Modern pharmaceutical technology still seeks new excipients and investigates the further use in already known ones. An example is magnesium aluminometasilicate Neusilin® US2 (NEU), a commonly used inert filler with unique properties that are usable in various pharmaceutical fields of interest. We aimed to explore its application in hypromellose matrix systems (HPMC content 10-30%) compared to the traditionally used microcrystalline cellulose (MCC) PH 102. The properties of powder mixtures and directly compressed tablets containing individual fillers NEU or MCC, or their blend with ratios of 1.5:1, 1:1, and 0.5:1 were investigated. Besides the routine pharmaceutical testing, we have enriched the matrices' evaluation with a biorelevant dynamic dissolution study and advanced statistical analysis. Under the USP apparatus 2 dissolution test, NEU, individually, did not provide advantages compared to MCC. The primary limitations were the burst effect increase followed by faster drug release at the 10-20% HPMC concentrations. However, the biorelevant dynamic dissolution study did not confirm these findings and showed similarities in dissolution profiles. It indicates the limitations of pharmacopoeial methods in matrix tablet development. Surprisingly, the NEU/MCC blend matrices at the same HPMC concentration showed technologically advantageous properties. Besides improved flowability, tablet hardness, and a positive impact on the in vitro drug dissolution profile toward zero-order kinetics, the USP 2 dissolution data of the samples N75M50 and N50M50 showed a similarity to those obtained from the dynamic biorelevant apparatus with multi-compartment structure. This finding demonstrates the more predictable in vivo behaviour of the developed matrix systems in human organisms.
- Keywords
- HPMC, Neusilin® US2, USP apparatus 2 dissolution test, dynamic dissolution study, matrix tablets, microcrystalline cellulose,
- Publication type
- Journal Article MeSH
In the pharmaceutical industry, silicates are commonly used excipients with different application possibilities. They are especially utilized as glidants in low concentrations, but they can be used in high concentrations as porous carriers and coating materials in oral solid drug delivery systems. The desirable formulations of such systems must exhibit good powder flow but also good compactibility, which brings opposing requirements on inter-particle interactions. Since magnesium aluminometasilicates (MAS) are known for their interesting flow behavior reported as "negative cohesivity" yet they can be used as binders for tablet compression, the objective of this experimental study was to investigate their particle interactions within a broad range of mechanical stress from several kPa to hundreds of MPa. Magnesium aluminometasilicate (Neusilin® US2 and Neusilin® S2)-microcrystalline cellulose (Avicel® PH102) physical powder mixtures with varying silicate concentrations were prepared and examined during their exposure to different pressures using powder rheology and compaction analysis. The results revealed that MAS particles retain their repulsive character and small contact surface area under normal conditions. If threshold pressure is applied, the destruction of MAS particles and formation of new surfaces leading to particle interactions are observed. The ability of MAS particles to form interactions intensifies with increasing pressure and their amount in a mixture. This "function switching" makes MAS suitable for use as multifunctional excipients since they can act as a glidant or a binder depending on the applied pressure.
- Keywords
- formulation development, glidant, magnesium aluminometasilicates, particle interactions, threshold behavior,
- Publication type
- Journal Article MeSH
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%).
- MeSH
- Hypromellose Derivatives * chemistry pharmacokinetics pharmacology MeSH
- Polymethacrylic Acids * chemistry pharmacokinetics pharmacology MeSH
- Lactose analogs & derivatives chemistry pharmacokinetics pharmacology MeSH
- Delayed-Action Preparations pharmacokinetics pharmacology MeSH
- Methylcellulose analogs & derivatives chemistry pharmacokinetics pharmacology MeSH
- Nonoxynol * chemistry pharmacokinetics pharmacology MeSH
- Drug Liberation MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Hypromellose Derivatives * MeSH
- hydroxypropylmethylcellulose-lactose matrix MeSH Browser
- Polymethacrylic Acids * MeSH
- Lactose MeSH
- Delayed-Action Preparations MeSH
- Methylcellulose MeSH
- methylmethacrylate-methacrylic acid copolymer MeSH Browser
- Nonoxynol * MeSH
