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

European Journal of Pharmaceutical Sciences 19 (2003) 67–75 www.elsevier.com / locate / ejps

Development and characterization of naproxen–chitosan solid systems with improved drug dissolution properties a, b a a b Paola Mura *, Naima Zerrouk , Natascia Mennini , Francesca Maestrelli , Chantal Chemtob b

a Dipartimento di Scienze Farmaceutiche, Facolta` di Farmacia, Universita` di Firenze, Via Gino Capponi 9, 50121 Firenze, Italy ´ , Faculte´ de Sciences Pharmaceutiques et Biologiques, Universite´ de Paris V, 4 Avenue de l’ Observatoire, Laboratoire de Pharmacie Galenique 75270 Paris Cedex 06, France

Received 29 July 2002; received in revised form 28 February 2003; accepted 17 March 2003

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-L w ) and medium (CS-M w ) 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-L w was more efficacious than CS-M w . 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-L w an optimal carrier for developing fast-release oral solid dosage forms of naproxen.  2003 Elsevier Science B.V. All rights reserved. Keywords: Naproxen; Chitosan; Dissolution enhancement; Cogrinding; Differential scanning calorimetry

1. Introduction Chitosan [(1–.4)-2-amino-2-deoxy-b-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 *Corresponding author. Tel.: 139-055-275-7292; fax: 139-055-240776. E-mail address: [email protected] (P. Mura).

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, 1983; Shiraishi et al., 1990; Acarturk et al., 1993a,b; 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; Ac¸ikgoz 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 8C), 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, 1999) or polyvinylpyrrolidone

0928-0987 / 03 / $ – see front matter  2003 Elsevier Science B.V. All rights reserved. doi:10.1016 / S0928-0987(03)00068-X

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(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.

2. Materials and methods

2.1. Materials Naproxen and chitosan of low (CS-L w ) and medium (CS-M w ) 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 8C was 100 and 200 mPas for CS-L w and CS-M w respectively. The solubility of the polymers in pure water (pH¯7) at room temperature was 2.5% w / v for CS-L w and ,0.5% w / v for CS-M w .

2.2. Phase-solubility studies Solubility measurements of naproxen were carried out by adding an excess of drug (15 mg) to 15 ml of water or aqueous solution of polymer (from 0.25 to 2% w / v), in sealed glass containers which were electromagnetically stirred at constant temperature (25 8C) until equilibrium was achieved (2 days). The pH of the solutions at equilibrium ranged from 5.3 to 5.5, due to the presence of the acidic drug. At these pH values, the solubility of both polymers increased, making solubilization possible up to

2% w / v (the highest concentration used in phase-solubility studies) also for the less soluble polymer, i.e. CS-M w . An aliquot of solution was withdrawn and filtered (pore size 0.45 mm), and the drug concentration was determined by a second derivative ultraviolet absorption method (Perkin Elmer 552S spectrophotometer) (Bettinetti et al., 1989). Each experiment was performed in triplicate (coefficient of variation C.V.,3.5%).

2.3. Preparation of solid systems Naproxen–polymer binary systems in different (w / w) ratios (5:5, 3:7, 1:9) were prepared from the individual components by: a) tumble mixing with a turbula mixer for 10 min at 50 rpm (physical mixtures); b) ball-milling in a ¨ high energy vibrational micromill (Retsch, GmbH, Dusseldorf, Germany) for 60 min at 24 Hz (coground products); c) kneading with ethanol–water 6:1 (v / v) (kneaded products); d) coevaporation of ethanol–water 5:5 (v / v) naproxen–polymer solutions (coevaporated products). All these techniques were applied also to the pure drug in order to exclude any effect of sample preparation method on the drug physicochemical characteristics. Sieved products (75–150 mm) were used for all subsequent studies.

2.4. Differential scanning calorimetry ( DSC) DSC analysis was performed with a Mettler TA4000 apparatus equipped with a DSC 25 cell on 5–10 mg samples (Mettler M3 microbalance) scanned in pierced Al pans at 10 8C min 21 between 30 and 200 8C under static air.

2.5. X-ray powder diffractometry X-ray powder diffraction patterns were collected with a Philips PW 1130 powder diffractometer (Co Ka radiation), over the 10–50 2u range at a scan rate of 18 min 21 .

2.6. Infrared analysis Fourier transform infra red (FT-IR) spectra were obtained on KBr disks using a Perkin–Elmer Mod. 1600 apparatus.

2.7. Scanning electron microscopy ( SEM) SEM analysis was carried out using a Hitachi model S-250 scanning electron microscope. Prior to examination, samples were gold sputter-coated to render them electrically conductive (fine coat ion sputter JFC-1100 JEOL). Magnification selected was 10003 since it was enough to appreciate in detail the general morphology of the powders under study.

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2.8. Dissolution rate studies In vitro dissolution rate studies of the pure drug and the different drug–polymer combinations were performed according to the dispersed amount method (Nogami et al., 1969). Solid systems freshly sieved (75–150 mm) containing 60 mg of drug were added to 75 ml of water at 3760.5 8C and stirred at 100 rpm. At fixed time intervals, samples were withdrawn with a syringe filter (pore size 0.45 mm) and spectrophotometrically assayed (Perkin Elmer 552S) for drug content according to a second derivative method (Bettinetti et al., 1989). A correction was calculated for the cumulative dilution caused by replacement of the sample with an equal volume of original medium. Each test was repeated four times (coefficient of variation C.V.,1.5%). Dissolution efficiency (D.E.) was calculated from the area under the dissolution curve at time t (measured using the trapezoidal rule) and expressed as a percentage of the area of the rectangle described by 100% dissolution in the same time (Khan, 1975).

Fig. 1. Phase-solubility diagrams of naproxen (NAP) in the presence of chitosan (CS) at low (d) or medium (j) molecular weight in aqueous solution at 25 8C.

3. Results and discussion

3.1. 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 A N 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 stabilizing complexation can be supposed, due to the anionic nature of the drug and the strong positive charge of the polymer at pHs of ,6.5 (Paul and Sharma, 2000). The negative curvature in the line, typical of Type A N diagrams, was probably due to self-association phenomena of chitosan molecules at higher concentrations (Higuchi and Connors, 1965). No attempts were made to calculate the apparent stability constants of such complexes, since the exact drug / polymer stoichiometric ratio cannot be known. However, the different slopes of the initial straight-line portions of the curves, considered indicative of the relative affinity of the drug for each polymer (Najib and Suleiman, 1989), showed the highest solubilizing power of CS-L w , which made it possible to achieve a 17-times increase in drug solubility in the presence of 2% w / v polymer.

3.2. Solid state studies The thermal curves of naproxen, CS-L w , CS-M w and of the different examined binary combinations are collected

in Figs. 2 and 3. The DSC curve of naproxen was typical of a crystalline anhydrous substance, showing a sharp endothermal peak (T onset 5153.460.3 8C, T peak 5 156.760.4 8C, fusion enthalpy 14066 J g 21 , 4 runs), corresponding to the drug melting. The different treatments (kneading, evaporation or grinding) did not produce significant modifications of the drug thermal behavior in comparison with that of the intact NAP. The DSC traces of both CS-L w and CS-M w were typical of amorphous hydrated compounds, showing a broad endothermal effect, ranging between 50 and 130 8C, due to their dehydration. The characteristic thermal profile of the drug was present in physical mixtures with both polymers at all the examined drug–polymer (w / w) ratios, even though a progressive size reduction of its endothermal peak, with a concomitant lowering of the onset temperature, was observed with increasing the carrier content in the mixture. This effect became more marked in coevaporated systems, due to the finest and more homogeneous dispersion of the drug into the polymeric matrix obtained through the solid dispersion preparation. An even more intense reduction of drug fusion enthalpy, which can be considered directly related to the loss of naproxen crystallinity, was observed in kneaded and particularly in coground systems, as a consequence of the sample mechanical treatment. However, the complete disappearance of the drug thermal profile, indicating complete drug amorphization, was observed in all the 10 / 90 (w / w) drug–polymer products. Moreover, on the basis of DSC results, the amorphizing properties of the two polymers towards naproxen can be considered almost equivalent.

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Fig. 2. DSC curves of naproxen (NAP), chitosan at low molecular weight (CS-L w ) and their 5:5 (a), 3:7 (b), or 1:9 (c) (w / w) physical mixtures (P.M.), coevaporated (COE), kneaded (KN) and coground (GR) products.

Fig. 3. DSC curves of naproxen (NAP), chitosan at medium molecular weight (CS-M w ) and their 5:5 (a), 3:7 (b), or 1:9 (c) w / w physical mixtures (P.M.), coevaporated (COE), kneaded (KN) and coground (GR) products.

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X-ray powder diffraction patterns in the 10–50 2u range showed that the typical diffraction peaks of naproxen were still detectable and emerged on the diffuse background of the amorphous additive in the respective physical mixtures with both amorphous polymers, showing a slight progressive decrease of drug crystallinity with increasing carrier amount in the blend. A more evident loss of drug crystallinity was observed in ground mixtures, probably as a consequence of loosening of crystal forces of naproxen finely dispersed within the amorphous polymer. The amorphization phenomenon became gradually more pronounced as a function of the polymer content, up to complete disappearance of naproxen diffraction peaks at 10 / 90 (w / w) drug / carrier combination (as is shown for example in Fig. 4 for the series of drug–CS-L w systems). These results were in agreement with DSC findings and allowed exclusion of a possible effect of drug amorphization due to the thermal energy supplied during the DSC scan, as, on the contrary, we previously found for naproxen ground mixtures with randomly methylated b-cyclodextrin (Mura et al., 2001b). Representative FT-IR spectra of the pure components and the 3:7 (w / w) drug–CS-L w physical and coground

Fig. 4. X-ray powder diffraction patterns of naproxen (a), chitosan at low molecular weight (CS-L w ) (b), and their 5:5 (w / w) physical (c) and co-ground (d) mixture; 3:7 (w / w) physical (e) and coground (f) mixture; 1:9 (w / w) coground mixture (g).

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mixtures in the region of diagnostic value for naproxen characterization are shown in Fig. 5. The spectra of the physical mixtures as well as those of the different examined binary systems did not differ from that of the drug alone in the area of the main naproxen absorption bands, and, in particular, the frequencies of its characteristic quartet of bands in the carbonyl stretching region appeared almost unchanged, indicating the absence of any hydrogen bonding interaction between drug and polymer. The morphology of the naproxen–CS-L w systems prepared by the different methods was investigated by means of SEM analysis (Fig. 6). Naproxen particles appeared as small plate-like crystals (5–10 mm) with smooth surfaces of homogeneous morphology, whereas CS-L w consisted of amorphous particles of rather irregular size and shape. Crystals of naproxen mixed with carrier particles were clearly evident in the 3:7 (w / w) drug–polymer physical mixture, whereas the original morphology of both drug and carrier disappeared in the coevaporated product of the

Fig. 5. FT-IR spectra of chitosan at low molecular weight (CS-L w ), naproxen (NAP), and their 3:7 (w / w) physical (P.M.) and coground (GR) mixtures.

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Fig. 6. SEM micrographs of naproxen (NAP), chitosan at low molecular weight (CS-L w ) and their 3:7 (w / w) physical mixture (P.M.), coevaporated (COE), kneaded (KN) and coground (GR) products. The 10 mm calibration bars are located in the bottom right corner.

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same composition, where it was no longer possible to differentiate the two components. The corresponding kneaded system appeared as a substantially amorphous product where only some small naproxen crystals finely dispersed or adhered on the surface of the larger CS-L w particles were still detectable. Both drug amorphization degree and particle size reduction, produced by the shear and impact stresses during the high-energy cogrinding treatment, were clearly more marked in the coground product.

3.3. Dissolution studies The effects of varying chitosan molecular weight, drug / chitosan (w / w) ratio and preparation method of the drug– polymer mixture on naproxen dissolution rate are shown in Fig. 7 (A and B) and summarized in Table 1, in terms of dissolution efficiency, percent dissolved at 10 min and relative dissolution rate at 5 min in comparison to the drug alone. The different treatments (kneading, evaporation or grinding) of pure drug did not produce important variations of its dissolution properties, and the various dissolution curves were practically superimposable. It is evident that the presence of the polymer positively influenced the naproxen dissolution properties and that the extent of this effect depended on all the investigated variables. In particular, as for the influence of the polymer molecular weight, CS-L w was more effective than CS-M w in all the examined combinations, and the difference in performance between the two polymers became more marked in mixtures at higher carrier content. This behavior can be reasonably explained on the basis of both the greater viscosity of the aqueous solutions of the polymer with higher molecular weight and the better water solubility of the low-molecular weight one. However, independent of the polymer type, all drug dissolution parameters progressively improved with increasing the polymer proportion in the mixture and reached the highest values at the 1:9 (w / w) drug / polymer ratio. The slight positive effect on drug dissolution rate shown by simple physical mixtures could be due to a reduction of the interfacial tension between the hydrophobic drug particles and the dissolution medium, owing to the presence of the hydrophilic polymer, as well as to a local solubilizing effect acting during the early stages of the dissolution process in the microenvironment surrounding the drug particles (Najib and Suleiman, 1989). The evident improvement obtained with coevaporated products was a consequence of the closer contact between the components and the better dispersion of the drug into the hydrophilic carrier obtained through the coprecipitation technique. Finally, the best performance shown by kneaded and even more so by coground mixtures could be attributed, in addition to the very intimate physical contact between naproxen and hydrophilic carrier and to the particle size reduction brought about by the mechanical treatment, also to a decrease in drug crys-

Fig. 7. A) Relative increase of dissolution efficiency (D.E.) for 3:7 (w / w) physical mixtures (P.M.), coevaporated (COE), kneaded (KN) and coground (GR) products of naproxen with chitosan at low (CS-L w ) or medium (CS-M w ) molecular weight; B) Dissolution curves of naproxen (NAP) alone (3) and from 5:5 (j, h), 3:7 (d, s), and 1:9 (m, n) (w / w) coground products with chitosan at low (open symbols) or medium (closed symbols) molecular weight.

tallinity during cogrinding with the amorphous carrier (Sawayanagi et al., 1982, 1983; Acarturk et al., 1993a). These findings were consistent with the results of solid state studies, confirming that the best dissolution performance of coground products is mainly ascribable to the almost complete drug amorphization achieved in these systems. As for the final aim of preparing naproxen fast-dissolving tablets, the 1:9 (w / w) drug / polymer coground product, even though it was the most effective, was discarded since it was considered unsuited to yielding solid oral dosage forms of appropriate dimensions. On the contrary, the 3:7 (w / w) coground product was able to give directly com-

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Table 1 Dissolution efficiency (D.E.) at 60 min, percent dissolved (PD) at 10 min, and relative dissolution rate at 5 min in comparison with drug alone (r.d.r.) of naproxen from systems with low (CS-L w ) or medium (CS-M w ) chitosan molecular weight a Type of CS

Drug / CS w / w ratio

Prepar. techn.

D.E.60

PD10

r.d.r.

CS-L w CS-M w CS-L w CS-M w CS-L w CS-M w CS-L w CS-M w CS-L w CS-M w CS-L w CS-M w CS-L w CS-M w CS-L w CS-M w CS-L w CS-M w CS-L w CS-M w

5:5 5:5 5:5 5:5 5:5 5:5 5:5 5:5 3:7 3:7 3:7 3:7 3:7 3:7 3:7 3:7 1:9 1:9 1:9 1:9

phys. mix. phys. mix. coevap. coevap. kneading kneading cogrinding cogrinding phys. mix. phys. mix. coevap. coevap. kneading kneading cogrinding cogrinding kneading kneading cogrinding cogrinding

8.2 7.8 14.2 10.3 15.6 12.1 19.3 14.7 14.3 9.2 18.1 13.2 21.3 17.0 32.1 25.8 34.2 23.1 47.6 29.7

7.7 7.2 14.0 9.3 15.0 11.4 18.2 14.4 13.0 8.5 17.0 12.5 20.0 16.5 28.4 23.2 32.7 22.8 45.5 26.1

1.4 1.3 3.1 1.9 3.6 2.7 3.6 3.9 3.0 1.8 3.5 2.9 4.6 3.4 6.7 5.0 7.0 4.7 11.2 6.1

a

Naproxen alone: D.E.60, 6.2; PD10, 5.1.

pressed tablets, containing the proper dosage of the drug (200 mg), whose dissolution behavior was practically superimposable on that of the starting coground powder. The drug dissolution profiles from these tablets appeared unchanged after 4 weeks of storage at room temperature in closed glass containers. In conclusion, this study showed that chitosan can favorably affect the naproxen dissolution properties, yielding a D.E. (dissolution efficiency) improvement of up to about 8 times in 1:9 (w / w) drug–CS-L w coground products. This effect was influenced by the polymer molecular weight but principally depended on both the polymer content in the mixture and the system preparation method. The amorphizing effect of chitosan appeared as the main driving force for the enhanced drug dissolution, even though other factors such as improved wettability, reduced aggregation phenomena, increased effective surface area and local solubilization effect played a contribution role. The most effective preparation method was the cogrinding technique, which not only showed the best dissolution performance but also was the easiest for possible scale-up and industrial applications, without requiring addition of solvents or high temperature for its preparation. Moreover, the possibility of obtaining tablets by direct compression and the antiulcer and antiacid properties of chitosan make the use of this polymer particularly advisable for developing a fast-release solid dosage form for oral naproxen administration.

Acknowledgements Financial support from the Italian MURST is gratefully acknowledged.

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