Review article Design space and critical points in solid dosage forms  Angela Aguilar-de-Leyva * , María Dolores Campi ~ nez, Marta Casas, Isidoro Caraballo Departamento de Farmacia y Tecnología Farmac eutica, Facultad de Farmacia, Universidad de Sevilla. C/ Profesor García Gonz alez nº2 41012, Sevilla, Spain article info Article history: Received 26 February 2017 Received in revised form 3 June 2017 Accepted 5 June 2017 Available online xxx Keywords: Critical points Design space Percolation theory Quality by design (QbD) Matrix systems abstract The current regulatory environment based on the ICH guidelines encourages a systematic and science- based approach in the pharmaceutical development, required by the “Quality by design” concept. This methodology implies that the quality of a product must be designed instead of assayed in the final dosage form. For this purpose, a deep knowledge of the factors affecting the quality of the product is needed to establish the design space. This design space is limited by critical points of the formulation whose knowledge is essential in order to develop a robust dosage form. This papers deals with the main critical points that must be taken into account in the design of solid dosage forms such as inert and hydrophilic matrices as well as controlled released systems based in new biopolymers. The influence of factors such as the particle size or the rheology of powders in these critical points has been analysed. Moreover, in silico simulation software has been employed to elucidate the release mechanism leading to unexpectedly low critical points in sustained release matrices prepared with two new polyurethanes. © 2017 Elsevier B.V. All rights reserved. Contents 1. PAT, design space and critical points .................................................................................................. 00 2. Critical points and particle size ....................................................... ............................................... 00 3. Critical points and rheology of powder blends ............................................... ......................................... 00 4. Design space in matrix systems ...................................................... ............................................... 00 4.1. Inert matrices ............................................................................................................... 00 4.2. Hydrophilic matrices ........................................................ ................................................ 00 5. SR-systems obtained with new biopolymers ................................................ .......................................... 00 5.1. In silico modelization, image analysis and release mechanism ...................................................................... 00 Acknowledgement ................................................................................................................. 00 References ........................................................................................................................ 00 1. PAT, design space and critical points In 2002 the FDA identified a significant number of ongoing problems in pharmaceutical manufacturing, revealing the need of a rigorous science-based approach for the design of formulations and processes. The number of defects was enormous comparing with other sectors, as the chip industry, which had achieved to reduce errors in the manufacturing process to 2 ppb, seeking the “six sigma” objective, while pharmaceutical manufacturing perfor- mance was only about two sigma, equivalent to 46,000,000,000 ppb [1]. For this reason, the Agency launched a new initiative entitled “Pharmaceutical CGMPs for the 21st Cen- tury: A Risk-Based Approach” in order to facilitate industry appli- cation of modern quality management techniques, including implementation of quality systems approaches. So, the concept of quality by design (QbD), firstly outlined by Juran in 1992 [2], was introduced in pharmaceutical industries to enhance robust manufacturing process and to facilitate product quality [3]. Following this approach, the quality of a product has to be ensured since its design, instead of measuring it in the final dosage form. * Corresponding author. E-mail addresses: aguilardeleyva@us.es (  A. Aguilar-de-Leyva), mcampinez@us.es (M.D. Campi ~ nez), mcasas@us.es (M. Casas), caraballo@us.es (I. Caraballo). Contents lists available at ScienceDirect Journal of Drug Delivery Science and Technology journal homepage: www.elsevier.com/locate/jddst http://dx.doi.org/10.1016/j.jddst.2017.06.004 1773-2247/© 2017 Elsevier B.V. All rights reserved. Journal of Drug Delivery Science and Technology xxx (2017) 1e10 Please cite this article in press as:  A. Aguilar-de-Leyva, et al., Design space and critical points in solid dosage forms, Journal of Drug Delivery Science and Technology (2017), http://dx.doi.org/10.1016/j.jddst.2017.06.004