(T1430-11-64) Reducing Cycle Time While Maintaining Acceptable Granule and Tablet Properties for a Semi-Continuous Fluidized Bed Granulation Process

Purpose: Recently an integrated semi-continuous Fluidized Bed Granulation (FBG) and continuous direct compression technology has been introduced to the industry. The mass throughput of such an integrated system is limited by the batch size and cycle time (time taken for FBG and drying) for manufacturing granules. The goal of this study was to reduce the cycle time of the FBG and drying steps to maximize throughput, while maintaining acceptable granule and tablet properties, by varying various formulation-based aspects. The duration to add the desired liquid amount and corresponding drying time determine the overall cycle time, therefore three variables were studied to target the liquid amount; 1) total quantity of binder in the formulation, 2) percentage of that total binder quantity that is added as dry powder versus dissolved in the liquid, 3) degree of pre-wetting as preliminary data indicates it may be beneficial for fluidization control.

Methods: A 13-run multifactorial DoE (Table 1) was executed, varying total binder in the formulation (1.96%, 2.91%, 3.85%), quantity of binder added dry (0%, 25%, 50%), and prewetting level (0%, 10%, 15%). The formulation comprised 50%wt micronized acetaminophen, 50%wt microcrystalline cellulose PH102, with the total batch size ranging 2.8kg-2.86kg depending on the amount of binder added dry. An 8% hydroxypropylcellulose binder liquid was used with sufficient liquid sprayed to achieve the target binder quantity, with liquid/solid ratio being adjusted accordingly. All experiments were performed in a FBG (Xelum R&D, Syntegon). The preblend was prepared in a food processor and pneumatically conveyed into the pre-heated FBG. The FBG recipe remained constant for all runs; inlet airflow 110m³/hr, inlet air temperature 80°C, spray rate 70g/min. Representative samples were collected using a chute and spinning riffler, and characterized by dynamic image analysis (SolidSizer, Canty) for size and span (geometric mean diameter, GMD, and geometric standard deviation, GSD), and bulk and tapped densities (GranuPack) for Hausner ratio calculation. Compaction properties were evaluated using a Mechanical Testing System (MTS Criterion Model 43). Tablets were prepared at 0.82, 0.85 and 0.88 solid fraction and tested for tensile strength, compressibility (Walker index) and compactibility (bonding capacity).

Results: Figure 1 presents a prediction profiler for cycle time, and key granule and tablet properties. Desirability constraints were weighted as cycle time 25%, GSD 37.5% and tablet tensile strength 37.5%. Table 2 shows the cycle time for all runs compared to model predicted baseline of 2980sec assuming aqueous 3.3% total binder. Runs 2 and 7 resulted in unacceptable processing and were excluded from DoE analysis. Several themes are evident: a. Total HPC in formulation: Increasing HPC resulted in a decrease in GSD and Hausner ratio, indicating a narrower span and improved flow. The compactibility decreased slightly, whereas Walker index and tablet tensile strength both increased slightly. However, these benefits come at the cost of a significant increase in cycle time due to the increased volume of liquid required to dissolve the HPC. b. Re-distributing HPC from binder liquid to dry powder resulted in increased GSD and Hausner ratio, indicating a wider size span and worse flow. Increasing dry HPC also decreased tablet tensile strength slightly. However, a significant reduction in cycle time was achieved by removing HPC from the binder liquid due to the reduction in the total quantity of liquid being sprayed and subsequently dried. c. Pre-wetting. Pre-wetting decreased GSD and Hausner ratio. When considering tablet properties, prewetting results in increased bonding capacity, however decreased Walker index and tablet tensile strength. Adding the pre-wetting step also increases the cycle time slightly due to the increased water added which requires a longer drying time. The study goal was to minimize cycle time while creating granules with GSD < 1.6 and tensile strength >2MPa. However, GSD and cycle time are opposed to each other, possibly because a longer cycle time results in a greater amount of binder spray and time for incorporation of fine particles into the granule structure resulting in a narrower GSD. When considering the need to balance these competing priorities, a prediction profiler desirability of 77.8% can be achieved using 3.8% HPC in the overall formulation with 50% of the HPC being added as dry powder and 50% dissolved and sprayed as liquid, and 0% pre-wetting level.

Conclusion: FBG cycle time can be significantly reduced by decreasing the formulation HPC content and moving part of the HPC to the dry powder in the preblend. However, when taken to the extreme these changes negatively impact GSD and tensile strength therefore a compromise is needed to satisfy the defined desirability constraints. If there is need to further manipulate granules properties and/or improve the stability of the powder fluidization, a pre-wetting step can be incorporated, though the balance between increased cycle time, and granule and tablet properties should be considered.

Acknowledgements: This research was funded by Eli Lilly & Company


Table 1: Design of Experiments


Table 2: Summary of cycle time reduction achieved (%) versus baseline process recipe.


Figure 1: Desirability prediction profiler showing the effect of study variables on cycle time, and key granule and tablet properties.