Kinetics of racemization of (+)- and (?)-diethylpropion: Studies in aqueous solution, with and without the addition of cyclodextrins, in organic solvents and in human plasma

Abstract

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‐β‐CD (SBE‐β‐CD) and methylated‐β‐CD (Me‐β‐CD) retarded racemization; whereas hydroxypropyl‐β‐CD (HP‐β‐CD), acetyl‐γ‐CD (Ac‐γ‐CD), acetyl‐β‐CD (Ac‐β‐CD), γ‐CD, and β‐CD showed a weak destabilising effect. In contrast to the described CDs, α‐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 α1‐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. © 1998 Wiley‐Liss, Inc.

Racemisation in Chemistry and Biology

“…[37] Amfepramone( 11,T able 4) racemisation rates werem easured over ap Hr ange of 5.5 to 8a nd with varying phosphate buffer concentrations (as well as in human plasma). [38] Racemi-sation rate constants increased with increasing pH and with increasing buffer concentrations, butn either increase was linear.T here is no obvious site for equilibrium deprotonation, making general-base catalysis resulting from rate-determining deprotonation the most likely mechanism for racemisation. This interpretation does not explain the non-linear behaviour,h owever.C ompound 11 might also undergo equilibrium protonation on the nitrogen, followed by rate-determining deprotonation of the stereogenic centre.…”

“…[65] Liquid chromatographic techniques, such as chiral HPLC, are used widely for studying stereochemistry and racemisation. [33,38,50,88] Typical approaches involve either full separation of the enantiomerso rp eak shapea nalysisf or compounds racemising in the HPLCe luent. [10,89] Al iquid-chromatography methodh as been adapted to include an artificial membrane intendedt om imic cell membranes, an environment that many drugs partitioni nto.…”

Role of racemization in optically active drugs development

“…The partial racemization of the above cited drug was reported with aminoalcohols as free base for the corresponding esters and no racemization was reported with aminoalcohols as hydrochloride salts. 50 Mey et al 51 reported 23-25 min as half life of racemization for (þ)-and (À)-diethylpropion (DEP) in human plasma. Tumambac et al 52 reported half life of 2-benzoylcylohexanone in hexanes and ethanol as 552 and 23.8 min respectively at 668C.…”

“…The authors described a rapid racemization in many solvents and in dog and human plasma. Mey et al 51 studied the kinetics of racemization of (þ)-and (À)-diethylpropion (DEP) and reported that on increasing pH and phosphate buffer concentration, the rate of racemization increased in aqueous solution but in cyclodextrins (CDs), the racemization rates of the enantiomers of DEP did not vary so much.…”