title: Mechanistic basis for the effects of process parameters on quality attributes in high shear wet granulation.
abstract: Three model compounds were used to study the effect of process parameters on in-process critical material attributes and a final product critical quality attribute. The effect of four process parameters was evaluated using design of experiment approach. Batches were characterized for particle size distribution, density (porosity), flow, compaction, and dissolution rate. The mechanisms of the effect of process parameters on primary granule properties (size and density) were proposed. Water amount showed significant effect on granule size and density. The effect of impeller speed was dependent on the granule mechanical properties and efficiency of liquid distribution in the granulator. Blend density was found to increase rapidly during wet massing. Liquid addition rate was the least consequential factor and showed minimal impact on granule density and growth. Correlations of primary properties with granulation bulk powder properties (compaction and flow) and tablet dissolution were also identified. The effects of the process parameters on the bulk powder properties and tablet dissolution were consistent with their proposed link to primary granule properties. Understanding the impact of primary granule properties on bulk powder properties and final product critical quality attributes provides the basis for modulating granulation parameters in order to optimize product performance.
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, NJ 08903, USA. sherif.badawy@bms.com
authors.forename: Sherif I F
authors.initials: SI
authors.lastname: Badawy
authors.forename: Ajit S
authors.initials: AS
authors.lastname: Narang
authors.forename: Keirnan
authors.initials: K
authors.lastname: LaMarche
authors.forename: Ganeshkumar
authors.initials: G
authors.lastname: Subramanian
authors.forename: Sailesh A
authors.initials: SA
authors.lastname: Varia
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000737:chemistry; D004339:Drug Compounding; D007555:Isoxazoles / Q000737:chemistry; D010316:Particle Size; D016062:Porosity; D011208:Powders / Q000737:chemistry*; D011720:Pyrazoles / Q000737:chemistry; D011786:Quality Control; D012995:Solubility; D013607:Tablets / Q000737:chemistry*; D013678:Technology, Pharmaceutical; D014227:Triazines / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D007555:Isoxazoles; D011208:Powders; D011720:Pyrazoles; D013607:Tablets; D014227:Triazines; D014867:Water; C500057:razaxaban; C509922:brivanib; C542342:pexacerfont; D000409:Alanine