Racemization and hydrolysis of tropic acid alkaloids in the presence of cyclodextrins

Abstract

Because of the constantly increasing demand for optically pure drugs it is of great importance to elucidate factors affecting stereochemistry, in order to provide a stable formulation with a high chiral quality of the desired isomer. Therefore, the effects of cyclodextrins (CyDs) and their alkylated and hydroxyakylated derivatives on racemization and hydrolysis of (-)-(S)-hyoscyamine and (-)-(3-scopolamine were examined kinetically and spectroscopically (NMR). Direct methods, based on a chiral and achiral chromatographic phase system, were used to determine their degradation products and enantiomer composition during stability tests. All different CyDs, except a-CyD, retarded racemization and hydrolysis. The inclusion of the drug substances in CyDs inhibits the attack of hydroxyl ions andor water molecules and thus retards the racemization and hydrolysis. The racemization of the tropic acid alkaloids is dependent on the pH and temperature. NMR studies were used to evidence the formation of a soluble 1: 1 complex in aqueous solution.0 1993 Wiley-Liss, Inc.

Isothermal titration calorimetry (ITC) study of natural cyclodextrins inclusion complexes with tropane alkaloids

“…The values of K constant (Table 2) calculated, based on the very well fit (Fig. 1) of the enthalpy of complex formation, are about 50 times higher than the equilibrium constant calculated by the use of the Benesi-Hildebrand method [19], from the 1 H-NMR data [17]. It is necessary to notice that the value of K calculated from the 1 H-NMR data [17] was obtained by the procedure [19] which is very imprecise for protons which do not experience large shifts upon complex formation or for signals which are partially obscured by other peaks [17].…”

“…scopolamine complex and the literature data [17]. The values of K constant (Table 2) calculated, based on the very well fit (Fig.…”

“…1) plot revealed, in this case, best accordance with a stoichiometry of 1:1 (b-CD:scopolamine). The only data, concerning a stoichiometry of b-CD with scopolamine, could be found in the Blaschke et al paper [17]. The authors estimated the complex stoichiometry from 1 H-NMR data, based on the continuous variation method [18], and found out that the Job plot (both aromatic protons and H proton) for b-CD ?…”

“…Inclusion complexes of b-CD with scopolamine have been studied ( 1 H-NMR) by Blaschke et al [17], but in the literature there is the lack of direct information concerning thermodynamic properties of the studied complexes.…”

Effect of Cyclodextrins on the Hydrolysis of an Oxazolidine Prodrug of (1R,2S)-(−)-Ephedrine-cis-2-(4-Methoxyphenyl)-3,4-dimethyl-5-phenyloxazolidine

“…Several other studies have also proposed that the smaller cavity of α-CD permits a lower degree of penetration of the guest and thus provides marginal or no stabilization effect in a particular catalytic reaction. [17][18][19][20][21][22][23][24][25] Nonetheless, factors such as concentration of the CD, temperature, pH, type and concentration of the buffer and substitution on the aromatic moiety of the guest molecule (II) could potentially vary the rate of hydrolysis. min at 37°C.…”