Kinetics of racemization of (+)- 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 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-beta-CD (SBE-beta-CD) and methylated-beta-CD (Me-beta-CD) retarded racemization; whereas hydroxypropyl-beta-CD (HP-beta-CD), acetyl-gamma-CD (Ac-gamma-CD), acetyl-beta-CD (Ac-beta-CD), gamma-CD, and beta-CD showed a weak destabilising effect. In contrast to the described CDs, alpha-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 alpha 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.
Mey
B
B
Central Institute, Federal Armed Forces Medical Service, Munich, Germany.
Paulus
H
H
Lamparter
E
E
Blaschke
G
G
D001067:Appetite Depressants / Q000737:chemistry* / Q000494:pharmacology; D001798:Blood Proteins / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D003505:Cyclodextrins / Q000737:chemistry*; D004053:Diethylpropion / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D011485:Protein Binding; D011487:Protein Conformation; D013696:Temperature
D001067:Appetite Depressants; D001798:Blood Proteins; D003505:Cyclodextrins; D004053:Diethylpropion