title: Resolution and Sensitivity of Inline Focused Beam Reflectance Measurement During Wet Granulation in Pharmaceutically Relevant Particle Size Ranges.
abstract: Real-time process monitoring using a process analytical technology for granule size distribution can enable quality-by-design in drug product manufacturing. In this study, the resolution and sensitivity of chord length distribution (CLD) measured inline inside a high shear granulator using focused beam reflectance measurement (FBRM) C35 probe was investigated using different particle size grades of microcrystalline cellulose (MCC). In addition, the impact of water and impeller tip speed on the measurement accuracy as well as correlation with offline particle sizing techniques (FBRM, laser diffraction [Malvern Mastersizer®], microscopy [Sympatec QicPic®], and nested sieve analysis) was studied. Inline FBRM resolved size differences between different MCC grades, and the data correlated well with offline analyses. Impeller tip speed changed the number density of inline CLD measurements while addition of water reduced the CLD of dry MCC, likely due to deagglomeration of primary particles. In summary, inline FBRM CLD measurement in high shear granulator provides adequate resolution and reproducible measurements in the pharmaceutically relevant size range both in the presence and in the absence of water. Therefore, inline FBRM can be a valuable tool for the monitoring of high shear wet granulation.
authors.affiliation: Drug Product Science & Technology, Bristol-Myers Squibb Company, One Squibb Dr., New Brunswick, New Jersey 08903. Electronic address: Narang.Ajit@Gene.com.
authors.forename: Ajit S
authors.initials: AS
authors.lastname: Narang
authors.affiliation: Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, One Squibb Dr., New Brunswick, New Jersey 08903.
authors.forename: Timothy
authors.initials: T
authors.lastname: Stevens
authors.affiliation: Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, One Squibb Dr., New Brunswick, New Jersey 08903.
authors.forename: Mario
authors.initials: M
authors.lastname: Hubert
authors.affiliation: Drug Product Science & Technology, Bristol-Myers Squibb Company, One Squibb Dr., New Brunswick, New Jersey 08903.
authors.forename: Srinivasa
authors.initials: S
authors.lastname: Paruchuri
authors.affiliation: Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, One Squibb Dr., New Brunswick, New Jersey 08903.
authors.forename: Kevin
authors.initials: K
authors.lastname: Macias
authors.affiliation: Drug Product Science & Technology, Bristol-Myers Squibb Company, One Squibb Dr., New Brunswick, New Jersey 08903.
authors.forename: Dilbir
authors.initials: D
authors.lastname: Bindra
authors.affiliation: Drug Product Science & Technology, Bristol-Myers Squibb Company, One Squibb Dr., New Brunswick, New Jersey 08903.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Drug Product Science & Technology, Bristol-Myers Squibb Company, One Squibb Dr., New Brunswick, New Jersey 08903.
authors.forename: Sherif
authors.initials: S
authors.lastname: Badawy
mesh_terms: D002482:Cellulose / Q000032:analysis / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods* / Q000592:standards*; D010316:Particle Size
chemical_list: D002482:Cellulose; C109691:microcrystalline cellulose
keywords: FBRM; focused beam reflectance measurement; formulation; granulation; high shear wet granulation; high throughput technologies; powder technology; process analytical technologies; processing; unit operations