Pharmaceutical powder compressibility - a science-based approach

Background:
The compressibility is a crucial property of powder formulations. For being able to compress a powder mixture to tablets with satisfactory pharmacocinetical behaviour, its compressibility has to be within a certain range.
Especially nowadays, where powder formulations for tablets can contain a big number of different compounds, a reliable determination and monitoring of the compressibility is very important.
Objective:
Investigation of three methods to determine powder compressibility (Heckel-Plot, modified Heckel-Plot, Leuenberger equation) with focus on their scientific reliability and their ability to show the influence of small composition adjustments to the compressibility of the formulation.
Development of a method to determine and monitor powder compressibility and additional quality aspects by scanning the final tablet with Near-Infrared Spectroscopy.
Materials and Methods:
Binary mixtures of poorly compressible API and well-compressible excipient were compressed to tablets within a range of relative densities. The compaction pressure, the relative density of the tablet and its tensile strength were used to calculate the compressibility value of the formulation. In a second step, the API of the formulation was increased to detect and investigate the change of the compressibility values.
An investigation with compaction and analysis of the final compacts was performed with 12 different powder formulations. Relative density and tensile strength were the main investigation targets since these elements are used to establish the powder compressibility with the chosen approaches.
One part of the final compacts was tested for relative density and tensile strength with the traditional method, while another part of the tablet collection was investigated with Near-Infrared Spectroscopy. These research steps led to a development of a method for compressibility determination with Near-Infrared Spectroscopy.
Results and Discussion:
The results of the investigated binary mixtures showed the values for compressibility to be really individual for the three different approaches. Additionally, it could be shown that the change of the compressibility value with increase of the poorly-compressible API led to individually different changes in compressibility values for the three different plots.
The developed NIR-method showed really similar results in comparison to the traditional method for the compressibility values, calculated with the Heckel-Plot and the modified Heckel-Plot. Additionally the values of relative density and tensile strength could be detected in a reliable way with the established method.
Conclusion:
The importance of a reliable compressibility determination and all the challenges associated with it could be shown clearly with the research work of this thesis. Especially the sensitivity of the chosen method to small variations within the formulation could be identified and shown.
The developed NIR-method showed promising results and underlined its usability for online monitoring of the tablet production and of the final compact quality.