KINETICS OF RACEMIZATION OF (-DIETHYLPROPION AND (-)-DIETHYLPROPION -STUDIES IN AQUEOUS-SOLUTION, WITH AND WITHOUT THE ADDITION OF CYCLODEXTRINS, IN ORGANIC-SOLVENTS AND IN HUMAN PLASMA())

The configurational stability of (+)- and (-)-diethylpropion [(+)- and (-)-2-(diethyl)-1-phenyl-1-propanone or (+)- and (-)-DEP] was investi gated systematically from chemical, pharmaceutical, and pharmacologica l aspects. The enantiomeric ratio was monitored directly with a recent ly developed stability-indicating enantioselective HPLC method. In aqu eous solutions, the rate of racemization increased non-linearly with i ncreasing pH and with increasing phosphate buffer concentration. The r acemization rate showed a positive slope with increasing temperature a nd decreasing ionic strength. The racemization rates of (+)- and (-)-D EP in the presence of cyclodextrins (CDs) did not differ significantly . CDs that were added to (+)- and (-)-DEP in a molar ratio 5:1 showed the following effects after dissolution in 10 mM phosphate buffer (fin al pH 6.7): sulfobutyl ether-beta-CD (SBE-beta-CD) and methylated-beta -CD (Me-beta-CD) retarded racemization; whereas hydroxypropyl-beta-CD (HP-beta-CD), acetyl-gamma-2D (Ac-gamma-CD), acetyl-beta-CD (Ac-beta-C D), gamma-CD, and beta-CD showed a weak destabilising effect. In contr ast to the described CDs, alpha-CD distinctly accelerated the rate of racemization. The configurational stability of (+)- and (-)-DEP was al so studied under physiological conditions. The half-life of racemizati on in heparinised human plasma was for both enantiomers determined to be approximately 23-25 min. In phosphate buffer (10 mM, pH 7.4), rac-D EP showed a high, but unselective affinity towards human alpha(1)-acid glycoprotein (orosomucoid) immobilised on silica (Chiral AGP). The ra te of racemization of the free base of (-)-DEP dissolved in organic so lutions generally increases with the polarity of the solvating agent. (C) 1998 Wiley-Liss, Inc.