RESEARCH ARTICLE

Biodegradable polymethacrylic acid grafted psyllium forcontrolled drug delivery systems

Ranvijay KUMAR (✉), Kaushlendra SHARMA

Birla Institute of Technology, Patna 800014, India

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2013

Abstract Polymethacrylic acid (PMA) was synthesizedon the backbone of psyllium (Psy) by a microwave assistedmethod to prepare polymeric grafted materials designatedas (Psy-g-PMA). Various grades of Psy-g-PMA wereprepared by changing the degree of grafting from 35%–58% and the materials were then made into tablets.Swelling and biodegradability studies of the tablets werecarried out. Acetyl salicylic acid was incorporated in thevarious Psy-g-PMA samples and tablets were prepared tostudy the in vitro drug release in acidic (pH = 4), neutral(pH = 7), and basic (pH = 9) media. In the acidic medium,the swelling was more than 1300%. In addition, thebiodegradable Psy-g-PMA had the highest drug release inthe acidic medium. This may be attributed to Fickiandiffusion since the drug and the medium in which it wasreleased have the same acidic nature.

Keywords psyllium, acetyl salicylic acid, in-vitro drugrelease, swelling, biodegradation

1 Introduction

Polymeric biomaterials are components of various for-mulations and devices that are routinely used for deliveringdrugs to the body in a controlled manner. Variouscommercial formulations have been developed since the1940s. The first known formulation was “Snapsules” (atype of formulation containing small drug sphere coatedwith a soluble coating) which were used to increase theduration of orally administrated drugs. However, thereleased drug concentrations in blood plasma above certainlimits can become toxic and those below certain limits arenot therapeutically effective.Several biopolymers have been evaluated for drug

release in recent years. Extracts from nigella sativa seed(discovered in king Tutankhamen’s tomb in Egypt) hasbeen found to exhibit antioxidant properties. Proteinfractions of the aqueous extract of nigella sativa seed areresponsible for the hepatoprotective and immunopotentiat-ing activities [1]. Chitoson has been chemically modifiedto produce water-soluble low molecular weight nanopoly-mers which enables matrix to process insulin under mildconditions. The water soluble nanopolymers adhere themucosa without being completely removed which cankeep opening of the paracellular channels for insulintransport continuously [2]. Carboxy methyl tamrind(CMT), which is synthesized by the carboxymethylationof tamrind karnel polysaccharides (TKP), has been foundto be a good matrix candidate for controlled drug release inin-vitro drug release systems [3]. Copolymers of 2-Hydroxyethyl methacrylate and acrylic acid (HEMA-coAA) are synthesized. On xanthan gum polysaccharides(XG), HEMA-co AA are grafted to produce XG-g-Poly(HEMA-co-AA) hydrogels. These hydrogels showedthe high swelling capacity at 1:2 (v/v) ratio of HEMA:AA due to diffusion type of release mechanism [4].Sterculia and poly vinyl alcohol (PVA) can be loaded withan antimicrobial agent and used to prepare wounddressings with double action (antimicrobial and controlledrelease) [5]. pH-sensitive poly methylethylene glycol-caprolactone-co-methacrylic acid-co-poly (ethylene gly-col) methyl ether methacrylate [P (CE-MAA-MEG)]hydrogels have been used for oral drug delivery systems[6].Psyllium based drug delivery systems have been

investigated as drug delivery systems in recent years dueto the inexpensive and ready availability of the rawmaterials. N-Hydroxymethylacrylamide [N-MBAAm] –psyllium systems are pH sensitive and can act as targeteddrug delivery devices [7]. Often drug delivery systemsdepend upon the pH of the medium, the ionic strength ofthe solution and the temperature. Mixtures of acrylamideand 2-acrylamido-2-methylpropane sulphonic acid have

Received September 21, 2012; accepted November 15, 2012

E-mail: ranvijay143@gmail.com

Front. Chem. Sci. Eng. 2013, 7(1): 116–122DOI 10.1007/s11705-013-1310-0

been used to prepare psyllium-based hydrogels which canact as dual drug delivery systems in pH 2.2 buffers [8]. Theabove mentioned effect is due to the release of therapeuticagent indinavir sulfate for the AIDS from the polymermatrix and curative action of psyllium to cure diarrheawhich may lead to synergistic effect for the AIDS anddiarrhea [8]. Due to therapeutic importance of psylliumand its gel-forming nature, hydrogels developed from itcan also act as dual drug delivery devices [9]. It has beenreported that the use of particular grade of hydroxypro-pylmethyl cellulose with psyllium husk enhanced thefloating duration of tablet and helped to maintain thedimensional stability of matrix tablet during the initialstage of the gastroretentive tract [10]. The reason is thatpsyllium husk has gut-stimulatory components which aremediated through muscarinic or 5-HT4 receptor activation[11]. Psyllium and acrylic acid based superabsorbentmaterials are used for sustained fungicide delivery systemsand are superabsorbents which are sensitive toward pH aswell as temperature [12]. Polymethacrylic acid (PMA) is awater soluble acrylic based polymer having the greatfeasibility of PMA based hydrogels and superabsorbents. Ithas been also explored by various researchers [13,14].There are several reports related to psyllium basedbiomaterials for drug delivery systems. However, thereare few reports on PMA based psyllium hydrogels. Thismanuscript discusses a new type of hydrogel that has beensynthesized using psyllium (Psy) and polymethacrylic acid(PMA). The hydrogel was studied for drug release usingacetyl salicylic acid as the drug. Swelling studies and drugrelease in acidic (pH 4), neutral (pH 7) and basic (pH 9)media were performed. In addition, biodegradation studiesof the PMA based psyllium hydrogels were carried out.

2 Materials and methods

2.1 Materials

Psyllium was purchased from the Dholpur Sat IsabgolFactory, Gujrat, India (Lot No. SF-1843-A3). Silver sulfatewas purchased from E. Merck (Lot No. MA8M572292),Mumbai, India. Methacrylic acid was purchased fromCDH (Lot No. SC9S590099), Mumbai, India. Annulargrade acetone was supplied by E. Merck, Germany (LotNo. SC 1F610141), and acetyl salicylic acid was

purchased from Otto, India (Lot No. A 1354). All thechemicals were used as received; without further purifica-tion.A “25-liter” LG microwave oven model number:

MC7688DP, 900 Watt, India and a hydraulic hand presstablet making machine (Jublee enterprises), Kolkata, Indiawere used.

2.2 Synthesis

Microwave assisted synthesis of polymethacrylic acidgrafted psyllium (Psy-g-PMA) was done using silversulfate as the free radical initiator. The synthesis of Psy-g-PMA has been discussed in detail in a previous paper [15].In the typical process, 1 g of psyllium was dissolved in

100 mL of distilled water and a catalytic amount ofAg2SO4 was added. The mixture was mixed well and thenthe desired amount of methacrylic acid was added. Thereaction mixture was then transferred into a 1-L reactionvessel and was subsequently placed on the turntable of amicrowave oven. The vessel was then irradiated with 900W of microwave power. The microwave irradiation waspaused periodically before boiling of the reaction mixturecould occur (65°C) and the mixture was cooled by placingthe reaction vessel in ice-cold water. This was done toprevent homopolymerization and vapor formation of themethacrylic acid which is toxic and carcinogenic.The grafting of this microwave assisted synthesized Psy-

g-PMA was calculated as:

graf ting% ¼ ½W2 –W1�=W1

whereW1 is the weight of psyllium andW2 is the weight ofthe grafted copolymer.The optimized grade i.e., Grade V is indicated by the

highest percentage of grafting of prepared grades of Psy-g-PMA which is proportional to molecular weight. Thesynthesis details and the designation of the samples aretabulated in Table 1. From Table 1, the best grafting result(Grade V) was achieved with 0.177 mol of PMA, 1.5 g ofsilver sulfate and 180 s of irradiation at 900W. Themechanism of the microwave assisted grafting is depictedin Scheme 1 and it has been discussed in a previous report[15]. A summary of that mechanism is given here.The mechanism involves generation of a Ag+ free

radical which participates in the formation of a chelatingcomplex between the hydroxyl group of the psyllium and

Table 1 Synthesized grades of Psy-g-PMA

Grade Wt. of psyllium /mg Wt. of silver sulfate/mg Amount of PMA /mol Time of irradiation/s Grafting/%

I 1.0 1.5 0.177 150 35

II 1.0 0.8 0.177 180 41

III 1.0 1.5 0.177 210 45

IV 1.0 1.0 0.177 180 47

V 1.0 1.5 0.177 180 58

Ranvijay KUMAR et al. Polymethacrylic acid grafted psyllium for controlled drug delivery 117

the oxidant. This complex being unstable forms freeradicals onto the polysaccharides (psyllium) backbone.The microwave radiation rotates the methacrylic acidmolecule leading to the elongation of its bonds. As theC–C double bond electron cloud splits into two localizedclouds, the free radical sites created on the psylliumbackbone by the silver sulfate and those on the methacrylicacid created by the microwave irradiation interact througha typical free radical reaction mechanism to yield thegrafted copolymer [15].

2.3 Purification of the grafted copolymer by solventextraction

Any occluded polymethacrylic acid (PMA) formed by theformation of a competing homopolymer reaction wasremoved from the grafted copolymers by solvent extrac-tion using a mixture of formamide and acetic acid (1∶1 byvolume). Figure 1 shows the FTIR spectrum of psylliumand the best grade of Psy-g-PMA. The FTIR spectra ofplantago psyllium mucilage and that of Psy-g-PMA wererecorded in the solid state using a KBr pellet method.Scans were performed on an FTIR spectrophotometer(Model IR-Prestige 21, Shimadzu Corporation, Japan)between 400 and 4000 cm–1. The spectrum of plantagopsyllium mucilage has several peaks and their designationsare given below [16]:� 3739.97 and 3614.6 cm–1: O–H stretching of the

carbohydrates,

� 2939.52 and 2885.51 cm–1: CH2 asymmetric stretch-ing,� 1337.53, 1315.45 and 1245.02 cm–1: CH, CH2 and OH

in-plane carbohydrate bending,� 1014.56 cm–1: C–O stretching of complex bonds

resulting from C–O and C–O–C stretching vibrations,� 894.97 and 545 cm–1: pyranose rings.In addition to the above peaks, Psy-g-PMA has peaks at

1662.64 cm–1 (C = O stretching of COOH groups),2924.09 cm–1 (CH2 stretching), 896.50 cm–1 (CH2 inplane bending) and 615.29 cm–1 (OCOH defragmentationof COOH. All of these bands are related to PMA and hencethe FTIR spectra confirm the grafting of PMA on psylliumhas been carried out successfully.

2.4 Preparation of Psy-g-PMA based tablets for drugrelease study

The samples Psy-g-PMA and acetyl salicylic acid (as drug)were powdered in a blender, in a 10∶1 ratio. The mixturewas made moist by adding a little bit of acetone and thenmixed further. The dried paste, after removal of volatileacetone, was sieved below 50°C and tablets containing250 mg each were prepared by compression in a standardlaboratory press at 2 ton pressure/cm2. The tablets were 10mm in diameter and 4 mm thick. Each tablet was loadedwith about 22.72 mg of acetyl salicylic acid. The graftedmaterial is sticky in nature and therefore no binders wereneeded for the preparation of the tablets.

Scheme 1 Schematic representation for ‘Microwave Assisted’ Synthesis of Psy-g-PMA

118 Front. Chem. Sci. Eng. 2013, 7(1): 116–122

2.5 Swelling study

The swelling study was carried out by putting the tablets indifferent media (acidic, neutral, and basic). The tabletswere first weighed and then soaked in the different media.Every hour, the tablets were removed from the solution andweighed. After weighing, the tablets were put back into thesolutions. This process was continued until the weight ofthe tablets became constant.

2.6 Biodegradation study

The biodegradability test was carried out in flower potscontaining farmland soil having a pH of 7.5–7.7. A highrelative humidity of ~98% was maintained by dailysprinkling water on the soil. Each tablet was buried inthe soil in the flower pot (30-cm diameter) and the pot waskept at room temperature (25�5°C). Each specimen wasdug out of the soil after being buried for 15 days and thenwashed with water and dried at 60°C in an air oven for48 h. Biodegradability was determined by measuring lossin weight of the specimen.

2.7 In vitro drug release study

For the in vitro drug release study, the United Statespharmacopeia (USP) rotating paddle [17] method wasapplied. In vitro drug release studies were carried out byimmersing various grades of the synthesized polymer (Psy-g-PMA) in 900 mL of different buffer solutions. The drugdissolution apparatus used was a standard digital rate testapparatus (Ikon India) and the experiments were per-formed at constant temperature (37�1°C) with constantstirring (60�2 r$min–1) maintained with the paddle stirrer.Aliquots were removed every 60 min, and the concentra-tion of the drug (acetyl salicylic acid) was analyzedspectrophotometrically at lmax of 192 nm.

3 Results and discussion

3.1 Effect of pH on swelling

Figure 2(a) shows the photographs of a virgin psylliumtablet and a swollen psyllium tablet. Figures 2(b–d)show the swelling of the psyllium and Psy-g-PMA(Gr. V i.e., best grade with 58% grafting) in acidic, neutraland basic aqueous media, respectively. Both psylliumand Psy-g-PMA are hydrophilic in nature and henceboth absorb very large amounts of moisture. However inthe first 12 h, there are differences in the degrees ofswelling in the different media. In all the solutions, theswelling of Psy-g-PMA is higher than that of thecorresponding psyllium. Figure 3 shows the percentswelling in the acidic, neutral and basic media. Theswelling occurred faster in the acidic medium (pH 4) thanin the other two media (neutral (pH 7) and basic (pH 9)).This may be attributed to the fact that the Psy-g-PMAtablets are acidic in nature and thus most compatible withthe acidic medium.

3.2 Biodegradation studies

From Fig. 4, the weight loss of the Psy-g-PMA tablets after15 days of the soil burial tests confirm biodegradationbehavior of Psy-g-PMA tablets. The maximum weight losswas around 5% and occurred for the Gr. I Psy-g-PMA. TheGr. V which had the highest grafting percent had the lowestweight loss after 15 days which is due the bettercompatibility of psyllium and PMA at this degree ofgrafting.

3.3 Drug release kinetics

Figures 5–7 show the drug release for the tablets immersedin different media. The drug release in the acidic medium(pH 4) is much faster than in the neutral (pH 7) and basic(pH 9) media. It released 80% of the medicine in the first

Fig. 1 FTIR spectra of (a) psyllium and (b) Psy-g-PMA

Ranvijay KUMAR et al. Polymethacrylic acid grafted psyllium for controlled drug delivery 119

Fig. 3 Percent swelling in acidic, neutral and basic mediaFig. 4 Weight loss of the Psy-g-PMA tablets after 15 days of thesoil burial tests

Fig. 2 (a) Photograph of psyllium tablet before and after swelling. Swelling study in (b) acidic, (c) neutral and (d) basic media

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hour and 84.65% within three hours. In the neutralmedium, the tablet released 55.12% in the first hour and82.04% within 11 h which is Fickian type diffusion. In thebasic medium, there was release of 27.51% drug in the firsthour (initial slow release) followed by 59% released at 7 h.The release then became constant at longer times.In the case of the acidic medium, the drug release is

much faster than the other two media. The reason is thatacetyl salicylic acid is acidic in nature and this increases itssolubility in the acidic medium on the basis of the concept“like dissolves like.” Also in the acidic medium, the poresizes become larger due to the fast swelling of the matrixand according to Fick’s law diffusion takes place faster inlarger pores [18]. Further Fick’s law also states that a solute

will move smoothly and systematically from areas of high-concentration to areas of low concentration. In drugdelivery, the drug is loaded in a matrix (the tablet) and thetablet has a higher concentration of the drug than themedium. So the drug tends to flow toward the lowerconcentration of the acidic solution medium.Figure 8 shows the proposed mechanism to explain the

drug release based on Fickian diffusion. The Psy-g-PMAtablets are acidic in nature and when these tablets areimmersed in an acidic medium then the equilibrium isreached quickly. Hence the release of the drug is fast. Butin a basic medium, the equilibrium is reached more slowlyand hence the release of the drug is slower.

Fig. 5 Drug release in acidic medium (pH 4) from drug loadedPsy-g-PMA tablets

Fig. 6 Drug release in neutral medium (pH 7) from drug loadedPsy-g-PMA tablets

Fig. 7 Drug release in basic medium (pH 9) from drug loadedPsy-g-PMA tablets

Fig. 8 Proposed mechanism for drug release from Psy-g-PMAtablets on the basis of Fickian diffusion

Ranvijay KUMAR et al. Polymethacrylic acid grafted psyllium for controlled drug delivery 121

4 Conclusions

A new material (Psy-g-PMA) has been synthesized bygrafting polymethacrylic acid onto the backbone ofpsyllium using a microwave assisted method. Thesebiodegradable materials have been tested for in vitrocontrolled drug release and their swelling in various mediahas been studied. This material is good for the fast releaseof medicine in acidic environments such as the humanstomach. The material also demonstrated superabsorbentcapacity for water and may be useful in diapers andfeminine sanitary pads.

Acknowledgements The authors gratefully acknowledge the generous andkind cooperation of Dr. Rakesh Kumar, Assistant Professor, Department ofApplied Chemistry, Birla Institute of Technology, Mesra, Ranchi, PatnaCampus India for helping in the preparation of this manuscript.

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