Use of in-die powder densification parameters in the implementation of process analytical technologies for tablet production on industrial scale Marco Cespi a , Diego R. Perinelli a , Luca Casettari b , Giulia Bonacucina a , Giuseppe Caporicci c , Filippo Rendina c , Giovanni F. Palmieri a, * a School of Pharmacy, University of Camerino, via S. Agostino 1, 62032 Camerino, MC, Italy b Department of Biomolecular Sciences, University of Urbino, Piazza Rinascimento 6, PU, 61029 Urbino, Italy c Janssen-Pharmaceutical Company of Johnson & Jonhson, via C. Janssen, Borgo S. Michele, Latina, Italy A R T I C L E I N F O Article history: Received 30 June 2014 Received in revised form 30 September 2014 Accepted 2 October 2014 Available online 7 October 2014 PubChem: Ibuprofen lysine salt (PubChem CID: 9,841,440) Acetaminophen (PubChem CID: 1983) Tramadol hydrochloride (PubChem CID: 63,013) Keywords: Heckel Yield pressure PAT QbD Tablets Compression A B S T R A C T The use of process analytical technologies (PAT) to ensure final product quality is by now a well established practice in pharmaceutical industry. To date, most of the efforts in this field have focused on development of analytical methods using spectroscopic techniques (i.e., NIR, Raman, etc.). This work evaluated the possibility of using the parameters derived from the processing of in-line raw compaction data (the forces and displacement of the punches) as a PAT tool for controlling the tableting process. To reach this goal, two commercially available formulations were used, changing the quantitative composition and compressing them on a fully instrumented rotary pressing machine. The Heckel yield pressure and the compaction energies, together with the tablets hardness and compaction pressure, were selected and evaluated as discriminating parameters in all the prepared formulations. The apparent yield pressure, as shown in the obtained results, has the necessary sensitivity to be effectively included in a PAT strategy to monitor the tableting process. Additional investigations were performed to understand the criticalities and the mechanisms beyond this performing parameter and the associated implications. Specifically, it was discovered that the efficiency of the apparent yield pressure depends on the nominal drug title, the drug densification mechanism and the error in pycnometric density. In this study, the potential of using some parameters derived from the compaction raw data has been demonstrated to be an attractive alternative and complementary method to the well established spectroscopic techniques to monitor and control the tableting process. The compaction data monitoring method is also easy to set up and very cost effective. ã 2014 Elsevier B.V. All rights reserved. 1. Introduction The term “process analytical technologies (PAT)” describes a system for designing and controlling manufacturing through timely measurements (during processing) of critical quality and performance attributes of raw and in-process materials, as well as of processes, with the goal of ensuring final product quality. Thus, PAT focuses on building quality into the product and manufactur- ing processes. In fact, Quality by Design (QbD) is an established concept in the pharmaceutical industry. Even before the introduc- tion of the Common Technical Document (CTD), the regulatory systems required information on the pharmaceutical development of the medicinal products. For this reason, during the last decade many studies have been devoted to analytical technologies for improving product quality through control of the manufacturing process, in accordance with the fundamental principle that quality cannot be tested into products, but instead should be built-in or should be designed with the production process. In most cases, spectroscopic techniques, including Raman spectroscopy, UV–vis spectroscopy, nuclear magnetic resonance (NMR), and especially near infrared spectroscopy (NIR) have been proposed for monitoring the process (Bakeev, 2010). Examples of the applica- tion of such techniques on pharmaceutical process include reaction monitoring (Cue et al., 2009; Streefland et al., 2013), crystallization (Schaefer et al., 2013; Yu et al., 2004), powder blending (De Beer et al., 2008; El-Hagrasy et al., 2006a,b; * Corresponding author. Tel.: +39 737 402233; fax: +39 737 637345. E-mail address: gianfilippo.palmieri@unicam.it (G.F. Palmieri). http://dx.doi.org/10.1016/j.ijpharm.2014.10.009 0378-5173/ ã 2014 Elsevier B.V. All rights reserved. International Journal of Pharmaceutics 477 (2014) 140–147 Contents lists available at ScienceDirect International Journal of Pharmaceutics journa l home page : www.e lsevier.com/loca te/ijpharm