Development and characterization of naproxen–chitosan solid systems with improved drug dissolution properties

https://doi.org/10.1016/S0928-0987(03)00068-XGet rights and content

Abstract

The solubilizing and amorphizing properties toward naproxen (a poorly water-soluble antiinflammatory drug) of chitosan, an emerging pharmaceutical biopolymer, have been investigated. Solid binary systems at different drug/polymer ratios have been prepared according to different techniques (mixing, cogrinding, kneading, coevaporation) using chitosan at low (CS-Lw) and medium (CS-Mw) molecular weight, and tested for dissolution properties. Drug-carrier interactions were investigated in both the liquid and solid state, by phase solubility analysis, differential scanning calorimetry, X-ray powder diffractometry, FT-IR spectroscopy, and scanning electron microscopy. Drug dissolution parameters improved with increasing the polymer amount in the mixture, reaching the highest values at the 1:9 (w/w) drug/polymer ratio, and CS-Lw was more efficacious than CS-Mw. Cogrinding was the most effective technique, showing the strongest amorphizing effect toward the drug and enabling an increase of more than ten times its relative dissolution rate. Coground mixtures at 3:7 (w/w) drug/polymer ratio were able to give directly compressed tablets which maintained unchanged the improved drug dissolution properties. Enhancer dissolution properties combined with its direct compression feasibility and antiulcerogenic action make CS-Lw an optimal carrier for developing fast-release oral solid dosage forms of naproxen.

Introduction

Chitosan [(1–>4)-2-amino-2-deoxy-β-d-glucan] is a linear cationic polysaccharide obtained by N-deacetylation of chitin, a naturally-occurring structural polysaccharide abundant in crab and shrimp shells. It has recently emerged as one of the most promising biopolymers for a variety of potential applications in both the biomedical and pharmaceutical fields since it exhibits several desirable biological properties such as non-toxicity, good biocompatibility and biodegradability, accompanied by wide availability in nature, low cost and high flexibility in use (Felt et al., 1998, Illum, 1998, Paul and Sharma, 2000). In addition to its use as an excipient for direct compression (Upadrashta et al., 1992; Ritthidej et al., 1994), chitosan has been thoroughly examined for its potential in the development of a variety of drug delivery systems, due to its polymeric cationic character, gel- and film-forming abilities, bioadhesiveness and transmucosal penetration enhancer properties (Artursson et al., 1994; Henriksen et al., 1996; Kas, 1997; Felt et al., 1998; Illum, 1998; Kristl et al., 1999; Paul and Sharma, 2000). Moreover, some authors also refer to its effectiveness in enhancing the dissolution properties and bioavailability of poorly-soluble drugs (Sawayanagi et al., 1982, Sawayanagi et al., 1983; Shiraishi et al., 1990; Acarturk et al., 1993a, Acarturk et al., 1993b; Portero et al., 1998). Finally, its antiacid and antiulcer properties can be exploited to prevent or reduce gastric irritation induced by some active compounds, such as anti-inflammatory drugs (Kawashima et al., 1985; Açikgoz et al., 1995).

Naproxen is a non-steroidal anti-inflammatory drug which, as a consequence of its scarce wettability and very poor water-solubility (0.025 mg/ml at 25 °C), can exhibit low and/or variable bioavailability after oral administration. Several approaches have been conducted in order to adequately improve the naproxen dissolution properties, mainly via the use of solid dispersions with polyethylene glycol (Mura et al., 1996, Mura et al., 1999) or polyvinylpyrrolidone (Bettinetti and Mura, 1994) or complexation with cyclodextrins (Bettinetti et al., 1989; Melani et al., 1995; Mura et al., 1995).

Taking all this into account and considering the numerous favorable biopharmaceutical properties of chitosan, including its antiulcerogenic activity, and with the idea of further extending chitosan applications to pharmaceutical preparations, we considered it worthy of interest to evaluate this polymer as a potential carrier for improving naproxen dissolution behavior. Based on the positive results of preliminary studies which demonstrated the actual effectiveness of chitosan in promoting the dissolution performance of naproxen (Mura et al., 2001a), in the present work we investigated in-depth the influence of several factors such as the chitosan molecular weight, the drug/polymer mixing weight ratio and the method used to disperse the drug within the polymer on naproxen dissolution rate. Solid binary systems prepared at different drug/polymer ratios and with different techniques (mixing, cogrinding, kneading, coevaporation) were characterized by differential scanning calorimetry, X-ray powder diffractometry, FT-IR spectroscopy, and scanning electron microscopy and tested for dissolution rates, whereas drug–polymer interactions in aqueous solution were investigated by phase-solubility analysis. The best binary products were then selected for the final aim of preparing directly compressed tablets with improved drug dissolution properties.

Section snippets

Materials

Naproxen and chitosan of low (CS-Lw) and medium (CS-Mw) molecular weight (150 000 and 400 000, respectively) were supplied by Sigma Chem. Co. (St. Louis, USA). According to the supplier’s specifications, the degree of deacetylation was 75–85% for both polymers, and the viscosity of 1% solution in 1% acetic acid at 20 °C was 100 and 200 mPas for CS-Lw and CS-Mw respectively. The solubility of the polymers in pure water (pH≈7) at room temperature was 2.5% w/v for CS-Lw and <0.5% w/v for CS-Mw.

Phase-solubility studies

Phase-solubility studies

In order to gain insight into the nature of a possible interaction in solution between naproxen and chitosan, phase-solubility experiments were performed. The drug solubility was increased as the polymer concentration increased, and a Type AN phase-solubility diagram (Higuchi and Connors, 1965) was obtained (Fig. 1). These results are consistent with the formation of weak soluble complexes between naproxen and chitosan (Chiou, 1977). The presence of electrostatic interactions favouring and

Acknowledgments

Financial support from the Italian MURST is gratefully acknowledged.

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