Compaction of enteric-coated pellets: influence of formulation and process parameters on tablet properties and in vivo evaluation.

The aim of this study was to investigate the influence of formulation and compression parameters on the properties of tablets, containing enteric-coated pellets, and on the integrity of the enteric polymer of the individual pellets after compression. In addition the piroxicam plasma concentrations were determined after single and multiple oral administration of powder, pellet and tablet formulations at a dose of 0.3 mg piroxicam/kg bodyweight to dogs. Tablets consisted of enteric-coated pellets (containing 2.5% (w/w) piroxicam in combination with microcrystalline cellulose and sodium carboxymethylcellulose (using Avicel PH 101 and Avicel CL 611 in a ratio of 1-3), cushioning waxy pellets and 10% Kollidon CL (as an external disintegrator). From the D-optimality experimental design it was concluded that the ratio of coated pellets to cushioning pellets (CoP/CuP) affected all tablet properties evaluated. Variation of the pellet size and the CoP/CuP ratio resulted in different in vitro tablet disintegration times. Enteric coating of the pellets or compression of the coated pellets did not have a significant influence (P >0.05) on AUC(0-->72 h). Cmax values obtained after oral administration of coated pellets and compressed coated pellets were significantly lower than for the other formulations. Differences in in vitro tablet disintegration times were not reflected in the onset of the piroxicam plasma concentrations. A dosing interval of 48 h prevented piroxicam accumulation following multiple dose administration.

Influence of the punch diameter and curvature on the yield pressure of MCC-compacts during Heckel analysis.

The volume reduction behaviour of powders has been quantified by means of the 'in-die' yield pressure (YP) using Heckel analysis. However, because different YPs are reported for the same material, the experimental conditions influencing this material-constant were investigated. Silicified microcrystalline cellulose was compressed into flat-faced and convex tablets using a compaction simulator instrumented with load and displacement transducers. During compression, upper and lower punch force and displacement data were recorded and corrected for punch deformation. A symmetrical triangle wave compression profile was used and the instantaneous punch velocity was kept constant (5mm/s). Individual tablet height and weight were used for Heckel analysis. The influence of the 'effective compression pressure' (P(EFF)) (ranging from 10 to 350 MPa), punch diameter (PD) (4, 9.5 and 12 mm) and filling depth (FD) (4.5, 7.5 and 10.5mm) on YP was statistically evaluated using Response Surface Modelling software. A quadratic surface response equation, describing the relationship between P(EFF), PD, FD and YP, was proposed for concave (Adj R(2): 0.8424; S.D.: 14.60 MPa) and flat-faced (Adj R(2): 0.8409; S.D.: 4.49 MPa) punches. YP and tensile strength were mainly determined by P(EFF), irrespective of punch curvature. FD and PD had only a minor influence on the YP, although more pronounced for the concave punches. The method used resulted in reproducible P(EFF) and tensile strength values and the flat-faced tablets showed less weight variation. Flat-faced punches are preferred over punches with a concave surface when investigating the volume reduction behaviour of a powder by means of Heckel analysis and the experimental parameters should be reported.

Development and in vitro evaluation of an enteric-coated multiparticulate drug delivery system for the administration of piroxicam to dogs.

The aim of the study was to develop enteric-coated pellets for the administration of piroxicam (a poorly water-soluble drug) to small animals in order to avoid local gastrointestinal irritation, one of the major side effects of nonsteroidal anti-inflammatory drugs after oral ingestion. Pellets were made by an extrusion-spheronization process. The influence of several excipients on the in vitro drug release was evaluated. Piroxicam release from the uncoated pellets was measured in phosphate buffer (pH 6.8) using the paddle dissolution method (USP XXIII). The enteric-coated pellets were tested in 0.1 N HCl and phosphate buffer, pH 6.8. The addition of sodium croscarmellose (Ac-Di-Sol) did not influence the piroxicam release from microcrystalline cellulose pellets. Sodium carboxymethyl starch (Explotab) increased the release from 30 to 65% at 45 min. The incorporation of sodium carboxymethyl cellulose on its own or as a co-processed blend with microcrystalline cellulose (Avicel RC 581 and CL 611) enhanced the release of piroxicam at 45 min from 30% (pure Avicel PH 101) to 95% (combination of Avicel PH 101 and CL 611 in a ratio of 1:3). Additional use of cyclodextrins had only a minor influence on the dissolution rate. An Eudragit L 30 D-55 and FS 30 D (6/4) film was applied to the core pellets (containing 2.5% (w/w) piroxicam and a combination of Avicel PH 101 and CL 611 in a ratio of 1:3) in order to obtain gastroresistant properties. The coated pellets retained their dissolution characteristics after compression into fast disintegrating tablets because waxy cushioning beads were added to minimize film damage.