The configurational stability of (+)-and (-)-diethylpropion [(+)-and (-)-2-(diethyl)-1-phenyl-1-propanone or (+)-and (-)-DEP] was investigated systematically from chemical, pharmaceutical, and pharmacological aspects. The enantiomeric ratio was monitored directly with a recently developed stability-indicating enantioselective HPLC method.
In aqueous solutions, the rate of racemization increased non-linearly with increasing pH and with increasing phosphate buffer concentration. The racemization rate showed a positive slope with increasing temperature and decreasing ionic strength.
The racemization rates of (+)-and (-)-DEP 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 (final pH 6.7): sulfobutyl ether--CD (SBE--CD) and methylated--CD (Me--CD) retarded racemization; whereas hydroxypropyl--CD (HP--CD), acetyl-␥-CD (Ac-␥-CD), acetyl--CD (Ac--CD), ␥-CD, and -CD showed a weak destabilising effect. In contrast to the described CDs, ␣-CD distinctly accelerated the rate of racemization.
The configurational stability of (+)-and (-)-DEP was also studied under physiological conditions. The half-life of racemization in heparinised human plasma was for both enantiomers determined to be approximately 23-25 min.
In phosphate buffer (10 mM, pH 7.4), rac-DEP showed a high, but unselective affinity towards human ␣ 1 -acid glycoprotein (orosomucoid) immobilised on silica (Chiral AGP).
The rate of racemization of the free base of (-)-DEP dissolved in organic solutions generally increases with the polarity of the solvating agent. Chirality 10: 307-315, 1998.