Handling Challenging Powders in Tableting Operations

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During a hands-on seminar held in July 2019 in Leverkusen, Germany, the authors compared the performance of five medium-sized rotary tablet presses to see how well they handle formulations that are prone to causing poor flowability, overlubrication, and capping. The equipment vendors IMA, Kikusui, Korsch, Romaco Kilian, and Syntegon (formerly Bosch), whose presses were used in the tests, were allowed to adapt filling system configurations for each formulation, without changing punches or dies.In order to ensure anonymity, no actual names were assigned to the results; the presses are identified as RP 1, RP 2, RP 3, RP 4, and RP 5.

The following trials were performed for each of the formulations at the same theoretical dwell time: A force-hardness profile was generated to compare the tableting behavior of the various presses. The next step was either to minimize the standard deviation of tablet weight (s_rel), or to investigate the influence of precompaction pressure. The final challenge was to maximize output while staying in spec.

Materials and methods

Rotary tablet presses. Tables I and II provide overviews of the relevant properties of the participating rotary tablet presses and the used fill shoe configurations. All rotary presses used the same standard Euronorm EuB tooling with a punch tip diameter of 8 mm and a radius of curvature of 12 mm. EuBB dies with the same tapering dimensions were used.

Table I. Key numbers of the participating rotary tablet presses.

Formulations. To test the rotary tablet presses, the formulations consisted mainly of excipients that are seldom used for direct tableting, or are used in smaller quantities. All of the formulations were blended in a drum hoop mixer (J. Engelsmann AG, Germany).

Table II. Fill shoe configurations of the rotary presses for the different formulations.

Formulation 1: Poor flowability. Formulation 1 contained of 74% GranuLac 200 (lactose, Meggle), 24.5% Tablettose 70 (lactose, Meggle), and 1.5% LIGAMED MF-2-V (magnesium stearate, Peter Greven). This formulation is characterized by its poor flowability (Table III), because of the large amount of GranuLac 200. GranuLac 200 has an average particle size of 30 μm, and is typically used in wet or dry granulation processes. To improve the flowability, some Tablettose 70, an agglomerated lactose with an average particle size of 190 μm, was added. Despite the difference in particle size, the flowability of this blend was still sufficiently poor so that segregation would not likely occur.

Table III. Bulk + tap density, Hausner ratio, and Carr’s index for the three formulations that were tested.

Formulation 2: Overlubrication. Formulation 2 was compounded of 84% UNI-PUR WG 220 (pregelatinized corn starch, Ingredion), 14.5% VIVAPUR 105 (microcrystalline cellulose, JRS), and 1.5% LIGAMED MF-2-V (magnesium stearate, Peter Greven). Formulation 2 was sensitive to densification speed and prone to overlubrication. The latter was tested before the seminar began. Increasing mixing times and intensities resulted in a decrease in tablet strength. The flowability of UNI-PUR was reduced by adding a poorly flowing microcrystalline cellulose with an average particle size of 15 μm. This forced the tablet presses to use a higher impeller speed and mixing intensity.

Formulation 3: Capping. For Formulation 3, 78% of the brittle TRI-CAFOS 500, a spray-dried tribasic calcium phosphate (Budenheim), which is mainly used as a disintegration enhancer in concentrations of 10–30% (1), was mixed with 20% highly elastic corn starch MAIZE STARCH BP (Ingredion) and 2% LIGAMED MF-2-V. The goal was to obtain a formulation that showed capping at higher tableting speeds.

To compare the density of the powder during filling with the bulk and tap density, the filling density of the powder was calculated from the filling height, the dimensions of the die, and the tablet weight. Tablet mass, height (thickness), diameter (D), and crushing force (CF) were determined with a semi-automated tablet hardness tester (ST-50, Sotax). The tensile strength (TS) of the tablets was calculated according to Francke (2) using the formula for equivalent tablet height (h_eq), as shown in Equation 1.

In order to characterize tableting properties, tensile strength was plotted against compaction pressure or tablet density. These plots included the single values of 10 tablets per compaction pressure level as well as their average value. The standard deviation of tablet weight (s_rel) is based on the weight of 50 tablets. The maximum allowed s_rel was determined by modifying past approaches (3). The experimental setup for all three formulations was quite similar. At first, extended force-hardness profiles were made at compaction pressures of 50 MPa to 300 MPa without precompaction pressure.

The second task was either to minimize the standard deviation of tablet weight (as with Formulations 1 and 2), or to examine the influence of the precompaction force (Formulations 2 and 3). Finally, the presses were challenged to maximize the output without allowing a standard deviation of tablet weight above 2% or a tablet crushing force of less than 80 N (Formulation 1), 40 N (Formulation 2), or 60 N (Formulation 3).

Results

Problem formulation 1: Poorly flowing material. Figure 1 shows the extended force-hardness profiles for all five rotary tablet presses. In Figure 1a, tablet tensile strength is plotted as a function of compression pressure and in Figure 1b as a function of tablet density. Three presses had to be used with a small precompaction force of 1.3 – 2.1 kN (precompaction pressure: 25–40 MPa) to prevent damage to the main compression roll.

Figure 1. Formulation 1; dt = 9.0 ms; (a) Tablet tensile strength vs. compaction pressure; (b) Tablet tensile strength vs. tablet density, (* = a precompaction force of 1.3 – 2.1 kN was applied in order to prevent damage to the machine).

All figures courtesy of the authors. Click figures to enlarge.

As obvious from Figure 1a, the tensile strength versus compaction pressure profiles were not identical for the various presses. This is not unexpected, because this plot is based on the machine parameter compaction pressure. Any differences that were seen could have resulted from differences in the following:

• Densification process of the powder bed height (e.g., due to small differences in the overall densification profiles).
• Die fill process, due to specific machine vibrations.
• Force measurement systems, which are calibrated statically, without proof that the statically obtained calibration data are also valid during the dynamic tableting process.

Figure 1b, which shows tensile strength versus tablet density, is based on tablet properties only, and is independent of machine parameters. Data from four of the five presses coincided. Only RP 1’s results differed slightly from those of the other presses: At the same tablet density, a lower tensile strength was obtained. This might be due to differences in the rearrangement phase of the powder particles. Additionally, this might be explained by mixing intensity within the fill shoe.

The latter hypothesis is supported by the results from Figure 2, showing the powder densities during filling, calculated as percentage of the tab density. RP 1 was the only tablet press that densified the powder bed during filling.

Figure 2. S_rel of tablet weight (n= 50, Ø: average tablet weight) and fraction of tap density during filling.

Figure 2 shows the standard deviations of tablet weight (s_rel) at two different dwell times: 9 ms and 6.5 ms. All rotary presses were able to produce tablets with an srel of 1.5% or less, which is sufficient for a tablet weight of 240 mg.

Interestingly, RP 1 achieved the lowest s_rel of 0.54% and 0.65% for the higher tableting speed. This seems to correlate with die-fill density, which is equal to tap density, and therefore higher than it is for the other tablet presses. For RP 2, RP 3 and RP 4, the die fill density nearly equaled the bulk density of the powder, while, for RP 5, the obtained die-fill density was even slightly lower than the bulk density. These differences are most likely due to differences among the fill shoe devices in the various presses. Higher powder density was achieved within the RP 1 fill shoe than within the fill shoes of the RP 2, RP 3, and RP 4 presses. At the same time, the powder in the RP 5 fill shoe appeared to have fluidized, slightly.

For Formulation 1, densification of the powder bed within the fill shoe is beneficial for achieving the standard deviation of tablet weight. In this case, the small loss in binding capacity (Figure 1) was irrelevant because, with all presses, the minimally required tablet strength was achieved. In Figure 3, the results of the challenge are summarized. Upon an increase of the tableting speed, s_rel became larger for RP 1, RP 2, and RP 3, while it stayed constant for RP 4 and RP 5 (compare to Figure 2).

Figure 3. S_rel of tablet weight (n = 50; Ø: average tablet weight) in relation to the largest achieved output challenge (output rounded to 10,000 tbl/h).

For the other presses, a slight increase of s_rel was observed, but all presses achieved an s_rel of less than the requested 2%, surprising results, given the poor flowability of Formulation 1. The target crushing force of 80–100 N was achieved for all presses, and the maximum outputs of all presses are comparable. Relating these outputs to the maximum possible levels would have been an interesting exercise but would have allowed the identities of the individual presses to be identified. The range was 83–100% of the maximally possible output. From these data, it can be concluded that even very poorly flowing material can be processed with modern rotary tablet presses at high speed and an appropriate standard deviation of tablet weight.

Problem formulation 2: Tendency to overlubricate. Figure 4 shows the extended force-hardness profiles of Formulation 2. As with Formulation 1, the compaction pressure versus tensile strength profiles (Figure 4a) were not identical, and deviated more than the tensile strength versus density profiles (Figure 4b). The explanation for the larger differences is the same as it is for Formulation 1. Differences between the tensile strength versus density profiles, if any, are practically irrelevant. With RP 3, the lowest tablet density and therefore the lowest tablet strength was obtained, most likely because this was one of the two presses that operated at zero precompaction force.

Figure 4. Formulation 2; dt = 38 ms. (a) Tablet tensile strength vs. compaction pressure; (b) Tablet tensile strength vs. tablet density (* = a precompaction force of 1.8 – 2.3 kN that was applied to prevent damage to the machine).

Figure 5 summarizes the tensile strength values obtained, as well as the applied pre- and main compaction forces and the speed of the fill shoe impeller.

Figure 5. Tablet hardness achieved vs. applied precompaction (PCF) and main compaction pressures and impeller speed used (* = a precompaction force of 1.8 – 2.3 kN was applied to prevent damage to the machine).

All presses were able to produce tablets that provided the requested crushing force of at least 40 N. By applying a larger main compaction pressure, larger crushing forces were also achieved. Additionally, applying a precompaction pressure in general resulted in stronger tablets. When increasing the tableting speed, the impeller speed had to be increased as well. Nevertheless, no relevant overlubrication could be observed. The target crushing force of 40 N was still achieved with all five rotary presses.

Differences between the presses could be observed with respect to the impeller speed used, which is much higher for RP 1, RP 2, and RP 3 than for RP 4 and RP 5. The risk of overlubrication by the impellers distributing the lubricant more intensively within the powder bed is therefore smaller for RP 4 and RP 5. In addition, differences in the applied compaction pressure could be observed. Whereas a much higher pressure was applied for achieving the requested tablet strength with RP 1 and RP 3, the rotary presses RP 2, RP 4, and RP 5 could manage with less.

Whether these differences in force are caused by a reduction of tablet strength due to intensive stirring in the fill shoe or by the speed sensitivity of the formulation could not be concluded from this experimental setup. Figure 6 compares the tablet crushing force with the achieved output in tablets per hour, and shows the variations in tablet weight that were obtained.

Figure 6. Tablet crushing forces (CF) obtained in relation to the largest achieved output challenge (output rounded to 10,000 tbl/h).

All of the presses tested fulfilled the required values: 40 N crushing force and the s_rel of tablet weight of less than 2% having an output of about 300,000 tbl/h or more. For three of the five rotary presses, the fill shoe configuration was changed between Formulation 1 and 2 (Table II).

Problem formulation 3: capping tendency. The tableting properties of Formulation 3 are shown in Figure 7 for all five presses at a theoretical dwell time of 15 ms. Although for RP 1, RP 3, and RP 4 a precompaction force had to be applied to keep from damaging the main compaction roll, capping tendencies were still present for RP 3, as obvious from the reduction of the tablet strength at 300 MPa main compaction pressure.

Figure 7. Formulation 3; dt = 15 ms (a) Tablet tensile strength vs. compaction pressure; (b) Tablet tensile strength vs. tablet density (* = a small precompaction force of 0.5 – 1.8 kN that was applied in order to prevent damage to the machine).

In contrast, RP 2 showed no capping, even though no precompaction pressure was applied. As seen with Formulations 1 and 2, when plotting compaction pressure versus tensile strength (Figure 7a) differences between the rotary presses were larger than they were when plotting tablet density versus tensile strength (Figure 7b).

It is remarkable that tablet tensile strength varied only slightly, from approximately 2 MPa to 2.7 MPa, whereas the corresponding values obtained for tablet density ranged from 1.41 g/cm³ to 1.57 g/cm³. The tablets with the highest density were produced with RP 2, as shown in Figure 8. These tablets also proved to be the strongest. To this end, at RP 2 the largest main compaction pressures of approximately 300 MPa had to be applied, followed by the main compaction forces of approximately 200 MPa at RP 3, required for obtaining tablet strengths of 2–2.5 MPa.

Figure 8. Tablet density vs. tablet tensile strength for different precompaction pressure levels, dt = 9 ms. Numbers positioned near the data points correspond to precompaction pressure levels.

For the three remaining tablet presses RP 1, RP 4, and RP 5, distinctly lower main compaction pressures had to be applied (130–160 MPa). For RP 1, RP 4, and RP 5, 90% precompaction pressure resulted in the highest tablet strength, whereas for RP 2, precompaction pressure of 20% (10% for RP 3) seemed to be optimal. This result confirms that the level of precompaction pressure depends on the properties of the powder that is to be compressed. Figure 9 shows results of maximizing the output while realizing tablets with at least 60 N hardness and a standard deviation of less than 2%. The maximum output obtained ranged from 260,000–320,000 tbl/h. For precompaction, a low level between 5% and 13% of the main compaction force was chosen, except with RP 4, where a precompaction force of 84% of the main compaction force was applied. For all presses, the filling density was slightly lower than the bulk density. Table II shows which filling system was used to test this type of formulation.

Figure 9. Tablet crushing forces (CF) obtained relative to largest output challenge (rounded to 10,000 tbl/h). PCF is precompaction force.

Summary

Regarding Formulation 1, all presses were able to handle this poorly flowing material. Even at high to maximum speeds, excellent standard deviations of tablet weight of less than 1.54% were obtained. The predensification of this powder to tap density within the fill shoe of one of the rotary presses seemed to be beneficial for this blend, resulting in the smallest standard deviation of tablet weight.Formulation 2 could also be processed into in-spec tablets. All presses achieved the tablet crushing force and maximally allowed standard deviation of tablet weight. Formulation 3’s capping tendency could be reduced by applying precompaction force.In short, results of these tests show that modern rotary tablet presses have been designed to be able to adapt to the specific properties of the powders that they are processing, resulting in in-spec tablets.

Acknowledgments

The authors wish to thank I.M.A. (Industria Macchine Automatiche); Kikusui; Romaco Kilian; Korsch; and Syntegon Technology (formerly Bosch), for participating in these tests.

They also thank Meggle Excipients & Technology; Chemische Fabrik Budenheim; J. Rettenmaier & Söhne (JRS Pharma); and Sotax for contributing the materials and equipment that were used for the testing.

The authors also send their appreciation to the doctoral students at the University of Bonn’s pharmaceutical technology department, who helped to analyze the tablets that were processed during the seminar.

References

1. D. Zakowiecki, M. Lachmann, T. Hess, Express Pharma 13, 90–92 (2017).
2. J.N. Francke, Untersuchung Mechanischer Eigenschaften von Tabletten: Vergleich Wissens- und Computerbasierter Prognosemodelle, Shaker Verlag, 2008.
3. P. Wilrich, R. Rupp, G.Schmidt, Pharm Ind. 47, 881–889 (1985).

About the authors

Barbara Fretter, barbara.fretter@solids-development.com*, and Maarten Lammens are managing directors of Solids Development Consult GmbH, Leverkusen, Germany; Karl G. Wagner is professor of pharmaceutical technology at The University of Bonn, Germany; Robert F. Lammens is a freelancer on the advisory board of Solids Development Consult GmbH, Leverkusen, Germany.

*To whom all correspondence should be addressed.

Article details

Pharmaceutical Technology
Supplement: Solid Dosage Drug Development and Manufacturing
April 2021
Pages: 12–18

Citation

When referring to this article, please cite it as, B. Fretter, M. Lammens et. al., “Handling Challenging Powders in Tableting Operations,” Pharmaceutical Technology Supplement: Solid Dosage Drug Development and Manufacturing
April 2021.