title: Impact of the counterion on the solubility and physicochemical properties of salts of carboxylic acid drugs.
abstract: OBJECTIVE
  Salt formation is a widely used approach to improve the physicochemical and solid state properties of an active pharmaceutical ingredient. In order to better understand the relationships between the active drug, the selected counterion and the resultant salt form, crystalline salts were formed using four different carboxylic acid drugs and a closely related series of amine counterions. Thirty-six related crystalline salts were prepared, characterized and the relationship between solubility and dissolution behaviour and other properties of the salt and the counterion studied.
  
  
  METHODS
  Salts of four model acid drugs, gemfibrozil, flurbiprofen, ibuprofen and etodolac were prepared using the counterions butylamine, hexylamine, octylamine, benzylamine, cyclohexylamine, tert-butylamine, 2-amino-2-methylpropan-1-ol, 2-amino-2-methylpropan-1,3-diol and tris(hydroxymethyl)aminomethane. Salt formation was confirmed, the salts were characterized and their corresponding solubilities determined and rationalized with respect to the counterions' properties.
  
  
  CONCLUSIONS
  The properties of the salt highly dependent on the nature of the counterion and, although there is considerable variation, some general conclusion can be drawn. For the alkyl amines series, increasing chain length leads to a reduction in solubility across all the acidic drugs studied and a reduction in melting point, thus contradicting simplistic relationships between solubility and melting point. Small, compact counterions consistently produce crystalline salts with high melting point accompanied with a modest improvement in solubility and the nature of hydrogen bonding between the ions has a major impact on the solubility.
authors: Formulation Process and Analysis, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex.
authors: S E
authors: SE
authors: David
authors: P
authors: P
authors: Timmins
authors: B R
authors: BR
authors: Conway
mesh_terms: D000588:Amines / Q000737:chemistry; D002264:Carboxylic Acids / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization / Q000379:methods; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D007477:Ions / Q000737:chemistry; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012492:Salts / Q000737:chemistry*; D012995:Solubility; D044366:Transition Temperature
chemical_list: D000588:Amines; D002264:Carboxylic Acids; D007477:Ions; D004364:Pharmaceutical Preparations; D012492:Salts