title: The Impact of Granule Density on Tabletting and Pharmaceutical Product Performance.
abstract: The impact of granule densification in high-shear wet granulation on tabletting and product performance was investigated, at pharmaceutical production scale. Product performance criteria need to be balanced with the need to deliver manufacturability criteria to assure robust industrial scale tablet manufacturing processes. A Quality by Design approach was used to determine in-process control specifications for tabletting, propose a design space for disintegration and dissolution, and to understand the permitted operating limits and required controls for an industrial tabletting process.
  
  
  
  Granules of varying density (filling density) were made by varying water amount added, spray rate, and wet massing time in a design of experiment (DoE) approach. Granules were compressed into tablets to a range of thicknesses to obtain tablets of varying breaking force. Disintegration and dissolution performance was evaluated for the tablets made. The impact of granule filling density on tabletting was rationalised with compressibility, tabletability and compactibility.
  
  
  
  Tabletting and product performance criteria provided competing requirements for porosity. An increase in granule filling density impacted tabletability and compactability and limited the ability to achieve tablets of adequate mechanical strength. An increase in tablet solid fraction (decreased porosity) impacted disintegration and dissolution. An attribute-based design space for disintegration and dissolution was specified to achieve both product performance and manufacturability.
  
  
  
  The method of granulation and resulting granule filling density is a key design consideration to achieve both product performance and manufacturability required for modern industrial scale pharmaceutical product manufacture and distribution.
authors.affiliation: GSK Global Manufacturing and Supply, Priory St, Ware, SG12 0DJ, UK. sander.2.vandenban@gsk.com.
authors.forename: Sander
authors.initials: S
authors.lastname: van den Ban
authors.affiliation: GSK Research and Development, New Frontiers Science Park, 3rd Avenue, Harlow, CM19 5AW, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Goodwin
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D016062:Porosity; D012995:Solubility; D013607:Tablets / Q000737:chemistry*; D013678:Technology, Pharmaceutical / Q000379:methods; D014867:Water / Q000737:chemistry
chemical_list: D004364:Pharmaceutical Preparations; D013607:Tablets; D014867:Water
keywords: QbD; design space; granule density; manufacturability; microstructure; solid fraction; tabletability; tensile strength