title: Real-time assessment of granule densification in high shear wet granulation and application to scale-up of a placebo and a brivanib alaninate formulation.
abstract: Real-time monitoring and control of high shear wet granulation (HSWG) using process analytical technologies is crucial to process design, scale-up, and reproducible manufacture. Although significant progress has been made in real-time measurement of granule size distribution using focused beam reflectance measurement (FBRM), real-time in-line assessment of granule densification remains challenging. In this study, a drag force flow (DFF) sensor was developed and used to probe wet mass consistency in real-time. In addition, responses from FBRM and DFF sensors were compared to assess complementarity of information on granulation progress from the two probes. A placebo and a brivanib alaninate formulation were granulated with different concentrations of binder or water, respectively, while measuring granule size growth, densification, and DFF sensor response. The DFF sensor was able to quantitatively characterize with high resolution a response of wet mass consistency distinct from granule size distribution. The wet mass consistency parameter correlated well with granule densification, which was shown as a critical material attribute that correlated with tablet dissolution. In addition, application of DFF sensor to scale-up of granulation was demonstrated. These results showed the value of wet mass consistency measurement using DFF for WG monitoring and control.
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb, Co., One Squibb Dr., New Brunswick, New Jersey, 08903.
authors.forename: Ajit S
authors.initials: AS
authors.lastname: Narang
authors.forename: Valery A
authors.initials: VA
authors.lastname: Sheverev
authors.forename: Vadim
authors.initials: V
authors.lastname: Stepaniuk
authors.forename: Sherif
authors.initials: S
authors.lastname: Badawy
authors.forename: Tim
authors.initials: T
authors.lastname: Stevens
authors.forename: Kevin
authors.initials: K
authors.lastname: Macias
authors.forename: Avi
authors.initials: A
authors.lastname: Wolf
authors.forename: Preetanshu
authors.initials: P
authors.lastname: Pandey
authors.forename: Dilbir
authors.initials: D
authors.lastname: Bindra
authors.forename: Sailesh
authors.initials: S
authors.lastname: Varia
mesh_terms: D000284:Administration, Oral; D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D002266:Carboxymethylcellulose Sodium / Q000737:chemistry; D002482:Cellulose / Q000031:analogs & derivatives / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D004867:Equipment Design; D005079:Excipients / Q000737:chemistry; D007700:Kinetics; D007785:Lactose / Q000737:chemistry; D008956:Models, Chemical; D015233:Models, Statistical; D010316:Particle Size; D010919:Placebos; D016062:Porosity; D011208:Powders; D011786:Quality Control; D012995:Solubility; D013607:Tablets; D013678:Technology, Pharmaceutical / Q000295:instrumentation / Q000379:methods* / Q000592:standards; D014227:Triazines / Q000008:administration & dosage / Q000737:chemistry*; D014867:Water / Q000737:chemistry
chemical_list: D005079:Excipients; D010919:Placebos; D011208:Powders; D013607:Tablets; D014227:Triazines; D014867:Water; D002482:Cellulose; C008079:hydroxypropylcellulose; C509922:brivanib; D007785:Lactose; D002266:Carboxymethylcellulose Sodium; D000409:Alanine; C109691:microcrystalline cellulose
keywords: analysis; drag force flow sensor; focused beam reflectance measurement; granulation; particle size; physical characterization; porosity; powder technology; process analytical technology; quality-by-design