Pelletization for the manufacture of modified release multiparticulate drug delivery systems is often considered to be well defined and robust. However, small differences in formulation conditions can lead to surprising changes to the expected outcomes. We observed that extended release tramadol hydrochloride pellets, prepared by solution layering an ethanolic solution of drug on a non-pareil, resulted in highly unusual pellet architecture with deep indentations which prevented the application of a homogeneous outer coating of ethylcellulose and talc, and negatively influenced the desired modified release characteristics. Modification of outer coating thickness and process temperature showed no improvement in release characteristics. A solution to the problem was found in the incorporation of 10% v/v water into the ethanolic drug layering solution, resulting in the production of drug-loaded pellets with a smooth morphology which allowed the application of a coherent outer coating able to retard drug release. The surprising difference in pellet morphology between the two solvent drug layering systems may be attributed to differences in solvent evaporation rates. This demonstrates that established techniques are sometimes less straightforward than thought as small changes in formulation have significant effects on the resulting product in a way which is not always well understood.