(M1030-09-58) Effects of Tableting Speed, Blending Time, and Feed Frame Shear Sensitivity on Tablet Properties

Purpose: Compression speed, blending time, shear rate sensitivity can have significant effects on the mechanical properties of the pharmaceutical powders during the scale up and technology transfer of a pharmaceutical product. ¹ To mitigate this risk, it is recommended to evaluate the effects of these parameters during early process development before the formulation is locked. Powder compression properties can be characterized by compressibility, tabletability, and compactibility (CTC) profiles, which describes the relationship between compaction pressure (P), tablet porosity (ε), and tablet tensile strength (σ).² An experiment was carried out to evaluate the effects of tableting speed, blending time, and feed frame shear sensitivity on tablet properties. For this experiment, the final blend of the formulation containing model plastic API was used to make CTC profiles at four different speeds, three tablets at around 150 MPa for eight blending times, and CTC profiles at five feed frame shear times. This experiment was performed with a material sparing approach, so a single compaction pressure in the range of expected manufacturing pressure was chosen for the blending sensitivity study.

Methods: The intragranular components of the dry granulation formulation include a mixture of a model plastic API, microcrystalline cellulose, mannitol, crospovidone, colloidal silica, and magnesium stearate, while the extra-granular ingredients included microcrystalline cellulose, crospovidone, colloidal silica, and magnesium stearate. Six round flat-faced tablets with an 11.28 mm diameter were made at 50, 100, 150, 200, 250, and 300 MPa compression stress at 20, 50, 80, and 97 rpm on a compaction simulator (Styl’One Evolution, MedelPharm, Beynost, France) simulating a Courtoy Modul S (Euro B) tableting press with 10% precompression. To evaluate tablet tensile strength, the cylindrical tablets were broken diametrically by a Texture Analyzer (TA-XT2i, Texture Technology Corps, NY, equipped with a 30 kg load cell, trigger force of 5 g) at a test speed of 0.01 mm/s. For blending sensitivity, about 20 g final blend was placed in a container with about 50% headspace and blended for 5, 10, 15, 20, 25, 30, and 45 minutes in a Turbula blender at 49 rpm. At each time point, three round flat-faced tablets with an 11.28 mm diameter were made at ≈150 MPa while simulating a Courtoy Modulo S (Euro B) tableting press at 35 rpm with 10% precompression. For shear rate sensitivity, 50 g of the remaining final blend (enough to completely fill the feed frame) was loaded into a force-feed shoe, spun at 100% speed for 1, 3, 5, 10, and 20 min. Six round flat-faced tablets with an 11.28 mm diameter were made at 50, 100, 150, 200, 250, and 300 MPa at each time point simulating a Courtoy Modulo S (Euro B) tableting press at 35 rpm with 10% precompression.

Results: The results show that with increasing tableting speed, tabletability decreases slightly. For a tensile strength of 2 MPa, the required pressure increases from about 100 MPa at 20 rpm to about 140 MPa at 97 rpm (Figure 1). Despite the slight decrease in tabletability, this confirms that tablets with appropriate mechanical strength can be made even at very high speeds. Compactibility and compressibility did not change significantly with increased tableting speed. As blending time increased, tablet tensile strength showed a decreasing trend (Figure 2). However, the differences are small, with values scattered within a 0.4 MPa region. For the shear sensitivity evaluation, ejection force was found to decrease with subsequent spinning times (Figure 3a). The slight increase in ejection force at 1 min may be attributed to the faster compression speed of the feed frame shear sensitivity tests (35 rpm) compared to the control test (20 rpm). The decrease in ejection force with subsequent spinning in the feed shoe may be attributed to increasing the coverage of magnesium stearate throughout the blend, thus improving ejection at the expense of a slightly worsened tabletability (Figure 3b).

Conclusion: Results showed that the tabletability of the final blend was affected by an increase in speed, whereas the compressibility and compactibility profiles were essentially independent of tableting speed. Since the compactibility profile (tensile strength vs. porosity) is independent of tableting speed, it can be used to predict tablet strength during formulation development and scale up.¹ It was also noted that the blend was affected by change in blending time as well as shear rate sensitivity. Early detection of these challenges could help in determining the compression parameters which can produce tablets with consistent mechanical properties.

References: 1. Tye, C.K., Sun, C. C. & Amidon, G. E. Evaluation of the effects of tableting speed on the relationships between compaction pressure, tablet tensile strength, and tablet solid fraction. J. Pharm. Sci. 94, 465 (2005).
2. Vreeman, G. & Sun, C. C. A powder tabletability equation. Powder Technol. 408, 117709 (2022).

Acknowledgements: This research work was performed as a part of collaborative effort between Mirati Therapeutics and University of Minnesota. Authors do not report any conflict of interest.

Figure 1: Effects of tableting speed on CTC profile

Tensile strength at different blending times

Figure 3. a) Ejection force profiles for different feed shoe spinning times; b) Tabletability profiles for different feed shoe spinning times.