Several drying techniques can be used in single-pot processing but the basic drying principle relies on the application of a vacuum in the bowl, thus drastically lowering the evaporation temperature of the granulation liquid. This paper compares the efficiency of two additional techniques: microwave drying and gas-stripping.

Improving Drying Efficiency

Single-pot processing is an established pharmaceutical production technique for high-shear wet granulation and drying, often used when high containment is required for the production of potent oncology substances or hormones. Several drying techniques can be used in single-pot processing but the basic drying principle relies on the application of a vacuum in the bowl, thus drastically lowering the evaporation temperature of the granulation liquid. The traditional heat source is the heated dryer walls, and heat transfer is directly related to the surface area of the walls and the volume of the product, making this method most effective for small-scale use. To enhance the drying process and reduce drying times, particularly for larger-scale operations, additional drying techniques can be implemented.

Background Information

 A literature search comparing the different drying techniques for single-pot processors showed the following:

  • gas-stripping reduces the drying time by injecting an inert gas through the product mass to enhance evaporation, reducing drying time by up to 50%1
  • shorter drying times can be achieved owing to continuous, efficient strip-gas feeding2
  • the continuous strip-gas supply system replaces expensive, high-maintenance accessories such as tilting options or microwave technology without extending drying times.3

A study was done to verify these claims, particularly that gas-stripping can substitute microwave technology without prolonging drying times.

Drying Technique Principles

Vacuum Drying: All single-pot processor drying techniques are based on vacuum drying.4 The basic premise is that the boiling point of a liquid is reduced at lower pressures (the boiling point of water at 40 mbar is 28 °C, for example); this results in lower drying temperatures and, thus, less energy input is required to heating the product. The energy required for evaporation is supplied by conduction through the single pot’s heated and jacketed bowl and lid. The contact surface area ratio to product volume is, therefore, very important for the vacuum drying process, and it is this ratio that limits its use in production-scale units: the larger the process vessel, the less favorable the contact surface/volume ratio becomes and the longer the drying times (Figures 1a and 1b).

Gas-Stripping: Gas-stripping enhances vacuum drying by injecting a small amount of gas through the product mass during the drying phase. There are several theories regarding how this works:

  • by increasing the partial pressure drop over the powder bed in the vessel and thereby improving evaporation
  • by improving the heat flow from the wall into the product
  • by moisture absorption
  • by enhancing the transport of vapor to the vacuum system.

There are, however, some limitations:

  • usually, the gas is not heated, so the heated wall is still the only source of drying energy
  • the pressure in the vessel may be higher — compared with ‘pure’ vacuum drying — owing to the addition of the gas, which may offset the effect of the improved evaporation rate.

So, although gas-stripping should produce lower final moisture levels compared with vacuum drying, its effect on drying time largely depends on the process settings. And, as the drying energy is still only derived from the heated bowl jacket — so is still dependent on available contact surface and maximum possible wall temperature — the issue of scale-up remains. In addition, drying times will be longer for production-scale equipment. As such, this technology will be most beneficial for smaller-scale installations, and less so at production-scale.

Microwave Drying: Microwave drying relies on additional energy being supplied that’s preferentially absorbed by the solvents in the process to enhance evaporation. Microwaves are a form of electromagnetic energy (300 Mhz–300 GHz), generated by magnetrons under the combined force of perpendicular electric and magnetic fields. In the pharmaceutical industry, the most common frequency used is 2450 MHz, because of the advantages that this frequency offers in conjunction with a vacuum.5

Microwave heating is a direct heating method. In the rapidly alternating electric field generated by microwaves, polar materials orient and reorient themselves according to the direction of the field. The rapid changes in the field — at 2450 MHz, the orientation of the field changes 2450 million times per second — cause rapid molecular reorientation, resulting in friction and heat. Different materials have different properties when exposed to microwaves, depending on the extent of energy absorption, which is characterized by the loss factor.

Given the characteristics of the materials commonly used in pharmaceutical production, microwave energy is well suited for drying pharmaceutical formulations. The liquids most frequently used in wet granulation (water and alcohol) have much higher loss factors than the other standard wet granulation ingredients (lactose, corn starch, for example), leading to higher microwave energy absorption and the preferential heating of these liquids.

Figure 1a: Ratio between contact surface and bowl volume (baseline = 75 L size).

Figure 1b: Scale-up of drying times for vacuum and microwave drying.

Scale-up of drying processes

Theoretical Efficiency Comparison

To theoretically compare gas-stripping and microwave drying, calculations were made for the additional amount of water that can be removed (in addition to the amount of water removed by vacuum drying alone) by the gas or microwave energy, based on the physical properties of dry air absorbing moisture and microwaves providing energy.

As a basis, the specifications of a 75 L single-pot processor (pilot-scale) were used to compare the amount of water that can be absorbed/evaporated by the two different drying techniques.

To be able to compare the two methods, some initial assumptions must be made regarding the theoretical calculation:

  •  it is assumed that the energy supplied by the heated jacket (thermal conductivity via the bowl wall) is identical for the two drying systems; even though one of the theories is that gas-stripping enhances this energy transfer, this is disregarded in the theoretical calculation
  • the strip-gas is completely dry upon entering the bowl and 100% saturated with moisture after passing through the product
  • all the microwave energy is applied to evaporate the used solvent
  •  the granulation solvent used is water.

Regarding these assumption, it must be noted that in reality, not all of the microwave energy will be used for evaporation, nor will the stripping gas be 100% saturated when it exits the machine: the real evaporation rate can therefore be expected to be lower than the calculated result.

Gas-Stripping Calculations

In a 75 L machine, the gas flow used depends on the equipment manufacturer. According to our data, however, the maximum flow varies between 35 and 100 L/min.5 The calculations were based on the use of dry purified air at room temperature (20 °C). At this temperature, the maximum water content of air is 17.3 g/m3.

Assuming the air is absolutely dry when entering the product (0% RH), and is fully saturated when exiting the machine, a maximum of 0.9169 g/min and 1.73 g/min of water can be removed at airflows 35 L and 100 L per minute, respectively.

It is well known that when air is heated, its moisture holding capacity increases. For example, air at 60 °C can contain a maximum of 130 g/m3 of water. However, supplying heated air to the process would not result in an additional water removal of 4.55 g/min at an airflow of 35 L/min, or 13 g/min at an airflow of 100 L/min. This is because when the air comes into contact with the product, its temperature is adjusted to that of the product. If drying is done at 40 mbar, for example, the temperature of the product would be 28 °C, meaning that the air will also be 28 °C, and the moisture absorption capacity is thus limited to approx. 30 g/m3 (or 1.05 g/min and 3 g/min, respectively).

The energy of the heated air, when it cools down to the temperature of the product, provides energy for evaporation, but this does not impact the absorption capacity of the air and is not taken into account for this calculation. The may explain why, in gas-stripping, the air is seldom heated (as well as increased complexity and cost of the installation).

Microwave Calculations

A 75 L single-pot processor contains a 3 kW magnetron. The actual microwave output is limited to 2.4 kW, which corresponds to an energy supply of 2.4 kJ/second. If the pressure in the bowl is 40 mbar (bowl pressure must be 30–100 mbar when working with microwaves), the latent heat of evaporation of water is 2433 kJ/kg. With a microwave output of 2.4 kW, 144 kJ of energy is delivered to the product every minute, which is sufficient to provide enough energy to evaporate 59.19 g of water.


Comparing the extra amount of water that can be removed/evaporated by the two drying techniques per minute, it is clear that microwave technology is capable of removing significantly more water from the process per time unit than gas-stripping: 0.9169 g/min for gas-stripping, compared with 59.19 g/min for microwaves (Table II). Even if the air used for gas-stripping is heated to 60 °C and a maximum flow of 100 L/min is used, the water absorption capacity remains significantly below that of microwaves (12.74 g/min compared with 59.19 g/min).

Experimental Comparison

To confirm the theoretical calculations, a small-scale trial was done using an UltimaPro™ 25 (25 L bowl capacity single-pot processor, GEA Pharma Systems, Belgium). To avoid any particle size or porosity effects on the drying times, the trial was done using lactose powder (Lactochem Fine Powder, Domo) that was wetted with water without granulating.

Lactose monohydrate (8 kg) was manually loaded into the machine. Purified water (1 kg) was sprayed onto the lactose using a pressure vessel at 2 bar and a flat beam spray nozzle (LX2, Delavan) while the impeller was running at 200 rpm to obtain a homogenous water/lactose mixture, without creating a granule. After the water was added, mixing was continued for 1 minute before the drying phase was starting.

Samples were taken of the raw material, after liquid addition and during the drying phase to determine the moisture content of the product (using a Mettler Toledo Halogen moisture balance at 100°C, until stable [program 2]). The drying endpoint was selected as 2% loss on drying. The parameters used during the drying phase are summarized in Table III. For these trials, jacket heating was kept to a minimum to be able to demonstrate the different water removal capacities of the two drying technologies. The results, as summarized in Table IV and Figure 2, confirm the theoretical calculations, showing that microwaves have a much higher water removal capacity that gas-stripping. Using the settings in Table III, microwaves were capable of removing the water (approx. 1 kg) in 40 minutes, whereas gas-stripping required more than 3 hours to remove the same amount.

Regarding the results of this study, it must be noted that in an actual process environment, the bowl jacket would be heated, providing energy to augment the evaporation. Real drying times will therefore be shorter than the experimental set-up described above (for both gas-stripping and microwave drying). The energy supplied through the bowl jacket is the most important energy source for water evaporation in a gas-assisted vacuum drying process, although it is less important in microwave drying as most of the evaporation energy is provided by the microwaves. This is an especially important consideration when scaling up the drying process.

With microwave drying, the power of the magnetron correlates to the size of the machine, resulting in a constant energy supply per kg of product, regardless of scale. This is reflected in (almost) identical drying times in small- and large-scale applications (the energy from the heated jacket will have some effect on the drying time, but it’s negligible). For gas-assisted vacuum drying processes, the effect of the energy supply from the heated jacket on the drying time is much higher and, as such, it also affects scale-up. So, although the flow of strip gas is scaled-up linearly according to the size of the machine (and, thus, also its capacity to remove moisture), drying times will not remain constant when moving from small- to large-scale, but will be longer, owing to the changing ratio of volume and surface area when the dimensions of the machine are enlarged, similar to vacuum drying (see also Figure 1b).




3. Product Brochure: High-Shear Mixer Granulator Systems. Mixing, Granulating, Drying; Huttlin GmbH, A Bosch Packaging Technology Company.

4. H. Stahl and G. Van Vaerenbergh, “Single-Pot Processing,” in D.M. Parikh, Ed., Handbook of Pharmaceutical Granulation Technology Second Edition, Drugs and the Pharmaceutical Sciences; Vol. 154 (Taylor and Francis,London, UK) pp 311-331.