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The aim of the study was to investigate caffeine release in fed and fasted state media from three controlled release matrix tablets containing different HPMC viscosity grades. The biorelevant in vitro dissolution methods utilize the USP 3 dissolution apparatus and biorelevant media to simulate fed and fasted gastro-intestinal dissolution conditions. The effect of tablet reciprocation rate (dip speed) in dissolution media (10 and 15 dips per minute) and media (water, fed and fasted) on caffeine release rate from – and erosion rate of – 100, 4000 and 15,000mPas HPMC viscosity tablets was investigated using factorial designed experiments. Furthermore, the mechanism of release in Ensure Plus®, a nutrition drink similar in composition to the FDA standard meal, was investigated by studying tablet swelling using texture analysis. Altering dip speed has negligible effect on release and erosion rates. Using fasted media instead of water slightly decreases caffeine release from 100 and 4000mPas HPMC viscosity tablets as well as erosion rates, while 15,000mPas tablets remain unaffected. Fed compared to fasted media decreases caffeine release rate, and the food effect is greater for the 100mPas viscosity tablets compared to the 4000 and 15,000mPas viscosity tablets. The investigation using texture analysis indicates that Ensure Plus® becomes rate-limiting for caffeine release from HPMC tablets by forming a hydrophobic barrier around the tablets. The barrier decreases tablet water permeation, which decreases erosion rate in 100mPas viscosity tablets, swelling in 15,000mPas viscosity tablets and caffeine release from both tablets. This observed interaction between Ensure Plus® and the HPMC tablets may translate into decreased drug release rate in the fed stomach, which may decrease the amount of drug available for absorption in the small intestine and thus reduce systemic drug exposure and maximum plasma concentration. [ABSTRACT FROM AUTHOR]