A contribution to the design of solid state drug properties.

OLIVERA, M.E.; RAMÍREZ RIGO, M.V; BASCHINI, M.; MANZO, R. H.

Orlando- Florida- E.E.U.U.

Congreso; Pharmaceutical Congress of the Americas.; 2001

American Association of Pharmaceutical Scientists

  Purpose: among a set of potential antiarrithmic derivatives of the structure p-HOOC-R-CO-NH-C6H4-CO-X-C2H5-N(C2H5)2, compounds I (R= -C2H5-, X= -NH-, mp= 186.2ºC) and II (R= -C2H5-, X= -O-, mp= 156.9ºC) although having similar acid-base speciation (zwiterionic (+-) to neutral (00) forms ratio of 104)exhibited rather different aqueous solubility (S). SI was 14 times higher than SII with a difference in free energy of solution (DDFR) of 1.17 Kcal/mol. Similar behavior was observed with III (R= -CH=CH-, X= -NH-) and IV (R= -CH=CH-, X= -O-). Such differences are far to be accounted for only by changes in excess free energy (DFE). Then, the goal was identify differences in the solid state properties of I, III versus II, IV to be further relates to the structural changes introduced in the compounds. Methods. Solid samples were subjected to infrared spectroscopy, thermal analysis (DSC, TGA), NMR and powder X-Ray diffraction. Molecular modeling and analysis of thermodynamic parameters were also performed. Results. FTIR spectroscopy of hydrochlorides of I to IV and compounds II and IV showed a strong band at about 1725 cm-1 assignable to C=O (COOH) st. vibration. In contrast, compounds II and IV showed a strong band but a new one assignable to C=O (COO-) appeared.  DSC showed that enthalpy of fusion (DHff) of I and III were higher than those of II and IV. Conclusions. FTIR spectroscopy would indicate that I and III are as (+-) and II and IV as (00). I and III exhibited higher DHff and at the same time higher solubility than II and IV. This apparent inconsistency would be accounted for by considering that solubility equilibria of I and III are determined by (+-) solid ó (+-) soln.