1 Mini-tablets versus pellets as promising multiparticulate modiﬁed 2 release delivery systems for highly soluble drugs Q1 3 Dina M. Gaber a Q2 , Noha Nafee b, *, Osama Y. Abdallah b 4 a Department of Pharmaceutics, Pharos University, Alexandria, Egypt 5 b Department of Pharmaceutics, Alexandria University, Alexandria, Egypt A R T I C L E I N F O Article history: Received 12 December 2014 Received in revised form 8 April 2015 Accepted 9 April 2015 Available online xxx Keywords: Mini-tablets Pellets Venlafaxine hydrochloride Modiﬁed release Multiparticulate system A B S T R A C T Whether mini-tablets (tablets, diameters 6 mm) belong to single- or multiple-unit dosage forms is still questionable. Accordingly, Pharmacopoeial evaluation procedures for mini-tablets are lacking. In this study, the aforementioned points were discussed. Moreover, their potential for oral controlled delivery was assessed. The antidepressant venlafaxine hydrochloride (Vx), a highly soluble drug undergoing ﬁrst pass effect, low bioavailability and short half-life was selected as a challenging payload. In an attempt to weigh up mini-tablets versus pellets as multiparticulate carriers, Vx-loaded mini-tablets were compared to formulated pellets of the same composition and the innovator Effexor 1 XR pellets. Formulations were prepared using various polymer hydrogels in the core and ethyl cellulose ﬁlm coating with increasing thickness. Mini-tablets (diameter 2 mm) showed extended Vx release (<60%, 8 h). Indeed, release proﬁles comparable to Effexor 1 XR pellets were obtained. Remarkably higher coating thickness was required for pellets to provide equivalent retardation. Ethyl cellulose in the core ensured faster release due to polymer migration to the surface and pore formation in the coat. mini-tablets showed higher stability to pellets upon storage. Industrially speaking, mini-tablets proved to be superior to pellets in terms of manufacturing, product quality and economical aspects. Results point out the urgent need for standardized evaluation procedures for mini-tablets. ã 2015 Published by Elsevier B.V. 6 1. Introduction 7 Oral Q3 multiparticulate drug delivery systems such as 8 nano-/microparticles, granules, pellets and mini-tablets are dosage 9 forms mainly consisting of a multiplicity of small discrete units, 10 each exhibiting some desired characteristics. In these systems, the 11 dosage of the drug substance is divided on a plurality of subunit, 12 typically consisting of particles with diameter of 0.05–2 mm 13 (Kulkarni et al., 2010; Srivastava and Mishra, 2010). To deliver the 14 recommended total dose, these subunits are typically ﬁlled into a 15 sachet, encapsulated or compressed into a tablet (Kulkarni et al., 16 2010). Recently, much emphasis is being laid on the development 17 of multiparticulate dosage forms in preference to single unit, 18 monolithic systems because of their potential beneﬁts such 19 as better distribution, facilitated disintegration, increased 20 bioavailability, reduced risk of both systemic toxicity and local 21 irritation (Asghar and Chandran, 2006). 22 Mini-tablets, also termed as mini-matrices in 1990s, were 23 considered as multiparticulate system that combine the physio- 24 logical advantages of multiple unit dosage forms and the economic 25 advantages of single unit dosage forms (Sujja-areevath et al., 1996). 26 Compared to other multiparticulate systems such as granules or 27 pellets, mini-tablets reveal several advantages; compression of 28 mini-matrices represents an attractive alternative to irregularly- 29 shaped granules or pellets. The deﬁned size, robust mechanical 30 properties, constant speciﬁc surface area, smooth outer surface, 31 small variability within and between batches contribute to more 32 reproducible coating with less coating material than granules 33 (Abdulhadi et al., 2012; Tissen et al., 2011). When related to single 34 unit dosage forms, mini-tablets exhibit several beneﬁts like minor 35 risk of dose dumping and independence of the rhythm of food 36 transport (Follonier and Doelker, 1992; Tissen et al., 2011). 37 Mini-tablets are prepared either by dry mixing or wet 38 granulation and then compressed using conventional rotary 39 compressing machine equipped with multi-tip punches. For 40 application, the compacts can be ﬁlled into hard gelatin capsules 41 or can be administered with a dose dispenser for individual dosing * Corresponding author. Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, 21521El Khartoom Square, Alexandria, Egypt. Tel.: +20 34868482/1098012062; fax: +20 34871668. E-mail addresses: dinagaber84@gmail.com (D.M. Gaber), n.nafe3@gmail.com, noha.nafee@pharmacy.alexu.edu.eg (N. Nafee), Ossama.Y.Abdallah@gmail.com (O.Y. Abdallah). http://dx.doi.org/10.1016/j.ijpharm.2015.04.021 0378-5173/ ã 2015 Published by Elsevier B.V. International Journal of Pharmaceutics xxx (2015) xxx–xxx G Model IJP 14811 1–9 Please cite this article in press as: Gaber, D.M., et al., Mini-tablets versus pellets as promising multiparticulate modiﬁed release delivery systems for highly soluble drugs. Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.04.021 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsev ier.com/locate /ijpharm