title: Optimization of a pharmaceutical tablet formulation based on a design space approach and using vibrational spectroscopy as PAT tool.
abstract: The aim of the present study was to optimize a tablet formulation using a quality by design approach. The selected methodology was based on the variation of the filler grade, taking into account the particle size distribution (PSD) of active pharmaceutical ingredient (API) in order to improve five critical quality attributes (CQAs). Thus, a mixture design of experiments (DoE) was performed at pilot scale. The blending step was monitored using near infrared (NIR) spectroscopy as process analytical technology tool enabling real-time qualitative process monitoring. Furthermore, some tablets were analyzed by Raman imaging to evaluate the API distribution within the samples. Based on the DoE results, design spaces were computed using a risk-based Bayesian predictive approach to provide for each point of the experimental domain the expected probability to get the five CQAs jointly within the specifications in the future. Finally, the optimal conditions of the identified design space were successfully validated. In conclusion, a design space approach supported by NIR and Raman spectroscopy was able to define a blend that complies with the target product profile with a quantified guarantee or risk.
authors: University of Liege (ULg), Department of Pharmacy, CIRM, Laboratory of Analytical Chemistry, CHU, B36, 4000 Liege, Belgium. Electronic address: pfchavez@ulg.ac.be.
authors: Pierre-François
authors: PF
authors: Chavez
authors: University of Liege (ULg), Department of Pharmacy, CIRM, Laboratory of Analytical Chemistry, CHU, B36, 4000 Liege, Belgium.
authors: Pierre
authors: P
authors: Lebrun
authors: University of Liege (ULg), Department of Pharmacy, CIRM, Laboratory of Analytical Chemistry, CHU, B36, 4000 Liege, Belgium.
authors: Pierre-Yves
authors: PY
authors: Sacré
authors: University of Liege (ULg), Department of Pharmacy, CIRM, Laboratory of Analytical Chemistry, CHU, B36, 4000 Liege, Belgium.
authors: Charlotte
authors: C
authors: De Bleye
authors: University of Liege (ULg), Department of Pharmacy, CIRM, Laboratory of Analytical Chemistry, CHU, B36, 4000 Liege, Belgium.
authors: Lauranne
authors: L
authors: Netchacovitch
authors: UCB Pharma S.A., Avenue de l'Industrie, 1420 Braine-l'Alleud, Belgium.
authors: Serge
authors: S
authors: Cuypers
authors: UCB Pharma S.A., Avenue de l'Industrie, 1420 Braine-l'Alleud, Belgium.
authors: Jérôme
authors: J
authors: Mantanus
authors: UCB Pharma S.A., Avenue de l'Industrie, 1420 Braine-l'Alleud, Belgium.
authors: Henri
authors: H
authors: Motte
authors: UCB Pharma S.A., Avenue de l'Industrie, 1420 Braine-l'Alleud, Belgium.
authors: Martin
authors: M
authors: Schubert
authors: University of Liege (ULg), Department of Pharmacy, CIRM, Laboratory of Pharmaceutical Technology, CHU, B36, 4000 Liege, Belgium.
authors: Brigitte
authors: B
authors: Evrard
authors: University of Liege (ULg), Department of Pharmacy, CIRM, Laboratory of Analytical Chemistry, CHU, B36, 4000 Liege, Belgium.
authors: Philippe
authors: P
authors: Hubert
authors: University of Liege (ULg), Department of Pharmacy, CIRM, Laboratory of Analytical Chemistry, CHU, B36, 4000 Liege, Belgium.
authors: Eric
authors: E
authors: Ziemons
mesh_terms: D001499:Bayes Theorem; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D005079:Excipients / Q000737:chemistry; D010316:Particle Size; D019265:Spectroscopy, Near-Infrared; D013059:Spectrum Analysis, Raman; D013607:Tablets / Q000737:chemistry*
chemical_list: D005079:Excipients; D013607:Tablets
keywords: Design space; Optimization; Pharmaceutical tablet formulation; Process analytical technology; Quality by design; Vibrational spectroscopy