Low impact of relative humidity on granules compactibility when using modified starch as granulation binder
Case Study

Low impact of relative humidity on granules compactibility when using modified starch as granulation binder



Wet granulation is widely used in the pharmaceutical industry due to its versatility and reliability in achieving the desired granule properties. Wet granulation can be applied to all drugs and is considered as a universal way to produce tablets. 
Traditionally, wet granulation is a process in which powders are brought together with a granulating liquid in solution to form granules. Today, this process tends to be limited to the use of water as solvent. Wet granulation improves flow, powder compactibility and content uniformity, generates uniform particle size and shape, and minimizes the impact of minor changes in drug substance and excipient properties. 
It can be practiced as a low-shear technique, high-shear process or fluid bed granulation. Recently, wet granulation process improvements have involved continuous processing in particular twin-screw extrusion. 
To ensure good adhesion and cohesion between interparticules surface in the wet state, binders with appropriate properties are added. Appropriate binder is important to obtain good plasticity, compactibility and binding ability after the granules are dried and size reduced. 
In addition, granulation binders must have a low sensitivity to relative humidity (RH) changes in order to provide consistent granules properties and therefore consistent tablet characteristics.


Experimental Strategy 

In this study, mannitol was granulated using either polyvinylpyrrolidone (PVP), pregelatinized hydroxypropyl pea starch (HPS) or pregelatinized octenyl succinate starch (OSS) in aqueous solution. After drying, granulated mannitol powders were stored for one week at three different relative humidities (30%, 50% and 60% RH) prior to compression. The tablets’ characteristics were measured to compare the RH stability of modified starches granulated mannitol with the reference PVP granulated mannitol.


Materials and Methods


PEARLITOL® 50C, crystalline mannitol powder (Roquette Frères, France)
CLEARGUM® CO O3, pregelatinized octenyl succinate starch (Roquette Frères, France)   
LYCOAT® RS 780, pregelatinized hydroxypropyl pea starch (Roquette Frères, France)
Kollidon® 30, povidone K30 (PVP) (BASF, Germany) 
Vegetal magnesium stearate 

Granulation trials 

1455 g of mannitol were granulated in a high shear mixer Diosna® P1-6 (Diosna, Germany) (impeller at 250 rpm and chopper at 1800 rpm) by spraying 195 g of an aqueous binder solution containing 45 g of CLEARGUM® CO 03, LYCOAT® RS 780 or Kollidon® 30 as binder (3% of the total dry substance after granulation). 
Obtained granules were dried in an Aeromatic Strea-1TM (Aeromatic, UK) at 60°C and calibrated with a conical screen mill Comil® U5 (Quadro, Canada) using 800 µm sieve at 2500 rpm.

Powder preconditioning

Once the granules were calibrated, they were separated in three fractions of same weight and stored for one week in HPP110 (Memmert GmbH, Germany) constant climate chamber with 30%, 50% or 60% of relative humidity at 25°C.

Tableting trials

After 1 week pre-conditioning, the granules were compressed to obtain tablets. Prior to the compression step, the lubrication was carried out by mixing the powder and the magnesium stearate at 1.2% by weight for 5 min at 34 rpm in a Turbula® mixer. 400 mg tablets were done on a Korsch XP1 press (Korsch AG, Germany) equipped with 10 mm diameter punches, 9 mm concavity. The used compression forces were 5, 10, 15, 20 and 25 kN. For each compression force, 80 tablets were produced with a tablet output of 20 tablets/min.

Tablets’ evaluation

Weight, thickness, diameter, hardness were evaluated with a Pharmatron® ST50 (Sotax AG, Switzerland).
Disintegration time was measured with a Pharmatron® DT50 (Sotax AG, Switzerland)
Analytical characterization of the binders
The viscosity of the binding solutions was measured using a Brookfield Digital Viscometer DV-I (Brookfield, UK) at 25°C. The rotation speed was 100 rpm.
The surface tension of the binding solutions were measured using a tensiometer KRUSS K12 (Krüss, Germany) equipped with the Krüss standard plate (Wilhelmy plate, width: 19.9 mm - thickness: 0.2 mm - height 10 mm) made of rough platinum. 
The glass transition temperatures of the binders with different water activities were measured by Differential Scanning Calorimetry using Q200 equipment (TA Instrument, USA). Experiments were performed at 5°C/minute using a tightly sealed aluminum pan. Prior to measurements, binder powders were equilibrated for 1 month at different relative humidities (11% RH, 23%RH, 33% RH, 53% RH, 62% RH and 75% RH). The water activity (aw) of the equilibrated powders was measured using Hygrolab (Rotronic, Switzerland). The water content of equilibrated powders was measured using Karl Fisher titration (Metrohm, Austria).



Table 1 shows viscosity and surface tension values of the three studied binder solutions. In all cases, the viscosity values remain within the acceptable range to ensure a good processability (it is generally considered that 300 mPa.s is the upper limit for a homogeneous spray of the binding solution). In addition, the surface tension values highlight the great surfactant effect of OSS and of the HPS to a lower extent (for reference, the surface tension of pure water at 25°C is 72 mN/m). Such property is of great interest when hydrophobic compounds are granulated. In fact, a lower surface tension of the binding solution ensures a greater wettability of the hydrophobic powder leading to a better efficiency of the granulation process.


Table 1: viscosity and surface tension characteristics of the binding solutions


Surface tension of the binding solution (23% dry weight, 25°C) - (mN/m)

Viscosity of the binding solution (23% dry weight, 25°C) - (mPa.s)

Kollidon® 30










Figure 1 shows the compactibility of mannitol granulated with PVP or LYCOAT® RS 780 or with CLEARGUM® CO 03. All powders were stored at 25°C/30% RH prior to compression for one week. 


Figure 1. Compactibility of mannitol granulated with 3% PVP or with hydroxypropyl pea starch (HPS) or with octenyl succinate starch (OSS). Powders were stored 1 week at 25°C/30% RH prior to compression. The compactibility of mannitol without granulation is indicated for comparison.


It appears clearly on figure 1 that the three powders present similar compaction behavior up to 15 kN compression force, with tablet hardness about three times higher than that of ungranulated mannitol. This demonstrates that all binders own similar binding properties. 

Figure 2 presents the compaction behavior of mannitol granulated with 3% PVP, LYCOAT® RS 780 and CLEARGUM® CO 03 after storage in different RH conditions.


Figure 2. Compactibility of mannitol granulated with 3% (A) PVP, (B) hydroxypropyl pea starch (HPS) or octenyl succinate starch (OSS). Powders were stored 1 week at 25°C and 30% RH, 50% RH and 60% RH prior to compression.


Figure 2-A shows the influence of the relative humidity on the compactibility of PVP granulated mannitol. A clear relationship between the storage humidity and the tablet hardness is visible. Higher humidity causes higher tablet hardness. For a compression force of 15 kN, the difference between the lowest and highest hardness values obtained (respectively after storage at 30% RH and 60% RH) is 36.6 N. In similar conditions, modified starches present much less variation of the tablet hardness. In fact, at 15 kN compression force, the maximum differences noticed for LYCOAT® RS 780 and CLEARGUM® CO 03 are respectively 13.6 N and 10.7 N. Those results highlight the lower dependance of starch binders on the relative humidity for constant tableting results.

Figure 3 and 4 present respectively the water content of the pure binders and their glass transition temperature as a function of their water activity (aw).


Figure 3. Water content of the pure binders (PVP, CLEARGUM® CO 03 and LYCOAT® RS 780) as a function of their water activity.


Figure 4. Glass transition temperature of the pure binders (PVP, CLEARGUM® CO 03 and LYCOAT® RS 780) as a function of their water activity.

The water sensitivity of the three binders presented on figures 3 and 4 shows a great difference between PVP and starches. In fact, while PVP sees its water content regularly increase on the observed range (0< aw<0.8), both starches instead present a slowdown in the water uptake for 0.1<aw<0.6. Difference in water content between CLEARGUM® CO 03 and PVP thus culminates at 8% for aw=0.6.
The glass transition temperatures shown on figure 4 seem to have parallel evolution for water activity above 0.1. However, starches have an advantage by their higher Tg values that are around 50°C above the ones of PVP. Such greater Tg values enable to guarantee a better stability over a wide range of aw/RH conditions. For example, in the case of PVP, Tg=24°C for aw=0.6. This means that, from this water activity, PVP becomes liquid at room temperature. Regarding starches, they remain solid even for aw=0.8 with Tg=40°C.

The different water sensitivity between PVP and starches explains the differences in the stability of the tablets shown on figure 3. The high water uptake of PVP, associated with a low Tg value, leads to changes of the physical state upon storage at 50% RH and 60% RH. High humidity makes PVP become softer and stickier, explaining the observed variation of the obtained tablet hardness. Under similar conditions, both starches have their Tg values at least 50°C above room temperature (Tg=75°C for aw=0.6), preventing them from any change and guaranteeing the stability of the tablet properties over time. 



This study compares two modified starches (CLEARGUM® CO 03 and LYCOAT® RS 780) with PVP as binder in high shear wet granulation.
It was shown that both starches present similar binding properties compared to PVP. In addition, CLEARGUM® CO 03, owing to its octenyl succinate modification, has tension-active properties that are of high interest when granulating hydrophobic powders, as demonstrated by Vandevivere et al.
Finally, a much higher independence of starches as wet granulation binder on the relative humidity was demonstrated. This better stability is correlated to higher glass transition temperature associated with a lower water uptake of starches compared to PVP in similar storage conditions.


  1. Descamps, N., Le Bihan, G., Lefèvre, P., Haeusler, O., EP 3819336, 2021
  2. Vandevivere, L.; Denduyver, P.; Portier, C.; Häusler, O.; De Beer, T.; Vervaet, C.; Vanhoorne, V., Influence of binder attributes on binder effectiveness in a continuous twin screw granulation process via wet and dry addition, Int. J. Pharm., 2020;585 

Kollidon® 30 is a registered trademark of BASF, Germany. 

® Registered trademark(s) of Roquette Frères


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