(M1130-08-45) Predicting Tablet Properties Using In-Line Measurements and Evolutionary Equation Discovery

Purpose: This study presents an opportunity of predicting granule and tablet properties through torque measurement of the granulation bowl and the force exerted on a probe within the powder bed. The model developed from Design of Experiment (DoE) matrix and evolutionary equation discovery show that the cumulative force during water addition in high shear granulation process has a strong contribution towards tablet tensile strength. The capability to predict tablet tensile strength and rotary press compaction force from upstream data will minimises waste and eliminates operator trial runs to get the best compression machine settings. High shear wet granulation (HSWG), dry granulation and direct compression are extensively used unit operations in manufacturing of tablets (Badawy et al. 2012). High shear wet granulation is a process involving addition (in most cases by spraying through a nozzle) of a liquid binder onto a powder bed which is agitated by an impeller with the liquid binder facilitating the formation of bonds between particles (Iveson et al. 2001). HSWG minimises segregation, facilitating the desired content uniformity within granules, improving powder flowability thus preventing tablet weight variability (Gabbott, Al Husban, and Reynolds 2016; Dun and Sun 2018). In addition, content uniformity and powder flow are key granule CQAs which have to be optimised to ensure successful tablet production (Dun and Sun 2018). This shows that HSWG is an important unit operation that can influence granule and tablet properties such as granule density, compressibility, flowability, particle size and shape, tablet crushing force, weight, disintegration, and dissolution.

Methods: Acetaminophen was high shear wet granulated with D-mannitol, microcrystalline cellulose, sodium starch glycolate, povidone and water as the binding liquid. Torque and Lenterra force in-line measurements monitor the granulation process in real time and show how the material properties evolve during the dry mixing, water addition and wet massing phases. Granules produced were characterised by basic flowability energy, specific energy, compressibility, and permeability using Freeman rheometer technology (FT4) and by particle size using QicPic gravity dispersing system (GRADIS). In addition, tablets were generated using a Gamlen press characterising tablets by compressibility, tabletability and compactibility.

Results: The results showed that the torque and Lenterra force in-line measurements are providing unique rich information about the granulation process (see Fig. 1&2). The Lenterra force probe is more sensitive during the water addition phase (see Fig. 2). The cumulative torque during water addition has a strong contribution on the bulk granule compressibility and permeability. In addition, the cumulative force during water addition phase has a strong contribution on granules specific energy, basic flowability energy and tablet tensile strength (see Table 1). Model developed using evolutionary discovery equation shows that the force during water addition and tablet compression force are key parameters in predicting tablet tensile strength.

Conclusion: In conclusion measurements by the Lenterra force probe can be used to predict tablet tensile strength which will minimise material waste and improve performance of tablet compression operators.

References: Badawy, Sherif I.F., Ajit S. Narang, Keirnan Lamarche, Ganeshkumar Subramanian, and Sailesh A. Varia. 2012. “Mechanistic Basis for the Effects of Process Parameters on Quality Attributes in High Shear Wet Granulation.” International Journal of Pharmaceutics 439 (1–2): 324–33. https://doi.org/10.1016/j.ijpharm.2012.09.011.
Dun, Jiangnan, and Changquan Calvin Sun. 2018. “Structures and Properties of Granules Prepared by High Shear Wet Granulation.” Handbook of Pharmaceutical Wet Granulation: Theory and Practice in a Quality by Design Paradigm, 119–47. https://doi.org/10.1016/B978-0-12-810460-6.00004-X.
Gabbott, Ian P., Farhan Al Husban, and Gavin K. Reynolds. 2016. “The Combined Effect of Wet Granulation Process Parameters and Dried Granule Moisture Content on Tablet Quality Attributes.” European Journal of Pharmaceutics and Biopharmaceutics 106: 70–78. https://doi.org/10.1016/j.ejpb.2016.03.022.
Iveson, Simon M., James D. Litster, Karen Hapgood, and Bryan J. Ennis. 2001. “Nucleation, Growth and Breakage Phenomena in Agitated Wet Granulation Processes: A Review.” Powder Technology 117 (1–2): 3–39. https://doi.org/10.1016/S0032-5910(01)00313-8.

Acknowledgments: I would like to express my gratitude and thanks to my supervisors for their encouragement and continual support. I would also like to give special thanks to Lenterra Inc for providing the Lenterra force probe. Finally, my sincere gratitude to GSK and EPSRC for funding my Engineering Doctorate. I would also like to thank members of Material Science department at GSK, Ware for their support and part hosting this project.

Fig. 1. Torque measurement during granulation



Fig. 2. Force measurement during granulation



Table 1. Tablet tensile strength predictor screening at 500kg compression load
a Cumulative torque (Nm.s) or force (N.s) during water addition,
b Cumulative torque (Nm.s) or force (N.s) during wet massing,
c Cumulative torque (Nm.s) or force (N.s) of the granulation process.
FPM: Force Pulse Magnitude
Max FPM: is the maximum FPM during the granulation process.