Polymorphs of donepezil salts, preparation methods and uses thereof

Abstract

Preparation methods of mesylate, para-toluenesulfonate, succinate, tartrate, sulphate, nitrate, phosphate, salicylate, fumarate, maleate, gallate, acetylsalicylate, benzenesulphonate, citrate, aspartate, glutaminate, lactate, gluconate, ascorbate, malonate, malate, sorbate, acetate or formate of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine (i.e., Donepezil). Novel polymorphs formed from these salts and their preparation methods. Co-crystals formed from Donepezil hydrochloride and maleic acid, fumaric acid, citric acid, salicylic acid, tartaric acid or succinic acid.

1 . A polymorph of a compound of formula (I) or a polymorph of a solvate of a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein XH represents salicylic acid, gallic acid, acetylsalicylic acid, maleic acid, or benzoic acid; 
         with a provision that the polymorph of the solvate of the compound of formula (I), when XH represents maleic acid, is excluded. 
       
     
     
         2 . The polymorph of  claim 1 , wherein the polymorph is selected from the group consisting of:
 the polymorph of the compound of formula (I), wherein XH represents salicylic acid, having the following physical characteristics: X-ray powder diffraction pattern as shown in FIG.  8 -A- 1 , infrared absorption spectrum as shown in FIG.  8 -A- 2 , thermogravimetric and differential thermal analysis spectrum as shown in  8 -A- 3 , and nuclear magnetic resonance spectrum as shown in FIG.  8 -A- 4 ; and   the polymorph of the compound of formula (I), wherein XH represents maleic acid, having the following physical characteristics: X-ray powder diffraction pattern as shown in FIG.  10 -B- 1 , infrared absorption spectrum as shown in FIG.  10 -B- 2 , thermogravimetric and differential thermal analysis spectrum as shown in  10 -B- 3 , and nuclear magnetic resonance spectrum as shown in FIG.  10 -B- 4 .   
     
     
         3 . A composition comprising a polymorph of a compound of formula (I), or a polymorph of a solvate of a compound of formula (I) and a pharmaceutically acceptable excipient, wherein the composition is in a form of oral liquids, granules, buccal tablets, effervescent tablets, orally disintegrating tablets, lyophilized rapid dissolving tablets, ordinary tablets or chewable tablets: 
       
         
           
           
               
               
           
         
         wherein XH represents salicylic acid, gallic acid, acetylsalicylic acid, maleic acid, or benzoic acid; 
         with a provision that the polymorph of the solvate of the compound of formula (I), when XH represents maleic acid, is excluded. 
       
     
     
         4 . The composition of  claim 3 , wherein the composition is in the form of orally disintegrating tablets prepared from the following components expressed in weight percentage: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   a compound of formula (I) wherein 
                       1-20% 
                 
                     
                   XH represents salicylic acid, 
                 
                     
                   gallic acid, benzoic acid, or 
                 
                     
                   acetylsalicylic acid: 
                 
                     
                   disintegrant: 
                       1-30% 
                 
                     
                   lubricant: 
                   0.1-10% 
                 
                     
                   colorant: 
                     0-1% 
                 
                     
                   filler: 
                    35-90% 
                 
                     
                   flavoring agent: 
                   0.00-5% 
                 
                     
                   glidant: 
                   0.01-5% 
                 
                     
                   binder: 
                      0-5%. 
                 
                     
                     
                 
             
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         5 . A method for the treatment and/or amelioration of diseases, physiological dysfunctions or pains, which are caused by a low level of acetylcholine, comprising administration of a polymorph of a compound of formula (I), or a polymorph of a solvate of a compound of formula (I) or a composition comprising a polymorph of a compound of formula (I), or a polymorph of a solvate of a compound of formula (I) and a pharmaceutically acceptable excipient to a subject: 
       
         
           
           
               
               
           
         
         wherein XH represents salicylic acid, gallic acid, acetylsalicylic acid, maleic acid, or benzoic acid, 
         with a provision that the polymorph of the solvate of the compound of formula (I), when XH represents maleic acid, is excluded. 
       
     
     
         6 . The method of  claim 5 , wherein the diseases or physiological dysfunctions caused by the low level of acetylcholine include senile dementia (AD), attention deficient disorder of childhood, memory deterioration, paralysis agitans (demeritia), brain injury, multiple sclerosis, Down's Syndrome, delirium, mood disorder, Huntington's disease, and sleep disorder. 
     
     
         7 . The method of  claim 6 , wherein the unit dosage of the polymorph of the compound of formula (I), or the polymorph of the solvate of the compound of formula (I) ranges from 0.5 mg to 50 mg.