SYNTHESIS, IDENTIFICATION, CHARACTERIZATION, STABILITY, SOLUBILITY, AND PROTEIN-BINDING OF ESTER DERIVATIVES OF SALICYLIC-ACID AND DIFLUNISAL

O-Acyl esters were prepared from salicylic acid and diflunisal by este rification with the appropriate acyl anhydride (in the presence of sul furic acid at 80 degrees C) or acyl chloride (in the presence of pyrid ine at 0 degrees C). Synthesis, identification and characterization of these compounds is described. In vitro hydrolysis, solubility and pro tein binding studies of these O-acyl esters were performed. For the di flunisal esters, the melting points fell as the side chain was increas ed from ethyl to pentyl. The melting points showed no significant diff erence as the length of the side chain was increased from pentyl to he ptyl. The aspirin analogues showed a similar trend, The relationship b etween solubility and carbon chain length agreed closely with that for the melting points with carbon chain length. In vitro non-enzymatic h ydrolysis studies concluded that: (1) hydrolysis rate constants genera lly decreased with carbon chain length; (2) the diflunisal esters have shorter half lives compared with their salicylate counterparts; and ( 3) the in vitro hydrolysis of these compounds was retarded by the pres ence of bovine serum albumin. Protein binding experiments showed that the strength of binding of the aspirin and diflunisal analogues to bov ine serum albumin increased with carbon chain length. (C) 1997 Elsevie r Science B.V.