Premium
Kinetics of racemization of (+)‐ and (−)‐diethylpropion: Studies in aqueous solution, with and without the addition of cyclodextrins, in organic solvents and in human plasma
Author(s) -
Mey Boris,
Paulus Hanns,
Lamparter Erich,
Blaschke Gottfried
Publication year - 1998
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/(sici)1520-636x(1998)10:4<307::aid-chir4>3.0.co;2-4
Subject(s) - chemistry , racemization , enantiomer , aqueous solution , ionic strength , chromatography , nuclear chemistry , stereochemistry , organic chemistry
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 α 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. © 1998 Wiley‐Liss, Inc.