Using a model formulation of 80% gabapentin and 20% hydroxypropyl cellulose (KlucelTM), we investigate how differences in the geometry of mixing elements in the Leistritz Nano-16 and Micro-18 extruders affect granulation mechanisms and the properties of the resulting granules. Two extruders, Leistritz Nano-16 and Micro-18, commonly used in development and manufacturing, respectively, were used. The kneading blocks of the Nano-16 extruder are less efficient in dispersive mixing than the kneading blocks of the Micro-18 due to the thinner discs (2.5 mm wide) of the Nano-16. Therefore, our model formulation could be granulated only under a higher degree of fill (DF) by enhancing the axial compaction and heating of the barrel. In contrast, the thicker (5 mm wide) kneading blocks of the Micro-18 extruder provide efficient dispersive mixing that enables granulation without axial compaction and barrel heating. The higher specific mechanical energy (SME) achieved at higher screw speeds and lower feed rates led to more granulation. Because of the difference in granulation mechanisms between the two extruders, critical processing parameters also differed. Tabletability and degradant content of granules correlated positively with DF for the Nano-16 but with SME for the Micro-18 extruder.