Are Natural Lubricants Suitable for Texturized Mannitol Oral Dispersible Tablets?

Situation

Mannitol has physical and chemical inertness in addition to its several advantageous organoleptic properties. Therefore, mannitol is the excipient of choice for the formulation of nutraceutical tablets. The [starch and mannitol] compound PEARLITOL® Flash is a ready-to-use directly compressible platform which allows the production of orally dispersible tablets.

Challenge

However, mannitol is known to have a high lubrication need to reach moderate ejection forces and to avoid related tableting problems such as stickiness and lamination.3 Literature reports levels of > 1 % Magnesium Stearate (Mg stearate) for optimal tableting of pure mannitol. Mg stearate is known to have an impact on different aspects of the compaction process of pharmaceutical powders. Its main function is to prevent interaction between the compressed powder and the surface of the die walls and punches that leads to gripping, sticking and tablet etching. It also interfere in the inter-particular interactions of the powder being compressed. Thus, it influences the re-arrangement of individual particles and the cohesive properties after compaction. The effect of Mg stearate lubricant during powder compaction is mainly observed on plastic materials such as microcrystalline cellulose (MCC),1 rather than on fragmentary materials such as lactose, textured mannitol3 and dicalcium phosphate.2

Solution

Materials

Lubricants of natural origin were used and compared with magnesium stearate as reference:

• Nu-Mag® (Ribus Corp, USA), a blend of secondary products rice and triglycerides
• Compritol® 888 ATO (Gatefossé, France), glyceryl dibehenate,
• L-Leucine, coarse spray dried grade
• Magnesium stearate (Bärlocher, Germany)

PEARLITOL® Flash (Roquette Frères, France), a mannitol and maize starch compound, batch E061F, was used as the sole tablet filler.

Tableting trial

Binary blends of PEARLITOL® Flash and the lubricant were produced using a TURBULA® mixer at 23 rpm for 5 min.

For each lubricant, an initial concentration was selected:

• 2% for Nu-Mag®, Compritol® and Leucine
• 3% for Leucine
• 0.8% Mg Stearate as reference.

The lubricant concentration was then increased until the tableting reached low ejection forces without sticking issues.

Tableting trials parameters:

• Compression simulator STYLCAM 200R (MedelPharm) using a gravity feeder.
• Flat 10 mm diameter punches (ELIZABETH).
• Compression speed of 10 tabs/min.
• Compression and ejection forces measured.
• Tablets characterization (done on correctly lubricated powder blends only): hardness thickness, diameter and weight (Pharmatron DT50, Sotax AG).

Results

Figure 1: Ejection forces measured during PEARLITOL® Flash tableting using different lubricants concentrations

Leucine and Nu-Mag®, gave a very high ejection force value, even with a lubricant concentration of 5%. It was therefore not possible to make tablets using mannitol PEARLITOL® Flash with leucine and Nu-Mag®.

Typical binding marks are visible on the tablet when using 2% and 3% Compritol® or 0.8% and 1% Mg stearate. These marks reveals the continuous tablet adhesion and friction in the die. This could cause tableting problems during longer production cycles.

Using 4% Compritol® concentration results in tablets comparable to those made with Mg stearate.

Figure 2: Tablet with typical stickiness marks

Whatever the compression force (5 kN up to 20 kN) measured, tablet hardness was comparable. The tablet friability for both recipes was under 1%.

No significant difference was noticed using Compritol® or Mg stearate, and especially no negative impact of the tablet hardness and friability was observed.

Figure 3: Tablet hardness in function of compression force using functionally equivalent lubrication systems

Conclusion

Mannitol is known to need a high amount of lubrication in tableting compared to cellulose microcrystalline powder. Anyhow, there are significant differences in the application value of commercially proposed lubricant excipients. Mg stearate has been found as the most suited lubricant for mannitol. The optimum used level is 1.2%. The natural choice for replacing it is glyceryl dibehenate (Compritol® 888). It results in similar tablet hardness and ejection forces, but using a concentration of 3% or 4%, which is higher than requested for magnesium stearate. Not all commercially available lubricants fit with PEARLITOL® Flash. A full characterization of tablet lubricants should necessarily include both the visual aspects of tablets with the analytical measures, using the tablet press ejection sensor values.

References

1. Roberts, R.J., Rowe, R.C., 1987. The compaction of pharmaceutical and other model materials—a pragmatic approach. Chem. Eng. Sci. 42, 903-11.
2. Wang, J., Wen, H., Desai, D., 2010. Lubrication in tablet formulations. Eur. J. Pharm. Biopharm. 75, 1-15.
3. Tarlier, N., Soulairol, I., Bataille, B., Baylac, G., Ravel, P., Nofrerias, I., Lefèvre, P. Sharkawi, T., 2015. Compaction behavior and deformation mechanism of directly compressible textured mannitol in a rotary tablet press simulator. Int. J. Pharm. 495,410-19.

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