(M1430-10-56) Material Sparing Dry Granulation via RoCo Simulation Enables Technical Transfer of SDI-Based Formulations

Purpose: A large portion of drugs in the pharmacuetical pipeline require bioavailibility (BA) enhancement to achieve sufficient solubilities. A spray dried intermediate is one way to improve BA, however, SDI physical stability and poor flow require dry granulation prior to tablet compression. An engineering batch is required to nominate process parameters or identify manufacturing challenges for dry granulation. This work evaluates the merit of roller compaction simulation and handmilling for material sparing workflows in lieu of full scale demonstration batches.

Methods: At-scale ribbon solid fraction was measured by envolope density while compact solid fraction was calculated via physical measurement. Specific compaction force (SCF) and solid fraction (SF) were graphed for each condition to evaluate the kp factor for the Gerteis Minipactor on the Styl’One Evolution. Additionally, a comparison in-line vs handmilling was performed by generating ribbons (SDI-based blends containing spray dried HPMCAS or Eudragit) at-scale and milling them in line with either a pocket or star rotor and comparing to the Gerteis handmill. Finally, representative SDI-containing blends were manufactured in the proposed material sparing workflow and compared to the Gerteis Minipactor. The proposed workflow includes generation of compacts at a low, target, and high solid fraction followed by downstream characterization of each condition to confirm acceptable flow, compressibility, and particle size distribution. Using the established processing range, ribbons were manufactured at-scale using the predicted target roll force established during simulation and compared to the bench-scale processing range.

Results: Excipient SCFs were plotted against SF confirming the kp value of 0.667. An analysis of 5 representative SDI-containing blends demonstrated in an average error in solid fraction prediction of 1.4% ± 0.7%. This provides good confidence in compacts generated on the Styl’One Evolution to accurately predict solid fraction of ribbons manufactued on the Gerteis Minipactor. Furthermore, ribbons milled via the handmill demonstrated almost negligible difference from in-line milled ribbons, indicating the utility of these two tools to simulate at-scale granulation.

Conclusion: Using ~100g of material, clinical roller compaction parameters were nominated with dramatically reduced material consumption (25-50X). For two representative SDI-containing blends, the at-scale ribbon solid fractions fell within the studied range, indicating a robust method. Practical applications of this method include paper technical transfer to clinical manufactures or early investigation of acceptable operating ranges with minimal material use.

References: 1. Hannah L. Reimer, Peter Kleinebudde, Hybrid modeling of roll compaction processes with the Styl'One Evolution, Powder Technology, Volume 341, 2019, Pages 66-74, https://www.sciencedirect.com/science/article/pii/S0032591018301803
2. Layla Hassan, Rene Jensen, Andrew Megarry, Lasse I. Blaabjerg, Simulation of roller compaction by combination of a compaction simulator and oscillating mill – a material sparing approach, International Journal of Pharmaceutics, Volume 644, 2023

SF vs SCF plots for microcrystalline cellulose (MCC) and lactose monohydrate (LM) comparing ribbons manufactured on the Gerteis minipactor to compacts manufactured on the Styl’One Evolution compaction simulator with SCF adjusted using a kp of 0.667.

Comparison of in-line mill (2 rotor conditions) versus the Gerteis handmill.

Compacts generated at three predicted roll force conditions for two SDI-containing blends created an acceptable processing space within which at-scale ribbons manufactured at the predicted roll force fell.