Solution and solid state properties of a set of procaine and procainamide derivatives.

OLIVERA, M. E; RAMÍREZ RIGO, M.V.; CHATTAH, A. K.; LEVSTEIN, P.R.; BASCHINI, M.; MANZO, R.H.

EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES

Elsevier

Lugar: Amsterdam; Año: 2003 vol. 18 p. 337 - 348

0928-0987

A set of potential Class III antiarrhythmic agents of structure p-HOOC–R–CO–NH–C6 H4 –CO–X–C2 H5 –N(C2 H5 )2 were isolated as crystalline solids of the amide and ester derivatives, I: succinylprocainamide (X=–NH–, R=–C2 H4 –); II: succinylprocaine (X=–O–, –NH–, R=–C2 H4 –); II: succinylprocaine (X=–O–, R=–C2 H 4–); III: maleylprocainamide (X=–NH–, R=–C2 H2 –) and IV: maleylprocaine (X=–O–, R=–C2 H2 –). Although compounds  I–IV exhibit similar solution properties (i.e. acid–base speciation, with zwitterionic (+-) to neutral (00) form ratios higher than 10 exp4 ), aqueous solubility of –NH– derivatives is significantly higher than that of –O– derivatives and also, solvent effects on solubility (i.e. the change of water by ethanol) is clearly different in both series. Solution and solid-state properties of I–IV were characterized to account for the observed differences. Results indicate that procainamide derivatives I and III crystallizes as (+-) but procaine derivatives II and IV as (00) . Besides, I is anhydrous but II–IV are hydrates. Aqueous solubility and solvent effect on solubility are controlled by the intrinsic solubility of the species (+-) in I and III and (00) in II and IV. The rise of hydrophilicity of species (00) due to the structural change from –O– to –NH– would determine the change in the structure of the precipitating crystals from (00) to (+-) . Solid structure zwitterionic or neutral), as well as composition (anhydrous or hydrated) may be recognized as the main factors in determining the rank of aqueous solubility of the set: (+-) mayor que (+-.H2O) mayor que (00.H2O).