Intercalation of L-Dopa into Layered Double Hydroxides: Enhancement of Both Chemical and Stereochemical Stabilities of a Drug through Host-Guest Interactions

This paper describes a systematic study on the intercalation of an unstable chiral drug L-dopa into layered double hydroxides (LDHs) and the enhancement of its chemical and stereochemical stabilities through host-guest interactions, by virtue of combining experimental and theoretical investigations. L-Dopa has been intercalated into a magnesium-aluminum LDH, and the structural characterization reveals that L-dopa anions are accommodated vertically in the interlayer region as a monolayer of partially superimposed species. Thermogravimetry-mass spectroscopy and polarimetry indicate that both the chemical and stereochemical stabilities of L-dopa are enhanced significantly in a confined region between LDH sheets compared with pristine L-dopa. The racemization phenomenon of pristine L-dopa has been rationalized by quantum mechanical calculations at the B3PW91/6-31 G(d,p) level. The computed results suggest that in the solid state L-dopa undergoes racemization via an enol intermediate formed by hydrogen transfer from the chiral carbon atom to the carboxylate group. After intercalation in the interlayer galleries of the LDH, the carboxylate group of the L-dopa becomes involved in strong host-guest interactions with the layers, with the computed binding energy of L-dopa to the LDH layers being ca. -1100 kJ/mol. The host-guest interactions, including electrostatic and hydrogen bonding between L-dopa and LDH host, thus inhibit the racemization reaction of the guest because the carboxylate group is no longer able to act as a hydrogen acceptor. Therefore, the results of theoretical study are in good agreement with those of the experimental ones. The results show that these layered materials have potential applications as the basis of a novel storage and delivery system for L-dopa or other unstable chiral pharmaceutical agents.