Crystal form comprising lithium ions, pharmaceutical compositions thereof, methods for preparation and their uses for the treatment of depressive disease

Abstract

Stable crystal forms comprising lithium ions and the conjugate base of an organic acid which is in the form of anhydrous coordination polymer that exhibit improved in vivo performance with respect to lithium carbonate.

1 . A stable crystal form comprising lithium ions and a conjugate base of an organic acid which is in the form of anhydrous coordination polymer. 
     
     
         2 . A stable crystal form according to  claim 1  wherein the organic acid is a carboxylic acid. 
     
     
         3 . A stable crystal form according to  claim 2  wherein the carboxylic acid is selected from aromatic carboxylic acids and dicarboxylic acid other than salicylic acid or benzoic acid. 
     
     
         4 . A stable crystal form according to  claim 3  wherein the carboxylic acid is selected from fumaric acid, succinic acid and 4-methoxybenzoic acid. 
     
     
         5 . A stable crystal form according to  claim 1  which includes one or more further molecules. 
     
     
         6 . A stable crystal form according to  claim 5  wherein the one or more further molecules is selected from isonicotinamide, nicotinamide, L-proline and 4-hydroxyproline. 
     
     
         7 . A stable crystal form according to  claim 1  which is selected from:
 (a) an anhydrous coordination polymer comprising lithium cations, fumarate anions and isonicotinamide molecules, suitably in a molar ratio of 2:1:2; 
 (b) an anhydrous coordination polymer comprising lithium cations, succinate anions and isonicotinamide molecules, suitably in molar ratio of 2:1:2; and 
 (c) an anhydrous coordination polymer comprising lithium cations, 4-methoxybenzoate anions and L-proline molecules, suitably in a molar ratio of 1:1:1. 
 
     
     
         8 . A method of preparing a crystal form according to  claim 1 , the method comprising dissolving lithium hydroxide, an organic acid and optionally one or more further molecules, in a solvent and allowing the solvent to evaporate. 
     
     
         9 . A pharmaceutical composition comprising a drug substance which is a stable crystal form as claimed in  claim 1 . 
     
     
         10 . A method of preparing a pharmaceutical composition, the method comprising preparing a crystal form according to the method of  claim 8  and optionally admixing the crystal form with one or more additional pharmaceutically acceptable ingredients. 
     
     
         11 - 13 . (canceled) 
     
     
         14 . A method of treating a mental illness, the method comprising administering to a patient the pharmaceutical composition of  claim 9 . 
     
     
         15 . A method of treating a patient, the method comprising administering to the patient a stable crystal form comprising lithium ions and a conjugate base of an organic acid which is in the form of an anhydrous coordination polymer as defined in  claim 1 . 
     
     
         16 . The method according to  claim 15  which provides one or more advantages compared to treatment with lithium carbonate selected from:
 an enhanced therapeutic effect for a given dose of lithium; 
 a reduction in toxicity; 
 a reduced dose to achieve the same therapeutic effect; 
 less frequent administration; and 
 improved compliance. 
 
     
     
         17 . A compound comprising lithium ions, a conjugate base of one or more acids selected from fumaric acid, succinic acid and 4-methoxybenzoic acid and a further molecule selected from isonicotinamide and L-proline. 
     
     
         18 . A compound according to  claim 17  which is selected from:
 (a) a compound comprising lithium cations, fumarate anions and isonicotinamide molecules, suitably in a molar ratio of 2:1:2; 
 (b) a compound comprising lithium cations, succinate anions and isonicotinamide molecules, suitably in molar ratio of 2:1:2; and 
 (c) a compound comprising lithium cations, 4-methoxybenzoate anions and L-proline molecules, suitably in a molar ratio of 1:1:1. 
 
     
     
         19 . A pharmaceutical composition comprising a compound as claimed in  claim 17 . 
     
     
         20 . (canceled) 
     
     
         21 . The stable crystal form of  claim 1  which exhibits a lower maximum concentration in blood plasma (C max ) and a later time of maximum concentration in the brain (T max ) after a single oral dose compared with an equivalent single oral dose of lithium carbonate. 
     
     
         22 . A method of treating a depressive disease, the method comprising:
 administering to an individual at least one of the following:
 stable crystal form comprising lithium ions and a conjugate base of an organic acid which is in the form of anhydrous coordination polymer; or 
 a pharmaceutical composition comprising a drug substance which is a stable crystal form comprising lithium ions and a conjugate base of an organic acid which is in the form of anhydrous coordination polymer; or 
 a compound comprising lithium ions, a conjugate base of one or more acids selected from fumaric acid, succinic acid and 4-methoxybenzoic acid and a further molecule selected from isonicotinamide and L-proline.