Ampholytic and Polyelectrolytic Starch as Matrices for Controlled Drug Delivery.

The potential of the polyampholytic and polyelectrolytic starch compounds as excipients for drug controlled release was investigated using various tracers differing in terms of solubility and permeability. Ampholytic trimethylaminecarboxymethylstarch (TMACMS) simultaneously carrying trimethylaminehydroxypropyl (TMA) cationic groups and carboxymethyl (CM) anionic groups was obtained in one-step synthesis in aqueous media. Trimethylaminestarch (TMAS) and carboxymethylstarch (CMS) powders were also synthesized separately and then homogenized at equal proportions in liquid phase for co-processing by spray drying (SD) to obtain polyelectrolytic complexes TMAS-CMS (SD). Similarly, equal amounts of TMAS and CMS powders were dry mixed (DM) to obtain TMAS:CMS (DM). Monolithic tablets were obtained by direct compression of excipient/API mixes with 60% or 80% drug loads. The in vitro dissolution tests showed that ampholytic (TMACMS) and co-processed TMAS-CMS (SD) with selected tracers (one from each class of Biopharmaceutical Classification System (BCS)), were able to control the release even at very high loading (80%). The presence of opposite charges located at adequate distances may impact the polymeric chain organisation, their self-assembling, and implicitly the control of drug release. In conclusion, irrespective of preparation procedure, ampholytic and polyelectrolytic starch materials exhibited similar behaviours. Electrostatic interactions generated polymeric matrices conferring good mechanical features of tablets even at high drug loading.

A stereoselective approach to nucleosides and 4'-thioanalogues from acyclic precursors.

D- and L-nucleosides and analogues thereof, including the 4'-thionucleoside series, are one of the most important biological and pharmaceutically active classes of compounds. A novel approach to their synthesis from chiral acyclic thioaminal, bearing the nucleobase, is described.

A convergent synthesis of the cardenolide skeleton: intramolecular aldol condensation via reduction of alpha-bromoketones.

Synthesis of the highly biologically valuable cardenolide backbone was achieved via anionic polycyclization. Bromoketone 18, obtained from double-Michael cycloaddition between cyclohexenone 14 and gamma,delta-unsaturated beta-ketoester 16, was efficiently aldolized under reductive conditions. The highly functionalized tetracyclic compound 52 is an important synthetic intermediate that is potentially amenable to natural cardenolide total synthesis.

Synthesis of N-glycosides. An alternative approach based on diastereoselective base coupling and S(N)2 cyclization.

[reaction: see text] Acyclic diastereoselection is achieved for the formation of thioaminyl acetals. The highly intramolecular stereocontrolled S(N)2 displacement of the thioaminyls allows for the formation of cyclic nucleoside derivatives. This versatile approach may provide easy access to a large variety of N-glycosides.