Scale-Up of Pharmaceutical Manufacturing Operations of Solid Dosage Forms

Wet Granulation by the High Shear Process

Wet Granulation

Wet granulation involves adding a liquid (aqueous, non-aqueous, hot-melt, etc.) to a powder to achieve desired properties for subsequent processes. It entails forming granules by introducing a granulating liquid onto a moving powder bed.

Purpose of Wet Granulation

1. Densification

2. Improve flowability

3. Improve compressibility

4. Improve uniformity

5. Improve wettability

Granulation Mechanism

The distribution of liquid binder among powder particles occurs in three states:

1. Pendular State (Low Moisture): Particles are held together by the liquid; air is the main component.

2. Funicular State (Intermediate): Air starts to be displaced from between particles.

3. Capillary State: All air is displaced; liquid penetrates particle pores, creating strong bridges. This leads to the strongest adhesion after liquid evaporation.

Granulation Stages

The granulation mechanism is divided into three stages:

1. Nucleation

2. Transition

3. Ball Growth

1. Nucleation

Granulation starts with adhesion between particles in the pendular state. Agitation leads to the formation of capillary state bodies, which act as nuclei for further granule growth.

2. Transition

Nuclei grow by:

• Single particles adding to nuclei via pendular bridges.

• Combining two or more nuclei.

This stage features numerous small granules with a suitable wide size distribution, which is ideal for granules used in capsule and tablet manufacturing. However, an excessively large distribution may cause issues in small-diameter dies due to bridging and uneven fill.

3. Ball Growth

Continued granule growth leads to large, spherical granules. Further agitation results in granule coalescence, producing an unusable, over-massed system.

• Slower processes like planetary mixers allow enough time to halt the process before over-massing occurs.

• The transition to an over-massed system is rapid, necessitating operator monitoring to stop granulation at a predetermined point, known as Granulation End-Point Control.

Types of Granulation Equipment

Wet granulation equipment includes:

1. V-blender

2. Double-cone blender, ribbon blender

3. Low-shear mixer

4. High shear granulator

5. Fluid-bed granulator

Main Types of Closed Granulating Systems

• High-shear mixers

• Fluid-bed granulators

The two techniques differ in the type of solid agitation and granule growth.

Equipment Selection Considerations

Common factors affecting process choice:

1. Drug properties (size, structure, density, solubility, porosity, stability, etc.)

2. Flowability of final granules

3. Degree of densification required

4. Better size control

5. Moisture control of final granules

6. Limitations of process design (limited filled depth, etc.)

7. Process issues: sticking, lubrication, dust deposit, heat, etc.

8. Manufacture cost improvement (acceptable process time, including granulation and drying if needed)

9. Availability of equipment

High shear granulators are widely used in the pharmaceutical industry for wet granulation due to their relatively short process time compared to other equipment.

High Shear Granulation Process Steps

1. Unmixed dry powders are placed in the bowl and mixed at high impeller speeds for a few minutes (approx. 2-5 min).

2. Liquid binder (granulating liquid) is added by pouring it through a port in the granulator lid onto the powder while the impeller runs at low speed.

3. The chopper is activated when a moist mass forms to break up the wet mass and produce a bed of granular material.

4. Wet massing occurs with both agitators running at high speed (approx. 1-5 min).

5. Once satisfactory granules are produced, the granular product is discharged through a wire mesh, breaking up any large aggregates, into a fluidized-bed dryer or hot oven trays.

6. The granulate is then dried and dry-sieved.

Factors Affecting the High Shear Process

1. Amount of Granulating Agent

The amount of granulating agent affects the size and density of granules.

• Generally, increasing the granulating agent leads to larger granules.

• However, sometimes, more granulating agent can result in smaller granules because materials attach to the blade, altering its geometry and reducing granulation ability. Excess agent may not further increase size or densification.

• For each formulation in a certain equipment with other factors constant, there is an optimal density related to the amount of granulating agent added.

2. Extent of Wet Mass Time

The more energy applied, the larger the granules become.

3. Peripheral Speed/Tip Speed

The faster the energy is applied, the larger the granules become. A typical high shear granulator will have a peripheral speed/tip speed around $8 – 12$ meters/second.

4. Temperature of Granulation Agent

The warmer the granulation agent, the larger/faster the granules grow. This temperature should be optimized case by case.

5. Position of Nozzle(s)

1. Maintain the balance between wet mass formation time and spray rate.

2. The nozzle-to-bed distance may require adjustment if bed height decreases significantly during processing.

• Case Study: Poor uniformity in end-point granules was due to bed height decreasing significantly. Improvement was achieved by adjusting the nozzle to maintain a similar spray zone.

6. Method of Infusion

Introducing the granulating liquid to the powder bed can be done by spray or pump/pour. General guidelines:

• For formulations with a majority of ingredients soluble in the granulation agent, different infusion methods may impact granulation outcome.

• For formulations containing ingredients that can absorb a high degree of granulation agent, different methods may not have a significant impact.

• Poor uniformity may result from improper selection of infusion method.

• Infusion by spraying produces smaller granules compared to pump/pour methods.

• Significant differences in end-point particle size distribution are observed when using a hydrophilic formulation with water as the granulation agent. No significant difference is observed with a hydrophobic formulation using water as the granulation agent.

7. Different Drying Methods

Drying process by using a fluid-bed dryer may affect the size of the final dried granules.

• Case Study: Wet granulation was performed by high shear and fluid-bed processes. Drying was done by oven-tray-drying or fluid-bed dryer. Results showed differences in size based on the drying method.

  • High shear process:

    • Drying by oven tray: $430.4 \mu m$

    • Drying by fluid bed: $381.7 \mu m$

  • Fluid-bed process:

    • Drying by oven tray: $227.4 \mu m$

    • Drying by fluid bed: $164.7 \mu m$

8. Difference in Chopper Design

Formulations containing extremely effective binders may not benefit from certain chopper designs.

9. Impact by Residue Heat and by Residual Materials in Multi-batch Consecutive Process

Many manufacturing processes granulate multiple batches consecutively with $1 – 2$ hours in between. For some formulations, residual heat and residual material inside the chamber may impact the granulation outcome.

Application of Process Analytical Technology (PAT)

Process analytical technology (PAT) guidelines, defined by the FDA, are a mechanism to design, analyze, and control pharmaceutical manufacturing processes by measuring critical process parameters (CPP) that affect the quality of the end product.

The formulator can define the endpoint as:

• A target particle size mean or distribution.

• In terms of granulate viscosity or density.

Once the desired endpoint is reached, granule and subsequent tablet properties are very similar regardless of granulation processing factors like impeller or chopper speed or binder addition rate. This is called “the principle of equifinality.”

The goal of any measurement in a granulation process is to estimate viscosity and density of the granules and obtain an indication of the particle size mean and distribution. The optimal end point can affect some granule and tablet properties, such as mean particle size, disintegration, friability, and hardness.

Considerations of End Point

1. Even with the best formulation, process, and equipment, the end point will consist of granules with different sizes, shapes, moisture contents, and strengths.

2. Evaluate the impact of the end point on the performance of the final dosage form, e.g., dissolution failure due to a heavy end point.

3. The process should consider the impact on subsequent processes such as drying, milling, compression, and coating.

PAT Role in Granulation

Manufacturing Considerations

1. Avoid an endpoint of extremely heavy granules that may unnecessarily challenge the reproducibility of future manufacture. Consider light to medium or medium granules as the end point.

2. Monitor any changes in API and other raw materials.

3. Consider the following processes such as drying, milling, blending, etc.

4. For formulations with poor flow or compression, end-point particle size distribution may be correlated to the size of the resulting tablet/capsule size (e.g., avoid extremely fine granules for a large tablet).

Foam Granulation

Definition: A foam generator is used to introduce the binder as a foam, rather than spraying or pouring the binder onto a powder bed.

Advantages of Foam Granulation:

• Evenly distributes the liquid binder phase throughout a powder bed much better than a spray could do.

• Scaling up is thought to be easier in foam granulation.

Types of Foam Granulation:

• Continuous foam granulation: Binder foam is introduced onto a moving powder bed.

• Batch foam granulation: Binder foam is introduced onto a static powder bed.

Why Batch Foam Granulation?

• It simplifies the wet granulation process even further than the continuous foam addition process.

• It may reduce worker exposure to potent APIs.

Scale-Up Study: Batch Versus Continuous Foam Addition

A study for an initial evaluation of the scalability of foam granulation technology was conducted, comparing batch and continuous foam addition.

Components of IR and CR formulations

TABLE 29.7 Model immediate-release (IR) formulation

TABLE 29.8 Model controlled-release (CR) formulation.

TABLE 29.6 Protocol for immediate-release and controlled-release scale-up trials

Trial Steps

Powders (except magnesium stearate) were charged into the granulator and premixed.

1. Continuous Foam Incorporation

• Foamed binder solution was incorporated at a continuous rate onto the moving powder beds in the high shear granulators.

• After the addition of the foamed binders, the laboratory-scale trials were mixed for an additional 30 seconds, while pilot-scale and full-scale trials were mixed for an additional 5 minutes. This is called the wet massing phase, done to distribute the liquid/binder system evenly throughout the powder mass.

• The authors suggest that when using foam technology, this wet massing step is not necessary because foam is capable of spreading among powder particles and distributing much quicker and more efficiently than current conventional spray techniques.

2. Batch Foam Incorporation

• Identical quantities of foamed binder were used compared to continuous foam incorporation.

• Foam was pumped into the granulator on top of the static powder bed.

• Half of the foam quantity (19.3 kg) was added to the static powders, then the mixer was turned on and mixed for 5 minutes to distribute the foam. The mixer blades were then turned off, and the remaining portion of the foam (19.0 kg) was pumped onto the static powder mass. The mixer was again turned on and mixed for 5 minutes to fully incorporate the foam into the powders.

Post-Granulation Steps

• After granulation, the trials were wet milled.

• After milling, granulations were dried in trays for laboratory-scale and in a fluid-bed dryer for pilot and manufacturing scales.

• The dried granulations were then sized.

• Tablet Preparation, Powder/Granule Testing, and Tablet Property Testing were performed.

Results of IR Scale-up Study

TABLE 29.9 IR Scale-up Study. Tablet and granule testing results for the immediate-release trials

The results of IR scale-up study show a high degree of similarity between different scales.

Results of CR Scale-up Study

TABLE 29.10 CR Scale-up Study. Tablet and granule testing results for the controlled-release trials

The results of CR scale-up study show a high degree of similarity between different scales.

Comparison of Batch Versus Continuous Foam Addition

The results show a high degree of similarity between the two foam addition techniques. The processing flexibility inherent in the foam technology is also notable. The foam did not over-saturate the powders that it was in close contact with, even though it had been in contact for several minutes, unlike conventional spray techniques.