376905 Evaluation of Different Combinations of Continuous Mixing Operations Across a Range of Formulations

Wednesday, November 19, 2014: 9:45 AM
203 (Hilton Atlanta)
Ian Leavesley1, Carla Luciani1, Ahmad Almaya1, Jeremy Merritt2 and Wyatt Roth1, (1)Eli Lilly & Co., Indianapolis, IN, (2)Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, IN

Feeders and mixers are the biggest equipment differences between batch and continuous pharmaceutical processing for the direct compression and roller compaction platforms.  For pharmaceuticals, the loss-in-weight feeder design has emerged as the best design for continuously metering powder.  However, for mixers there are more design options available.  The requirements of the mixing step vary depending on the formula and on whether it is for the short and rapidly changing runs in development or the steady and stable runs in manufacturing.   The first requirement is content uniformity.  This measures how well an ingredient is spatially distributed.   Variation with time is also an issue.  The mixing elements must serve as a low pass filter to reduce intrinsic high frequency fluctuations in screw feeders.  Therefore, the feeder variability must be known in order to specify the mixer requirements.    A surprising amount of mixing also occurs in the tablet press feedframe which serves as an excellent low pass filter for the feeders and reduces the requirement to achieve that result in the mixer itself.  With appropriate measurements and modeling, the effects of all these different mixing actions on the subsequent processes can be assessed. 

Several negative phenomena can occur in a mixer as well.   Examples include accumulation either in the mixer or due to the mixer, particle breakage, and/or distribution of lubricant at a higher level than desired (“over-lubrication”).  While sufficient residence time distribution is required to filter the feeders, too much residence time distribution can reduce the system responsiveness.  Most of these negative phenomena are very material dependent.  The accumulation may be at the same concentration as the in-feed or it may selectively accumulate by species or by size.  For the development of a new platform it is required to look at a wide-range of physical properties and formulations to assess the performance, both desired and undesired, of the mixing strategy.

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