The effects of improper mixing and preferential wetting of active and excipient ingredients on content uniformity in high shear wet granulation

Sarang Oka, Heather Emady, Ondřej Kašpar, Viola Tokárová, Fernando Muzzio, František Štěpánek, Rohit Ramachandran

Research output: Contribution to journalArticlepeer-review

52 Scopus citations


This work focuses on the content non-homogeneity in granules across size classes in a high shear wet granulation process as a result of powder segregation during dry mixing coupled with preferential wettability of one of the ingredients with the binder fluid.A two component API-excipient system comprised of acetaminophen (APAP) and microcrystalline cellulose PH-101 (MCC) is investigated in a high shear granulation environment for content uniformity of the granules with respect to APAP. It was found that the fine granules were super potent while the coarse granules were starved of the APAP. This was attributed to a dual cause of powder segregation during dry mixing and superior wettability of the MCC compared to APAP. Post the dry mixing stage, the top layer of the powder bed is found to be sub-potent due to percolation of the smaller APAP particles to the bottom of the bed as they find spaces between the larger MCC particles. Thus, a drop of the binder fluid which falls on the bed is likely to be surrounded by MCC particles, which give them a higher chance of being incorporated in the nucleus. Moreover, MCC being the superior wetting of the two ingredients, also preferentially attaches itself to the growing granules. The granules are thus starved of the APAP leading to disparity in content across size classes.Lastly, the effect of content non-uniformity was categorically quantified on the rate of active release. It was observed that content non-uniformity results in a lack of predictability and consequently control, on the rate of release of the active ingredient from the granules. This work highlights the need for qualitative understanding and quantitative analysis of factors that contribute to the occurrence of granule content non-uniformity, if one is to enable inherently robust pharmaceutical product design.

Original languageEnglish (US)
Pages (from-to)266-277
Number of pages12
JournalPowder Technology
StatePublished - Jul 1 2015


  • Granule growth
  • High shear granulation
  • Non-homogeneity
  • Pharmaceutical
  • Segregation

ASJC Scopus subject areas

  • General Chemical Engineering


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