In situ cross-linking of sodium alginate with calcium and aluminum ions to sustain the release of theophylline from polymeric matrices Ali Nokhodchi *, Anish Tailor Pharmacy Department, Kings College London, 150 Stamford Street, Franklin-Wilkins Building, SE1 9NN, London, UK Received 7 July 2004; accepted 14 August 2004 Available online 30 September 2004 Abstract Small matrices of calcium alginate or aluminium alginate have been investigated as possible controlled release systems for drugs. The objective of the present study was to sustain the release of theophylline from alginate matrices using different concentrations of aluminium chloride and calcium chloride in presence and absence of HPMC. Tablets containing differing concentrations of aluminium and calcium chloride were produced and the release rate of theophylline was tested using the basket dissolution apparatus over 8 h. Increasing amounts of aluminium chloride from 0.0001 to 0.00068 moles decreased the release of theophylline from 95.1 ± 0.27 to 29.5 ± 1.5, indicating a significant effect of aluminium ions on a reduction in the release rate of theophylline from sodium alginate matrices. In the case of matrices containing different concentrations of calcium ions, as the concentration of calcium chloride increased, the release rate increased to an optimum then declined after this. This was due to insufficient calcium ions being available to cross-link with the sodium alginate to form an insoluble gel. The effect of aluminium ions, as this is a trivalent ion compared to calcium, which is a divalent ion, aluminium ions are able to decrease the release rate with a smaller concentration compared to calcium ions. The results also showed that the presence of HPMC caused a reduction in release rate of theophylline from alginate matrices containing calcium chloride. Whereas, in the case of alginate matrices containing aluminium chloride the release rate of theophylline increased in presence of HPMC. For comparing the dissolution data, dissolution efficiency (DE) was used. The values of DE are consistent with the dissolution data. The results show that within a formulation series, DE values generally decrease when the cation concentration increases and this criterion can be used to describe the effect of calcium and aluminium ions on the release behaviour of theophylline from polymeric matrices. © 2004 Published by Elsevier SAS. Keywords: In situ cross-linking; Release rate; Cations; Theophylline; HPMC; Matrices 1. Introduction Theophylline, an alkaloid found in the leaves of the Came- liai sinesis is used clinically as a bronchodilator in the mana- gement of Chronic Obstructive Pulmonary Disease [1]. Conventional dosage forms of theophylline are administered 3–4 times a day to avoid large fluctuations in plasma concen- trations [2]. Sustained release dosage forms, on the other hand, provide desirable serum concentrations for prolonged periods without frequent dosing thereby providing patient compliance. Recently, the use of natural polymers in the design of drug delivery formulation has received much attention due to their excellent biocompatibility and biodegrability [3]. Among them, alginate is very promising and has been widely exploi- ted in pharmaceutical industry for controlled release [4]. Alginate is a polysaccharide composed of D-mannuronic acid and D-guluronic acid. It is found in brown seaweeds [5] and is commercially available as a sodium salt. It is extensi- vely used as a gelling agent in food industry [6]. Alginate has a unique property of gel-formation in the presence of multi- valent cations such as calcium ions in aqueous media, which takes place mainly at junctions in the G–G sequence rich chain region known as the ‘egg box junction’ [7,8]. Alginate is an attractive polymer for the development of drug carriers and controlled release delivery systems [9–12]. Drug delivery systems have been extensively studied over the years and polymers are now being studied as one method of controlling the release of drug molecules. Cross-linking is * Corresponding author. Tel.: +44-20-7848-4787; fax: +44-20-7848-4800. E-mail address: ali.nokhodchi@kcl.ac.uk (A. Nokhodchi). IL FARMACO 59 (2004) 999–1004 http://france.elsevier.com/direct/FARMAC/ 0014-827X/$ - see front matter © 2004 Published by Elsevier SAS. doi:10.1016/j.farmac.2004.08.006