Compaction Mechanisms of DC Textured Mannitol in a Rotary Tablet Press Simulator

Situation

Mannitol manufacturing

• Synthetically produced, hydrogenation or fermentation.1, 2
• Naturally present in certain plants, extraction from algae.

Mannitol uses

• Mainly as diluent in tablets, capsule or freeze-dried formulations, or as a drug carrier in dry powder inhalers.3, 4
• Low moisture content and non-hygroscopic character, use with active ingredients that are sensitive to moisture.

STYLCAM 200 R press simulator

• A rotary single punch tablet press.
• Simulate the compression profiles of various rotary tablet presses.
• Strain gauges and potentiometric displacement transducers on the upper and lower punch.
• Variation of the velocities of compaction.
• Including precompression before the main compression.

Challenge

Understanding the deformation mechanism of a textured mannitol using a rotary press simulator.

Solution

Products DC

• Textured mannitol (PEARLITOL®200 SD, Roquette)
• Microcrystalline Cellulose (MCC) (VIVAPUR® 200, JRS Pharma)
• Lactose (TABLETTOSE® 80, Meggle)
• Dibasic Calcium Phosphate (DCP) (EMCOMPRESS® Premium, JRS Pharma)
• Magnesium stearate (MgSt) (Wiga-Pharma GmbH)

Particles characterization

Compression

STYLCAM 200R – Flat punches EURO B ø11.28 mm / Compression speed (1, 25, 50 tabs/min)

Heckel modeling: Ln (1/(1-D)) = k P + A

Mean yield pressure: Py = 1/k

Walker modeling: 100V = - W log P + C

k and W are the coefficient of the linear part of the Heckel and Walker plot.

• Mannitol: Lubricant concentration of 0%, 1.2% and 2% / mixing time of 2.5 min, 5 min and 10 min
• MCC: Lubricant concentration of 0% and 1.2% / mixing time of 5 min
• Lactose: Lubricant concentration of 0% and 1.2% / mixing time of 5 min
• DCP: Lubricant concentration of 0% and 1.2% / mixing time of 5 min

Strain Rate Sensitivity (SRS) value: Py value between 1 and 50 tabs/min (corresponding to 4 mm/s and 200 mm/s).

SEM Photography: mannitol powder and mannitol tablet after hardness measurement.

Results

Table 1. True density and mean particle size value

Table 1
It shows true density and particle size mean diameter for all materials. DCP has higher true density value while other excipients have roughly the same values. For particle size, MCC has the higher particle size diameter while other excipients have roughly the same values.

 Graph 1. Impact of lubricant concentration and mixing time

Graph 2
Tabletability of textured mannitol is shown in graph 1 at different lubricant concentration and mixing time. Textured mannitol is not sensitive to these parameters as the tabletability is still the same at each concentration (1.2% and 2%) and mixing time (2.5 min, 5 min and 10 min).

Graph 2. Impact of lubricant concentration and mixing time

Graph 2
It shows the influence of the MgSt lubricant on the different tested materials. Although there was a slight decrease in tablet hardness, the difference is not significant for the compaction of textured mannitol, lactose and DCP. As for MCC, the compaction profile was significantly influenced by the presence of the MgSt lubricant. Indeed, lubricated MCC tablets have significantly lower hardness than non-lubricated MCC.

Graph 3. Py value depends on compression force

Graph 3
It shows the evolution of the Py values calculated from the linear slopes k as compaction pressures increase. As these values increase with compaction pressures, the deformation mechanism is also evolving. The DCP Py evolution is significantly more important than lactose and textured mannitol followed by lactose and MCC.

Graph 4. Walker plot for all material at a compression pressure of 100 MPa

Table 2. True density and mean particle size value

W coefficients were calculated from the graph 4; these plots are summarized in Table 2. All W coefficients were calculated with the best correlation coefficient (R²) disregarding compaction pressure range in which it was calculated.

At all compaction pressures, the higher values of W coefficients were obtained for the MCC followed by the textured mannitol, DCP and finally the lactose. MCC showed higher values of SRS (between 16% and 18%) than other materials. For DCP, lactose and textured mannitol, SRS values were between 0% and 7.3%.

After compaction, SEM pictures showed the fragmentation of the textured mannitol since the agglomerated structure was not visible anymore.

Conclusion

The results of this work show that it was possible to characterize the deformation behavior of textured mannitol in conditions of industrial tableting using an instrumented rotary press simulator. The textured mannitol compaction behavior was shown to be unaffected by MgSt lubricant concentration or mixing time which is typical of fragmentary deformation. Compressibility characterization by Heckel and Walker modeling showed that the mean yield pressure and the W coefficient were also typical of a more fragmentary than plastic material. Furthermore, the low strain rate sensitivity index is characteristic of fragmentary material

References

1. Devos, Francis (1995). Brevet américain n°5, 466, 795. FRANCE: U.S. Patent and Trademark Office.
2. Soetaert, W., D. Schwender, K. Buchholz, and E.J. Vandamme. “A wide range of carbohydrate modifications by a single organism: Leuconostoc mesenteroides. “Prog. Biotechnol, no.10 (1995): 351-58.
3. Bolhuis, G.K., Erik G.Rexwinkel, and Klaas Zuurman. “Polyols as Filler-binders for Disintegrating Tablets Prepared by Direct Compaction. “Drug Development and Industrial Pharmacy 35, no.6 (June 2009).
4. Kaialy, Waseem, Mohammed N.Momin, Martyn D. Ticehurst, John Murphy, and Ali Nokhodchi. “Engineered Mannitol as an Alternative Carrier to Enhance Deep Lung Penetration of Salbutamol Sulphate from Dry Powder Inhaler. “Colloids and Surfaces B: Biointerfaces 79, no.2 (September 2010): 345-56.

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