An in-vivo and in-vitro taste masking evaluation of bitter melt-extruded drugs.

OBJECTIVES: The purpose of this study was to investigate the potential of hot-melt extrusion (HME) for masking the taste of bitter active pharmaceutical ingredients (APIs) when incorporated into different polymer formulations. METHODS: Extrudates were produced by HME using two water soluble cationic model drugs (cetirizine HCl and verapamil HCl) processed with various grades of anionic polymers (Eudragit L100 and Eudragit L100-55 (Acryl EZE)). The process was optimised by using a single screw extruder to produce extruadates with the desirable characteristics. KEY FINDINGS: In-vivo results obtained from a panel of six healthy human volunteers demonstrated that the HME extruded formulations improved the taste significantly compared with that of the pure APIs. In addition, an in-vitro evaluation carried out by an Astree e-tongue equipped with seven specific sensors demonstrated significant taste improvement of the extrudates compared with placebo polymers and the pure APIs. Furthermore, the extrudates characterised by SEM, X-ray and differential scanning calorimetry studies showed the existence of molecularly dispersed APIs while in-vitro dissolution showed fast release for all drug substances. CONCLUSIONS: HME can effectively be used to mask the taste of bitter APIs by enhancing drug-polymer interactions.

Taste masking of paracetamol by hot-melt extrusion: an in vitro and in vivo evaluation.

The purpose of this study was the in vitro and in vivo evaluation of the masking efficiency of hot melt extruded paracetamol (PMOL) formulations. Extruded granules containing high PMOL loadings in Eudragit EPO (EPO) or Kollidon VA64 (VA64) were prepared by hot-melt extrusion (HME). The taste masking effect of the processed formulation was evaluated in vivo by a panel of six healthy human volunteers. In addition, in vitro evaluation was carried out by an Astree e-tongue equipped with seven sensors. Taste sensing technology demonstrated taste improvement for both polymers by correlating the data obtained for the placebo polymers and the pure APIs alone. The best masking effect was observed for VA64 at 30% PMOL loading. The e-tongue results were in good agreement with the in vivo evaluation. In vitro dissolution of the extruded granules showed rapid PMOL releases.

Palladium-Catalyzed 1,4-Acetoxy-Trifluoroacetoxylation and 1,4-Alkoxy-Trifluoroacetoxylation of Cyclic 1,3-Dienes. Scope and Mechanism.

Palladium-catalyzed unsymmetrical 1,4-functionalizations of cyclic 1,3-dienes are described. Trifluoroacetate in combination with acetate or alcohols is utilized to obtain 1-acetoxy-4-(trifluoroacetoxy)-2-cycloalkenes and 1-alkoxy-4-(trifluoroacetoxy)-2-cycloalkenes, respectively, with good regio- and stereoselectivities. The chemoselectivity of these reactions relies on the different kinetic stability of the intermediate 4-(trifluoroacetoxy)-, 4-acetoxy-, and 4-methoxy-[eta(3)-(1,2,3)-cycloalkenyl]palladium complexes. Under the acidic reaction conditions employed, the 4-trifluoroacetoxy pi-allyl intermediate is the least stable of the three. Certain mechanistic aspects of the reactions are discussed in the light of DFT calculations.

Syntheses of Theaspirone and Vitispirane via Palladium(II)-Catalyzed Oxaspirocyclization.

Total syntheses of theaspirone (A and B) and vitispirane (A and B) are described. The key step in the syntheses is the palladium(II)-catalyzed intramolecular oxaspirocyclization of diene alcohol 4 to either vitispirane or the allylic alcohol 9. The outcome of the oxaspirocyclization is very much dependent on the solvent employed. In water-acetic acid (4:1) a 1:1 mixture of the diastereomeric alcohols 9A and 9B was exclusively formed. In water with 8 equiv of a strong non-nucleophilic acid, vitispiranes A and B (1:1) were obtained. An alternative procedure to obtain vitispirane with the use of LiCl and K(2)CO(3) is described. In the latter reaction vitispirane B is formed preferentially. This result is explained by an equilibrium between the two possible pi-allyl complexes 5A and 5B, the kinetically favored 5B being transformed into vitispirane 3B before isomerization to 5A occurs.