Highly Soluble Drugs Directly Granulated by Water Dispersions of Insoluble Eudragit® Polymers as a Part of Hypromellose K100M Matrix Systems

Abstract

The aim of the present study was to investigate the suitability of insoluble Eudragit® water dispersions (NE, NM, RL, and RS) for direct high-shear granulation of very soluble levetiracetam in order to decrease its burst effect from HPMC K100M matrices. The process characteristics, ss-NMR analysis, in vitro dissolution behavior, drug release mechanism and kinetics, texture profile analysis of the gel layer, and PCA analysis were explored. An application of water dispersions directly on levetiracetam was feasible only in a multistep process. All prepared formulations exhibited a 12-hour sustained release profile characterized by a reduced burst effect in a concentration-dependent manner. No effect on swelling extent of HPMC K100M was observed in the presence of Eudragit®. Contrary, higher rigidity of formed gel layer was observed using combination of HPMC and Eudragit®. Not only the type and concentration of Eudragit®, but also the presence of the surfactant in water dispersions played a key role in the dissolution characteristics. The dissolution profile close to zero-order kinetic was achieved from the sample containing levetiracetam directly granulated by the water dispersion of Eudragit® NE (5% of solid polymer per tablet) with a relatively high amount of surfactant nonoxynol 100 (1.5%). The initial burst release of drug was reduced to 8.04% in 30 min (a 64.2% decrease) while the total amount of the released drug was retained (97.02%).

Figure 1

¹³C CP/MAS NMR spectra of (a) the neat levetiracetam; (b) granules levetiracetam with Eudragit® RS; (c) levetiracetam with Eudragit® RL; (d) levetiracetam with Eudragit® NM; (e) levetiracetam with Eudragit® NE.

Figure 2

Release amount of levetiracetam from (a) formulation NM and NE and (b) formulation RL and RS during the dissolution tests in comparison with the reference sample (R) at pH 6.0.

Figure 3

PCA scores and loadings plot: (a) PCA scores plot: objects included in model: reference sample R and Eudragit® samples; (b) PCA loadings plot: variables included in model: hardness, release exponent n for the Korsmeyer-Peppas kinetic model n (KPM), coefficient of determination for zero-order kinetics R² (0), the amount of the released drug at time 30 min (burst effect), dissolution time 300 min and 720 min, and penetration force for time point 300 min.

Figure 4

Gel layer thickness and the penetration force through the gel layer of tested samples during 360 minutes: (a), (c) Set 2.5: SD_max 0.58 mm; Set 5: SD_max 0.31 mm; (b), (d) Set 2.5: SD_max 0.02 N; Set 5: SD_max 0.04 N.

Figure 5

Surface gel layers of the matrix formulation NM2.5 by the cryo-SEM technique during the dissolution test with pH 6 after 3 hours: (a) cross-section of surface gel layer (the gel layer marked with an arrow), (b) nonhydrated core of the tablet, and (c) detail of the surface of a gel layer.