Study of Different Chitosan/Sodium Carboxymethyl Cellulose Proportions in the Development of Polyelectrolyte Complexes for the Sustained Release of Clarithromycin from Matrix Tablets

This study investigated the combination of different proportions of cationic chitosan and anionic carboxymethyl cellulose (CMC) for the development of polyelectrolyte complexes to be used as a carrier in a sustained-release system. Analysis via scanning electron microscopy (SEM) Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD) confirmed ionic interactions occur between the chitosan and carboxymethyl cellulose chains, which increases drug entrapment. The results of the dissolution study in acetate buffer (pH 4.2) showed significant increases in the kinetic profiles of clarithromycin for low proportions of chitosan/carboxymethyl cellulose tablets, while the tablets containing only chitosan had high relaxation of chitosan chains and disintegrated rapidly. The Korsmeyer–Peppas kinetic model for the different interpolymer complexes demonstrated that the clarithromycin transport mechanism was controlled by Fickian diffusion. These results suggest that the matrix tablets with different proportions of chitosan/carboxymethyl cellulose enhanced the ionic interaction and enabled the prolonged release of clarithromycin.


Introduction
Sustained-release systems prolong the time taken for a drug to reach maximum plasma concentrations, allowing for a reduced frequency of dosage, and they are associated with decreased adverse side effects and good safety profiles. Matrix tablets have been widely used by the pharmaceutical industry for drug delivery mainly due to their simple preparation process and low production costs.
Since the development of polyelectrolyte complexes (PECs), there has been growing interest in their use in the control and modulation of drug release from hydrogel matrices. Electrostatic attractions between the ionized amino (NH 3 + ) group of chitosan and the carboxylic (COO − ) groups of the anionic polymer are the main interactions in the formation of polyelectrolyte hydrogels with a high swelling ratio in the dissolution medium [1,2].
Chitosan (CS) is the most widely used cationic polymer; it has good biocompatibility and is nontoxic and biodegradable [3]. Its molecular weight control and degree of deacetylation also allow its use in PECs for the sustained release of drugs [4,5]. boxymethyl cellulose, whereby the drug and polymers had previously been sieved through a 0.45 mm mesh.
The hydrogel tablets were produced by sieving 1000 mg of clarithromycin and different proportions of chitosan through a 0.45 mm mesh and mixing these materials in a ceramic bowl using a polymeric spatula, which were then directly compressed on a single punch tableting machine (Bonal type A; Barcelona, Spain) using a 6 mm diameter punch. Tablet weights were adjusted to 50 mg and 40-80 N of hardness.
PEC tablets of clarithromycin were prepared by mixing 1000 mg of the active ingredient with the different proportions of chitosan and carboxymethyl cellulose in a ceramic bowl, whereby the mixed components had first been sieved through a 0.45 mm mesh. The PEC tablets were prepared using a single punch tableting machine (Bonal type A; Barcelona, Spain) with a 6 mm diameter punch. Tablet weights were adjusted to 50 mg and 40-80 N of hardness.

Scanning Electron Microscopy (SEM) Studies
The samples were mounted on an aluminum sample mount. After coating with a thin layer of gold-palladium, the hydrogel samples were analyzed via SEM using a Jeol ® 6400. All micrographs were the product of secondary electron imaging used for surface morphology identification at different magnifications and an accelerating voltage of 20 kV.

Fourier Transform Infrared Spectroscopy (FTIR)
The different samples were prepared by pressing 2 mg of powder with 200 mg of potassium bromide at 10 T (Carver hydraulic press Model C-3912; Carver Inc., Wabash, IN, USA). Absorbance spectra were measured using a Fourier transform infrared spectroscopy (FTIR) spectrophotometer (Perkin Elmer 1600 FTIR spectrophotometer; Perkin Elmer Inc., Waltham, MA, USA). The spectra were obtained at a 2 cm −1 resolution with an average of 32 scans, with air as background. The infrared region was analyzed in the range of 4000-500 cm −1 .

Differential Scanning Calorimetry (DSC)
DSC thermograms were obtained using an automatic thermal analyzer system (Mettler Toledo TC 15, TA controller). The temperature was calibrated using an indium reference standard for calibration (transition point 156.60 XC). All dried samples were accurately weighed into aluminum pans, hermetically sealed with aluminum lids, and heated from 25 to 250 • C at a rate of 10 • C/min under constant purging with dry nitrogen at 30 mL/min. An empty pan was sealed and used as a reference with the same sample conditions.

Powder X-ray Diffraction (PXRD)
PXRD patterns were recorded on a Philips X'Pert-MPD X-ray diffractometer (Malvern Panalytical; Almelo, Netherlands) in the CAI (Centro de Asistencia a la Investigación, Universidad Complutense, Madrid, Spain). The samples were radiated using a monochromatized CuKα radiation (λ = 1.542 Å) then analyzed in the range of 5-50 • (2θ) at a step size of 0.04 • and a time of 1 s per step. The voltage was 30 kV with a current of 30 mA.
The evaluation was conducted in a dissolution bath (Vankel ® VK 700). A USP Apparatus 2 (paddle) was set up at 37 • C, with a rotational speed of 50 rpm and 500 mL of 0.1 N HCl or acetate buffer (pH 4.2). The pH 4.2 dissolution test method for clarithromycin is  A sample of 5 mL was  removed at time points of 15, 30, 45, 60, 90, 120, 180, 240, 300, 360, 420, and 480 min and filtered through a 0.45 µm filter (Acrodisc ® ; New York, NY, USA).
The quantity of clarithromycin was determined using the HPLC method, consisting of a UV detector (Jasco UV-1575 Intelligent UV/VIS Detector), a pump (Jasco PU-1580 Intelligent HPLC pump), a degasser (Jasco DG-2080-53), and an automatic injector (Gilson ® 231 XL Sampling Injector). The HPLC method was developed from previous studies with the following changes [11]: The selected wavelength was 210 nm. A C18 column (4.6 mm × 15 cm) was used with a particle size of 5 µm, and the temperature was maintained constant at approximately 60 • C (Pickering Laboratories CHX700 Column Temperature Controller). The flow rate was 1.0 mL per minute. The mobile phase consisted of a mixture of methanol and 0.079 M monobasic potassium phosphate (65:35, v/v), and the pH was adjusted to 4.2 with phosphoric acid. The cumulative amount of clarithromycin released from the system was determined from the appropriated calibration curve. The determination at each time point was performed in triplicate, and the error bars on the graphs represented the standard deviation.
To investigate the effect of polyelectrolyte complex formation on the release of clarithromycin more precisely, the results were analyzed according to the Korsmeyer-Peppas Equation for M t /M ∞ < 0.6, which can be expressed as the following Equation [17]: where M t /M ∞ is the fractional drug released at time t (h) from the total amount released M ∞ . K d (min −1 ) is the kinetic dissolution constant and n is a diffusional exponent characteristic of the release as a function of time t. For drug release from tablets, which contains hydrophilic polymers, the exponent n is the diffusional constant that characterizes the drug release transport mechanism. When n = 0.5, a Fickian diffusion process was observed, where drug diffusion through the polymeric matrix is the dominant release mechanism.
When n values are between 0.5 < n < 1, drug diffusion occurs via anomalous transport (non-Fickian). In anomalous diffusion, it is assumed that the mechanism of CL release is a combination of swelling, erosion, and diffusion. When n = 1, Case II transport or zeroorder release kinetics could be observed. An n value of about 1.0 indicates that polymer relaxation, polymer dissolution, or tablet erosion are the dominant mechanisms [16,18]. For the mathematical evaluations, we characterized drug release kinetics by fitting standard release to zero-order, Higuchi, and first-order models [19,20].
where M t /M ∞ is the fractional drug released at time t (min) from the total amount released M ∞ . K H , K 0 , and K 1 (min −1 ) are the kinetic dissolution constants for zero-order, Higuchi, and first-order kinetic models, respectively, which characterize release as a function of time t. The high R 2 values in the zero-order model indicate that polymer relaxation or tablet erosion is the dominant mechanism and is related to Case II transport for the Korsmeyer-Peppas Equation.
The high R 2 values in the Higuchi model indicate the better fit of release data for diffusion kinetics, which are related to a Fickian diffusion process in the Korsmeyer-Peppas equation.
The high R 2 values in the first-order model indicated swelling and erosion phenomena and could be related to non-Fickian (anomalous transport) for the Korsmeyer-Peppas equation. To study the influence of the proportion of CS within the interpolymer network structure, micrographs of these formulations were taken at a magnification of 80×.

Peppas Equation.
The high R 2 values in the Higuchi model indicate the better fit of release data for diffusion kinetics, which are related to a Fickian diffusion process in the Korsmeyer-Peppas equation.
The high R 2 values in the first-order model indicated swelling and erosion phenomena and could be related to non-Fickian (anomalous transport) for the Korsmeyer-Peppas equation. To study the influence of the proportion of CS within the interpolymer network structure, micrographs of these formulations were taken at a magnification of 80×.  Figure 1B). The high proportion of carboxymethyl cellulose produces a dense interpolymer structure which hinders the presence of connections (channels) with the interior of the system. Highly porous structures (150-200 μm) forming connections (channels) with the interior of the system were observed in both formulations. Similar highly porous structures have been reported before for a chitosan interpolymer complex of matrix tablets, whose characteristics are related to the gel layer formed by the polymer relaxation with the absorption of the dissolution medium [21].

Scanning Electron Microscopy (SEM) Characterization
These differences in the surfaces can be explained by the slower repulsion between ionized chains due to a greater number of cationic moieties in formulations that have high proportions of chitosan. The presence of more anionic chains of carboxymethyl cellulose favored the formation of interpolymer complexes with fewer pores on the surface of the matrix tablets [22].  After 1 h in the dissolution medium (acetate buffer, pH 4.2), the PEC tablets CL:(CS:CMC) 80:(18:2) demonstrated rapid swelling and disintegration, and these characteristics made it difficult to evaluate the changes in the surface of the tablets during dissolution studies ( Figure 1A). The PEC tablets with a high proportion of carboxymethyl cellulose, CL:(CS:CMC) 40:(30:30), showed a smooth structure, with smaller pores observed on the surface ( Figure 1B). The high proportion of carboxymethyl cellulose produces a dense interpolymer structure which hinders the presence of connections (channels) with the interior of the system. Highly porous structures (150-200 µm) forming connections (channels) with the interior of the system were observed in both formulations. Similar highly porous structures have been reported before for a chitosan interpolymer complex of matrix tablets, whose characteristics are related to the gel layer formed by the polymer relaxation with the absorption of the dissolution medium [21].

FTIR Spectroscopy Analysis
These differences in the surfaces can be explained by the slower repulsion between ionized chains due to a greater number of cationic moieties in formulations that have high proportions of chitosan. The presence of more anionic chains of carboxymethyl cellulose favored the formation of interpolymer complexes with fewer pores on the surface of the matrix tablets [22].   respectively [2,5,25]. The CMC spectrum also presents a band at 3315 cm −1 corresponding to O-H stretching vibrations (Figure 2A), while the band at 2918 cm −1 is due to C-H stretching vibrations of the CH 2 groups. The bands at 1620 and 1372 cm −1 correspond to the stretching vibrations of carboxylic and C-O groups [9,25]. The physical mixture CL:(CS:CMC) 80:(18:2) showed a broad band characteristic of O-H at 3394 cm −1 , and the broad band between 2950 and 2800 cm −1 is due to alkyl-CH 3 substitution bands (Figure 2A). The bands at 1733 and 1620 cm −1 correspond to C=O stretching vibrations in the lactone ring of CL, and the bands at 1457 and 1376 cm −1 correspond to the stretching vibrations of the C-CH 3 and C-O bands.

FTIR Spectroscopy Analysis
The PEC CS:CMC (18:2) without CL, shown in Figure 2A, does not present bands corresponding to the stretching vibration in the lactone ring of CL and only presents bands at 1620 and 1372 cm −1 , which correspond to the stretching vibrations of carboxylic and C-O groups [25].
In the PEC tablets of CL:(CS:CMC) 80:(18:2) and 40:(30:30) at the initial time (t = 0), the CL spectra, shown in Figure 2B, showed no changes in vibrations bands, indicating that there are no interactions between the CL and the polymeric complexes during the compression process. Similar results have been observed between PEC tablets and other active ingredients with carboxylic groups, such as azithromycin [24].  Figure 2B) [5,25]. The absence of new bands in mixtures, in contrast to the individual polymers, confirm that no chemical reactions occurred between both polymers. The intensity of peaks could be correlated to the intensity of ionic interactions. In the dissolution medium, an interaction between the CS/CMC chains was produced, determining the formation of a stable ionic complex [26]. The polymer interactions indicated the formation of PEC between CS/CMC [2,8].  Figure 3B.

DSC Studies
The DSC of the CL raw material corresponds to the CL polymorph II ( Figure 3A), characterized by an endothermic peak at 227.47 • C [27,28]. The CS exhibited ( Figure 3A) an endothermic peak at 162.27 • C [8], and the CMC polymer at 191.46 • C [29]. The glass transition temperature (T g ) for CS was observed between 100 and 110 • C [8,27]. T g of CMC was not observed in the DSC curve due to the presence of intermolecular bonds in the cellulose chains that hindered its determination [29]. The physical mixture PM-CL:(CS:CMC) 80:(18:2) showed two endothermic peaks at 164.62 and 191.69 • C corresponding to CS and CMC, respectively ( Figure 3A), and the endothermic peak at 228.13 • C corresponds to CL raw material. This physical mixture showed a T g value for CS between 100 and 110 • C.
The thermograms of PEC tablets CL:(CS:CMC) 80:(18:2) and 40: (30:30) showed no significant differences in the melting temperatures of both polymers and CL, indicating that there are no drug/polymer interactions during the preparation process of PEC tablets [22]. The slight decrease in the CL endothermic peak and a small endothermic peak of CMC in CL:(CS:CMC) 80:(18:2) tablets compared to the physical mixture PM-CL:(CS:CMC) 80:(18:2) have been attributed to the formation of a PEC during tablet compression, indicating an entrapment of CL in the PEC [30]. The CL:(CS:CMC) 40:(30:30) showed a significant decrease corresponding to the CS melting peak due to the reduction of the polymer crystallinity after tablet compression with higher proportions of CS and CMC. These findings are consistent with the results observed in the FTIR studies.  After 1 h in the dissolution medium (acetate buffer, pH 4.2), the PEC tablets with low CS:CMC proportions, CL:(CS:CMC) 80:(18:2), showed a slight shift in the endothermic peaks of CS and CMC at 158.92 and 188.61 °C, respectively. The decrease in the melting peak of CS was due to CS/CMC interaction during the swelling process in the dissolution medium [31]. However, higher CS/CMC proportions in the complex CL:(CS:CMC) 40:(30:30) presented broad endothermic peaks of CMC and CL and a non-crystalline structure of CS owing to the formation of a polyelectrolyte complex in the dissolution medium [31]. Similar interpolymeric structures with CS have been previously observed [19]. After 1 h in the dissolution medium (acetate buffer, pH 4.2), the PEC tablets with low CS:CMC proportions, CL:(CS:CMC) 80:(18:2), showed a slight shift in the endothermic peaks of CS and CMC at 158.92 and 188.61 • C, respectively. The decrease in the melting peak of CS was due to CS/CMC interaction during the swelling process in the dissolution medium [31]. However, higher CS/CMC proportions in the complex CL:(CS:CMC) 40:(30:30) presented broad endothermic peaks of CMC and CL and a noncrystalline structure of CS owing to the formation of a polyelectrolyte complex in the dissolution medium [31]. Similar interpolymeric structures with CS have been previously observed [19].

Powder X-ray Diffraction (PXRD)
The X-ray diffraction patterns in Figure 4A indicate a crystalline structure for CL raw material, with representative peaks at 8.54, 9.58, 10.83, and 11.56 • 2θ. This crystalline structure corresponds to the CL form II [27]. The CS showed a broad semi-crystalline halo between 18 and 25 • 2θ [32,33], while the CMC showed a small semi-crystalline halo between 18 and 26.5 • 2θ, characteristic of cellulosic polymers [34]. The physical mixture PM-CL:(CS:CMC) 80:(18:2) shows peaks of CL raw material and a broad semi-crystalline halo between 18.5 and 26 • C corresponding to CS and CMC polymers ( Figure 4A).

In Vitro Drug Release
The dissolution of CL from CS hydrogel tablets and different PEC CS/CMC co plexes were studied in two different systems for representing gastric pH: 0.1 N HCl (si ulated gastric fluid) and acetate buffer (pH 4.2).
Previous studies indicated that the highest solubility values of CL are obtained a pH lower than 3.0 [15]. For this reason, we selected CS/CMC complexes with high ratios for dissolution studies in 0.1 N HCl, namely CL:(CS) 80: (20), CL:(CS:CMC) 40:(54 The X-ray spectra of the PEC tablets CL:(CS:CMC) 80:(18:2) and 40:(30:30) showed significant decreases in the intensity of the diffraction peaks of CL compared to the physical mixtures ( Figure 4B). These results are due to entrapment of CL within the CS/CMC interpolymer complexes during the compression process [22]. The distribution of drugs within the PEC tablets induces a favorable energy effect compared to the physical mixture. In this approach, drug-chitosan interactions are able to control drug dissolution [32]. The lower intensity of the semi-crystalline halo of CS also indicates the formation of an ionic interaction between the cationic amino groups and the anionic carboxylic groups [5,33]. These results confirmed the formation of PEC observed in the DSC studies.
After 1 h in the dissolution medium (acetate buffer, pH 4.2), the PEC tablets CL:(CS:CMC) 80:(18:2) showed a diffraction peak at 10.06 • 2θ due to the formation of a CL hydrate form within the PEC [27]. The CS/CMC semi-crystalline halo could not be observed in the X-ray spectra of the PEC tablets CL:(CS:CMC) 80: (18:2). However, the light semi-crystalline halo of CS between 18 and 26 • 2θ observed in PEC tablets CL:(CS: CMC) 40:(30:30) indicates the possible formation of a hydrogel structure of CS around the interpolymer complexes during dissolution. Possibly, in these PEC tablets, the high proportion of CS used in the formation of the ionic double layer may mean that the CS chains are not available to form a hydrogel structure around the CS/CMC interpolymer complexes. Similar decreases in CS crystallinity have previously been observed due to the formation of PEC in the dissolution medium [32].

In Vitro Drug Release
The dissolution of CL from CS hydrogel tablets and different PEC CS/CMC complexes were studied in two different systems for representing gastric pH: 0.1 N HCl (simulated gastric fluid) and acetate buffer (pH 4.2).
The treatment of CL with omeprazole increases gastric pH to over 4.0 during 24 h [15]. The analysis of different CS/CMC complexes allows us to show different profiles of sustained CL release at pH 4.2. Figure 5 shows the CL release profiles obtained at pH 4.2 from hydrogel tablets of CL:(CS) 80: (20) and 40:(60) and different PEC tablets of CL:(CS:CMC) 80:(18:2), 80:(10:10), 40:(54:6), and 40: (30:30). The hydrogel tablets present a gel structure with a high dissolution percentage at 30 min (83.92 ± 4.62%) for CL:(CS) 80: (20), whereas the high CS proportion of CL:(CS) 40:(60) showed percentages of 56.12 ± 3.67% at 30 min. The burst release of the hydrogel structure CL:(CS) 80: (20) is attributed to the partially protonated amine groups of the CS chains in the dissolution medium (acetate buffer pH 4.2). The electrostatic repulsion of the cationic groups and high matrix swelling allow uptake in the dissolution medium [1]. This process results in fast-disintegrating hydrogel tablets that favor rapid drug release [4]. The kinetic parameters of these hydrogel tablets could not be evaluated due to their fast dissolution. of the hydrogel structure CL:(CS) 80: (20) is attributed to the partially protonated groups of the CS chains in the dissolution medium (acetate buffer pH 4.2). The e static repulsion of the cationic groups and high matrix swelling allow uptake in t solution medium [1]. This process results in fast-disintegrating hydrogel tablets tha rapid drug release [4]. The kinetic parameters of these hydrogel tablets could not b uated due to their fast dissolution. The PEC tablets with high proportions of carboxymethyl cellulose, CL:(CS 80:(10:10) and 40: (30:30), showed a decrease in dissolution percentages at 8 h with of 55.08 ± 1.46 and 50.07 ± 3.62%, respectively ( Figure 5). The stronger interaction be CS/CMC resulted in low polymer swelling due to a greater attractive force betwe polymer chains [5,33]. These sustained the release of CL for 6-8 h at pH 4.2 and suitable alternative for gastric treatment of Helicobacter pylori [11].
To evaluate the influence of CL within the PEC tablets, drug release kinetic determined for the different PEC tablets. Figure 6 Figure 5). The stronger interaction between CS/CMC resulted in low polymer swelling due to a greater attractive force between the polymer chains [5,33]. These sustained the release of CL for 6-8 h at pH 4.2 and are a suitable alternative for gastric treatment of Helicobacter pylori [11].
The Korsmeyer-Peppas kinetic model (Table 1) exhibits anomalous (non-Fickian) dissolution with n values close to 0.86, suggesting that the rate of water uptake into the matrix and CL release were controlled by diffusion through the hydrogel structure and swelling/erosion processes [16]. The absence of burst effects in the CS/CMC complexes justified the efficient interpenetration of CL within the network [35].  The Korsmeyer-Peppas kinetic model (Table 1) exhibits anomalous (non-Fickian) d solution with n values close to 0.86, suggesting that the rate of water uptake into the matr and CL release were controlled by diffusion through the hydrogel structure and swe ing/erosion processes [16]. The absence of burst effects in the CS/CMC complexes justifie the efficient interpenetration of CL within the network [35].    Table 2. The highest value of K 0 were found in CL:(CS:CMC) 80:(18:2) and 80:(54:6) with values of 0.0019 and 0.0015 min −1 , respectively. These PEC tablets presented the formation of CS/CMC polyelectrolyte complexes that were surrounded by a large hydrogel layer formed by CS chains. These results indicate that CL release is controlled by rapid swelling and erosion processes from the CS/CMC hydrogel. These PECs showed kinetics of CL dissolution that fit Case II transport rather than non-Fickian transport ( Table 1). The high n values in the Korsmeyer-Peppas equation indicate that in the dissolution medium, expansion of the CS chains is favored due to the repulsion between cationic charges, producing a hydrogel layer around the interpolymer complex [9]. Previous studies showed that the formation of a spherical hydrogel structure with n values > 0. 85 was also possible for Case II transport using the Korsmeyer-Peppas Equation [6,7]. The PEC tablets with high CS/CMC interactions, CL:(CS:CMC) 80:(10:10) and 40:(30:30), presented lower R 2 values in the zero-order and Higuchi kinetic models ( Figure 6 and Table 2). Previous studies showed that the optimal ratio of CS:CMC in the complex layer is 1:1 for sustained release [9]. Lower K 0 values of CL:(CS:CMC) 80:(10:10) and 40: (30:30) were due to the higher CS/CMC interactions. The CL:(CS:CMC) 40: (30:30) showed the lowest values of K 0 (0.0010 min −1 ) and K H (0.0254 min −1 ), which is due to the dense layer of polyelectrolyte between the cationic and anionic charged groups. These results correlate with the lowest n values (from 0.8611 and 0.8108) and fit for non-Fickian transport according to the Korsmeyer-Peppas equation (Table 1).
In CL:(CS:CMC) 40: (30:30), it is possible that the CS cationic groups are employed in the layer polyelectrolyte and that no free CS cationic groups are available to produce a hydrogel layer with cationic charges around the interpolymer complex [16]. Under these conditions, the entry of water will be delayed and the CL kinetics diminished. A similar delay in dissolution profiles was observed in PEC with CS as cationic polymer, with different proportions of xanthan gum or carboxymethyl starch as anionic polymers [8,33,35].

Conclusions
CS/CMC interpolymer complexes are good drug carriers for developing systems whereby drug release can be sustained for 8 h. During the compression process, intermolecular CS/CMC ionic interactions were observed via SEM, FTIR, DSC, and PXRD. According to SEM morphological studies, the different PEC tablets with CS/CMC exhibited changes in the density of their porous structures, which are related to the gel layer formed in the dissolution medium. The decrease in the crystallinity of CL was indicative of efficient interpenetration of CL within the interpolymer network. The FTIR studies of the PEC tablets in the dissolution medium (acetate buffer pH 4.2) showed a decrease in the amide groups of CS, which is related to the formation of the PEC.
Drug dissolution studies in acetate buffer (acetate buffer pH 4.2) indicate that the intermolecular interactions between CS/CMC play an important role in clarithromycin release kinetics. Specifically, the low CS/CMC interaction in CL:(CS:CMC) 80:(18:2) produced a significant expansion of the interpolymer chains with a kinetic model, indicating fast release, whereas high CS:CMC ratios in CL:(CS:CMC) 40:(30:30) resulted in a dense structure of PEC with a kinetic model that could be attributed to more sustained release and non-Fickian transport. These PEC tablets have great potential for use as a carrier in drug delivery systems.