(41d) Early Development of a Modified Release Formulation and Process for Continuous Direct Compression: A Case Study

This study presents the evaluation of suitability of continuous direct compression (CDC) platform to manufacture a modified release formulation. To develop a robust process for CDC, lab-scale and material-sparing studies are necessary prior to testing the formulation prototypes on the CDC line. The target drug product profile requires a higher drug loading to limit the size of tablet and a higher concentration of rate controlling polymer to maintain dissolution profiles upon conversion of a 50 mg tablet to a 175 mg tablet. These requirements pose inherent challenges in developing an amenable formulation for CDC, i.e. adding , poor flowability of active and rate controlling polymer and high elasticity of the formulation in the presence of excessive polymer. Therefore the lab scale evaluation focus on optimizing level of polymers and actives in the formulation to achieve acceptable dissolution profile, flowability and tabletability.

Formulation development was conducted in the laboratory using a benchtop tablet compaction simulator (STYL'One Nano). Due to high levels of rate-controlling polymer, the modified release tablets tended to laminate at higher compression forces. Lamination issues were addressed through formulation adjustments, application of precompression force, and engineering solutions in tooling design. Formulation adjustments included changes to excipient types and levels. Precompression force and tapered die were used to reduce air entrapment. A dissolution model was also developed to predict the impact of formulation changes on the dissolution profile, aiding the optimization of the formulation. An optimal formulation was selected based on dissolution and compaction behaviors.

To allow the selected formuation to be operational on the CDC line, the flowability of the active ingredient and the final blend were assessed through shear cell flow measurements. This assessment was followed by loss-in-weight (LIW) feeding studies using a laboratory stand-alone feeder to ensure robust material handling and thus minimize blend variability. Various parameters such as top-up volume, gear ratio, and feed factors were investigated. The formulation was determined to be feasible for CDC process since consistent and reliable throughput were achieved via feed parameter optimization.

These development studies along with near-infrared (NIR) spectroscopy (discsused in a separate presentation), provided the foundation for further process optimization and scale-up on the CDC line. This study demonstrates how a systematic approach integrating material characterization, process optimization, and analytical testing can be leveraged to develop robust modified release formulations within a CDC environment.