Scientific papers
Hydroxypropyl methylcellulose (HPMC) stands out as the favored hydrophilic matrix former in the production of controlled release formulations via continuous twin-screw wet granulation. However, previous observations have highlighted a challenge: an uneven distribution of the active pharmaceutical ingredient (API) across sieve fractions, particularly resulting in underdosing in the fines fraction (<150 µm). Such non-uniformity could potentially lead to content uniformity issues in subsequent processing stages. Consequently, this study aims to delve into the underlying causes of this non-homogeneous distribution of theophylline. It explores the impact of both process parameters (such as L/S-ratio and screw configuration) and formulation parameters (including matrix former and filler type) on content uniformity. Furthermore, the investigation extends to examining how formulation parameters influence tableting and dissolution behavior. Despite attempts to adjust the L/S-ratio or employ a more aggressive screw configuration, achieving a homogeneous distribution of API across granule sieve fractions remained elusive. Interestingly, incorporating microcrystalline cellulose (MCC) as a filler proved beneficial, as it exhibited behavior akin to HPMC, thereby improving API distribution. Conversely, excluding HPMC or introducing a hydrophobic matrix former (Kollidon SR) resulted in granules with a more uniform API distribution. Consequently, HPMC was pinpointed as the root cause of the non-homogeneous API distribution, attributed to its rapid hydration and swelling upon addition of the granulation liquid, irrespective of HPMC grade.
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