Determination of Acetominophen Optimum Wet Granulation Endpoint using Effusivity
In the pharmaceutical industry, granulation refers to a process where small particles are induced to form larger, multi-particle complexes called granules. Granules are macroscopic solids, but may vary considerably in size depending on the properties of the mixture in question. Granulation processes which use solvent to aid in agglomeration are referred to as “wet granulation.” In wet granulation, physical changes may be observed in powder characteristics corresponding to initial seed formation, granulation process, optimal granulation endpoint, and over-granulation, but it is not practical to have an employee visually inspect each batch to determine whether the optimal granulation endpoint has been reached. In fact, reliable endpoint determination from a process control point of view has typically been a considerable technical challenge. It has previously been discovered that on-line effusivity measurements act as an effective Process Analytical Technology (PAT) for granulation endpoint determination. The use of effusivity testing as a PAT for granulation endpoint was also discussed in Drug Development and Industrial Pharmacy here. The C-Therm Effusivity Sensor Package (ESP) has been widely used in the pharmaceutical industry as a PAT for ensuring batch-to-batch consistency in powder mixing. Granulation endpoint detection is one of the wide variety of applications for which ESP has been proven a reliable PAT.
In the International Journal of Pharmaceutical Science and Research, Rutesh H. Dave and his colleagues from Long Island University published a study on the effects of preparation method and binder material on tablet stability with respect to humidity. Thermal effusivity measurements taken with the C-Therm ESP were used to determine the optimum endpoint of wet granulation. The results of this testing may be observed in Figure 1.
Figure 1. Effusivity as a function of binder solution addition. Regions of under-granulation, over-granulation, and slurry formation are evident, as is the optimum granulatijon endpoint.
In the figure above, the regions of under-granulation, over-granulation, and slurry formation are visible (indicated on the figure). During the under-granulation region, the effusivity slowly rises upon each successive addition of binder solution. The optimum wet granulation endpoint is defined as the addition point immediately prior to the sudden sharp rise in measured effusivity which characterizes the over-granulation region. In this case, it occurs at approximately 50% w/w binder addition. As over-granulation becomes overwhelmed by the solvent and slurry formation commences, the measured effusivity plateaus at an effusivity approaching that of the binder solution.
Figure 2. The C-Therm Effusivity Sensor Package (ESP). Shown is the laptop computer with control software, the controller with transmitter, four sensors, receiver, manual and supporting literature, and the off-line powder test kit.
This work illustrates the utility of the ESP (Figure 2) in identifying the optimum wet granulation endpoint and, thus, ensuring consistent granulation between batches.