Solution and solid state properties of a set of procaine and procainamide derivatives.
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).
Olivera
María Eugenia
ME
Departamento de Farmacia, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, 5000 Córdoba, Argentina.
Ramírez Rigo
María Veronica
MV
Chattah
Ana Karina
AK
Levstein
Patricia Rebeca
PR
Baschini
Miria
M
Manzo
Ruben Hilario
RH
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
D000889:Anti-Arrhythmia Agents; D002250:Carbon Radioisotopes; D012996:Solutions; D014867:Water; D011343:Procaine; D011342:Procainamide