(116b) Defining the Design Space for the Batch Granulation of an “over-the-Counter” Medicine

Wet granulation is a common unit operation in the pharmaceutical and chemical industries.  It converts fine powders into granules with a much larger particle size.  This yields benefits that include, improved flow properties, reduced segregation (especially of active ingredients) and hence better content uniformity.  Additional advantages are reduced dusting, increased density and lower packed volume which lead to improved compression properties.

The adoption of a Quality by Design approach to wet granulation requires manufacturers to fully understand the relationships between processing variables, including powder/granule properties, and Critical Quality Attributes (CQAs) of the resultant solid dosage form – the Design Space. 

The granule and tablet manufacturing process was undertaken using a pilot scale process incorporating a batch high shear wet granulation stage; a fluidized bed dryer; milling; mixing/lubrication and tabletting. The granule properties were measured using an FT4 Powder Rheometer® (Freeman Technology).

Two aspects of this Design Space were investigated for batch manufacturing an over the counter (OTC) medicine.  Firstly, a Design of Experiments (DoE) campaign investigated relationships between granulation process variables and resultant granule quality, as measured by their dynamic, bulk and shear behaviour.  The second stage was to investigate how granule quality affects the CQAs of the tablets.

Table 1 – Experimental granulation process variables

The granulation process variables used in the DoE campaign were based on the parameters used in the full scale manufacturing process and are shown in Table 1. 

Dynamic testing was used to evaluate the characteristics of the wet material. Characterisation of the wet mass has the major advantage of allowing early in-process evaluation of batches. However, most test methods are not practical due to the physical instability of the wet particles.  Dynamic testing overcomes this and provides a reliable robust analysis technique.

When the Basic Flowability Energy (BFE – a measure of dynamic flow behaviour of the powder as a function of the resistance to the motion of a bespoke blade through a fixed volume of sample) of the wet granules is measured, a robust relationship (P=0.0006 & R²=0.97) is observed with respect to the manufacturing parameters listed below.

• Solid to water ratio
• Impeller speed
  • Binder temperature

Following drying, the granules are more suitable for characterisation with an increased number of test methodologies.  Testing in the dry state still allows relatively early in-process evaluation of batches – although it is an additional step beyond post-granulation characterisation.

For example, the Permeability of dry granulate shows a robust relationship with the manufacturing parameters listed below:-

• Binder temperature
• Solid to water ratio
• Kneading time

Additionally, the Shear (Flow Function and Cohesion) and the Aeration behaviour of the dry granules can also be predicted from the manufacturing parameters.

The various flow properties of the wet and dry granules have also been shown to correlate well with the tablet hardness.

Previous studies of batch granulation have also demonstrated the link between granule quality and tablet properties [1].  This link between granule quality and tablet properties has also been recently observed in a continuous wet granulation study [2].

The results show that granulate properties are predictable from a knowledge of the processing parameters with respect to solid-to-water ratio, binder temperature, mixing time and impeller speed.  Thus manufacturing granules with specific properties can be undertaken.  Subsequent analysis of the tableting results shows that granule flow properties are also linked to tablet CQAs and thus a direct link between granulate manufacture and tablet properties can be inferred.

References

[1]        O.E. Cassidy & W.I. Thomas, Journal of Pharmacy and Pharmacology, 54 (2002), pp 25-46

[2]        T. Freeman, A. Birkmire & B. Armstrong, A QbD Approach to Continuous Tablet Manufacture, Procedia Engineering, 102 (2015), pp 443-449.