The Application of Mannitol In Wet Granulation

Wet granulation is commonly used in the pharmaceutical industry to manufacture oral solid dosage forms. Owing to many favorable attributes, mannitol is finding increasing use as a pharmaceutical binder in these formulations. Standard crystallized mannitol in β-polymorphic form, while excellent for fluidized-bed granulation and wet granulation in organic solvents, often lacks sufficient binding and tableting properties for use with high/low-shear wet granulation processes. In contrast, Parteck® Delta M, the only commercially available mannitol excipient in δ-polymorph crystals, offers the inertness of mannitol with excellent binding properties, enabling formulators to more easily develop challenging formulations via wet granulation.

Granulation in Pharma Manufacturing

Granulation is employed during production of oral dosage forms to convert small particles of powder ingredients and the active pharmaceutical ingredient (API) into large, free-flowing, dust-free, compressible granules, ensuring uniform distribution of ingredients throughout the resulting mixture.

While direct compression is an easier method for achieving tablet production, more traditional wet granulation is still recommended in certain applications, such as formulations in which the excipients are not suitable for direct compression. In addition, wet granulation is effective at providing enhanced flow properties and can be preferred for very-low-dose formulations to ensure uniform distribution of the API. Older wet granulation technology may also be selected to allow use of less-expensive and simpler excipients that are compatible with this technology.

Wet granulation is generally not suitable for APIs that degrade when exposed to moisture, heat, or oxygen, because it is typically performed using water as the granulating fluid. Organic solvents can be employed, although the hazards associated with flammable materials must be mitigated and controlled. Cost-sensitive products tend not to be produced using wet granulation because the process is complex and involves a high workload. 

Multiple Granulation Methods 

Of the several granulation processes available, the most widely used in the pharmaceutical industry is wet granulation. The wet granulation process generally includes blending, wetting, wet mass stage, drying, and sizing.

Several types of wet granulation processes exist, including low- or high-shear mixing, twin-screw granulation, and fluidized-bed granulation. In low-shear processes, simple mixing equipment is employed, and considerable time is often required to achieve a uniformly mixed state. High-shear processes use equipment that mixes the powder and liquid at a very fast rate by applying high shear forces, thus accelerating the manufacturing process.

Twin-screw granulation can continuously manufacture wet granulates at higher spacetime yield and improved product consistency. Fluidized-bed granulation is a multistep process in which the powders are pre-heated, granulated, and dried in the same vessel. This approach allows close control of the granulation process.

The parameters for each process are different and can impact the properties of the final granules and those of the tablets formed from them. For instance, the water (solvent) content of granules produced using high- and low-shear mixing processes is greater than that in granules obtained using fluidized-bed granulation.

Excipients Play a Crucial Role 

The success of a wet granulation process depends on the selection of the optimum excipients and process parameters that will provide excellent binding and compaction properties and flow. Among the most widely used fillers and binders in oral dosage forms are lactose, cellulose derivatives, and calcium phosphates. Excipients such as disintegrants and lubricants are added after wet granulation is complete.

Growing Interest in Mannitol 

Interest in the use of mannitol as a filler/binder is increasing due to its physicochemical properties, such as its lower hygroscopicity (when compared with other commonly used filler/binder excipients, Figure 1), chemical inertness, and advantageous tableting behavior, including compactability and the ability for specific DC-grades of this material to form extremely robust tablets.1

MSGM1357_Figure_1_hygroscopicityMannitol also imparts good taste (slightly sweet) and mouthfeel, enabling its use for chewable, sublingual, and orodispersible tablet formulations. In addition, unlike lactose, a traditional standard excipient often used as a filler, mannitol is not a reducing sugar. There are also no known human tolerance issues with mannitol, as there are for lactose.1 

Due to these many favorable attributes, mannitol is finding increasing use as a pharmaceutical binder and thus becoming a standard excipient in formulations intended for wet granulation (as well as other processing routes). 

Different Polymorphs with Different Properties 

Mannitol is available in four different polymorphic forms — alpha (α), beta (β), delta (δ) and gamma (γ). The β modification is the most stable crystalline form. It has been observed, however, that the δ modification shows outstanding properties during wet granulation.

Specifically, δ-mannitol undergoes a phase transformation, switching to the β crystalline form that leads to an increase in its surface area by up to a factor of ten (Figure 2). It must be stressed that this phase transformation from δ- to β-mannitol only occurs during wet granulation, and the extent of the conversion correlates directly with the water content (see discussion below).
MSGM1357_wp_figure_2The increase in surface area that occurs with the phase transformation from δ- to β-mannitol is considered to be a major contributing factor to improved compaction behavior.2 The larger surface area is associated with higher compressibility, which enables the production of harder tablets with shorter disintegration times.

MilliporeSigma is currently the only excipient supplier offering the delta (δ) polymorphic form of D(-)-mannitol for pharmaceutical applications. Parteck® Delta M excipient was specifically designed for use in wet granulation. While monographed as a standard mannitol, Parteck® Delta M excipient transforms into the β polymorph during granulation, creating an increased surface area and a porous structure, resulting in increased compressibility.
MSGM1357_figure_3_a_bDifferences in the compression profile (A) and disintegration (B) of wet granulated Parteck® Delta M excipient compared with standard β-mannitol are shown in Figure 3. Significantly faster disintegration was also observed for formulations based on Parteck® Delta M excipient compared with corresponding formulations with the β modification and correlated with the measured Brunauer-Emmett-Teller (BET) surface areas (Figure 4) .

MSGM1357_surface_area_figure_4Mannitol was granulated with 10% water and dried, and granules larger than 1 mm were removed. The remaining granules were mixed for five minutes with 1.5% magnesium stearate and compressed on a single punch press at various compression forces into 11-mm flat-faceted tablets with a final tablet weight of 400 mg. Tablets and granules were analyzed using a standard disintegration tester, tablet hardness tester, and BET surface analysis. 

Granulation Conditions Matter 

Various experiences internally at MilliporeSigma and of customers using Parteck® Delta M raised questions about the importance of the water content during wet granulation when using this novel excipient. To explore these issues, MilliporeSigma conducted a study in which varying granulation water concentrations (5%, 10%, 15%, 20%, 25%, and 30%, relative to the total amount of Parteck® Delta M excipient) were evaluated for wet granulation with the excipient. The results are shown in Figure 5.

MSGM1357_figure_5_a_b_cHigh-shear granulation with up to 25% water was shown to be an ideal means for leveraging the unique properties of the δ-mannitol polymorph; this approach produced granules with good flow and compression properties and tablets with optimized galenic properties. 

Analysis of the crystal modifications showed that at least 10% water had to be added to ensure more than 80% conversion of the δ- to β-polymorph (Figure 5A). This amount depends also on the process applied. Generally speaking, 15–20% water is recommended for low-shear granulation processes, while 20–25% might be needed for high-shear processes.

Figure 5B shows that, as the quantity of granulation fluid was increased, the flow properties of the resulting granules improved. The lowest bulk densities were observed with 10% water, which correlates with the surface area measurement results. By increasing the water concentration to 20%, the quantity of instable α-polymorph was reduced to < 1–5% (Figure 5A) while maintaining a high surface area and improving the flow properties due a simultaneous increase in the granule size and angle of repose (Figure 5B).

Tableting trials of the different granulates demonstrated that material derived from high-shear granulation resulted in tablets with very good galenic properties (high hardness, short disintegration time, low friability, low ejection forces; data not shown). This finding can be explained by the optimization of powder/granule characteristics as indicated by the smaller angles of repose and higher bulk densities.

Similarly, although wet granulation using mannitol with organic solvents, such as ethanol or propanol, is possible, owing to the lack of water under these conditions the conversion of the δ- to β-polymorphic form takes place to a lesser extent than when wet granulation is performed in the presence of water. As a result, granules are produced with smaller surface areas and a corresponding reduction in tableting performance. 

MSGM1357_figure_6In addition, fluidized bed granulation, while allowing close control of the granulation process, is a drier mode of operation than high/low-shear granulation. Here again, the reduced water content during the granulation process leads to lower levels of conversion from the δ- to β-polymorphic form of mannitol. It was found that, while higher spray rates and/or higher inlet air temperatures resulted in high polymorph conversion, at most 60% of Parteck® Delta M excipient was converted to the β polymorph during fluid-bed granulation, compared with 86–100% during high-shear wet granulation (Figure 6). 

Parteck® M 200 excipient, a spray-dried β-mannitol, is already present in its β-polymorphic form with the surface area needed for high compressibility and good flow properties when used with both water-soluble and poorly water-soluble APIs. Therefore, the use of Parteck® M 200 excipient is beneficial for wet-granulation processes with organic solvents and in fluidized-bed granulation, because it retains its excellent tableting properties and results in very hard tablets with a fast disintegration behavior.

Improved Dissolution with δ-Mannitol

The greater porosity of tablets prepared via wet granulation using formulations containing Parteck® Delta M excipient offer the additional benefit of increased water absorption, which translates to faster disintegration and enhanced API dissolution. Increasing the dissolution rate can support faster absorption of the API from the gastrointestinal tract and help overcome bioavailability issues associated with poorly soluble drug substances, potentially affording improved bioavailability in vivo.

To investigate this hypothesis, the effect of β-mannitol and Parteck® Delta M δ-mannitol on the in vitro dissolution of BCS3 class II model API fenofibrate, which exhibits high permeability but very poor water solubility, was evaluated. For comparison purposes and to assess the effect of granulation on tablet performance, four tablet types were created: each of the two mannitol excipients were granulated together with the API (co-granulation) and separately, with the API added to the dried granules (mixture).

The composition (Table 1) and manufacturing process for all tablets were identical except for the quantity of water, which was optimized for each granulation process. After wetting of the components in a universal mixer, the wet mass was granulated using a wet granulator with oscillating rotor (mesh size 0.8 mm), tray-dried at 50 °C to a water content < 0.5%, and sieved over a 1-mm sieve. Highly dispersed silicon dioxide and magnesium stearate were added and mixed with the dried granules. The blends were then tableted on a single-punch instrumented tablet press equipped with 12-mm biplanar, beveled punches into tablets, each with a total tablet weight of 500 mg. 


Compression forces were selected to obtain tablets with equal hardness of 75 ± 5 N for all formulations. The surface areas and pore volumes of the granules were assessed, and the dissolution behaviors of the resulting tablets were analyzed. 

MSGM1357_Figure_7_dissolution_of_tabletsSignificantly higher dissolution rates were observed for formulations based on δ-mannitol compared with the corresponding formulations containing the β modification (Figure 7). The t50% values for tablets with co-granulated fenofibrate based on δ-mannitol and β-mannitol were 23 and 54 minutes, respectively, and the granulates formed using δ-mannitol exhibited a significantly larger BET surface area, even though both granulates possessed very similar particle size distributions (D50 values of 109 μm and 82 μm, respectively).4

For the physical mixtures, the t50% values were 62 and 132 minutes for the tablets based on the δ-mannitol and β-mannitol granulates, respectively, with the former once again having a much larger surface area. It is worth noting that the co-granulated formulations performed better than the corresponding physical mixtures. This difference can be explained by the improved wetting effects and higher dispersion of fenofibrate in the mannitol matrix within the co-granulated formulations. 

It should be noted that the higher dissolution rates observed for formulations based on δ-mannitol correlated with the greater BET surface areas and pore volumes of the granules produced using Parteck® Delta M excipient (Figure 8).

MSGM1357_figure_8_RThe findings confirm that the combination of improved wetting and API dispersion characteristics and increase in surface area due to the polymorphic conversion from δ to β during the granulation process result in a significantly higher initial dissolution rate of the API when granulated together with Parteck® Delta M excipient. 

Don’t Forget Direct Compression 

While wet granulation has its place in the production of oral solid dosage forms, direct compression is an attractive alternative, as it is a much simpler process. Even when the uniform distribution of the API may be challenging, use of Parteck® M 200 excipient can be effective. In particular, in formulations containing micronized (<10 µm) particles, the API can often physically adsorb onto the surface of the Parteck® M 200 excipient in the dry mixture to form ordered mixtures.5 In these cases, there is no advantage to using wet granulation, because it is possible to achieve excellent flow and compressibility via direct compression. 

Product Options Backed by Experience and Expertise 

The success of a wet granulation process depends on the use of an excipient with excellent binding and compaction properties. Mannitol is frequently used for this purpose in solid dosage formulations owing to its physicochemical properties; it is chemically inert and has good compactibility and low hygroscopicity.1 

While mannitols in general are increasingly used in pharmaceutical formulations, the Parteck® mannitol family of excipients offers important advantages. As shown in these studies, standard crystallized mannitol in β-polymorphic form often lacks sufficient binding and tableting properties for use with wet granulation. In contrast, Parteck® Delta M, the only commercially available mannitol excipient in δ-polymorph crystals, offers the inertness of mannitol with excellent binding properties, enabling formulators to more easily develop challenging formulations via wet granulation. When fluidized bed granulation is used or granulation with organic solvents is necessary, Parteck® M 200 excipient is an excellent alternative, as it offers the surface area required to deliver the desired compaction and flow properties.

MilliporeSigma also offers several other Parteck® products to support a wide range of differentiating oral solid dosage forms, such as polyvinyl alcohol-based Parteck® SRP 80 excipient for sustained-release products and Parteck® ODT excipient for orally disintegrating tablets, as well as the Parteck® SI sorbitol range with tailored particle properties and a portfolio of lubricants. With these functional Parteck® excipients, we help customers reduce formulation complexity while still achieving their desired performance properties. 

The common denominator for all Parteck® products is the specialized particle technologies developed by MilliporeSigma to address unique performance demands. We work closely with customers to identify their needs and create pharmaceutical-grade excipient solutions at our global application laboratories. We also welcome the opportunity to collaborate with customers to solve their specific problems and achieve optimized formulations.

With access to the Parteck® toolbox of excipients, our particle engineering capabilities, and our commitment to quality-by-design and the use of modeling and simulation, MilliporeSigma is ideally positioned to identify the best formulation approach (wet granulation to direct compression to solubility-enhancing techniques hot-melt extrusion and inorganic carrier loading and more) and optimum excipients for any API and oral solid dosage form.


  1. Ohrem, HL, et al. “Why is mannitol becoming more and more popular as a pharmaceutical excipient in solid dosage forms?” Pharmaceutical Development and Technology. 19: 257-262 (2014). 
  2. Yoshinari, T, et al. “The improved compaction properties of mannitol after a moisture-induced polymorphic transition.” International Journal of Pharmaceutics.  258: 121–131 (2003). 
  3. Amidon, GL, et al. “A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability.” Pharmaceutical Research. 12: 413–420 (1995). 
  4. Koennecke, TG, et al. “Influence of beta and delta mannitol on dissolution of low soluble fenofibrate.” 2006 AAPS Annual Meeting and Exposition. San Antonio, Texas, USA. 
  5. Ohrem, H. L., R. Ognibene, et al. "Obtaining Stable Homogenous Mixtures with Micronized APIs." Pharmaceutical Technology. 36: 66–72 (2012).

Hans-Leonhard Ohrem

Leo brings 20 years of experience as Marketing Manager and expertise in solid dose excipients and formulation technologies to his current role. His responsibilities include coordination of customer projects, development of production processes in functional particle engineering, and regulatory support. Leo has five years’ experience leading the development group and pilot plant unit in central process development, with a focus on preparative chromatography and continuous reactor design. Leo received master’s degrees in chemical engineering from RWTH Aachen and Cornell University and a Ph.D. in biochemical engineering from RRTH Aachen.