Eye on Excipients: Binding in Wet Granulation

Wet granulation is one of the most commonly used methods of developing solid dosage drug products. Among the advantages of this classical granulation method over other technologies are a narrow particle size distribution (PSD) of the granules, few fine particles that yield little dust, more consistent powder flow, better control of granule size, very good binder homogeneity, and good powder compactability. 

The most important excipient group in a successful wet granulation formulation is the binder. Within this group are polymers with different chemistries, mechanical properties, and viscosity ranges. The polymer binder HPC has attracted the attention of formulators in the last decade due to its superior mechanical properties, chemical stability, and multi-functionality. This cellulosic ether appears to work even in challenging formulations with high dose, poorly compressible drug products, where other binders usually fail. Low-viscosity (low-MW) HPC grades are used as a binder for all types of wet granulation including high shear, fluid-bed, extrusion, and melt granulation. To select the suitable grade, scientists often must conduct many experiments, adjusting the desired powder and tablet characteristics. In this study, we focused on the influence of the HPC MW on the granule and tablet characteristics in fluid-bed and high shear wet granulation. 

Materials and Methods

The study used HPCs with MWs of 40,000 daltons (Nisso HPC-SSL and SSL SFP from Nippon Soda, Tokyo, Japan), 100,000 daltons (Nisso HPC-SL and SL FP), and 140,000 daltons (Nisso HPC-L and L FP). Paracetamol (Atabay, Istanbul, Turkey) was used as a model active pharmaceutical ingredient (API); use level was 85 percent by weight. Croscarmellose sodium (Vivasol, JRS Pharma, Patterson, NY) was used as a superdisintegrant and magnesium stearate (Lehmann & Voss, Hamburg, Germany) was used as a lubricant. A fluid-bed granulator (Solidlab 2, Bosch, Waiblingen, Germany) and high-shear granulator (Mycromix, Bosch) were used for the granulation of pure paracetamol. The PSD of the granules was analyzed by laser diffraction (Qicpic, Sympatec, ClausthalZellerfeld, Germany). Tablets were compressed using a rotary tablet press with 16 stations (TPR200, Bosch).

The model formulation included a high dose of paracetamol (85 percent) and 10 percent HPC, which served as the binder (Table 1). 

Six different grades of HPC were selected based on their MW and median particle size (Table 2). Grades of regular particle size HPC-SSL, SL, and L were used in the fluid-bed granulation and were added as an 8 percent aqueous solution. Grades of fine particle size HPC-SSL SFP HPC-SL FP, and HPC-L FP were used in the high-shear granulation. They were added dry, with purified water serving as the granulation liquid. 

Results and Discussion: Fluid-bed granulation 

Each HPC aqueous solution was prepared to the same 8 percent concentration. The average viscosity of the different solutions, expressed in millipascal-seconds, was 20 mPa·s for the SSL, 65 mPa·s for the SL, and 200 mPa·s for the L. Table 3 lists the main process parameters for fluid-bed granulation. 

PSD of the granules

A strong effect of the HPC’s MW on the granules’ PSD was observed. The lowest MW grade (HPC-SSL) produced finer granules with a very narrow PSD (Figure 2). The coarsest granules, with a broader PSD, were observed to result from HPC-L, which had the highest MW of the tested grades. 

There was a clear relationship between the HPC’s MW and the size of the granules: SSL < SL < L. This shows that changing the HPC grade makes it possible to modulate the granule particle size and PSD without changing the product’s formulation or granulation parameters. 

Powder compactability 

The granules obtained were formed into tablets at five different compression forces (Figure 3). The moisture content of all the powder blends was similar, thus its effect on the powder compaction properties can be excluded. 

At compression forces up to 15 kilonewtons (kN), the powders showed approximately the same compactability. At higher compression forces, the granules made with HPCSSL demonstrated much better compaction properties and yielded the highest tablet breaking forces. A possible reason for the superior deformability of the SSL could relate to the mobility of the polymer chain in the dry powder. The short polymer chain of SSL (MW of 40,000) is more linear, allowing more deformation after compression. HPC grades SL and L have higher MWs (100,000 and 140,000) and are more sterically bound in dry form, creating a binder with more elasticity and less deformability.

Tablet disintegration 

The disintegration of the tablets also showed a dependence on the HPC MW. It is well known that a high viscosity inside the tablet matrix can prolong disintegration by reducing water uptake. Figure 4 shows the disintegration time of tablets with a breaking force of 200 newtons. 

As expected, tablets made using the lowest-viscosity (lowest-MW) HPC (SSL) disintegrated fastest, followed by SL and L. 

Tablet friability

All the tablets showed acceptable friability results (Figure 5). No impact of the HPC MW was observed. 

Conclusions: High-shear granulation. From these results, the following conclusions can be drawn regarding highshear granulation: The HPC’s MW has a minor effect on the granules’ PSDs. Slightly fewer fines were created with HPC-SSL SFP; The lower MW HPCs (SSL and SL) have better compactability at higher compression forces (>15 kN); 

and Tablet disintegration time is inversely correlated to the HPC’s MW: The higher the MW, the faster the disintegration, which is counterintuitive and the opposite of the results observed in the fluid-bed granulation that used a dissolved binder. For high-shear granulation, disintegration time ranks thusly: L FP < SL FP < SSL SFP. 

Comparison: Fluid-bed versus high-shear granulation 

PSD of the granules

A comparison of the PSDs of granules prepared using these wet granulation methods appears in Figure 10. 

As the figure shows, fluid-bed granulation produced finer particles and a narrower PSD. The difference is most prominent at the lowest-MW HPC (SSL), followed by SL and L. This implies a strong MW dependence: The higher the MW, the smaller the difference between the granule PSDs obtained from both granulation techniques. The coarser granules resulting from high-shear granulation demonstrated better powder flow across all three HPC grades (Figure 11).

Powder compactability

The tablet compaction properties of the granules produced by fluid-bed granulation were much better than those produced by high-shear granulation (Figure 12). 

At a given compression force and HPC MW, the tablet breaking force was between 30 and and 90 percent higher when a dissolved binder is used (fluidbed granulation). This is likely due to the finer and more homogeneous particle size of granules produced by the fluid-bed method. Tablet disintegration

At a given MW, the disintegration time of tablets made from the high-shear granulations was much faster than that of tablets made from the fluid-bed granulations (Figure 13). This could be related to the more fragile nature of the granules made by the high-shear method (dry binder). They are more fragile because the bridges between the particles are not as strong as those made using a dissolved binder. This fragility is thought to facilitate tablet disintegration. 

Tablet friability 

Tablet friability was acceptable for all formulations (Figure 14), with no significant dependence on MW or granulation method. 

Conclusions: Fluid-bed versus high shear granulation

When comparing granulations with the same MW of HPC: 

Fluid-bed granulation produced smaller granules with narrower PSDs and better tablet compaction; 

High-shear granulation produced larger granules with broader PSDs and better flow properties; With fluid-bed granulation, disintegration times are shorter, and the lower the MW of the HPC, the faster the disintegration: SSL < SL < L; 

With high-shear granulation, the higher the MW of the HPC, the faster the disintegration: L < SL < SSL; 

and No significant differences in tablet friability were observed.