(T1330-09-59) Low-Substituted Hydroxypropyl Cellulose (L-HPC^®) Improves the Flowability and Compressibility of Acetaminophen via Twin-Screw Wet Granulation (TSWG): Comparison with Ac-Di-Sol^® and Kollidon^® CL

Purpose: Continuous manufacturing (CM) in pharmaceutical industry has gained popularity after the publication of the FDA guidance for process analytical technology (PAT) in 2004. Twin-screw wet granulation (TSWG) is a continuous process by which granules of the active pharmaceutical ingredient (API) are produced to improve its flow, compressibility and minimize the risk of segregation (1,2). Low-substituted hydroxypropyl cellulose (L-HPC^®) is a dual binder-disintegrant that can be applied for the wet granulation of API to improve their flow, compressibility, and tablet properties. In this study, we aimed to identify the optimal formulation and process parameters for the wet granulation of acetaminophen using L-HPC^®. Subsequently, L-HPC^® was substituted from the optimal formulation with Ac-Di-Sol^® and Kollidon^® CL and the resulting granule and tablet properties were evaluated.

Methods: TSWG of acetaminophen, with lactose monohydrate as filler, was done using a Pharma 11 twin-screw extruder. A 3² full factorial design of experiment (DOE) was used to determine the optimal LH-21 concentration (2.5 – 10%) and L/S ratio (0.05 – 0.20) which results in best granule and tablet properties. Granule properties such as bulk, tapped density, particle size and friability were evaluated. Milled granules were compacted into tablets (500 mg, 10 mm, biconcex, 15 kN compaction load) followed by tablet properties evaluation. An I-optimal design with desirability function was used for statistical data analysis to determine the best formula. L-HPC from the optimal formula was substituted with Ac-Di-Sol^® or Kollidon^® CL followed by TSWG and the resulting granule and tablet properties were evaluated.

Results: Increasing the L/S ratio was associated with significant improvement in powder flowability as demonstrated by lower CI and HR values, while increasing LH-21 concentration had no significant effect. Increasing LH-21 concentration resulted in reduction in the particle size D50 and increase in the span value and the opposite was observed with increasing the L/S ratio. Granule friability decreased with increasing the L/S ratio while no significant effect was observed with increasing LH-21 concentrations. Tablet hardness was improved at higher LH-21 concentrations and no effect was observed at different L/S ratios. Neither the concentration of LH-21 or the L/S ratio had a significant effect on tablet friability, while disintegration time reduced at higher LH-21 concentrations and increased with increasing the L/S ratio. The optimal formulation consisted of 7.5% LH-21 and an L/S ratio of 0.15. LH-21 in the formula resulted in improved granule and tablet properties in comparison to Ac-Di-Sol^® and Kollidon^® CL.

Conclusion: We evaluated the impact of changing LH-21 concentration and L/S ratio on powder flow, granule and tablet properties. Modelling the data using desirability function concluded that an LH-21 concentration of 7.5% coupled with an L/S ratio of 0.15 results in optimal granule and tablet properties of acetaminophen. LH-21 results in improved granule and tablet properties of acetaminophen in comparison to Ac-Di-Sol^® and Kollidon^® CL

References: 1- Bandari, S., Nyavanandi, D., Kallakunta, V. R., Janga, K. Y., Sarabu, S., Butreddy, A., & Repka, M. A. (2020). Continuous twin screw granulation – An advanced alternative granulation technology for use in the pharmaceutical industry. In International Journal of Pharmaceutics (Vol. 580). Elsevier B.V. https://doi.org/10.1016/j.ijpharm.2020.119215.
2- Portier, C., Pandelaere, K., Delaet, U., Vigh, T., Di Pretoro, G., De Beer, T., Vervaet, C., & Vanhoorne, V. (2020). Continuous twin screw granulation: A complex interplay between formulation properties, process settings and screw design. International Journal of Pharmaceutics, 576. https://doi.org/10.1016/j.ijpharm.2019.119004

Figure 1: Granule properties of acetaminophen following TSWG with LH-21. A- Carr's index, B- Hausner ratio, C- Granule friability, D- Oversize granules (%), E- Particle size D50, F- Span value of particle size distribution


Figure 2: Tablet properties of acetaminophen following TSWG with LH-21. A- Tablet hardness (N), B- Tablet friability (%), and C- Tablet disintegration time (sec). Data is presented as mean ±SD.


Figure 3: Granule and Tablet properties of acetaminophen following TSWG with LH-21 vs Ac-Di-Sol® and Kollidon® CL. A- Hausner ratio, B- Carr's index, C- Tablet Hardness (N), D- Compaction analysis (N), E- Tablet disintegration time (sec), and F- Tablet friability (%). Data is presented as mean ±SD.