(707h) Assessing Powder Segregation Potential by near Infrared (NIR) Spectroscopy and Correlating Bench Scale Segregation Tendency to Tabletting Performance

Segregation is one of the common
problems associated with low drug load formulations, particularly for those
made by a direct compression process. Segregation of active pharmaceutical
ingredient (API) from excipients can lead to
variation in content uniformity, which in turn may result in failure to meet
product specification. Segregation not only stems from variation of material
properties such as differences of API and excipient
particle size, shape and cohesion, but also is highly specific to process
handling and specific equipment used. The objective of this study was to
examine the effects of particle size and cohesion on the segregation tendency
of pharmaceutical powders measured by bench scale sifting and fluidization
segregation testers. The test blends consisted of 5% aspirin, 64.5% lactose,
30% microcrystalline cellulose (MCC) and 0.5% magnesium stearate
with various aspirin particle size and cohesion value.  Aspirin cohesion was varied
by coating aspirin particles with Cab-O-Sil M5P. The
blends were manufactured by a high speed rotary press
using a specially designed hopper, which was intended to simulate segregation
tendency at large scale tablet manufacturing. The segregation tendency of the
blends was also assessed using bench scale sifting and fluidization segregation
testers. NIR methods were developed to analyze aspirin
content uniformity of blends, segregation samples and tablets. The sifting
segregation tester and testing protocol (ASTM D 6940-04) were
modified to provide better correlation between the test results and
tablet content uniformity.  It was found that coating aspirin with Cab-O-Sil M5P can significantly reduce aspirin's cohesion but had
little impact on its segregation tendency. The effect of particle size on
segregation tendency was quite intriguing. It is commonly
believed that large particle size difference between the drug and excipients is a primary factor contributing to segregation.
However, our study indicated that one has to consider not only just the
particle size difference but also the interaction between aspirin and excipients. Contrary to the common belief, the batch with
larger particle size difference had lower segregation potential, which was probably attributed to favorable interaction between
aspirin and MCC. In addition to identify critical physical properties of the
blends that influence segregation tendency, the study also highlighted the
usefulness of NIR for quantitative analysis as well as the importance of using
performance based approach to establish correlation between bench scale powder
testing and larger scale manufacturing performance.