiuria, treatment of bladder functional disorder, urinary leakage, painful or difficult urination caused by neurogenic bladder, spastic or hypertonic bladder, dysfunctional bladder syndrome, gastrointestinal disorders including gastrointestinal hyperactivity, and relaxing effect on intestinal smooth muscle cells.  
     
     
         15 - 20 . (canceled)  
     
     
         21 . A process for providing hydrate, as defined in  claim 1 , in pharmaceutically pure form comprising subjecting (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide to an ionic exchange resin treatment followed by conversion to a toluene solvate which is in turn converted to said hydrate.  
     
     
         22 . A process according to  claim 21  further including the step of converting the hydrate to an acid addition salt of (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide.  
     
     
         23 . A process according to  claim 22 , wherein said acid addition salt is the hydrobromide salt.