Synthesis and application of photo-active carboxymethyl cellulose ...

Reactive and Functional Polymers 102 (2016) 137–146

Contents lists available at ScienceDirect

Reactive and Functional Polymers journal homepage: www.elsevier.com/locate/react

Synthesis and application of photo-active carboxymethyl cellulose derivatives M. Monier a,b,⁎, D.A. Abdel-Latif a,b, H.F. Ji c a b c

Chemistry Department, Deanery of Academic Services, Taibah University, Yanbu Branch, Yanbu El-Bahr, KSA Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt Department of Chemistry, Drexel University, Philadelphia, PA, USA

a r t i c l e

i n f o

Article history: Received 22 December 2015 Received in revised form 11 March 2016 Accepted 12 March 2016 Available online 18 March 2016 Keywords: Carboxymethyl cellulose Cinnamate Photo-crosslinking Cyclo-addition

a b s t r a c t In this work, the polysaccharide carboxymethyl cellulose (CMC) was first activated via periodate oxidation then modified by insertion of photo-active cinnamic acid hydrazide moieties to finally produce the photocrosslinkable CMC-CM with various extents of functionalizations. The chemical structures of the manufactured polymeric materials were entirely investigated utilizing FTIR, 1H, 13C NMR, and UV–vis spectra. Upon irradiation in UV light, the progress and kinetics of the cross-linking were detected using UV–vis spectra. Moreover, the crystallinity changes before and after chemical modification and subsequent UV irradiation were examined by XRD spectra. Also, the obtained hydrogels with various cross-linking densities were freeze dried to visualize the morphological changes using SEM. In addition, the rheological experiments indicated the improvement of the hydrogel mechanical properties by increasing both UV irradiation time and degree of cinnamate functionalization. The obtained hydrogel exhibited good swelling, gelation and biodegradation properties, which indicate a promising potential in different biomedical applications. © 2016 Elsevier B.V. All rights reserved.

1. Introduction Carboxymethyl cellulose (CMC) is regarded as one of the most commonly used polysaccharide derivatives. As a result of its water solubility, high availability, biocompatibility in addition to non-toxicity, CMC had been widely employed in various industrial applications such as pharmaceutics, cosmetics and textiles [1–3]. Moreover, the biodegradability of CMC enhanced its utility in various biotechnological applications such as drug delivery systems, enzyme immobilization and tissue engineering [4–7]. In most of these biomedical and pharmaceutical applications, CMC had to be cross-linked to form a three dimensional polymeric hydrophilic network, which is able to absorb large amounts of water and swells until reaching equilibrium between the thermodynamic swelling forces and cross-linking elastic retractive force. At this equilibrium point, a polymer–water state called a hydrogel is obtained [8–10]. Many types of cross-linking agents had been utilized for either ionic or covalent cross-linking of CMC such as Al3+ ions [11,12], 1,4-butanediol diglycidyl ether [13], polyethylene glycol diglycidyl ether (PEGDE) [14], and dicarboxylic acids [15] in addition to epichlorohydrin (ECH), which is a common CMC cross-linking agent due to the high tendency to form ether linkage with the \\OH groups [16–18]. All the aforementioned ⁎ Corresponding author at: Chemistry Department, Deanery of Academic Services, Taibah University, Yanbu Branch, Yanbu El-Bahr, Saudi Arabia. E-mail address: [email protected] (M. Monier).

http://dx.doi.org/10.1016/j.reactfunctpolym.2016.03.013 1381-5148/© 2016 Elsevier B.V. All rights reserved.

cross-linking agents were efficiently employed in manufacturing CMC based hydrogels for various biomedical and environmental applications. However, formation of carcinogenic and even toxic byproducts during the biodegradation process is considered a serious drawback and limits the implementation of these hydrogels in some pharmaceutical applications [14]. For these reasons, various attempts had been devoted to the development of novel cross-linking techniques that minimize the formation of these undesirable byproducts. Among these techniques, photoinduced cross-linking is considered one of the most efficient methods employed in safe cross-linking and gelation. The convenient photocrosslinking process includes the functionalization of the main polymeric chain with polymerizable vinyl moieties such as maleic anhydride or acrylate derivatives. Then, the cross-linking reaction will be performed by irradiation to UV or visible light in the presence of a suitable photoinitiator [19]. Although there are obviously better results obtained from this technique compared to the ordinary chemical cross-linking methods, the difficulty of removing the unreacted photo-initiator in addition to trace initiator byproducts could still restrict the employment of these hydrogels in some applications [20,21]. In this work we describe an efficient method for the synthesis of a novel modified photo-crosslinkable CMC. In the beginning, CMC was oxidized with sodium periodate, which selectively cleaves the C2\\C3 bond and form modified dialdehyde CMC [22]. Then, the resulting aldehyde groups were allowed to react with cinnamic acid hydrazide in order to introduce the photo-active cinnamate moieties onto the CMC backbone. The gelation of the obtained cinnamate modified CMC

138

M. Monier et al. / Reactive and Functional Polymers 102 (2016) 137–146

Scheme 1. Synthesis and photo-crosslinking of CMC-CM.

(CMC-CM) was performed upon irradiation in the UV region as a result of the dimerization of the active cinnamate units via [2π + 2π] cyclo-addition reaction [23]. The obtained polymeric materials were extensively characterized using Fourier transform infrared (FTIR), nuclear magnetic resonance (1H and 13C-NMR), wide angle X-ray diffraction (XRD) spectra in addition to a scanning electron microscope (SEM). 2. Materials and methods 2.1. Materials Carboxymethyl cellulose (CMC) sodium salt (degree of substitution 2.34, and Mw = 7.6 × 105 mol g−1) was obtained from Sigma-Aldrich (USA), sodium periodate, hydrazine hydrate, cinnamoyl chloride, cellulase (chromatographically purified, T. Reese) and ephedrine hydrochloride were all supplied from Alfa Aesar (USA). The other chemicals were of analytical grade and used as supplied without any further treatments. 2.2. Periodate oxidation of CMC The modified dialdehyde CMC (DCMC) was prepared according to the procedures proposed by Li et al. [1]. Three different samples with different oxidation extents were prepared as explained in the following; in three 250 mL conical flasks 100 mL 5% (w/v) aqueous CMC solutions were prepared, the pH 3 was adjusted using acetic acid then the flasks were placed in a shaker fitted with a water bath adjusted at 35 °C. To each flask we added 10 mL aqueous sodium metaperiodate solution with concentrations of 5.0 mM, 7.5 mM and 10 mM and the reaction continued for 4 h. The oxidized DCMC samples with different aldehyde contents were then precipitated by adding excess acetone then filtered and washed with water/ethanol and finally with dimethyl formamide (DMF).

2.3. Determination of aldehyde content For evaluation of the extent of periodate oxidation, the formed aldehyde groups were estimated by turning it into oxime groups through reaction with hydroxyl amine hydrochloride and titration of the released HCl against standardized NaOH solution [24]. In details, 25 mL 2% (w/v) aqueous DCMC solution was adjusted to pH 5 and allowed to react with 20 mL 0.75 M aqueous NH2OH·HCl solution for 4 h at 40 °C. The released HCl was then estimated by titration against 0.1 M NaOH. Another blank sample was prepared and treated in the same manner but using CMC. Eq. (1) was employed for determination of the aldehyde content (Ald%).

Ald% ¼

M NaOH ðV C −V b Þ m=211

ð1Þ

where MNaOH is the molar concentration of NaOH solution (0.1 M), VC is the consumed volume of NaOH in case of DCMC samples, Vb is the volume of consumed NaOH for the blank CMC and m is the weight of the polymeric samples. The obtained oxidized CMC samples with aldehyde contents 23%, 47% and 56% are named DCMC1, DCMC2 and DCMC3 respectively.

Table 1 Elemental analysis of modified and unmodified CMC samples. Sample

C (%)

H (%)

N (%)

DS (mmol/g)

CMC CMC-CM1 CMC-CM2 CMC-CM3

42.5 48.3 52.3 57.6

5.6 5.5 5.4 5.3

0.003 3.4 5.8 9.0

– 1.2 2.1 3.2


Fig. 1. FTIR spectra of (a) CMC, (b) DCMC and (b) CMC-CM2.

Fig. 2. 1H NMR spectra of (a) CMC, (b) DCMC and (b) CMC-CM2 in D2O as solvent.

139

140


2.4. Synthesis of cinnamic acid hydrazide (CMH) 1 g cinnamoyl chloride was added to 5 mL acetonitrile and the mixture was magnetically stirred till clear solution was obtained. The solution was then poured dropwise into a round bottomed flask containing 2 mL hydrazine hydrate. The reaction mixture was magnetically stirred in ice bath. After 15 min, the white CMH precipitate was filtered and washed with acetonitrile and ethanol. 2.5. Synthesis of photo-crosslinkable CMC-CM The previously prepared DMF wet DCMC samples were placed in round bottomed flasks and to which 20 mL of 2% CMH solution in DMF was added. The flasks were then fitted with a reflux condenser and reflux continued in the dark under heterogeneous condition at 120 °C with magnetic stirring. After 2 h, the modified polymeric samples were removed from the reaction mixture and washed with DMF to extract any unreacted CMH then dried in an oven for 24 h at 40 °C. The obtained three photo-crosslinkable samples that derived from

DCMC1, DCMC2 and DCMC3 were respectively named CMC-CM1, CMC-CM2 and CMC-CM3. 2.6. Photo-crosslinking The photo-crosslinking process was carried by UV irradiation of 5% aqueous CMC-CM solutions in quartz tubes utilizing a high pressure 200 W mercury UV lamp at 360 nm for a desired period of time. The obtained gel discs were then soaked in distilled water for 24 h at room temperature in order to extract the unreacted polymeric materials then removed and weighed. The gels were then dried under vacuum and weighed again. Eqs. (2) and (3) were then employed to estimate both gelation efficiency (GE) and degree of swelling (SD). GE% ¼

SD ¼

W dry 100 W solid

W wet −W dry W wet

Fig. 3. 13C NMR spectra of (a) CMC, (b) DCMC and (b) CMC-CM2 in D2O as solvent.

ð2Þ

ð3Þ


141

where Wsolid, Wdry and Wwet are the weights of CMC-CM, dry crosslinked CMC-CM and wet cross-linked CMC-CM, respectively. Schematic presentations for both synthesis and photo-crosslinking process are shown in Scheme 1. 2.7. In-vitro enzyme degradation The enzymatic bio-degradation of the photo-crosslinked CMC-CM hydrogels was performed by allowing 0.1 g of the dry hydrogel to swell in 20 mL acetate buffer at pH 5 for 24 h. 1 mL of the cellulase enzyme solution in the same acetate buffer (10 units/mL) was then added and the reaction was incubated at 37 °C. After predetermined time periods, a 0.25 mL aliquot was taken and replaced with equivalent cellulase solution in order to estimate the amount of the reduced sugar using a dinitrosalicylic acid method [25]. Eq. (4) was utilized for evaluation of the biodegradability.

Cellulase degradability%¼

Mb 100 Ms

ð4Þ Fig. 4. Changes in the UV spectral patterns of CMC-CM2 membrane after UV irradiation time t = 0, 5, 10, 15, 20, 25 and 30 min.

where Ms and Mb are the moles of the anhydro glucose units originally in the CMC and in the solution after cellulase degradation. 2.8. Ephedrine hydrochloride loading and in-vitro release The drug model ephedrine hydrochloride and the photocrosslinkable CMC-CM were mixed with a ratio of 30 mg/g. The mixture was dissolved in double distilled water until the homogeneous solution was clear, which was then irradiated in the UV region for 1 h. The crosslinked ephedrine loaded hydrogel was then removed, washed with distilled water and placed in the in-vitro release PBS medium at 37 °C and shacked at 50 rpm. Each hour, an aliquot from the PBS solution was withdrawn to estimate the molar concentration of the released ephedrine utilizing UV–vis spectroscopy. The absorbances were estimated at 257 nm against a calibration curve of ephedrine in the same buffer solution at pH 7.2 and 37 °C. 2.9. Instrumentation Elemental analysis in all the modification steps was performed using Perkin-Elmer 240C Elemental Analytical Instrument (USA). Fourier transform infrared spectra (FTIR) of the polymeric samples were carried out using a Perkin-Elmer spectrophotometer with ATR accessory. An Oxford NMR instrument (Model Unity Inova 500 MHz, USA) was employed to obtain the 1H and 13C NMR spectra of the modified samples. The progress of the photo-crosslinking reaction in addition to the ephedrine release from the cross-linked hydrogel was monitored using a Perkin-Elmer Bio UV–visible spectrophotometer. X-ray diffraction (XRD) spectra of the native CMC, DCMC and CMC-CM before and after photo-crosslinking were performed using an X-ray powder diffractometer (Japanese Dmax-rA, wavelength = 1.54 Å, CuKα radiation). The samples were scanned from 2θ = 5–70°, in steps of 0.02° using a generator intensity of 40 kV and a generator current of 50 mÅ. Scanning electron microscope (SEM) examinations were performed using an FEI Quanta-200 scanning electron microscope (FEI Company, The Netherlands). The hydrogel samples were first allowed to swell in distilled water for 24 h at room temperature. Then, the swollen hydrogels were freeze-dried before visualizing under the electron microscope. The rheological characterization of CMC-CM before and after photogelation was performed using an ARES rheometer (TA Co., USA). Both storage and loss moduli had been estimated as a function of frequency under oscillatory shear at a strain of 0.5%.

Fig. 5. The effect of irradiation time on the extent of CMC-CM-2 crosslinking (a). Linear second order integral plot of the reciprocal of the percentage of the uncrosslinking against the time (b).

142


3. Results and discussions 3.1. Sample characterization Elemental analysis data of the start material CMC and its obtained derivatives upon each modification step were collected in Table 1. As can be observed, the presence of nitrogen in the prepared CMC-CM samples indicated the successful Schiff base formation between the active\\NH2 of the cinnamic acid hydrazide and the aldehyde groups formed after periodate oxidation. Moreover, the nitrogen percentage displayed a significant increase by increasing the Ald% values related to the used DCMC. This of course could be attributed to the high availability of the aldehyde groups to which the hydrazide units can interact. The estimated degree of cinnamate functionalization was 1.2, 2.1 and 3.2 mmol/g for CMC-CM1, CMC-CM2 and CMC-CM3 respectively. The FTIR spectra of CMC, DCMC and CMC-CM2 are displayed in Fig. 1. The formation of the aldehyde groups upon periodate oxidation was clearly confirmed by the existence of the characteristic \\CHO peaks at about 1730 and 885 cm− 1 in the DCMC spectrum (Fig. 1b). Furthermore, the spectrum of CMC-CM2 (Fig. 1c) confirmed the insertion of the cinnamate units through the Schiff base formation by the appearance of new signals at approximately 1650, 1580, 1275 and 750 cm−1, which are related to C=N, C=C, N\\N and aromatic C\\H respectively. NMR spectra were also employed in evaluation of the CMC chemical modification process. Fig. 2 presents the 1H NMR spectra of CMC, DCMC and CMC-CM2. As can be seen in Fig. 2b, the formation of the aldehyde groups was revealed by the appearance of the singlet signal at δ 9.72 ppm, which is characteristic for the H\\C=O proton beside the diagnostic C\\H and O\\H multiple signals at an approximate range of δ 3.2–4.1 ppm. On the other hand, the incorporation of the cinnamate moieties was evidenced from the spectrum of CMC-CM2 (Fig. 2c) by the presence of the doublet–doublet signals at δ 6.89–7.37 ppm corresponding to trans cinnamate protons, doublet–doublet–triplet signals at δ 7.62–7.38–7.33, which are related to the aromatic protons and singlet signal of\\NH\\ proton at δ 12.04.

In addition, 13C NMR spectra (Fig. 3) reveal the periodate oxidation by the presence of the aldehyde carbon signal at 200 ppm (Fig. 3b). On the other hand, the spectrum of CMC-CM2 (Fig. 3c) displayed new signals at 168 ppm related to the hydrazide C=O group, 188, 145 ppm related to the cinnamate C=C and 127, 128 ppm related to the carbons of the aromatic ring. These results confirmed the successful modification of the DCMC by incorporation of the photo-active cinnamate moieties. Furthermore, the degree of functionalization was estimated by comparing the integral values of the characteristic cinnamate signals to that of C1 and the obtained results were in a good match with that obtained from the elemental analysis.

3.2. Photo-crosslinking The initiator-free photo-crosslinking reaction of the cinnamate modified CMC-CM2 was investigated by UV irradiation of a thin film using 200 W mercury UV lamp at 360 nm. The UV spectrum of the film was examined after predetermined time intervals and the results were presented in Fig. 4. As can be noticed, the characteristic cinnamate absorption band at 315 nm [26] exhibited an obvious lowering in intensity by increasing the UV irradiation time. In 30 min, the intensity of the band decreased by approximately 50%. These results indicated that the photo-crosslinking reaction was performed through the well known concerted [2π + 2π] cyclo-addition reaction of the photo-active cinnamate moieties, which resulted in cyclobutane rings connecting the polysaccharide chains together in a three-dimensional crosslinked network structure as shown in Scheme 1. For more understanding of the photo-crosslinking process, geometry optimization of the cinnamate modified CMC units before and after the [2π + 2π] cyclo-addition photo-reaction was carried out using an MM+ force field in HyperChem software version 8.03. The most stable conformation model is presented in Structure 1a and as can be observed, the cinnamate moieties are arranged away from each other providing a suitable position for approach with minimum steric hindrance and consequently formation of the cross-linked network as shown in Structure 1b.

Fig. 6. XRD crystalline patterns of CMC (a), DCMC (b), CMC-CM2 before (c) and after (d) photo-crosslinking.


143

Furthermore, the kinetic studies were performed by calculating the extent of cross-linking (ρt) Eq. (5) [27].

ρt ¼

A0 −At 100 A0

ð5Þ

where A0 is the initial absorbance intensity and At is the absorbance at time t. Fig. 5a displayed the change of the ρt as a function of time. The obtained kinetic data exhibited the best linear fit with the second order integral relationship (Eq. (6)), which was obtained by plotting the non-crosslinking (%) (1 / 100 − ρt) against the irradiation time (t) [23]. As can be seen in Fig. 5b, the estimated rate constant was 1.58 × 10−4%−1 min−1. These results revealed that the cross-linking process was performed through the bimolecular second order [2π + 2π] cyclo-addition reaction. 1 1 ¼ þ kt: A A0

ð6Þ

Fig. 7. SEM images of a cross-section of photo-crosslinked hydrogel derived from (a) CMC-CM1 and (b) CMC-CM3.

3.4. Rheological properties In these experiments, aqueous CMC-CN2 solution was examined before and after the photo-crosslinking performance for 30 min. Fig. 9 displayed the dependence of both storage (G\) and loss modulus (G\\)

The influence of oxidation and each subsequent modification step was examined utilizing XRD spectra. As presented in Fig. 6 the spectrum of native unmodified CMC (Fig. 6a) exhibited an intense peak at 2θ = 22.70, which indicate the semi-crystalline pattern of the polysaccharide chain. Upon periodate oxidation and further incorporation of the cinnamic acid hydrazide units, the intensity of the crystalline peak displayed a significant decrease as a result of the packing destruction due to the cleavage of some glucopyranoside units [1,24]. In addition, the spectrum of the photo-crosslinked CMC-CM2 (Fig. 6d) exhibited an almost amorphous pattern, which can be explained as a result of the formation of three dimensional cross-linked matrices and cleavage of the hydrogen bonding that hold and organize the crystalline segments of the polysaccharide chain. The influence of the photo-crosslinking density on the morphological structure of the obtained hydrogel was examined by visualizing scanning electron microscope images of the freeze-dried hydrogels obtained from CMC-CM1 and CMC-CM3 (Fig. 7). Both images exhibited a sponge like porous texture. However, the hydrogel derived from the highly functionalized CMC-CM3 exhibited relatively smaller pores size with a more compact structure, which could be explained as a result of the higher cross-linking density. 3.3. Gelation and swelling studies The gelation efficiency (GE) of both CMC-CM1 and CMC-CM3 was studied as a function of the irradiation time and the results were shown in Fig. 8a. As can be noticed, in a time range from 10 to 60 min, the GE displayed an obvious increase from 12.86 to 39.43% in case of CMC-CM1 and from 20.23 to 74.54% in case of CMC-CN3. This observed high GE values obtained with the highly functionalized CMC-CN3 could be attributed to the high availability of the inserted photo-active cinnamate units, which is essential in the UV-induced photo-crosslinking via [2π + 2π] cyclo-addition reaction. Also, the effect of irradiation time as well as the cinnamate content on the swelling degree (SD) was investigated (Fig. 8b). As can be seen, for both CMC-CM1 and CMC-CM3, the SD exhibited a significant decrease by increasing the UV irradiation time. On the other hand, the hydrogel derived from the highly functionalized CMC-CM3 presents a lower SD compared to the CMC-CM1 with the relatively lower cinnamate content. Generally, the hydrogels exhibited low SD values by increasing the cross-linking density of their matrix network, which could be achieved by increasing either UV-irradiation time or cinnamate content.

Fig. 8. Gelation efficiency as a function of irradiation time for aqueous solutions of CMCCM samples (a). The swelling degree as a function of irradiation time for the CMC-CM hydrogels (b).

144


on the angular frequency. As can be seen, the uncross-linked sample exhibited a viscous state with viscoelastic properties, which restrict the accurate measurements of both (G\) and (G\\) values. On the other hand, upon photo-crosslinking process, within the whole studied frequency range, G\ was greater than G\\. In addition, G\ was almost constant and slightly increased by increasing frequency. These results revealed that the CMC-CN2 solution exhibited semi-solid properties upon UV-irradiation, which could be explained as a result of the photo-induced cyclo-addition reaction of the inserted cinnamate units. Furthermore, the storage modulus was also examined as a function of frequency for both CMC-CM1 and CMC-CM3 in order to investigate the influence of functionalization degree on the mechanical properties. As can be seen in Fig. 9c, the highly functionalized CMC-CM3 displayed higher G\ values compared to that of CMC-CM1 with lower cinnamate content. This of course could be explained as a result of the formation of a highly cross-linked structure with more compact dense texture matrix. 3.5. Enzymatic degradability The bio-degradation studies were performed by incubating the studied hydrogel with cellulase enzyme at 37 °C. The influence of the incubation time on the degradation process is displayed in Fig. 10. Within three days, the hydrogel derived from CMC-CM1, CMC-CM2 and CMC-CM3 exhibited approximate degradation percents of 70, 48 and 34%, respectively. Moreover, the rate of the enzymatic degradation showed an obvious decrease by increasing the cinnamate content. These observations could be explained as a result of the chemical change that takes place upon cinnamate insertion and subsequent

Fig. 10. In vitro biodegradation of two CMC-CM hydrogels incorporated with various cinnamate contents in (10 units/mL) cellulase solution of pH 5 at 37 °C.

photo-crosslinking process, which will of course restrict the substrate– enzyme interaction. 3.6. In-vitro release studies The potential of the prepared CMC-CM photo-cross-linkable polymeric materials as a polymeric matrix for drug delivery systems was examined using ephedrine as a drug model. The sustained release profiles of the entrapped ephedrine from the cross-linked network of both CMCCM1 and CMC-CM3 at pH 7.2 and at 37 °C were displayed in Fig. 11. As can be noticed, ephedrine exhibited a slower release from the more functionalized CMC-CM3 cross-linked matrix compared to that observed from CMC-CM1. After 6 h the cumulative release of ephedrine was approximately 15% and 28% from CMC-CM3 and CMC-CM1, respectively. This observed slow release pattern with the highly functionalized CMC-CM3 could be attributed to the high cross-linking density, which will limit the drug diffusion out of the polymeric matrix

Fig. 9. Dynamic storage and loss moduli of aqueous CMC-CM2 solution (a) before and (b) after UV irradiation. (c) Storage modulus as a function of frequency for both CMCCM1 and CMC-CM3.

Fig. 11. In-vitro release profiles of ephedrine hydrochloride from the photo-crosslinked CMC-CM hydrogels incorporated with various cinnamate contents in a pH 7.2 phosphate-buffered saline at 37 °C.


145

Structure 1. Molecular model of CMC-CM before (a) and after (b) photo-crosslinking.

and consequently decreases the rate of the sustained release. These results were in great agreement with some previous reports [28,29], which focused on the influence of the gelation degree on the drug release profiles from the hydrogel polymeric matrices. Usually, the drugs exhibited a slower release profile from matrices with a smaller swelling degree, revealing the importance of the cinnamate content on the release of ephedrine from the cross-linked CMC-CM matrices. For more understanding of the mechanism by which ephedrine was released from the studied cross-linked polymeric matrices, the obtained data from the release profile were fitted with the semi-empirical Korsmeyer–Peppas equation (Eq. (6)) [30]. log

Mt ¼ logk þ n logt Mf

ð6Þ

where k is a kinetic constant related to the structure and geometry of the polymeric drug carrier, (n) is an exponent characteristic of the release mechanism, Mt and Mf are the released ephedrine amounts at t and equilibrium, respectively. The mechanism of ephedrine release from the polymeric network depends upon the anticipated ‘n’ values. If n = 5, the release is described as Fickian transport or diffusion controlled mechanism (Case I), where the drug diffusion is lower than the polymeric relaxation [31,32]. On the other hand, if n = 1 the drug release follows the non-Fickian mechanism (Case II) in which the rate of polymeric network relaxation is lower than the rate of drug diffusion. If the n values lie between 0.5 and 1, the drug release mechanism is a combination of both diffusion and polymer relaxation (anomalous case) [32]. The obtained n values from the kinetic pattern of both CMC-CM3 and CMC-CM1 were 0.75 and 0.83, respectively, which may give an evidence for non-Fickian

anomalous transport kinetics related to both diffusion and polymer relaxation release mechanisms.

4. Conclusion A bio-compatible photo-active cinnamate modified CMC derivative was manufactured and extensively characterized using various instrumental techniques. Upon UV irradiation, the modified polymeric chains were cross-linked through the [2π + 2π] cyclo-addition interaction of the inserted cinnamate moieties. The photo-crosslinking degree was found to significantly increase by increasing the degree of cinnamate functionalization. In addition, gelation efficiency exhibited an obvious increase accompanied by a significant decrease in swelling degree by increasing the cross-linking density either by increasing the degree of cinnamate functionalization or by increasing the time of UV irradiation. Also, the obtained hydrogel displayed an observed slower enzymatic biodegradation by increasing the degree of cross-linking. The potential of the fabricated hydrogels was evaluated as polymeric carriers in drug delivery systems using ephedrine hydrochloride as a drug model and the results indicated the significant dependence of the release rate on the cross-linking density of the polymeric hydrogel matrix.

Acknowledgement The authors would like to acknowledge financial support for this work, from the Deanship of Scientific Research, Taibah University Saudi Arabia, under grant no. 6959/1436.

146


References [1] H. Li, B. Wu, C. Mu, W. Lin, Concomitant degradation in periodate oxidation of carboxymethyl cellulose, Carbohydr. Polym. 84 (2011) 881–886. [2] A.E.H. Ali, H.A.A. El-Rehim, H. Kamal, D.E.S.A. Hegazy, Synthesis of carboxymethyl cellulose based drug carrier hydrogel using ionizing radiation for possible use as site specific delivery system, J. Macromol. Sci., Part A: Pure Appl. Chem. 45 (2008) 628–634. [3] R. Reeves, A. Ribeiro, L. Lombardo, R. Boyer, J.B. Leach, Synthesis and characterization of carboxymethyl cellulose–methacrylate hydrogel cell scaffolds, Polymers 2 (2010) 252–264. [4] L.Y. Jiang, Y.B. Li, L. Zhang, X.J. Wang, Preparation and characterization of novel composite containing carboxymethyl cellulose used for bone repair, Mater. Sci. Eng. C 29 (2009) 193–198. [5] R. Barbucci, G. Leone, A. Vecchiullo, Novel carboxymethyl cellulose-based microporous hydrogels suitable for drug delivery, J. Biomater. Sci. Polym. Ed. 15 (2004) 607–619. [6] K. Pal, A.K. Banthia, D.K. Majumdar, Development of carboxymethyl cellulose acrylate for various biomedical applications, Biomed. Mater. 1 (2006) 85–91. [7] S. Yandri, D. Susanti, T. Suhartati, S. Hadi, Immobilization of α-amylase from locale bacteria isolate Bacillus subtilis ITBCCB148 with carboxymethyl cellulose (CM-cellulose), Mod. Appl. Sci. 6 (3) (2012) 81–86. [8] A. Sannino, C. Demitri, M. Madaghiele, Biodegradable cellulose-based hydrogels: design and applications, Materials 2 (2009) 353–373. [9] S. Gulrez, S. Al-Assaf, G.O. Phillips, Hydrogels: methods of preparation, characterisation and applications, in: A. Carpi (Ed.), Progress in Molecular and Environmental Bioengineering—From Analysis and Modeling to Technology Applica-tions, InTech, Rijeka 2011, pp. 117–151. [10] R.A. Wach, B. Rokita, N. Bartoszek, Y. Katsumura, P. Ulanski, J.M. Rosiak, Hydroxyl radical-induced crosslinking and radiation-initiated hydrogel formation in dilute aqueous solutions of carboxymethyl cellulose, Carbohydr. Polym. 112 (2014) 412–415. [11] M. Monier, D.A. Abdel-Latif, Synthesis and characterization of ion-imprinted resin based on carboxymethyl cellulose for selective removal of UO2+ 2 , Carbohydr. Polym. 97 (2013) 743–752. [12] A.J. Braih, S.I. Salih, F.A. Hashem, J.K. Ahmed, Proposed cross-linking model for carboxymethyl cellulose/starch superabsorbent polymer blend, Int. J. Mater. Sci. Appl. 3 (6) (2014) 363–369. [13] M. Leonardis, A. Palange, R.F.V. Dornelles, F. Hund, Use of cross-linked carboxymethyl cellulose for soft-tissue augmentation: preliminary clinical studies, J. Clin. Interv. Aging 5 (2010) 317–322. [14] H. Kono, Characterization and properties of carboxymethyl cellulose hydrogels crosslinked by polyethylene glycol, Carbohydr. Polym. 106 (2014) 84–93. [15] E. Akar, K. Antinisk, Y. Seki, Preparation of pH- and ionic-strength responsive biodegradable fumaric acid crosslinked carboxymethyl cellulose, Carbohydr. Polym. 90 (2012) 1634–1641.

[16] C. Chang, B. Duan, J. Cai, L. Zhang, Super absorbent hydrogels based on cellulose for smart swelling and controllable delivery, Eur. Polym. J. 46 (2010) 92–100. [17] M. Ali Hebeish Hashem, M.M. AbdEl-Hady, S. Sharaf, Development of CMC hydrogels loaded with silver nano-particles for medical applications, Carbohydr. Polym. 92 (2013) 407–413. [18] S. Yang, S. Fu, H. Liu, Y. Zhou, X. Li, Hydrogel beads, based on carboxymethyl cellulose for removal heavy metal ions, J. Appl. Polym. Sci. 119 (2011) 1204–1210. [19] R. Hu, Y.-Y. Chen, L.-M. Zhang, Synthesis and characterization of in situ photogelable polysaccharide derivative for drug delivery, Int. J. Pharm. 393 (2010) 96–103. [20] J.M. Li, L.M. Zhang, Characteristics of novel starch-based hydrogels prepared by UV photopolymerization of acryloylated starch and a zwitterionic monomer, Starch 59 (2007) 418–422. [21] Q. Li, C.G. Williams, D.D.N. Sun, J. Wang, K. Leong, J.H. Elisseeff, Photocrosslinkable polysaccharides based on chondroitin sulfate, J. Biomed. Mater. Res. 68A (2004) 28–33. [22] A. Potthast, T. Rosenau, P. Kosma, Analysis of oxidized functionalities in cellulose, Adv. Polym. Sci. 205 (2006) 1–48. [23] M. Monier, Y. Wei, A.A. Sarhan, D.M. Ayad, Synthesis and characterization of photo-crosslinkable hydrogel membranes based on modified chitosan, Polymer 51 (2010) 1002–1009. [24] U.J. Kim, S. Kuga, M. Wada, T. Okano, T. Kondo, Periodate oxidation of crystalline cellulose, Biomacromolecules 1 (2000) 488–492. [25] G.L. Miller, R. Blum, W.E. Glennon, A.L. Burton, Measurement of carboxymethyl cellulase activity, Anal. Biochem. 1 (1960) 127–132. [26] M. Nagata, K. Inaki, Synthesis and characterization of photocrosslinkable poly(L-lactide)s with a pendent cinnamate group, Eur. Polym. J. 45 (2009) 1111–1117. [27] W. Tie, Z. Zhong, L. Li, A. Zhang, F. Shen, M.-H. Lee, X.-D. Li, Synthesis and characterization of novel photosensitive polysulfones with photocrosslinkable side pendants, Eur. Polym. J. 48 (2012) 2070–2075. [28] J. Nerurkar, H.W. Jun, J.C. Price, M.O. Park, Controlled-release matrix tablets of ibuprofen using cellulose ethers and carrageenans: effect of formulation factors on dissolution rates, Eur. J. Pharm. Biopharm. 61 (2005) 56–68. [29] N.L. Rosario, E.S. Ghaly, Matrices of water-soluble drug using natural polymer and direct compression method, Drug Dev. Ind. Pharm. 28 (8) (2002) 975–988. [30] R.W. Korsmeyer, R. Gurny, E. Doelker, P. Buri, N.A. Peppas, Mechanisms of solute release from porous hydrophilic polymers, Int. J. Pharm. 15 (1983) 25–35. [31] V.B. Bueno, R. Bentini, L.H. Catalani, D.F.S. Petri, Synthesis and swelling behavior of xanthan-based hydrogels, Carbohydr. Polym. 92 (2013) 1091–1099. [32] B.Y. Swamy, Y.-S. Yun, In vitro release of metformin from iron (III) cross-linked alginate–carboxymethyl cellulose hydrogel beads, Int. J. Biol. Macromol. 77 (2015) 114–119.