High shear wet granulation is a cornerstone of the formulator’s and process engineer’s pharmaceutical manufacturing toolbox. It is used to increase the density and particle size of a composition to improve powder flow and compressibility on the tablet press when dry processing methods are insufficient to produce tablets or capsules with acceptable uniformity, hardness, and friability.
Although the general principles of granulation technology have remained unchanged for several decades, the emergence of several process modifications seem to be gaining popularity among the pharmaceutical industry. Two of those modifications are wet milling operation and spraying in a controlled manner using a spray nozzle over an extended period of time.

Wet Milling
Wet milling is typically done by positioning a particle size reduction milling machine at the discharge of the high shear granulator. After granulation, the material is discharged through the milling equipment and can be either vacuumed into the bowl or into the drying equipment. The mill is equipped with a screen specially designed for wet milling with larger openings than typically used for final particle sizing. This allows the material to pass through the mill without causing material buildup and equipment blockage.
Different categories of milling equipment can be used to successfully wet mill granulation. The impact mill and screening mill are two of the most popular. As the names may indicate, the impact mill imparts more energy on the granules, while the screening mill is gentler on the granules. Each type has its own place in pharmaceutical processing and needs to be carefully evaluated when developing a process for a new product.
Wet milling provides several processing advantages. Larger granulation particles and lumps are reduced into smaller particles that are more uniform in size. This uniformity impacts the drying mechanism and therefore the drying efficiency. In order for moisture to dry from a particle, two things need to occur. First, the moisture needs to diffuse from the inner part of the granule to the surface. Second, heat transfer at the surface causes the moisture to evaporate. Drying can only progress at a rate that equals the slower of these two items. Wet milling increases drying efficiency by reducing the particle size distribution, minimizing the distance moisture needs to diffuse, and increasing the surface area for evaporation.
The elimination of large particles and lumps also prevents case hardening, an undesirable condition where the mass on the outside of a particle dries faster than the inside and creates a barrier that seals moisture in the particle core. Case hardening makes it difficult to reach a consistent drying endpoint and often causes problems with downstream processing due to moisture and content uniformity problems.
Wet milling also allows the granulation endpoint to be pushed to a more aggressive level. Traditional granulations that would be considered “over granulated” often work well and produce very acceptable results when wet milling is utilized. This is because the large, dense lumps of material are broken back down into particles that can be handled and dried.
Finally, because wet milling imparts a particle sizing step earlier in the process, final particle sizing after drying does not need to be as aggressive. The result is particle size distribution that is more uniform, further improving material powder flow.

Uniform Extended Spray Time
Although there are still processes that utilize the ladling or pouring methods of granulating liquid addition, most current high shear granulating equipment comes equipped with spray nozzle technology for liquid distribution. While the older “dump and mix” school of thought often works well in many situations, there is generally little downside to using a spray nozzle for liquid addition. Also, while rapid liquid addition might work at a lab scale with small quantities, at a larger scale more issues may be encountered when mass effects have a greater impact.  The upside of using a spray nozzle is a more controllable liquid feed rate and more uniform distribution. Not only do spray nozzles take operator variability out of the granulating process, they also allow for a significantly extended spray time at a controlled addition rate.
Traditional high shear granulating has three phases: dry mix, liquid addition, and wet massing. The dry mix ensures a uniform dry powder composition and lasts for about 2 – 5 minutes. The liquid addition adds the granulating liquid in about 1 – 10 minutes. Once the liquid has been added, the wet massing phase ensures uniformity and imparts mechanical energy to form a strong granule formation. This phase can last from about 2 minutes until a granulation end point is achieved.
Certain products have been demonstrated to benefit from extended liquid addition times of approximately 30 – 60 minutes, which is consistently achievable using spray nozzle technology. The longer liquid addition time produces a more uniform distribution of granulating liquid. This is an obvious advantage for a granulating liquid that contains an active ingredient, especially if the active ingredient is in low concentration in the final product.
Also, the longer granulating liquid addition rate allows for a slower, controlled granulation growth resulting in a tighter particle size distribution. Fine particles are well incorporated into the granulation and larger particles are hampered from forming.
Finally, the extended spray times allow a slower approach to a granulation endpoint. This slower approach can provide a more robust granulating process with less variability.
The disadvantages of using an extended spray time include longer processing times. In addition, heat accumulation due to the mechanical forces imparted during mixing  can cause elevated temperatures. Temperature rise can be combatted by using jacketed equipment.

The Future: Risk Management and QbD
Even though the foundation technologies in the pharmaceutical industry have not changed significantly over the past several decades, process knowledge and risk management expectations have. Regulators and industry alike are moving in the direction of increased process understanding and robust control strategies. This is where the risk management process and the knowledge base of the product and process comes into play. Gathering expertise from a cross functional team during the risk assessment process, and properly documenting the analysis, is important in developing this knowledge base.
With the advent of new technology, PAT is becoming highly important in the QbD approach. For example, endpoint determination has evolved from being a qualitative test based on material appearance and feel into a quantified scientific correlation. Mixer power and torque profiles, as well as PAT tools to measure particle size of the granules on-line, have increased control and lead to less processing risk. The implementation of PAT allows for a granulation endpoint to be determined in real time rather than relying on operator experience.
In conclusion, wet milling and extended spraying times are two parameters that can and should be evaluated during product development for wet high shear granulating processes. Additionally, new process analytical technologies are adding increased process understanding and control bringing high shear wet granulation from an art to a science.

About the Authors:
Raja Krishnan is a Senior Process Development Engineer at URL PharmPro. He has over 15 years industry experience in oral solid dosage and is a six sigma black belt.
Michael Buzecky is the Process Development Manager at URL PhamroPro. He has 10 years pharmaceutical industry experience in oral solid dosage including roles in quality assurance and process engineering.