An iterative process and mixture design approach for dry granulated ternary blends of filler-binders

Abstract

Roller compaction/dry granulation (RC/DG) is a key process in pharmaceutical manufacturing for improving powder flowability, density, and segregation resistance. Advanced statistical modeling was used to optimize RC/DG process parameters and subsequently binder compositions by employing process and mixture design experiments. The authors used microcrystalline cellulose (MCC), silicified MCC (SMCC), and dicalcium phosphate (DCP) as filler-binder examples in RC/DG experiments. Granule and tablet properties, including flowability, bulk and tapped densities, as well as resistance to crushing, were analyzed using compendial methods. The process design experiments confirmed that RC/DG reduces manufacturability compared to direct compression. Optimal processing conditions, balancing sufficient tablet strengths and granule formation, were identified to be between 20 (SCF * ϑ) [kN/cm] and ∼ 60 (SCF * ϑ) [kN/cm]. Thereby (ϑ) is defined as the screw-to-roll speed ratio and (SFC) as the specific compaction force. Mixture design experiments revealed optimal mixtures balancing SMCC, MCC, and DCP to achieve desired properties like low angle of repose, high bulk density, and strong tablets. These findings provide guidance for selecting formulations and process parameters in RC/DG applications. The derived ‘SCF * ϑ’- factor was found to effectively describe the granulation intensity. A superimposed mixture design model based on precise target values of the parameters bulk density, flow properties, and breaking force allowed identification of the best formulation.