International Journal of Pharmaceutics 322 (2006) 87–95 Optimization of poorly compactable drug tablets manufactured by direct compression using the mixture experimental design Tiago Martinello, Telma Mary Kaneko, Maria Val´ eria Robles Velasco, Maria Elena Santos Taqueda, Vladi O. Consiglieri ∗ Department of Pharmacy, School of Pharmaceutical Sciences, University of S˜ ao Paulo, 580 Prof. Lineu Prestes Avenue, Bl. 13, Conjunto das Qu´ ımicas, Cidade Universit´ aria, 05508-900 S ˜ ao Paulo, SP, Brazil Received 1 February 2006; received in revised form 13 April 2006; accepted 16 May 2006 Available online 24 May 2006 Abstract The poor flowability and bad compressibility characteristics of paracetamol are well known. As a result, the production of paracetamol tablets is almost exclusively by wet granulation, a disadvantageous method when compared to direct compression. The development of a new tablet formulation is still based on a large number of experiments and often relies merely on the experience of the analyst. The purpose of this study was to apply experimental design methodology (DOE) to the development and optimization of tablet formulations containing high amounts of paracetamol (more than 70%) and manufactured by direct compression. Nineteen formulations, screened by DOE methodology, were produced with different proportions of Microcel ® 102, Kollydon ® VA 64, Flowlac ® , Kollydon ® CL 30, PEG 4000, Aerosil ® , and magnesium stearate. Tablet properties, except friability, were in accordance with the USP 28th ed. requirements. These results were used to generate plots for optimization, mainly for friability. The physical–chemical data found from the optimized formulation were very close to those from the regression analysis, demonstrating that the mixture project is a great tool for the research and development of new formulations. © 2006 Elsevier B.V. All rights reserved. Keywords: Paracetamol; Tablets; Mixture experimental design; Response surface methodology; Direct compression 1. Introduction Paracetamol is a drug widely used in therapeutics for its analgesic and antipyretic properties. Usually it is formulated in tablets containing 300–500 mg of drug. Paracetamol exhibits poor compression ability, low flowability and its tablets show a tendency to cap (Hong-Guang and Ru-Hua, 1995; Yu et al., 1988). The poor compaction behavior of paracetamol and its reduced plastic deformation have been explained in terms of the crystal structure of the material, which is based on a mono- clinic crystal system (Jivraj et al., 2000; Nichols and Framptom, 1998). Due to these characteristics the production of paraceta- mol tablets is almost exclusively by wet granulation. The advantages of direct compression are well known: fewer processing stages, elimination of heat and moisture effects, increase of productivity and reduction of the final cost of the product. Furthermore, direct compression is considered an ∗ Corresponding author. Tel.: +55 11 3091 3623; fax: +55 11 3815 4418. E-mail address: siglieri@usp.br (V.O. Consiglieri). appropriate process for hygroscopic and thermo-sensitive sub- stances (Jivraj et al., 2000; Beyer et al., 2001). A serious limi- tation of this technique is the use of more than 30% of the drug in the formulation, mainly for drugs that present low flowability and segregation (Jivraj et al., 2000). Regarding to the manufac- turability, a good flowability of the blend, i.e., the dry mixture of excipients and drug, is critical for the compression of the tablets in terms of dissolution, friability and content uniformity. Some attempts have been made to modify the properties of paracetamol crystals using different crystallization techniques in order to improve the compaction properties of unmodified crystals (Fachaux et al., 1995; Di Martino et al., 1996; Abdelillah et al., 1995). However, the most common limitations of these methods were the relatively high solvent content remaining in the final agglomerates even after drying, the high temperature required, besides the strict control over atmosphere and time (Garekani et al., 2000a,b). Alternatively, a number of manufacturers have prepared paracetamol powders for direct compression. These materials have good compressibility, but all these paracetamols for direct compression are mixtures of paracetamol with either starch, 0378-5173/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2006.05.034