(M1230-09-61) Predicting Granule and 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 compaction force from in-line measurements will minimises waste and eliminates operator trial runs to get the best compression machine settings. High shear wet granulation (HSWG) is a common unit operation in manufacturing of tablets and is a process involving addition 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, facilitates desired content uniformity within granules, improves powder flowability thus preventing tablet weight variability (Gabbott et al., 2016; Dun and Sun, 2018). In addition, content uniformity and powder flow are key granule critical quality attributes (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 CQAs.

Methods: Material and

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 in-line rheometer 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 and specific energy, using Freeman rheometer technology (FT4) and by particle size using QicPic gravity dispersing system (GRADIS). In addition, tablets were generated using Styl’One Evolution compaction simulator.

Results: Sensitivity of Torque and Lenterra in-line measurements: Figure 1 and 2 shows the in-line measurements of the torque and the force exerted on the Lenterra in-line rheometer (LIR) probe at different operating conditions. Varying wet granulation process parameters result in minimal or no significant change in the measured torque during water addition and wet massing phases. The lack of sensitivity of the torque measurement elucidate that the torque measured is the total energy going into the entire granulation process hence no significant change during water addition and wet massing. Therefore, unable to provide accurate representation of the granule formation and evolution during the wet granulation process. The force probe is more sensitive to change of different process parameters compared with torque measurements. Figure shows that the force increases rapidly during water addition and plateaus during wet massing phase. This is a clear indication that the LIR probe provides meaningful information about the granule formation and evolution during the granulation process. After water addition starts, wetting phase follows that ends when all dry powder is wetted. During wetting process, the wet mass becomes heavier which is indicated by a recognisable increase in the force after 2 minutes of water addition (shown in figure 2). This is interesting as it will provide valuable information about the wetting stage of the granules and in real times shows when all dry powder is fully wetted. Predictor Screening: Assesses which of these variables have stronger contributions or dominant in predicting the tablet tensile strength at different compaction forces. The predictor screening reports the contribution, percentage of the contribution and rank of the predictors help the user to make informed decision in identifying the dominant predictors. Table 1 indicates that force during water addition have a strong contribution towards the tablet tensile strength compared with other process parameters.

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. The integrated Torque, force and force pulse magnitude measurements during water addition can be used to predict bulk granule compressibility. Furthermore, knowing the target tensile strength, the integrated force during water addition can be used to predict the compaction pressure.

References: Dun, J. and Sun, C.C. (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, pp. 119–147. doi:10.1016/B978-0-12-810460-6.00004-X.
Gabbott, I.P., Al Husban, F. and Reynolds, G.K. (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. doi:10.1016/j.ejpb.2016.03.022.
Iveson, S.M., Litster, J.D., Hapgood, K., et al. (2001) Nucleation, growth and breakage phenomena in agitated wet granulation processes: A review. Powder Technology, 117 (1–2): 3–39. doi:10.1016/S0032-5910(01)00313-8.
Acknowledgements: 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 and MedelPharm, Beynost for providing the Lenterra force probe and the Styl’One Evolution. Finally, my sincere gratitude to GSK and EPSRC for funding my Engineering Doctorate.

Fig. 1. Torque measurement during granulation.

Fig. 2. Force measurement during granulation.

Table 1. Tablet tensile strength predictor screening at 150kN, 100kN and 50kN