Understanding Dissolution Inconsistency Through In Situ Study of Disintegration Mechanisms

USP tablet dissolution testing is recognized as the standard analytical method used in the pharmaceutical industry. Traditionally dissolution has been performed in the analytical laboratory and tests were conducted with the final product. But in recent years dissolution testing has become a development tool for Quality by Design (QbD), and testing has expanded to include dissolution and disintegration tests which screen product performance during drug product development. These development tests require a more mechanistic understanding as to why tablets release Active Pharmaceutical Ingredients (API) with varying kinetics.

By understanding the mechanism for particle disintegration and dissolution with in situ particle characterization tools such as METTLER TOLEDO FBRM^®, one can correlate release inconsistencies to the upstream source of variability, i.e. changes in raw materials, granulation inconsistency¹, segregation during transfer and storage, varying impurity profile of API or tableting irregularities^2-4 (Figure 1). This process of linking dissolution to an upstream source of variability is often called root cause analysis.

Quickly identifying the source of dissolution inconsistency can speed development time and provide an early indication of a robust scalable process. In this study tablet disintegration and dissolution kinetics are presented for both innovator and generic versions of an acetaminophen-based over-the-counter painkiller. The percentage of active pharmaceutical ingredient [API] dissolved with respect to time was monitored in situ using an Opt Diss Fiber Optic UV Dissolution Testing System coupled with a Distek Evolution 6100 USP dissolution apparatus. The rate and degree of change to the particle dimension and population during the disintegration process was monitored in situ using METTLER TOLEDO FBRM^® (Figure 2).

Results and Discussion
A significant inconsistency between the acetaminophen tablet dissolution profiles is shown (Figure 3).  95% dissolution was attained after 4 minutes for the innovator and 10 minutes for generic tablet.  What si the root of this inconsistency? Inconsistent API, inconsistent solubility, or inconsistent particle disintegration? A model to describe this inconsistency was developed by considering the particle dimension and number measured in real time in the dissolution vessel with METTLER TOLEDO FBRM^®.  The relevant FBRM^® statistical trend data, specifically counts/second between 1 and 10 microns (#/s 1-10μm) and median chord length (μm) gave immediate insight to the potential root cause of the dissolution inconsistency. The rate of increase of small particulates, tracked by (#/s 1-10μm) is more rapid for the innovator tablet indicating it disintegrates at a faster rate (Figure 4). The number of small particulates is also significantly higher at the end of the experiment indicating the extent of the disintegration. The median chord length (μm), a measure of particlulate dimension, indicates that the generic tablet breaks apart into larger particles and subsequently disintegrates at a slower rate (Figure 5).The application of real-time analytical tools such as fiber optic UV solution measurement and in situ FBRM^® particle characterization can quickly identify dissolution inconsistency. These process analytical tools can also link dissolution inconsistency to the root cause. This application of QbD can speed development time and provide an early indication of a robust scalable process.

Conclusions
In this dissolution inconsistency case study, it is proposed that the inconsistency in the dissolution profiles is due to a combination of factors. First, the generic tablet breaks into large granules that persist until the end of the dissolution test (Figure 5).

This may be due to a difference in formulation, for example a difference in moisture content or raw materials in the granulator resulting in a larger granule distribution. The difference could also be due to a processing step prior to the dissolution test, for example a different compression force in the tablet press resulting in plastic deformation of the granules and subsequent aggregation. Such a phenomenon has previously been recorded in the literature for active pharmaceutical ingredient3. Secondly, it is clear from Figure 4 that the innovator tablet disintegrates and dissolves at a faster rate compared to the generic tablet. It is probable that the inter-granule forces holding the tablet together are greater for the generic tablet and disintegration is not as rapid. Once again, this may be due to a difference in the formulation or upstream processing step.  The model proposed indicates with a significant degree of certainty that while there is a clear difference in the dissolution profile the root cause of the difference is most likely the formulation or upstream processing step such as granulation, drying, milling, tableting etc. By understanding the real time particle disintegration using in situ FBRM^®, one can save costly time by narrowing down the source of the inconsistency and avoiding unlikely causes such as inconsistent Active Pharmaceutical Ingredient (API) solubility in the generic acetaminophen.