title: Real-time on-line blend uniformity monitoring using near-infrared reflectance spectrometry: a noninvasive off-line calibration approach.
abstract: A robust, noninvasive, real-time, on-line near-infrared (NIR) quantitative method is described for blend uniformity monitoring of a pharmaceutical solid dosage form containing 29.4% (w/w) drug load with three major excipients (crospovidone, lactose, and microcrystalline cellulose). A set of 21 off-line, static calibration samples were used to develop a multivariate partial least-squares (PLS) calibration model for on-line prediction of the API content during the blending process. The concentrations of the API and the three major excipients were varied randomly to minimize correlations between the components. A micro electrical-mechanical system (MEMS) based portable, battery operated NIR spectrometer was used for this study. To minimize spectral differences between the static and dynamic measurement modes, the acquired NIR spectra were preprocessed using standard normal variate (SNV) followed by second derivative Savitzky-Golay using 21 points. The performance of the off-line PLS calibration model were evaluated in real-time on 16 laboratory scale (30 L bin size) blend experiments conducted over 3 months. To challenge the robustness of the off-line calibration model, several blend experiments were conducted using a different bin size, faster revolution speed and variations in the potency of the API. Employing the PLS calibration model developed using the off-line calibration approach, the real-time API NIR (%) predictions for all experiments were all within 90-110%. These results were confirmed using the conventional thief sampling of the final blend followed by high performance liquid chromatography (HPLC) analysis. Further confirmation was established through content uniformity by HPLC of manufactured tablets. Finally, the optimized off-line PLS method was successfully transferred to a production site which involved using a secondary NIR instrument with a 15-fold scale-up in bin size from development.
authors.affiliation: Pharmaceutical and Analytical Development, Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936, United States. yusuf.sulub@novartis.com
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Sulub
authors.forename: Busolo
authors.initials: B
authors.lastname: Wabuyele
authors.forename: Paul
authors.initials: P
authors.lastname: Gargiulo
authors.forename: James
authors.initials: J
authors.lastname: Pazdan
authors.forename: James
authors.initials: J
authors.lastname: Cheney
authors.forename: Joseph
authors.initials: J
authors.lastname: Berry
authors.forename: Abhay
authors.initials: A
authors.lastname: Gupta
authors.forename: Rakhi
authors.initials: R
authors.lastname: Shah
authors.forename: Huiquan
authors.initials: H
authors.lastname: Wu
authors.forename: Mansoor
authors.initials: M
authors.lastname: Khan
mesh_terms: D002138:Calibration; D004304:Dosage Forms; D004339:Drug Compounding; D005079:Excipients; D016018:Least-Squares Analysis; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D019265:Spectroscopy, Near-Infrared / Q000295:instrumentation* / Q000379:methods*; D013997:Time Factors
chemical_list: D004304:Dosage Forms; D005079:Excipients; D004364:Pharmaceutical Preparations