Background: Clobazam (CLB) has been used as an anxiolytic, anticonvulsant and antiepileptic
drug under the trade names, Frisium, Urbanol, Onfi and Tapclob. Impurity profiling in the pharmaceutical
industries is a central task in the manufacturing of drug product. The quantification of impurities in
active pharmaceutical ingredients (APIs) is also receiving considerable importance from the regulatory
authorities in the point of stringent quality requirement. Thus, the provision of substantial quantity of impurities
as standards, which are accomplished either by isolation from crude reaction mass or the synthesis
of material with proposed structure using new synthetic route, to analytical method development and validation
is a good demand. Therefore, easily accessible synthetic routes to the preparation of impurities with
the lowest cost are sought after. To date, no synthetic specifics were found on the synthesis and characterization
of CLB Imp-B, -C, -D and –F, and the synthesis of CLB Imp-E. Therefore, the comprehensive
study was undertaken on the synthesis and characterization of CLB related impurities and this study
might be useful to prepare CLB impurities in the required quantity with purity to use as a reference standard
of analytical method development in pharmaceutical industry.
Methods: The synthetic routes were developed for the synthesis of CLB impurities such CLB Imp-B to
Imp-F and isolated them using purification techniques with purity in the required quantity. The commercially
available key starting materials, reagents and solvents were used in the course of synthesis of
impurities. The analytical techniques such as NMR, IR and mass were used to characterize the structure
of synthesized CLB related impurities.
Results: The easy accessible synthetic methods were developed for the synthesis of clobazam related impurities,
CLB Imp-B to F in good to excellent yields with purity as well as described the cause to formation
of these impurities. The KSM related impurity, 2-chloro-1-nitrobenzene and the active methylene hydrogens
in clobazam are caused to the formation of CLB Imp-B and CLB Imp-C&-D, respectively. CLB
Imp-E and –F are formed due to the degradation of drug molecule, CLB in the presence of base (NaOH).
CLB Imp-B was prepared from 2-chloro-1-nitrobenzene by following similar process of CLB reported in
the synthetic specific. CLB Imp-F was prepared from 5-chloro-N1
-phenylbenzene-1,2-diamine by coupling
with mono-methyl malonate followed by N-methylation using dimethyl sulfate. The rest of all impurities
were planned to prepare by taking CLB as starting material. CLB Imp-C and –D were synthesized
by treating CLB with methyl iodide in the presence of inorganic base. The mixture of aqueous NaOH and
CLB was agitated vigorously at 75-80°C to obtain CLB Imp-E. All the synthesized compounds were purified
using purification techniques such as crystallization and column chromatography, and well characterized
by IR, ESI-mass, 1H NMR, 13C NMR and DEPT analyses.
Conclusion: The immaculate discussion about synthetic approaches and structural elucidation using analytical
applications such as IR, NMR (1H, 13C and DEPT) of CLB Imp-B to F, which are listed in the
European pharmacopoeia monograph of clobazam, has been described. All the impurities were obtained
with stringent purity (>98%) in the described synthetic routes and the same impurities have been used in
analytical method development in our pharmaceutical industry. Also, the plausible mechanistic path ways to
the formation of impurities, keeping in view the regulatory importance of clobazam, were discussed in detail.