(314g) Understanding the Compression Behavior of Blends: The Application of Percolation Threshold Theory and Multivariate Analysis

Quality assurance of drug product manufacture and requires strategies to manage raw material variability, thereby ensuring consistent processing and product quality. Problems related to raw material variability are often encountered following development, during routine production. At this point, formulation modification is undesirable due to regulatory complexity and related costs. Hence it is important to design formulations that are robust with respect to raw material variability encountered during production.

Aim

The aim of this project was to apply the percolation threshold theory to determine a critical drug concentration. Above this critical concentration, given as percolation threshold, the level of drug substance could undermine the compactability of the blend, and therefore it should be avoided for a robust formulation of a direct compression blend. Multivariate analysis of compression data for formulations above and below the calculated threshold value was employed to demonstrate its validity.

Experimental

Blends of Ibuprofen and microcrystalline cellulose (MCC) were compacted under fourteen different pressures between 20 MPa and 400 MPa in a Piccola rotary tablet press. Two MCC grades with differing physical properties were employed: Vivapur^® 102 (air stream dried quality), and Emcocel^® 90 (spray dried quality) in order to evaluate raw material variability effects. Ibuprofen and MCC were analysed for particle size distribution (Malvern 3000), particle morphology (Morphologi G3-ID), bulk and tapped density and true density (Accupyc). Tablet blends containing 0%, 2.5%, 5%, 10%, 15%, 20%, 30% and 40% w/w ibuprofen were prepared. The blend with 40% ibuprofen did not flow from the hopper (rat-holing), therefore could not be compacted.

A range of mathematical models were implemented. Firstly, compaction triangle and out-die Heckle model were applied for screening direct compression behavior. Secondly, the percolation threshold theory was employed. This is a statistical model that has been identified to analyse and control raw material variability and its effect on tableting process during development. The model outputs a solid fraction range where properties of the blend undergo changes, and therefore should be avoided for robust tablet production and performance. Percolation threshold (ρ_c) is mathematically given by X=S·(ρ-ρ_c)^q (Leuenberger, 1999), which describes the behavior of a property X when the relative density (ρ) varies. Tensile strength was the reference property chosen due to its importance for tablet quality control. Coefficient q is dependent on the blend. At last, multivariate analysis was carried out in order to link compression behavior and the value of percolation threshold modeled by using compaction data to compare the formulations below and above the threshold.

Results

As ibuprofen concentration was increased in the direct compression blend, tabletability and compactibility decreased and compressibility increased. Comparing MCC grades, both grades revealed similar performance. The yield pressures determined using the Heckel model were 167 MPa for Vivapur and 182 MPa for Emcocel. Particle size and morphology were the main differences observed between these MCC grades. Morphologi G3-ID analysis showed that Vivapur had a greater number of needle shaped particles compared to Emcocel. Laser diffraction confirmed the particle size differences between grades.

For percolation threshold modelling, the coefficient q had not been previously determined for blends of Ibuprofen/MCC. Therefore, one of the goals of this study was to model the coefficient q, based on a modified Heckel equation. The value calculated was q = 3.5 ± 0.2 and there was no significant difference between the values found for the different MCC grades. Percolation threshold was modeled, not only with the empirical value from the previous step, but also using a theoretical coefficient (Guyon et al., 1987) for comparison. The best fits were obtained with the empirical coefficient resulting in the percolation threshold as solid fraction of 0.2056 for Vivapur and 0.1720 for Emcocel. An additional calculation transforms this value in drug mass concentration according to dilution capacity theory, which gave the critical mass fractions of 15.6% w/w and 17.5 %w/w ibuprofen in Emcocel and in Vivapur, respectively.

A principal component analysis (PCA) using the algorithm Singular Value Decomposition was performed for all the formulations, including the blanks of excipients using the software The Unscramble X 10.4.1, CAMO. The model performed applying full cross validation with 42 segments was proven efficient to distinguish between samples below and above the percolation threshold. Above the percolation threshold calculated, the tensile strength was lower, flowability poorer and tablet weight variability and compressibility higher, which shows that the overall properties of the blend were overwhelmed by ibuprofen and proves the percolation threshold determined to be correct. The model could also distinguish between blends containing Vivapur or Emcocel. These blends mainly differed in bulk and tapped densities, with Emcocel being denser than Vivapur.

Conclusions

The percolation coefficient for ibuprofen/MCC binary blend was calculated and the percolation threshold successfully modeled. Excipient variability had minimal impact on the percolation threshold determined. PCA analysis of compaction data demonstrated that the threshold value determined was correct. Percolation threshold modelling was shown to be a useful approach for developing robust tablet formulations.