Role of racemization in optically active drugs development

456 ALI ET AL.
Time (min)
TABLE 2. Enantiomeric ratio of Ibuprofen as
CoA-thioesters and free after incubation in liver
mitochondrial fraction of rat 31
(R)-Ibuprofen-CoA (S)-Ibuprofen-CoA
S/R CoA S/R Free R/S CoA R/S Free
10 0.76 0.61 0.77 0.67
20 0.62 0.69 0.58 0.78
30 0.70 0.67 0.56 0.77
60 0.56 0.67 0.63 0.77
with the amount of (S)-ibuprofen formed equal to lost
amount of (R)-ibuprofen. In the same way, (S)-ibuprofen-
CoA racemized to (R)-ibuprofen-CoA, and their rate of hydrolysis
and racemization was reported same as for
(R)- and (S)-ibuprofen-CoA. The mitochondrial fraction
mediated the racemization and hydrolysis of (R)- and (S)ibuprofen-CoA
in the same pattern as rat liver homogenate.
The enantiomer ratio of ibuprofen-CoA with rat liver
mitochondrial fraction was not altered even after 1 h period
of experiment. Table 2 31 shows the ratios of S/R CoA
as free S/R, which indicates different pattern of racemization
in rat liver mitochondrial fraction. A rapid racemization
and hydrolysis of (R)-ibuprofen-CoA to (S)-ibuprofen-CoA
was reported in microsomal fraction. (S)-Ibuprofen-CoA
racemized and hydrolyzed to (R)-ibuprofen-CoA with
microsomal fraction. But it was observed that the rate
of hydrolysis of (S)-ibuprofen was slower than that of
(R)-ibuprofen-CoA. In rat liver microsomal fraction, a
difference in enantiomer ratios was reported and given
in Table 3. 31 Knadler and Hall 32 reported the racemization
and hydrolysis of CoA thioesters of (R)-ibuprofen
and (R)-fenoprofen with rat liver microsomal and mitochondrial
fraction, which supported the findings of
Nakamura et al. 33 in 1981. Skalova et al. 34 reported chiral
inversion of R-(þ)-flobufen and (2S;4S)-dihydroflobufen
(DHF) in human hepatocytes. The authors also
reported the unidirectional chiral inversion of the enantiomers
of dihydroflobufen (DHF) as (2S;4S)-DHF to
(2R;4S)-DHF and from (2R;4R)-DHF to (2S;4R)-DHF in
hepatocyte cultures. The chiral inversion has also been
discussed for 2-aryloxypropionates 35,36 and for D-leucine
37 in human hepatocytes. Wsol et al. 38 studied in
vitro stereoselective biotransformation of flobufen enantiomers
in hepatocytes of male rat. The authors also
reported that bidirectional chiral inversion occurred in
flobufen enantiomers with hepatocytes.
Yang et al. 39–47 carried out a remarkable work on the
racemization of various optically active drugs. The
authors 45 reported that the conjugated benzylic C-H at chiral
center was responsible for the racemization reaction in
oxazepam. Yang and Lu 44 studied the temperature dependent
racemization of 3-methoxy-N-desmethyldiazepam in
acetonitrile and methanol having 0.5 M H 2SO 4. Yang and
Bao 42 reported base catalyzed racemization of 3-O-acyloxazepam.
The authors studied the kinetics of racemization in
alkaline solutions with and without buffered conditions.
The authors also indicated that in aqueous solutions the
Chirality DOI 10.1002/chir
racemization process took place with changing rates at pH
7.5–14. The authors also suggested that this racemization
reaction occurred due to keto-enol tautomerism between
C 2 carbon of CO group and C 3 carbon catalyzed by a
base. Similarly, Yang 43 reported acid catalyzed racemization
of 3-O-methyloxazepam in ethanol and 3-O-ethyl oxazepam
in methanol. The authors suggested that the above
cited reaction occurred via C 3 carbocation intermediate.
Yang et al. 41 reported that the enantiomers of oxazepam
(OX) and temazepam (TMZ) showed the racemization
reactions 40 times faster than of hydrolysis of these racemates.
The authors added that only hydrolysis results
showed racemization reaction. Furthermore, Yang 40 studied
the kinetics of spontaneous racemization and stereoselective
conversion of temazepam (TMZ) enantiomers to
3-O-methyltemazepam (MeTMZ) and 3-O-ethyltemazepam
(EtTMZ). The authors also reported that N 4-protonated
and unprotonated enantiomers of (S)-TMZ showed spontaneous
racemization. A highly stereoselective nature was
shown by three S-OH group of (S)-TMZ giving EtTMZ as
a substituted product, which has greater proportion of (S)-
EtTMZ. Sulla 48 reported that various aliphatic acid chlorides
[RCH(R’)COCl], having a chiral center adjacent to
carboxylic group, showed a high degree of racemization
with strong acids.
Ferorelli et al. 49 studied racemization of optically active
acid chlorides of clofibric acid with 3-tropanol. The authors
reported that methanolic KOH hydrolysis of the methyl
esters of 2-(4-chlorophenylthio)propanoic acid was produced
as racemic mixture. 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 ( )-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. Fernandez et al. 53 reported increasing racemization
of zopiclone (ZOP) enantiomers with increasing
pH and temperature. Lamparter et al. 54 studied the racemization
of (þ)-chlorthalidone with variation of pH and
reported a minimum pH 3 for log K/pH curve. The
authors also discussed that the rate of racemization
decreased with increasing liposome concentration. Teo
et al. 5 reported the racemization of S-enantiomer of CC-
4047 in phosphate buffer. The authors claimed S-enan-
Time (min)
TABLE 3. Enantiomeric ratio of Ibuprofen as
CoA-thioesters and free after incubation in liver
microsomal fraction of rat 31
(R)-Ibuprofen-CoA (S)-Ibuprofen-CoA
S/R CoA S/R Free R/S CoA R/S Free
2 0.19 0.18 0.10 1.30
5 0.22 0.19 0.19 0.57
10 0.27 0.18 0.23 0.70
20 0.47 0.19 0.21 0.98
30 0.56 0.21 0.13 0.95
60 0.76 0.25 0.10 0.82