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

MARÍA EUGENIA, OLIVERA; MARÍA VERÓNICA, RAMIREZ RIGO; CHATTAH KARINA,; LEVSTEIN PATRICIA,; BASCHINI MYRIAM,; RUBEN HILARIO, MANZO

EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES

ELSEVIER SCIENCE BV

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-C6H4-CO-X-C2H5-N(C2H5) 2 were isolated as crystalline solids derivatives of procainamide (where I: X= -NH-, R= -C2H4- and III: X= -NH-, R= -C2H2-) and procaine (where II: X= -O-, R= -C2H4- and IV: X: -O-, R= -C2H2-). Although having similar solution properties (i.e. acid-base speciation, with zwitterionic (+-) to neutral (00) forms ratios higher than 104), 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 -NH- 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 solid form of the precipitating crystals from (00)s to (+-)s. The solid form (zwitterionic or neutral)s, as well as composition (anhydrous or hydrated) of the set of crystalline compounds may be recognized as the main factors in determining the rank of aqueous solubility: (+-) > (+-.H2O) > (00.H2O).