Stable crystalline noribogaine salt ansolvates

Abstract

Stable noribogaine salt ansolvates are useful for preparing pharmaceutical compositions and for alleviating nociceptive pain in a patient. Such ansolvates can be prepared by slurrying solvated forms, preferably MeOH solvated noribogaine hydrochloride in EtOH/water.

1 . A stable pharmaceutically acceptable salt of noribogaine ansolvate. 
     
     
         2 . The stable salt of noribogaine ansolvate of  claim 1 , wherein the salt is a hydrochloride salt. 
     
     
         3 . The salt of  claim 2 , which is crystalline. 
     
     
         4 . The crystalline salt of  claim 3 , characterized by at least one X-ray powder diffraction peak (Cu Kα radiation) selected from 11.6°, 12.1°, 13.5°, 13.9°, 14.9°, 15.7°, 17.1, 17.9°, 18.3°, 19.8°, 20.8°, 21.0°, 21.9°, 22.8°, 23.3°, 24.9°, 25.9°, 26.4, 29.3°, and 29.8° 2θ (each ±0.2° 2θ). 
     
     
         5 . The crystalline salt of  claim 3 , which shows substantially no thermal transitions under 300° C. in its differential scanning calorimetry thermogram. 
     
     
         6 . The crystalline salt of  claim 3 , which shows substantially no weight loss at a temperature under 300° C. in its thermogravimetric analysis thermogram. 
     
     
         7 . The crystalline ansolvate salt of  claim 3 , which has a density that is at least 3% and up to 20% greater than the density of a solvated crystalline hydrochloride salt of noribogaine. 
     
     
         8 . The crystalline ansolvate salt of  claim 3 , which has a unit cell volume of less than about 1800 cubic angstrom, or less than about 1750 cubic angstrom, or less than 1700±2% cubic angstrom. 
     
     
         9 . A crystalline noribogaine hydrochloride solvate polymorph characterized by about 4% weight loss at temperatures under 125° C. in its differential scanning calorimetry thermogram. 
     
     
         10 . The crystalline solvate polymorph of  claim 9  characterized by at least one X-ray powder diffraction peak (Cu Kα radiation) selected from 9.7, 10.2, 12.0, 13.3, 13.7, 16.0, 16.3, 17.7, 18.0, 19.4, 21.4, 22.1, 22.8, 24.4, 25.1° 2θ (each ±0.2° 2θ). 
     
     
         11 . The stable ansolvate salt of noribogaine of  claim 1 , wherein the salt is a sulfate salt. 
     
     
         12 . The salt of  claim 11 , which is crystalline. 
     
     
         13 . The crystalline salt of  claim 12  characterized by at least one X-ray powder diffraction peak (Cu Kα radiation) selected from 8.5°, 11.4°, 12.0°, 13.3, 15.4°, 16.6°, 17.2°, 18.3° 2θ, 20.6, 21.0, and 21.5 (each ±0.2° 2θ). 
     
     
         14 . A composition comprising the stable noribogaine ansolvate salt of any one of  claims 1 - 8  and  11 - 14 . 
     
     
         15 . The composition of  claim 14 , further comprising a pharmaceutically acceptable excipient. 
     
     
         16 . A crystalline polymorph of a phosphate salt of noribogaine. 
     
     
         17 . A method of treating a patient to alleviate nociceptive pain in the absence of the treatment of drug dependence or drug abuse and in the absence of any concomitant opioid analgesic therapy, comprising: administering systemically to said patient a pharmaceutical composition comprising effective amount of the stable noribogaine salt ansolvate of any one of  claims 1 - 8  and  11 - 14 , or the composition of  claim 14  or  15 , to said patient effective to reduce or eliminate said nociceptive pain in said patient. 
     
     
         18 . A method of treating a patient to alleviate nociceptive pain in the absence of the treatment of drug dependence or drug abuse and in the absence of any concomitant opioid analgesic therapy, comprising: administering systemically to said patient a pharmaceutical composition comprising effective amount of the stable noribogaine salt ansolvate of  claim 1 , or the phosphate salt of  claim 16 , or the composition of  claim 14  or  15 , to said patient effective to reduce or eliminate said nociceptive pain in said patient.