(735ai) Direct Scale-up of a Dry Granulation Process Using a Material Lean Approach at Lab-Scale

Delivering uniform dosage forms to patients may be challenging for poorly flowing formulations through direct compression. Flowability issues and powder properties variability that spray dried amorphous solid dispersions (ASD) may bring [1], ultimately lead to higher weight variations during tableting and/or inconsistent drug content uniformity. Granulation processes (wet or dry) allow to overcome these issues through particle size and density increase [2,3]. Dry granulation is a continuous process with the advantage of being able to work with heat or moisture sensitive drugs while reducing costs compared to wet granulation. In this process, powders are fed between two counter-rotating rollers. Pressure from the rollers compacts the powder, forming thin ribbons which are then milled into granules used as drug product intermediaries for blending with excipients prior to tableting/capsule filling.

The present work is focused on a lean, streamlined material sparing approach for laboratory development to enable a direct scale-up of blending, roller compaction (RC) and tableting steps to the manufacturing facilities. For this purpose, commonly selected polymers for spray drying to enhance API bioavailability through ASD i.e., hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone-vinyl acetate (PVP/VA), were blended with conventional excipients used in the manufacture of oral dosage forms (microcrystalline cellulose, fumed silica, croscarmellose sodium, and magnesium stearate, at 50% w/w ASD content).

Ribbons were manufactured in a Gerteis Mini-Pactor at different densification conditions by changing roller compaction gap and force, generating granules with different particle size distribution and density. The roller compaction conditions to obtain different ribbon at gap solid fraction were estimated by leveraging a mechanistic RC model based on Johanson’s theory.[4].

At lab scale, leveraging compaction simulation capability (STYL’One Nano) and a lab scale granulator (FlexMill-Lab OsciloWitt), the roller compaction process train was simulated. To manufacture slugs at lab, the ribbon densification time at compaction simulator was estimated via roll geometry speed and nip angle simulated and the roller compactor milling tip speed was mimicked at lab. Ribbon (from manufacturing equipment) and slugs’ (from laboratory equipment) SF and their resulting particle size distribution and Hausner ratio were compared. An offset was observed between ribbons at gap / out of gap and slugs in die / out of die SF. The slugs presented a narrower difference between in die and out of die due to less elastic recovery. Between polymers at the same set of RC conditions, larger offset was observed for the HPMCAS based formulation. Aligned with mechanical properties (PVP/VA often used as a binder whereas HPMCAS is a cellulose based providing higher flexibility within the polymeric chain). Nonetheless, it was observed that slugs and ribbons with matching SF out of die or gap, respectively, yielded similar particle size distribution and Hausner ratio. Additionally, the application of higher roller compaction forces and narrower gap settings resulted in granules with larger particle size, as result of increased SF of the ribbons.

The tablets processability from manufacturing and laboratory routes were compared through compression profile analysis, friability, and disintegration results. The compression profile used simulated an 8 EU-D stations Korsch XL-100 at a nominal throughput. The results confirmed that similar ribbon SF out of gap and slugs’ SF out of die resulted in tablets with matching processability. Comparing the tableting results obtained from different RC conditions, an earlier overcompression onset for the trials produced at higher densification conditions (higher ribbon solid fraction) was observed.

The current work demonstrated it is possible to develop the dry granulation process using a lean methodology at the lab-scale. This methodology significantly minimizes the API needs and accelerates process development by enabling right-first-time scale-up from laboratory to industrial scale. This ultimately expands capacity, while reducing costs, materials and time which are critical in early-stage programs.

References:

[1] S. Page and R. Maurer, “Downstream Processing Considerations,” in Amorphous Solid Dispersions: Theory and Practice, N. Shah, H. Sandhu, D. S. Choi, H. Chokshi, and A. W. Malick, Eds. Springer-Verlag New York, 2014, pp. 395–417.

[2] S. A. Howard, “Solids: Flow Properties,” no. June 2016, doi: 10.1081/E-EPT3-100200005.

[3] W. J. Sun, J. Rantanen, and C. C. Sun, “Ribbon density and milling parameters that determine fines fraction in a dry granulation,” Powder Technol., vol. 338, pp. 162–167, 2018, doi: 10.1016/j.powtec.2018.07.009.

[4] Sousa, R., et al., “Roller Compaction Scale-Up Made Simple: An Approximate Analytical Solution to Johanson’s Rolling Theory,” J. Pharm. Sci., 2020, doi: 10.1016/j.xphs.2020.05.004.