Starch phosphates prepared by reactive extrusion as a sustained release agent Stephen O’Brien a , Ya-Jane Wang a, * , Chris Vervaet b , Jean Paul Remon b a Department of Food Science, University of Arkansas, 2650 N. Young Ave, Fayetteville, AR 72704, USA b Faculty of Pharmaceutical Science, Ghent University, Harelbekestraat 72, B-9000 Gent, Belgium article info Article history: Received 17 April 2008 Received in revised form 13 November 2008 Accepted 18 November 2008 Available online 27 November 2008 Keywords: Reactive extrusion Phosphorylation Starch phosphates Sustained drug release abstract Characteristics of native starch have limited its application in solid dosage forms as a sustained release agent. There is a growing interest in improving starch functionality for sustained release applications because of its non-toxicity and biodegradability. This study attempted to investigate extruded starch phosphates as an excipient in sustaining drug release. Starches from various botanical sources with dif- ferent amylose contents, including waxy corn, common corn, Hylon V (50% amylose), Hylon VII (70% amylose), and potato, were used to prepare starch phosphates at pH 9.0 or 11.0 using a reactive extrusion method. Phosphorous content was higher for starch phosphates prepared at pH 9.0 than at pH 11.0, and varied with starch type when phosphorylated at pH 9.0. Reactive extrusion produced starch extrudates that upon forming hydrogels were capable of sustaining release of metoprolol tartrate (MPT). The struc- tural features of the hydrogel as modified by the phosphorylation reaction were found to alter the kinet- ics of drug release from the swellable matrices. The unmodified extrudates formed weaker gels as evidenced by their rheological properties, and showed faster drug release. Waxy corn starch phosphory- lated at pH 9.0 as well as common corn and potato starches phosphorylated at pH 11.0 were found to exhibit more case-II-like properties attributed to a high density of cross-links and stronger chain entan- glement. Waxy corn starch phosphorylated at pH 9.0 exhibited the lowest degree of drug release. The entanglement among amylopectin molecules and branch chains was suggested to play a role in governing MPT release. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction Starch is one of the most commonly used excipients in the manufacturing of tablets as filler, a disintegrant, or a binder (Visavarungroj & Remon, 1992). Its availability and low cost have allowed it to be integrated into a wide variety of pharmaceutical formulations. However, inferior characteristics of native starches such as poor free flowing properties, stability limitations, and neg- ligible cold-water swelling have limited its application in solid dos- age forms as a sustained release agent. Many petroleum-derived products, such as polyethylene glycols or polymethacrylates (Eudragit) as well as the semi-synthetic cellulose derivatives, have shown success in sustaining drug release. Nonetheless, there is a growing interest in improving the functionality of polysaccharides for use in oral drug delivery systems because of their non-toxicity and biodegradability. Starch consists of two structurally different molecules: amylose, an essentially linear molecule, and amylopectin, a highly branched molecule. Starches from different botanical sources and genetic backgrounds are different in chemical composition and structure. Thermally modified or pregelatinized starches have shown some promise as hydrophilic matrices in sustained release systems (Herman, Remon, & De Vilder, 1989; Mohile, 1986; Sánchez, Torrado, & Lastres, 1995; Yoon, Kweon, & Lim, 2007). Herman et al. (1989) found that as excipients pregelatinized starches con- trolled the oral delivery of drugs through the formation of an obstructive gel layer. Further work by Herman and Remon (1989) demonstrated that the drug release behavior of pregelatinized starch matrices was mainly governed by the amylose/amylopectin ratio, the degree of gelatinization, and the starch concentration with waxy corn starch, 0% amylose content, showing the most promising results. Typically the kinetics of drug release from swel- lable matrices depends on the structural features of the hydrogel and the processes of hydration and swelling of the polymer carrier, with the gel layer formed around the glassy core being the main controlling factor (Michailova, Titeva, & Kotsilkova, 2005; Michailova, Titeva, Kotsilkova, Krusteva, & Minkov, 2001). Chemically modified starches have also shown promise in the pharmaceutical industry as sustained release matrices. For example, starches substituted with cationic groups-like carboxy- methyl (Nabais et al., 2007) or anionic groups-like aminoethyl (Mulhbacher, Ispas-Szabo, Lenaerts, & Mateescu, 2001) or acetate (Pohja, Suihko, Vidgren, Paronen, & Ketolainen, 2004), and starches cross-linked by various agents such as epichlorohydrin have all retarded drug release from solid dosage forms at various levels 0144-8617/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.carbpol.2008.11.024 * Corresponding author. Tel.: +1 479 575 3871; fax: +1 479 575 6936. E-mail address: yjwang@uark.edu (Y.-J. Wang). Carbohydrate Polymers 76 (2009) 557–566 Contents lists available at ScienceDirect Carbohydrate Polymers journal homepage: www.elsevier.com/locate/carbpol