title: Solution and solid state properties of a set of procaine and procainamide derivatives.
abstract: A set of potential Class III antiarrhythmic agents of structure p-HOOC-R-CO-NH-C(6)H(4)-CO-X-C(2)H(5)-N(C(2)H(5))(2) were isolated as crystalline solids of the amide and ester derivatives, I: succinylprocainamide (X=-NH-, R=-C(2)H(4)-); II: succinylprocaine (X=-O-, R=-C(2)H(4)-); III: maleylprocainamide (X=-NH-, R=-C(2)H(2)-) and IV: maleylprocaine (X=-O-, R=-C(2)H(2)-). Although compounds I-IV exhibit similar solution properties (i.e. acid-base speciation, with zwitterionic (+-) to neutral (00) form ratios higher than 10(4)), 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 (+-)(s) but procaine derivatives II and IV as (00)(s). 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)(s) to (+-)(s). 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: (+-)>(+-.H(2)O)>(00.H(2)O).
authors.affiliation: Departamento de Farmacia, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, 5000 Córdoba, Argentina.
authors.forename: María Eugenia
authors.initials: ME
authors.lastname: Olivera
authors.forename: María Veronica
authors.initials: MV
authors.lastname: Ramírez Rigo
authors.forename: Ana Karina
authors.initials: AK
authors.lastname: Chattah
authors.forename: Patricia Rebeca
authors.initials: PR
authors.lastname: Levstein
authors.forename: Miria
authors.initials: M
authors.lastname: Baschini
authors.forename: Ruben Hilario
authors.initials: RH
authors.lastname: Manzo
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis / Q000737:chemistry*; D002250:Carbon Radioisotopes; D003460:Crystallization; D004055:Differential Thermal Analysis; D009682:Magnetic Resonance Spectroscopy; D008970:Molecular Weight; D011342:Procainamide / Q000138:chemical synthesis / Q000737:chemistry*; D011343:Procaine / Q000138:chemical synthesis / Q000737:chemistry*; D012995:Solubility; D012996:Solutions; D017550:Spectroscopy, Fourier Transform Infrared; D013818:Thermogravimetry; D014867:Water / Q000032:analysis
chemical_list: D000889:Anti-Arrhythmia Agents; D002250:Carbon Radioisotopes; D012996:Solutions; D014867:Water; D011343:Procaine; D011342:Procainamide