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International Journal of Biological Macromolecules 58 (2013) 296– 300

Contents lists available at SciVerse ScienceDirect

International Journal of Biological Macromolecules

jo ur nal home p age: www. elsev ier .com/ locate / i jb iomac

odified tamarind kernel polysaccharide: A novel matrix for controlelease of aspirin

andipta Ghosha, Sagar Palb,∗

Hindustan Gum & Chemicals Ltd., Bhiwani 127021, Haryana, IndiaPolymer Chemistry Laboratory, Department of Applied Chemistry, Indian School of Mines, Dhanbad 826004, India

a r t i c l e i n f o

rticle history:eceived 18 January 2013eceived in revised form 13 March 2013ccepted 7 April 2013vailable online 12 April 2013

a b s t r a c t

pH dependent hydrogels of modified tamarind kernel polysaccharide (TKP) were synthesized by graftingwith polyacrylamide chains on TKP backbone in presence of microwave irradiation and initiator. Thepresent study is carried out to design oral controlled drug delivery systems for aspirin using synthe-sized hydrogels as carrier in form of tablets. TKP-g-PAM based hydrogels show significant enhancementfor control release of aspirin. Release behavior of aspirin has been evaluated using USP type I appara-

eywords:rug delivery systemsraft copolymersydrogelsolysaccharides

tus in 900 mL of buffer solutions (pH 1.2, 6.8, 7.4), maintained at 37 ◦C at 100 rpm. It is observed thatwith increase in percentage of grafting (% G), swelling of matrices increases whereas erosion and rateof drug release decrease. The effect of % G onto t50 value (time taken for release of 50% drug) has alsobeen discussed. The release characteristics from the matrices under study show non-Fickian diffusionmechanism, suggesting the controlled release of aspirin.

welling

. Introduction

Oral administration of drugs in form of tablets has long beensed, which is the natural, uncomplicated, convenient and safeoute [1]. In this route drug will pass through gastrointestinal tracthere pH differs widely. Stomach is acidic while lower GI tract iseutral or mildly alkaline in nature [2–8]. Thus it is a challengef controlled release or delayed release of drug in this route. Con-rolled drug delivery systems offer numerous advantages comparedo other conventional dosages. The advantage of control releases elimination of peaks and troughs resulting from periodic andneven dosing intervals. In addition, few drugs are required to elicithe same therapeutic effect. It is also required for improved, patientompliance and convenience [9,10].

Use of biodegradable polymeric hydrogels has gained lot ofmportance during the last decades in drug release research. Manyynthetic biodegradable polymers are being used as a matrix forontrol drug release for its efficacy. In spite of the advent of manyynthetic polymers, the use of natural polysaccharides and mod-fied polysaccharides based hydrogels to deliver drug is an activerea of research because of their easy availability, biocompatibility,

on-toxicity, and hydrophilicity [11–16].

One of the effective ways to modify the structure and proper-ies of natural polysaccharide is grafting. Controlled release systems

∗ Corresponding author. Tel.: +91 326 2235769; fax: +91 326 2296615.E-mail address: sagarpal1@hotmail.com (S. Pal).

141-8130/$ – see front matter © 2013 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.ijbiomac.2013.04.002

© 2013 Elsevier B.V. All rights reserved.

have been developed and studied to increase the drug pharmaco-logical action and reduce their side effects. The basic concept isbased on the fact that the rate of drug absorption may be adjustedthrough a controlled rate of drug release from the matrix. Vari-ous systems have been proposed over last two decades. Out ofthem, the simplest system is the matrix device, where the drugis dispersed within the polymer network [17]. The present studyreflects the application of a novel hydrogel (comprised of tamarindkernel polysaccharide grafted with polyacrylamide in presenceof microwave irradiation and initiator) [18] as matrix for controlrelease of aspirin using a diffusion mechanism. The purpose of thepresent work is to evaluate the effect of % grafting (% G) on thecontrolled release behavior of a model drug aspirin. A higher initialdosage of aspirin produces a high peak in the blood level contentwith potential toxicity and/or harmful side effects where as con-trol release of aspirin can relief pain for periods of 24 h or evenlonger and can maintain minimum effective concentration (MEC).The effect of % swelling and rate of erosion on the controlled releaseof the enclosed drug in the polymer matrix has also been studied,as it is well known that swelling and erosion of polymers may affectthe release rate of drugs significantly.

2. Materials and methods

2.1. Materials

Graft copolymers composed of polyacrylamide and tamarindkernel polysaccharide (TKP) were synthesized using microwave

Biological Macromolecules 58 (2013) 296– 300 297

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Table 1Details of graft copolymer based hydrogels, their % grafting, swelling and erosionresults.

Polymer % Grafting % Swelling % Erosion

pH 1.2 pH 6.8 pH 7.4 pH 1.2 pH 6.8 pH 7.4

TKP 0 395 256 288 87.03 78.95 60.38TKP-g-PAM 1 42 425 460 420 69.75 69.00 59.18TKP-g-PAM 2 52 490 510 495 62.29 65.32 58.25TKP-g-PAM 3 49 445 480 460 66.69 67.12 58.72TKP-g-PAM 4 64 570 540 590 51.24 64.32 57.28TKP-g-PAM 5 59 530 508 540 54.61 61.56 57.65

S. Ghosh, S. Pal / International Journal of

ssisted method [18], have selected for drug release study. Theroducts were dried in a hot air oven at 60 ◦C for 6 h, pulverizedy mortar and pastel to obtain powder samples. Sieve fractions of25 �m were selected for all graft copolymers as well as polysac-haride (TKP). TKP and various graft copolymers were kept in aesiccator using silica-gel as desiccant to obtain products dried toonstant weight.

Aspirin (Spectrochem Pvt. Ltd., Mumbai, India) was selected asodel drug, is freely soluble in water. TKP and guar gum were gift

amples from Hindustan Gum & Chemicals Ltd., Bhiwani, Haryana,ndia. All chemicals were used as received, without further modifi-ations.

.2. Preparation of hydrogel

The graft copolymer based hydrogel was synthesized by graft-ng synthetic polyacrylamide chains onto the backbone of tamarindernel polysaccharide using microwave assisted method. By vary-ng the reaction parameters, various graft copolymers wereynthesized and optimized the best one with respect to % G,ntrinsic viscosity and radius of gyration. The details of synthesisrocedure and reaction parameters have already been discussed inarlier report [18].

.3. Preparation of tablets

The polymer matrix under evaluation was finely ground in alender, with a model drug (aspirin) and binder (guar gum) in0:1:0.3 ratios [21]. The mixture was wetted with ethanol andixed further. The paste was dried at 50 ◦C to a constant weight and

round. Then a mixture of silicon dioxide and magnesium stearate2:1 ratios) was added as lubricant, in amount not exceeding 3% ofhe ground powder. After mixing and sieving (20 meshes), tabletf 250 mg was prepared by compression in a standard Carver lab-ratory press at 2–3 t/cm2. Eventually, the drug load of each tabletas 22.123 mg.

.4. FTIR spectroscopy

The FTIR spectra of matrix (TKP-g-PAM), drug (aspirin), andablet were recorded in solid state using KBr pellets with a FTIRpectrophotometer (Model IR-Prestige 21; Shimadzu Corporation,apan) between 500 and 4000 cm−1.

.5. Scanning electron microscope (SEM)

Surface morphology of matrix (TKP-g-PAM), drug (aspirin) andablet were analyzed in scanning electron microscopy (SEM) inowdered form (Model: JSM-6390LV; Jeol, Japan). The samplesere deposited on brass hold and sputtered with a thin of goldnder vacuum. Acceleration voltage used was 20 kV with the sec-ndary electron as a detector.

.6. Swelling and erosion test

The equilibrium swelling behavior of tablets was measured at7 ◦C temperature in buffer solutions similar to that of gastric and

ntestinal fluids. A small pre-weighed piece of tablet made by poly-er matrix is immersed in 200 mL of buffer solutions having pH

.2, 6.8, 7.4 at 37 ◦C for 24 h. Then the swollen piece was blottedith filter paper and weight again. The ratio between the swollen

nd dry weights is defined as the extent of swelling (Ps), which wasalculated as follows:

s = weight of swollen gel − weight of dried gelweight of dried gel

× 100 (1)

TKP-g-PAM 6 87 613 588 644 42.78 55.6 55.8TKP-g-PAM 7 79 585 541 621 48.12 58.23 57.01

During drug release, some tablets disintegrated partially. Thedegree of erosion (D) was calculated by the following equationbased on the difference between the initial dry weight of the tablet(Wi) and the dry weight of the tablet (Wd) at time t, consideringdrug release at time t (Mt/M˛),

D(t) = Wi − Wd(t) − Wdrug(1 − (Mt/M˛)Wi

(2)

where Mt is the amount of drug release at time t; M˛ is the totalamount of drug released after infinite time and Wdrug is the initialweight of drug.

2.7. In vitro study of drug release

The in vitro release of entrapped drug (aspirin) was determinedin various buffer solutions (pH 1.2, simulating gastric fluid, pH 6.8and 7.4, simulating intestinal fluid at 37 ◦C). The tests were con-ducted using standard USP type I (basket) drug dissolution rate testapparatus (M/s SECOR, India), in 900 mL of buffer solution main-tained at the physiological temperature (37 ◦C; using isothermalbath). The spindle rotation was maintained at 100 rpm. At defi-nite time intervals, an aliquot was withdrawn and its absorbancewas (at 294 nm, 274 nm and 268 nm in pH 1.2, pH 6.8 and pH 7.4,respectively) measured. The withdrawn sample was replaced withan equal volume of fresh buffer, to keep the volume of release mediaconstant. The drug content assayed spectrophotometrically and isgraphically expressed as drug release profile (plot of % cumulativedrug release vs. time).

3. Results and discussion

3.1. Hydrogel synthesis

TKP was grafted with polyacrylamide in presence of microwaveirradiation as well as ceric ammonium nitrate as initiator. Themechanism of graft copolymerization is based on the fact thatmicrowave energy is being adsorbed by the polysaccharide andforms free radicals. The microwave energy absorbed by the watermolecules is quickly transferred to the acrylamide molecules, caus-ing ‘dielectric heating’ which results in severing of double bonds,producing another set of free radicals. The free radicals recombinewith each other through initiation, propagation and terminationsteps to produce the graft copolymer as explained earlier [18,19].The various graft copolymers along with their corresponding % Ghave been reported in Table 1.

During the synthesis of graft copolymer based hydrogel, somehomopolymer (i.e. polyacrylamide) may produce. If any occluded

homopolymer formed, was removed from the grafted polymers bysolvent extraction using a mixture of formamide and acetic acid(1:1 by volume).

298 S. Ghosh, S. Pal / International Journal of Biological Macromolecules 58 (2013) 296– 300

g-PAM

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Fig. 1. FTIR spectra of (a) TKP-

.2. FTIR spectroscopy

The FTIR spectra of matrix (TKP-g-PAM), drug, and tablet (i.e.hysical mixture of matrix, binder and drug) are shown in Fig. 1a–c,espectively. In case of TKP-g-PAM (Fig. 1a), OH stretching bandf hydroxyl group and N H stretching band of amide group over-ap each other and provides a broad band at 3186 cm−1. Two sharpeaks 1670 and 1608 cm−1 are attributed to amide – I and amide –

I, respectively. Small peak at 2812 cm−1 attributed to C H stretch-ng frequency. In case of aspirin (Fig. 1b), peaks between 2600 cm−1

nd 3000 cm−1 attributes to OH stretching frequency of carboxyliccid groups. Band at 1757 cm−1 indicates stretching frequency of

O of ester group. Strong peak at 1689 cm−1 assigns for C O ofarboxylic acid group. Peaks between 1400 cm−1 and 1600 cm−1

ssigns for C C aromatic ring. Peaks at 1190 cm−1 and 1300 cm−1

ndicate C O stretching frequency of ester/carboxylic acid group. Its obvious from the spectrum of tablet (Fig. 1c) that the characteris-ic peaks of drug, and matrix were almost unchanged, indicating thebsence of chemical interaction between the drug and the matrix.his is suggesting drug-matrix compatibility in tablet formulation.

.3. Scanning electron microscopy (SEM) analysis

Fig. 2 explains the SEM micrographs of matrix (TKP-g-PAM 6),rug (aspirin) and tablet. It is obvious that morphological changesave been taken place. This indicates that the interaction betweenrug and matrix is not chemical, but only physical.

.4. Swelling and erosion study

Dynamic equilibrium swelling and erosion studies of tabletsave been investigated and reported in Table 1. Investigation ofolymer swelling is a valuable exercise to better understand theechanism of drug release from matrix. On exposure to water

r buffer solution, the dry polymer becomes hydrated, swells andorms a gel barrier layer, which retards the drug out of matrix. It haseen observed that TKP-g-PAM 6 shows highest swelling and low-st rate of erosion (Table 1). With increasing % G, molecular weights well as hydrodynamic volume of matrices also increased. As aesult, it swells higher after specific time [20]. This attributes thearger hydrodynamic volume occupied by high molecular weightolymer chains, when hydrated. As polymer chains became moreydrated, it will undergo simultaneous swelling, dissolution and

iffuse into the bulk medium [21]. After swelling, ionic strengthf matrices increases which results lower erosion rate. This phe-omenon supports the control or delayed release of the drug fromhe matrices. Since, with increase in equilibrium swelling, ionic

6, (b) aspirin, and (c) tablet.

strength of the matrices increases. This results in the decrease oferosion rate resembling the lower release rate of drug from matrix[20,21].

3.5. In vitro drug release study

The in vitro drug release study was performed by USP drug dis-solution (basket type) method, in different buffer solutions similarto that of gastric and intestinal fluids. Transit time of dosages instomach, small intestine and large intestine is 1–3 h, 3–12 h, and20–30 h, respectively. But the drug (aspirin) is completely releasedafter 24 h. So we have taken dissolution time 2 h for pH 1.2 (i.e.similar to gastric fluid), 10 h for pH 6.8 (i.e. similar to small intes-tine fluid), and 12 h for pH 7.4 (i.e. similar to large intestine fluid).In all the cases rotation of the spindle was 100 rpm and temper-ature of the isothermal bath was 37 ◦C. The corresponding drugrelease profiles i.e., cumulative drug release (%) vs. time (min) havebeen plotted for TKP and all the graft copolymers synthesized bymicrowave assisted method in pH 1.2 (Fig. 3a), pH 6.8 (Fig. 3b) andpH 7.4 (Fig. 3c), respectively.

From the drug release profiles (Fig. 3), it is obvious that higherthe % G, lower (hence more controlled) is the rate of drug release.This trend can be explained by the fact that with increase in % G,the molecular weight of the polymer increases as well as solubilityof the graft copolymers decreases [18]. The increasing molecularweight and decreasing solubility in turn results in higher equilib-rium swelling and lower erosion rate of the tablet, which leads toslower rate of drug release.

Further, an attempt has been made to correlate the percentage ofgrafting against its respective t50 (i.e. time taken for release of 50%of the enclosed drug) values, for all dissolution media investigated(Fig. 4). It is apparent from the figure that higher is the % G, loweris the rate of drug release and higher is the t50 value. Amongst TKPand various graft copolymers, TKP-g-PAM 6 is having highest t50value, indicating best matrix for controlled release of aspirin.

Although acrylamide is reported to be lethal neurotoxin and hasbeen found to cause cancer in the laboratory animals, but investiga-tions carried out by some researchers [22,23] reveal that acrylamideis not released from polyacrylamide during degradation. In fact,there seems to be a clear-cut difference of opinion over the break-down products of polyacrylamide degradation. Moreover, the PAMchains degrade very slowly (less than 10% in 28 days) while the total

gastrointestinal transit time for an oral formulation is not morethan 24 h. Hence, the system studied by us is expected to get dis-posed off along with other waste materials from the body withoutproducing toxic effect.

S. Ghosh, S. Pal / International Journal of Biological Macromolecules 58 (2013) 296– 300 299

Fig. 2. SEM micrographs of (a) TKP-g-PAM 6, (b) aspirin, and (c) tablet.

2, (b)

3

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Fig. 3. Cumulative drug release profiles at (a) pH 1.

.5.1. Drug release kinetics

Korsemeyer–Peppas model [24], expressed in Eq. (3) is very cru-

ial to find out the mechanism of drug release from a polymeratrix.

Mt

M˛= Ktn (3)

Fig. 4. Effect of % grafting onto

pH 6.8, and (c) pH 7.4. Results are mean ± SD; n = 3.

where ‘Mt/M˛’ is the fractional drug release at time ‘t’. K represents

kinetic constant, incorporating structural and geometrical charac-teristics of the release device and ‘n’ is the drug elution index whichcharacterizes the type of release mechanism during the dissolu-tion process. This equation must hold only for the first 60% of the

t50 values at various pH.

300 S. Ghosh, S. Pal / International Journal of Biolog

Table 2Drug elution index (n) and kinetic constant (K) for control release of aspirin.

Polymer pH 1.2 pH 6.8 pH 7.4

n K n K n K

TKP 0.76 0.0244 0.59 0.01819 0.84 0.0067TKP-g-PAM 1 0.79 0.0180 0.56 0.0177 0.87 0.0038TKP-g-PAM 2 0.77 0.0165 0.59 0.0136 0.87 0.0026TKP-g-PAM 3 0.82 0.0127 0.64 0.0102 0.91 0.0014TKP-g-PAM 4 0.86 0.0090 0.65 0.0088 0.93 0.0010TKP-g-PAM 5 0.91 0.0063 0.68 0.0073 0.95 0.0009

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TKP-g-PAM 6 0.91 0.0064 0.74 0.0045 0.95 0.0007TKP-g-PAM 7 0.95 0.0051 0.70 0.0060 0.97 0.0005

ractional drug release form the tablets, for which the one dimen-ional diffusion under a perfect sink condition holds true [21].he ‘n’ value is used to characterize different release mechanisms.

≤ 0.45 indicates Fickian diffusion, in which the rate of diffusion isess than that of relaxation. The value of ‘n’ in the range of 0.45 < n < 1ndicates the mechanism is non-Fickian diffusion or anomalous dif-usion, where the diffusion and relaxation rates are comparable.

hen n > 1, the major mechanism of drug release is Case II diffu-ion (relaxation-controlled transport) where diffusion is very rapidn compared to the relaxation process of polymer. The value of ‘n’

as estimated by linear regression of log(Mt/M˛) vs. log t.The drug elution index (n) for TKP and all graft copolymer based

atrices studied here are found to be in between 0.45 and 1.0Table 2), indicating the release of aspirin from matrices followson-Fickian release behavior.

. Conclusion

A novel hydrogel composed of TKP and PAM has been developedsing an innovative microwave assisted grafting method. The appli-ability of this hydrogel as matrix for controlled drug release haseen investigated by USP drug dissolution (basket type) method,t various pH environments. It has been found that rate of drugelease decreased with increase in % of grafting and was found toollow zero order kinetics. Further, it has been observed that theate of release of the enclosed drug from the matrix is low in acidic

nvironment and is much higher in neutral and alkaline environ-ent. This opens up the perspective of further optimization of this

ydrogel as a potential candidate for lower gastrointestinal tractargeted drug delivery.

[[[

ical Macromolecules 58 (2013) 296– 300

Acknowledgement

The authors earnestly acknowledge the financial support fromDepartment of Science and Technology, New Delhi, Govt. of Indiain form of a research grant (Project No. DST/TSG/WP/2006/28) tocarry out the reported investigation.

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