(M1430-11-70) A Strategy for Optimizing Precompression Pressure Using In-Die Elastic Recovery

Purpose: Tablet lamination via air entrapment can be a significant challenge that must be overcome during pharmaceutical tablet formulation development to produce high-quality tablets that have sufficient strength to withstand the various environments encountered during manufacturing, shipping, and distribution. Deaeration of the powder bed prior to a main compression step is a common way to avoid entrapped air that can significantly damage the tablet upon decompression.¹ Applying a precompression event prior to the main compression step is a widely used method for overcoming air entrapment.² However, the precompression pressure is usually chosen empirically and little work has been performed on optimizing it for a given formulation. Recently, in-die elastic recovery has been evaluated as a promising metric available to diagnose and assess the effectiveness of the strategy in addressing tablet lamination.³ This is especially useful since only in-die data is required, which makes it a fast and efficient way to assess precompression effectiveness, even when the internalized defects caused by air entrapment are not visible on the tablet exterior. Here, we report a strategy for optimizing precompression pressure utilizing in-die elastic recovery, which allows one to quickly assess the optimal precompression pressure to avoid potential lamination issues.

Methods: Microcrystalline cellulose PH102 (MCC PH102) was mixed with 2% magnesium stearate (MgSt) in a blender (Turbula, Glen Mills, Clifton, NJ) for 5 min at 49 rpm.⁴ The mixture was then compressed on a compaction simulator (Styl’One Evolution; MedelPharm, Beynost, France) simulating a Korsch XL100 TSM B machine with 11.28 mm round, flat-faced punches. Speeds of 60 rpm⁴ and 120 rpm were used to compress approximately 400 mg tablets at a variety of precompression and main compression pressures. Elastic recovery was calculated based on the difference between the in-die thickness after decompression and the minimum tablet thickness achieved during compression divided by the minimum thickness achieved during compression. Tablet tensile strength (𝜎) was calculated based on out-of-die thickness (t) and diameter (D) measurements taken with calipers, as well as the tablet diametrical breaking force (F) collected with a texture analyzer (TA-XT2i; Texture Technologies Corporation, Scarsdale, NY) according to the equation: 𝜎 = 2F/(πDT).

Results: Tablets were either obtained intact (Figure 1a), cracked in the band (Figure 1b), or completely laminated (Figure 1c). At each of the main compaction pressures, tablet elastic recovery as a function of precompression pressure revealed a parabola-shape relationship (Figure 2). At low precompression pressures, the deaeration step is insufficient at eliminating the air from the compact, while at high pressures, the air is sealed inside the compact and unable to escape during the precompression step. At the minimum of this parabola, intact tablets could be formed at all main compaction pressures. Exacerbation of the curvature of the parabola was apparent as the main compaction pressure increased. Additionally, as the speed increased from 60 rpm to 120 rpm at a 500 MPa main compaction pressure, the curvature was more severe. From this data, the optimum precompression pressure of around 70 MPa results in the lowest in-die elastic recovery, and provides the greatest allowance for operating deviation while still obtaining intact tablets. The tabletability profile (Figure 3) of the mixture was evaluated both with and without the optimized precompression event. Tablets could not be made over 100 MPa when no precompression was used as band cracks and lamination occurred immediately after compression. However, when the optimized 70 MPa precompression step was applied, tablets could be made over a wide range of compaction pressures, indicating the effectiveness of the precompression step in deaerating the powder bed prior to the main compression. From this study, we recommend a strategy to alleviate or eliminate defects related to air entrapment by identifying an optimal precompression pressure at a high main compaction pressures and speed, which exacerbates the air entrapment issue, leading to lowest in-die elastic recovery in an elastic recovery vs. precompression plot.

Conclusion: A strategy for determining the optimal precompression pressure for reducing or eliminating air-entrapment related defects during tablet manufacturing was outlined. In-die elastic recovery as a function of precompression pressure yields a parabola-shaped relationship, the minimum of which corresponds to an optimized precompression pressure at which air in the powder bed is minimized prior to the main compaction event. This method does not require any measurements outside of what is already collected with a compaction simulator during a compression, making it a fast and efficient optimization method.

References: 1. Hiestand, E. N., Wells, J. E., Peot, C. B. & Ochs, J. F. Physical processes of tableting. J. Pharm. Sci. 66, 510–519 (1977).
2. Sinka, I. C., Motazedian, F., Cocks, A. C. F. & Pitt, K. G. The effect of processing parameters on pharmaceutical tablet properties. Powder Technol. 189, 276–284 (2009).
3. Vreeman, G. & Sun, C. C. Air entrapment during tablet compression – Diagnosis, impact on tableting performance, and mitigation strategies. Int. J. Pharm. 615, 121514 (2022).
4. Mazel, V. & Tchoreloff, P. Lamination of pharmaceutical tablets: classification and influence of process parameters. J. Pharm. Sci. 111, 1480–1485 (2022).

Acknowledgements: Funding from the National Science Foundation through grant number IIP- 1919037, the American Foundation for Pharmaceutical Education (AFPE) through 2022 Dr. Paul B. Myrdal Memorial Pre-Doctoral Fellowship, and the Department of Pharmaceutics, UMN, through David and Marilyn Grant Fellowship in Physical Pharmacy (2022-2023) is gratefully acknowledged for partially supporting GV. CCS thanks the National Science Foundation for support through the Industry University Collaborative Research Center grant IIP-2137264, Center for Integrated Materials Science and Engineering for Pharmaceutical Products (CIMSEPP).

(a) An intact tablet, (b) a tablet exhibiting cracks in the tablet band, and (c) a laminated tablet.

In-die tablet elastic recovery versus precompression pressure at different main compaction pressures and speeds. Open symbols indicate the observance of tablet defects like lamination or cracking in the band.

Tabletability of the blend with (squares) and without (circles) an optimized precompression step. Open shapes and a tensile strength of zero indicate tablet lamination. Main compaction pressures below 65 MPa are not included for the precompression-optimized data because the precompression event would have a larger pressure than the main compression pressure.