(655e) Predicting Granule Flowability Changes Due to Friability Under Low Shear Conditions before Tablet Production

Powders are often granulated to improve their flow behavior before tableting. Granule friability is the tendency of granules to lose components due to abrasion, friction, or mechanical shock. The friability of granules becomes crucial when handling granules between granulation and tableting operations. It is affected by the strength of granules, the mechanical properties (elastic, plastic, brittle nature) of the material, and the size and porosity of granules. Friable granules (granules with low strength) lead to bimodal particle size distribution and fines generation [1], affecting powder flowability and potentially causing segregation in the final blend during die-filling. Fine particles are often re-granulated to improve yield, but studies have shown content non-uniformity issues related to the recycling of fines [2]. Considering flowability challenges, the risk of segregation, and tablet content non-uniformity, it is of interest to study the effect of granule friability on the flowability of granules.

This work presents a case study to systematically integrate granule friability and flowability models into the drug product development workflow. As a first objective, the granule friability during the powder-feeding operation is predicted using a population balance model framework. Granule chipping breakage mechanism is considered the dominant mechanism in the powder feeder, similar to the low shear conditions of a conveying element in twin screw granulator [3]. The granule strength-dependent breakage function proposed by Wang et. al. [4] is utilized. Subsequently, the flowability of friable granules is studied as the second objective. The granule size distribution is used to predict the flowability of granules using a modification to the rheology model suggested in the literature [5]. This work will highlight a practical methodology for adapting a mechanistic model to improve process understanding during process optimization studies during late-stage drug product development.

[1] Metta, Nirupaplava, et al. "Model development and prediction of particle size distribution, density and friability of a comilling operation in a continuous pharmaceutical manufacturing process." International journal of pharmaceutics 549.1-2 (2018): 271-282.

[2] Sheskey, Paul J., et al. "Use of roller compaction in the preparation of controlled-release hydrophilic matrix tablets containing methylcellulose and hydroxypropyl methylcellulose polymers." Pharmaceutical technology 18.9 (1994): 132-132.

[3] Dhenge, Ranjit M., et al. "Twin screw granulation using conveying screws: Effects of viscosity of granulation liquids and flow of powders." Powder Technology 238 (2013): 77-90.

[4] Wang, Li Ge, et al. "A breakage kernel for use in population balance modelling of twin screw granulation." Powder technology 363 (2020): 525-540.

[5] Roy, Sudeshna, Stefan Luding, and Thomas Weinhart. "A general (ized) local rheology for wet granular materials." New journal of physics 19.4 (2017): 043014.

Author Disclosure: All authors are Sanofi employees and may hold shares and/or stock options in the company.