Impact of Granulating Liquid Levels on MCC-Mannitol-Metformin Granules

INTRODUCTION

Formulations comprising microcrystalline cellulose (MCC) are often used in wet granulation processes. In high shear wet granulation, MCC as a filler helps to promote rapid wetting of the powder mix due to its swelling tendencies and wicking action.1 It may also impart some binding effect during granulation and facilitate water uptake to enable disintegration of the formulated granules or tablets. However, it has been reported that the advantageous properties of MCC could be diminished significantly during wet granulation if the granulating liquid levels are not well-managed.1,2 Over-wetting of the MCC-based granulation formulation may further densify and/or relinquish the disintegration-imparting properties of the MCC particles, resulting in lower tabletability and disintegration compared to the original MCC particles. To mitigate some of these issues, the use of MCC in concentrations between 5 and 20 %, together with another filler such as mannitol, is typically recommended. Given the interaction between MCC particles and water, it is hence of interest to understand the impact of granulating liquid (water) levels on the MCC-mannitol granules and the resultant tablets based on water requirement determinations.

MATERIALS AND METHODS

Vapor sorption isotherms were first determined for the granule fillers, mannitol (PEARLITOL® 50 C, Roquette Frères, France) and MCC (MICROCEL® 101 SD, Roquette Frères, France) to understand their differences in the liquid requirements. In this study, the power consumption curve was employed as a direct method to assess the rheological character or consistency of the wet MCC mass, where changes in the impeller power were recorded.3 Based on the results of the water requirement determination, granules were prepared by high shear wet granulation (DIOSNA P1-6 Laboratory Mixer, Diosna Dierks & SÖHne GmbH, Germany) based on three different granulating liquid (water) levels (figure 1). The granule formulation comprised of 15 %, w/w MICROCEL® 101 SD MCC, 20 %, w/w PEARLITOL® 50 C mannitol, 57.5 %, w/w metformin HCl (Granules India, India) as the model drug, 2.5 %, w/w sodium starch glycolate (GLYCOLYS®, Roquette Frères, France), and 5 %, w/w Kollidon® 30 polyvinylpyrrolidone K30 (BASF, Germany). The granules were wet-milled using a cone mill (Quadro Comil U5, Quadro Engineering, Canada) and dried in a fluid bed dryer (Midi-Glatt, Glatt GmbH, Germany) at 60 °C until the product temperature had plateaued.  

The granules were characterized for their size distribution by sieve analysis and bulk density. The granules were compacted with 2.5 %, w/w sodium starch glycolate as an extragranular disintegrant and 1 %, w/w magnesium stearate (Roquette magnesium stearate, Roquette Frères, France), and evaluated for their tabletability, dissolution and disintegration time.
540 mg tablets were prepared using a STYL’One Evolution press (Medelpharm, France) equipped with a 11.28 mm round flat punch. The used compression forces were 10, 15, 20 and 25 kN, with a pre-compression force of 1.2-1.4 kN. The simulated industrial press was Fette 2090-Euro B with a simulated speed of 54,000 tablets/hour.

 

Figure 1. Formulation of granules prepared by high shear granulation and the process parameters employed.

RESULTS

MCC displays a type II sorption isotherm while mannitol displays a type III sorption isotherm (figure 2). At the same relative humidity, MCC has a higher water affinity compared to mannitol, which suggests that MCC is more likely to adsorb water than mannitol. Mannitol tends to have loosely bound water compared to MCC, which helps to promote nucleation and granule growth. According to Kristensen et al., the amount of granulation liquid required for granulation depends on the mass fraction of MCC in the formulation.4 It was proposed that the amount of liquid required for granulation corresponds to the plateau in the power consumption profile.5 Beyond the plateau, over-wetting occurs, which is reflected by a sharp increase in the power consumption as the wet powder mass turns into to a highly cohesive paste.

  

Figure 2. Vapor sorption and desorption isotherm of MCC (MICROCEL® 101 SD; orange line) and mannitol (PEARLITOL® 50 C; blue line).

 

Figure 3. Power consumption curve of MCC (MICROCEL® 101 SD) in a high shear granulator.

Based on the power consumption profile for 225 g of pure MCC powder (figure 3), the plateau region corresponded to 84.8-116.5% of water with respect to the amount of MCC present. Three granulating liquid levels with respect to the amount of MCC present in the formulation (80 %, 95 % and 110 %) were selected for subsequent granulation.

Figures 4 and 5 present respectively the particle size distribution and the tabletability of granules prepared with the three granulating liquid levels. Figure 6 shows the influence of the amount of granulating liquid on the disintegration time of the tablets.

 

Figure 4. Particle size distribution of granules prepared with different granulating liquid levels.

 

Figure 5. Tabletability of granules prepared with different liquid levels.

 

Figure 6. Disintegration time of tablets with granules prepared from different liquid levels. All tablets were obtained at 15 kN compression force. 

 

The bulk density of the MICROCEL® 101 SD MCC / PEARLITOL® 50 C mannitol/metformin granules obtained was 0.44-0.47 g/mL while the median size was 240.5-381.5 µm (figure 4). With an increase in granulating liquid levels, the span of the granules was smaller, suggesting a narrower size distribution. When compacted, granules prepared with the lowest granulating liquid level exhibited the best tabletability (figure 5) and had the shortest disintegration time (figure 6). Consequently, the drug release rates were also the fastest for formulations with granules prepared with the lowest granulating liquid level (figure 7). These results were highly indicative of the impact of granulating liquid levels on the properties of the granules and resultant tablets. When the lower amounts of granulating liquid were used, the adverse impact on compactability and disintegration was reduced.

 

Figure 7. Dissolution profile of tablets with granules prepared from different liquid levels. All tablets were obtained at 15 kN compression force.

 

CONCLUSION

The liquid requirement of MCC is an important parameter to be managed so as to leverage on the advantageous properties of MCC in wet granulation. In this study, the power consumption curve of pure MICROCEL® 101 SD MCC powder served as a good reference for the amount of water to be used as the granulating liquid. It was demonstrated that the amount of granulating liquid added had an impact on the properties of the MICROCEL® 101 SD MCC / PEARLITOL® 50 C mannitol/metformin granules and tablets. For the given formulation, a lower granulating liquid level of 80% water was sufficient to form granules and produced tablets that had good technical properties.

REFERENCES

1. Chaerunisaa AY et al. Microcrystalline cellulose as pharmaceutical excipient. In Pharmaceutical Formulation Design-Recent Practices 2019 Jul 19. IntechOpen.

https://www.intechopen.com/chapters/68199 

2. Badawy SI et al. Use of mannitol as a filler in wet granulation. In Handbook of Pharmaceutical Wet Granulation 2019 Jan 1 (pp. 455-467). Academic Press.

https://doi.org/10.1016/B978-0-12-810460-6.00006-3

3. Chitu TM et al. Rheology, granule growth and granule strength: Application to the wet granulation of lactose–MCC mixtures. Powder Technology. 2011 Mar 25;208(2):441-53.

https://doi.org/10.1016/j.powtec.2010.08.041

4. Kristensen J et al. Direct pelletization in a rotary processor controlled by torque measurements. II: Effects of changes in the content of microcrystalline cellulose. AAPS PharmSci. 2000 Sep;2(3):45-52.

https://doi.org/10.1208/ps020324

5. Leuenberger H. Granulation, new techniques. Pharmaceutica Acta Helvetiae. 1982 Jan 1;57(3):72-82.

 

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