(424b) Simultaneous Fast Measurements of Tablet Porosity/Moisture: Real-Time Release Testing for QC Dissolution Prediction

Authors: 
Kheiripour Langroudi, M., Merck & Co., Inc.
Eickhoff, W. M., Merck & Co., Inc.
Ikeda, C. B., Merck & Co., Inc.
Klein, L., MERCK
Crawford, M., MERCK
The motivation for this work comes from the dissolution/disintegration sensitivity of a solid dispersion formulation with an erosion based mechanism of dissolution to compression force (which affects tablet solid fraction and hardness), moisture, and the interaction between the two. Solid dispersions were processed by spray drying and subsequent roller compaction which can generate granules with a wide range of quality attributes that impact compactability and compressibility of granules during compression and can be a challenge for obtaining similarities in dissolution rate for proven acceptable range of tablet hardness. We found that for this case dissolution strongly correlates to disintegration time and can be controlled by tablet moisture and density (solid fraction or porosity), but these properties as well as the disintegration test traditionally require separate off-line long measurements.

A novel at-line process analytical technology (PAT), di-electric probe, was developed for simultaneous measurement of solid fraction and moisture content for the tablets. The basic measurement principle of the probe is to estimate the physical properties of bulk solids (such as solid fraction and moisture) by standard correlation with the measured electrical properties (i.e. dielectric permittivity). It was demonstrated that while both real and imaginary component of di-electric permittivity depend on moisture and solid fraction, the phase lag (ratio of imaginary to real part of di-electric permittivity) and di-electric constant of the active formulation depend only on moisture content or relative humidity (RH%). A statistical model was then developed to show dependence of dissolution rate and disintegration time to solid fraction/moisture measured by di-electric probe.