Role of racemization in optically active drugs development

458 ALI ET AL.
Fig. 3. Rapid changes in S/R enantiomer concentration ratio within
first minute after racemic flobufen administration in rat. 87
were reported in the same range. Further, in 1996 Schmahl
et al. 93 studied the racemization of EM 12 enantiomers in
monkey, rat and mouse. R- and S-Enantiomers showed their
appearance in embryo of marmoset monkey, wistar rat and
NMRI mouse in organogenesis duration. The gestation day
of monkey, rat, mouse were 61, 12, 10 respectively. The
presence of EM 12 enantiomers was reported in maternal
plasma, placenta and embryo in marmoset monkey and
wistar rat. Low concentrations of EM 12 metabolites were
identified in plasma and embryo of rat and monkey, evaluating
the teratogenic effect of parent drug. Cuyue et al. 94
reported that blood samples of rat have only S-stiripentol
[(S)-STP] after oral administration of [(S)-STP]. But with a
same dose of [(R)-STP], samples showed the presence of
both R- andS-enantiomers indicating the racemization of Rform
only. The authors also suggested the entry route of
chiral inversion of stiripentol R-enantiomer. After oral dose
of any enantiomer of the drug, the authors observed that
drug has become enriched with R-form; during the course
of intestinal movement. Furthermore, the authors described
that acid catalyzed racemization and enantioselectivity
were main factors contributing metabolic chiral inversion
of (R)-STP. The study of degradation and racemization
of thioridazine (THD) and thioridazine 2-sulfone [THD 2-
SO 2 ] in human plasma and aqueous solutions has been performed
by de Gaitani et al. 95
The rate of racemization of N-a-phthalimidoglutarimide
(thalidomide) was studied by Nishimura et al. 96 and a half
life period of 566 min was reported at pH 7.4 and 378C
temperature. Heger et al. 97 studied racemization of S-( )-
EM 12, which was responsible for limb defects as amelia,
phocomelia and radius aplasia. The authors also reported
that no exposed fetus was free from skeletal defects.
Papini et al. 98 studied the pharmacokinetic racemization of
lorazepam in pregnant women and data given in Table 5
about phamacokinetics of lorazepam and its metabolite
(lorazepam-glucuronide) in pregnant women indicate racemization
process. Similarly, Pham-Huy et al. 99 reported
racemization of lorazepam in polar media. Teo et al. 5
Chirality DOI 10.1002/chir
reported the racemization of S-enantiomer of CC-4047 in
human plasma. Hainzl et al. 100 studied the possibility of
racemization of carbamazepine derivatives in human.
To make in vivo study more clearly to the readers one
experimental methodology used by Papini et al. 98 is summarized
in this paragraph briefly. The authors selected
10 healthy parturients aged 18–37 yr with a gestational
age of 36–40.1 wk and treated with single oral dose of
2.0 mg racemic lorazepam 2 to 9 h before delivery. The
maternal venous blood samples were collected via a venous
catheter at time 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 30, 36, and
48 h. The blood samples were also collected from the umbilical
vein after clamping. The urine samples were collected
at 12 h interval up to 48 h after lorazepam administration.
Heparin was used as an anticoagulant for blood
samples. The plasma and urine samples were separated by
centrifugation at 2000g for 10 min and stored at 208C.
The chiral analysis of lorazepam enantiomers was carried
out by using LC-MS technique.
EFFECT OF DIFFERENT VARIABLES ON
RACEMIZATION
In vitro racemization is controlled by pH of the solution,
temperature, ionic balance and concentration of the drug
itself. On the other hand, in vivo racemization is difficult to
control in animals; specially in human beings. However,
some workers tried to study the effect of various variables
on the racemization of optically active drugs. The effect of
some variables on racemization has been discussed in section
3.1 and 3.2 briefly but this section describes the effect
of these variables in detail. El-Nimr et al. 101 described the
racemization of L-noradrenaline bitartrate in the presence
of hydronium ion. Authors discussed the effect of ionic
concentration on the racemization of the above cited drug.
The kinetic study of racemization of chiral drugs such as
carbenicillin, ethiazide, etoposide and oxazepam acetate in
human serum albumin was studied by Aso et al. 102 Matsuo
et al. 103 studied the kinetics of racemization of meluadrine
tartrate at 1.2 to 12 pH and 40, 60, 808C in aqueous solu-
TABLE 5. Kinetic disposition of Lorazepam and its
metabolite glucuronide in parturients 98
Lorazepam
isomeric mixture
Lorazepam-glucuronide
isomeric mixture
Cmax (ng/ml) 12.96 (9.42–16.49) 35.55 (8.27–62.83)
tmax (h) 3.10 (2.57–3.63) 4.33 (2.90–5.77)
t1/2a (h) 3.16 (2.62–3.68) 1.37 (1.15–1.58)
Ka (h 1 ) 0.23 (0.19–0.28) 0.52 (0.44–0.59)
t1/2b (h) 10.35 (9.39–11.32) 18.17 (14.10–22.23)
b (h 1 ) 0.068 (0.061–0.075) 0.039 (0.032–0.047)
AUC 0-a
[(ng h)/mL]
175.25 (145.74–204.75) 481.19 (252.87–709.51)
ClT/ F [mL/
(min kg)]
2.61 (2.34–2.88) –
Vd/F (1) 178.78 (146.46–211.10) –