RESEARCH ARTICLE

Synthesis and evaluation of octenyl succinate anhydride derivativeof fenugreek gum as extended release polymer

Ajay Kumar Sav • Ritesh Amol Fule •

Meer Tarique Ali • Purnima Amin

Received: 3 June 2013 / Accepted: 7 August 2013

� The Korean Society of Pharmaceutical Sciences and Technology 2013

Abstract In current study, fenugreek gum (FG) plant

derived product was investigated as a release retarding

polymer. The octenyl succincate anhydride derivative of

fenugreek gum (OSFG) was synthesized to introduce

hydrophobic property and investigated for its drug release

retarding property with reference to FG. The reaction was

carried out in anhydrous conditions at different temperature

(40–98 �C) using NaHCO3 as a mild base catalyst and the

influences of three factors such as reagent/substrate con-

centration, reaction temperature and time on the degree of

substitution of OSFG were studied. Highly water-soluble

metoprolol succinate (MPS) and poorly water-soluble

carbamazepine (CBZ) were selected as model drug as for

release studies. It was observed that increase in reaction

temperature and reagent concentration resulted in high

degree of substitution with significant decrease in viscosity.

Reaction carried out at 98 �C for 2 h showed high degree

of substitution (0.133) with moderate retention of viscosity

compared to plain FG. FTIR, DSC, XRD, solid state

CPMAS 13C-NMR, and SEM studies provide structural

information of synthesized OSFG. MPS ER tablet prepared

with drug:OSFG:FG at the weight of 1:4:2 and CBZ ER

tablet with drug:OSFG at the weight ratio of 1:3, respec-

tively. Both formulations showed similar drug release

profile compared to marketed formulations. Optimized

tablet formulations were found to be stable under stability

condition according to ICH guidelines. It was concluded

that the developed formulations with OSFG have a release

retarding property and can be used alone or in combination

with other polymers for a controlled release.

Keywords Fenugreek gum � Octenyl succinic anhydride �Degree of substitution � Swelling � Viscosity

Introduction

In recent years, researchers have become increasingly

interested in the utilization of natural biopolymers due to

their wide ranging advantages over synthetic polymers

such as natural availability, biocompatibility, biodegrad-

able and nonimmunogenic (Bharadia et al. 2004; Srinivas

et al. 2003; Gilbert 2002; Khanna et al. 1988; Krishnaku-

mar et al. 2012; Sav et al. 2012). Chemical or enzymatic

modification of polysaccharides has been carried out to

alter the physicochemical properties for diverse applica-

tions. Majority of investigational studies on natural poly-

mers in drug delivery systems has been focused on

polysaccharides and proteins. It is reported that derivati-

zation to small degree of substitution (0.01) is sufficient

enough to change the physicochemical properties signifi-

cantly (Prashanth et al. 2006).

Hydrophilic matrix systems have been used since long

time to control the release of both water soluble and water

insoluble drugs. It is reported that drug release is function

of polymer type, polymer level and physico-chemical

nature of drug. Desired drug release profile can be achieved

by judicious combination of hydrophilic–hydrophobic

polymers and modulating the polymer content in the matrix

system (Reza et al. 2003; Gade and Murthy 2011).

Fenugreek (Trigonella foenum-graecum L. Legumino-

sae) is one of the oldest medicinal plants, originating in

India and Northern Africa. Fenugreek gum (FG) is consists

A. K. Sav (&) � R. A. Fule � M. T. Ali � P. Amin

Department of Pharmaceutical Sciences and Technology,

Institute of Chemical Technology, N. P. Marg, Matunga,

Mumbai 400019, India

e-mail: aksav.ict@gmail.com

123

Journal of Pharmaceutical Investigation

DOI 10.1007/s40005-013-0088-x

of a (1?4)-b-D-mannopyranosyl backbone having single

unit (1?6)-a0-D-galactopyranosyl side chain residues. The

leaves and seeds, which mature in long pods, are used to

prepare extracts or powders for medicinal use. In India it

used as condiment, lactation stimulant and also reported to

have hypoglycemic and antihyperlipidemic properties

(Basch et al. 2003). Fenugreek seeds contain a high per-

centage of mucilage which forms a thick viscous mass

when exposed to water.

Natural polysaccharides and its derivatives are reported to

be used as pharmaceutical excipients in formulation of liquid,

semi solid and solid dosage form. Cellulose derivatives has

been reported to be used as enteric coating, sustain release

polymer (Andreopoulos and Trantali 2002; Conti et al. 2007),

alginates as control release polymer in ophthalmic preparation

(Fuchs-Koelwel et al. 2004), gellan gum as release modifier in

ocular and oral drug delivery system (Miyazaki et al. 1999),

acacia and tragacanth are well known emulsifier, locust bean

gum and guar gum as modified release polymer in matrix

tablet formulation (Mughal et al. 2011; Kumar and Sinha

2012) and starch is reported to be used as bulking, binder,

disintegrant, controlled release polymer, film former (Ogaji

et al. 2012). An octenyl succinic anhydride (OSA) derivative

of starch has been reported for different applications in

pharmaceutical field like in ophthalmic preparation, emulsion

stabilizer and controlled release formulation (Baydoun

et al.2004; Wang et al. 2011; Tesch et al. 2002; Ntawukuli-

lyayo et al. 1996). A simple and cost effective method for

esterification of galactomanann (guar gum, tara gum and

locust bean) reported earlier was followed for synthesis of

OSA derivative of FG (Prashanth et al. 2006) and its appli-

cation in extended release drug delivery system was explored.

Through esterification process, the hydrophobic property of

OSA was introduced on FG backbone and the effect of

increasing the hydrophobicity on drug release was compared

to drug release from unmodified FG containing tablets.

The aim of current study was to synthesize OSFG with

high degree of substitution and evaluate the extended

release property of the polymer. Extended release tablet

formulations were prepared with highly water-soluble

metoprolol succinate (MPS) and poorly water-soluble

carbamazepine (CBZ) as drug models. Influence of reac-

tion parameters such as OSA/FG ratio, reaction tempera-

ture and time on the degree of substitution was also

studied. Various physicochemical properties of OSFG were

characterized including carbohydrate content, percentage

swelling, flow property, moisture content and morphology.

Materials and methods

FG (Canafen�) was obtained as a gift sample from

Emerald Seed Products Ltd., (Avonlea Saskatchewan,

Canada). Sodium bicarbonate was purchased from S.D.

Fine Chem-Limited (Mumbai, India). OSA, MPS and CBZ

was obtained as gift sample from Amit hydrocolloids,

Sweta Pharma Pvt. Ltd. (Mumbai, India) and Bajaj Health

Care Ltd. (Mumbai, India) respectively. All other chemi-

cals and reagents of analytical grades were used.

Synthesis of OSFG

In brief, finely ground FG sample (1–1.5 g) and solid

NaHCO3 (2–3 g) were surface wetted with absolute etha-

nol (99 %, 0.5–1 ml) and mixed well. OSA (2–5 ml) was

drop wise added and mixed well to give homogenous

mixture. This reaction mixture was kept at different tem-

perature namely 40 �C, 60 or 98 �C for 2–4 h. After

completion of reaction, the mixture was mixed with 50 %

ethanol (10 ml) followed by pH neutralization to pH 7 by

adding dilute HCl acid and centrifuged at 10,000 rpm for

10 min. The sediment was repeatedly washed with 75 %

ethanol followed by absolute ethanol and finally dried in

oven at 60 �C for 4 h. Product was initially identified by

thin layer chromatography method (TLC) in chloroform

and dichloromethane mixture (1:3).

Determination of total carbohydrate and viscosity

Total carbohydrate content was determined by the phenol–

H2SO4 method (Sadasivam and Manickam 2005; Dubois

et al. 1956). Viscosity of 1 % aqueous and modified FG

samples was determined in a Brookfield viscometer (UK)

with RVT model spindle no. 27 at 25 �C and 20 rpm. The

apparent viscosity was calculated using the constants pro-

vided by the manufacturer.

Determination of degree of substitution (DS) of OSA-

modified FG

The DS of OSFG was determined by titration method (Hui

et al. 2009; Kweon et al. 2001). An OSFG sample (5 g, dry

weight) was accurately weighed and dispersed in 25 ml of

2.5 M HCl isopropyl alcohol (IPA) solution by stirring for

30 min 100 ml of 90 % v/v IPA in water was added with

stirring for 10 min. This suspension was filtered through a

glass filter and filter cake was washed with 90 % v/v IPA

until the filtrate was negative for Cl- ions (checked with

0.1 N silver nitrate). Filter cake was further dispersed in

300 ml distilled water and cooked in a boiling water bath

for 10 min. After heat treatment, OSFG solution was

titrated with 0.1 M standard NaOH solution, using phe-

nolphthalein as an indicator. A blank was simultaneously

titrated with FG sample. The DS was calculated by the

following equation:

A. K. Sav et al.

123

DS ¼ 0:162 � A � M=W= 1� 0:210� A�Mð Þ� =W ð1Þ

where A is the titration volume of NaOH solution (ml), M

is the molarity of NaOH solution and W is the dry weight

(g) of the OSFG.

Physicochemical properties of OSFG

Acid insoluble matter was determined by sulphuric acid

treatment method. In brief, about 1.5 g of gum sample was

transferred to a 250 ml beaker containing 150 ml water and

1.5 ml of sulfuric acid. The mixture was heated on a steam

bath for 6 h by covering the beaker with watch glass to

prevent water loss and replacing any water lost during

heating. At the end of the 6 h heating period, 500 mg talc

as a filter aid was added and filtered through a suitable

preweighed, ashless filter. Residue was washed several

times with hot water and the residue was dried at 105 �C

for 3 h. The amount of acid insoluble matter was calculated

by subtracting the weight of filter aid from that of the

residue. Loss on drying was determined by heating at

105 �C for 5 h (USP 32). Ash content was determined

thermogravimetricaly by heating in a furnace at 550 �C for

5 h. Protein content was determined by nitrogen content

(N 9 6.25) by Kjeldhal’s method. Galactomannan content

was determined by subtracting the total percentages of loss

on drying, total ash, acid insoluble matter and protein from

100.0. Particle size distribution was analyzed by mechan-

ical sieve analysis method. The bulk density and tapped

bulk density was determined by using density apparatus

(VEEGO, India). Hausner’s ratio was calculated from the

obtained density values. Flow property was evaluated in

terms of angle of repose value by fixed funnel method (Sav

et al. 2013).

Microbial count

The microbial count of the FG and OSFG was performed

as specified in the Indian Pharmacopoeia for the presence

of bacteria and fungi. Total count of bacteria and fungi was

calculated using plate count method.

Swelling behaviour of FG and OSFG

Swelling behavior was evaluated by reported method with

some modification (Moussa et al. 1998). A weighed

quantity of gum sample was incubated at 37 �C for 24 h in

purified water, 0.1 M HCl (pH 1.2) and 0.1 M phosphate

buffer (pH 6.8). For incubation, samples were placed in

100 ml graduated glass cylinder containing 100 ml of

media. The percentage swelling (S %) was calculated by

following equation:

S %ð Þ ¼ Initial volume of gum=

final volume of swollen gum � 100 ð2Þ

Fourier transform infrared spectroscopy (FTIR)

The change in the chemical structure of FG was qualita-

tively evaluated by FTIR spectroscopy method. FG and

OSFG were compressed with KBr in hydrostatic pressure

to give a disk of uniform size. FTIR spectra of samples

were recorded using PERKIN ELMER FTIR spectropho-

tometer (Spectrum RX1, USA). Samples were scanned

between 400 and 4,000 cm-1 and the resolution was

4 cm-1.

Solid state CPMAS 13C- NMR

The solid state 13C-NMR spectra was recorded in a Bruker

AV 300 MHz NMR spectrometer using 4 mm CPMAS

probe at spinning speed of 10 kHz (Germany). The

chemical shifts (ppm) were measured from the intensity of

the peaks. Approximately 300 mg of dry sample was used

for analysis. The cross polarization sequence was utilized

for all samples, which were spun at magic angle at 10 kHz,

a constant time of 2 ms and a pulse (repetition) time of

5 ms with more than 1,000 scans being accumulated for

each spectrum.

Differential scanning calorimetry (DSC)

DSC analysis was performed to evaluate change in thermal

property of modified gum as compared to gum and char-

acterized using PERKIN ELMER DSC Pyris-6 (USA).

Samples were heated in an open aluminum pan at a rate of

10 �C min-1 within a 30–350 �C temperature range under

a nitrogen flow of 20 ml min-1. An empty sealed pan was

used as a reference.

Scanning electron microscopy (SEM)

Morphological evaluation of gum and modified gum was

performed by using JSM-6380 LA scanning electron

microscope (ZEOL Ltd., Tokyo, Japan). Samples were

fixed on an aluminum stub with conductive double sided

adhesive tape and coated with gold in an argon atmosphere

(50 Pa) at 50 mA for 50 s. The samples were scanned at a

voltage of 20 kV.

X-ray diffraction study (XRD)

The powder X-ray diffraction patterns were recorded using

Jeol JDX 8030 X-ray diffractometer (Tokyo, Japan) using

Ni filtered, CuKa radiation, a voltage of 40 kV and a

Synthesis and evaluation of octenyl succinate anhydride derivative of fenugreek gum

123

25 mA current. The samples were scanned between 0 and

90� diffraction angle (2h) range at a rate of 1� min-1.

Matrix tablet formulation development

Drug–excipients interaction

An FTIR study was performed to check the chemical

compatibilities between drug and excipients used in tablet

formulation. An infrared spectrum of pure drug and

1 month stored tablet formulation prepared from drug–

excipient mixture was recorded. A change in spectrum

pattern of pure drug will be an indication drug–excipients

interaction.

Preparation of matrix tablets

A matrix table contains core of drug and shell polymer

(OSFG). Matrix tablet was prepared by wet granulation

method using Povidone K90 as intragranular binder to

impart sufficient binding strength to the powder mixture.

Drug and excipients along with OSFG were sieved through

40 mesh and granulated using IPA as granulating agent.

The wet cohesive mass was dried in oven at 60 �C for 4 h

and sieved through 60 mesh. Dried granules were mixed

with magnesium stearate (lubricant) for 5 min and com-

pressed into a tablet of various sizes (9–12 mm) by using

single punch tableting machine (Cadmach, India).

Drug content determination

For MPS formulation, an amount of finely powdered tablet

equivalent to 20 mg of MPS was taken in 100 ml volu-

metric flask and dissolved in distilled water to make up the

volume to 100 ml. The mixture was then filtered to remove

the undissolved particle. Absorbance of the filtrate was

measured at 223 nm using double beam UV/visible spec-

trophotometer (Shimadzu, UV-1650, Tokyo, Japan) (Akter

et al. 2012). For CBZ formulation, an amount (50 mg) of

finely powdered tablet mixture was suspended in 50 ml

methanol to extract the CBZ content. The suspension

mixture was sonicated for 15 min in an ultra sonication

bath and centrifuged for 15 min at 4,000 rpm. This solu-

tion mixture was filtered through a 0.5 lm filter and

absorbance was measured after suitable dilution of super-

natant using UV spectroscopy at 285 nm (Barakat et al.

2009). Each determination was performed with three

powdered samples.

Water uptake (swelling) of compacted matrix tablets

Swelling property of matrix tablet was evaluated as water

uptake determined gravimetrically (Doddayya et al. 2011).

Weighed matrix tablet formulations were placed in small

baskets and soaked in vessels containing 100 ml of

respective dissolution medium kept at 37 ± 1 �C. After

24 h, the previously weighed baskets containing the tablets

were removed, gently wiped with a tissue to remove excess

surface water and reweighed. The degree of swelling was

calculated according to the following equation:

Degree of swelling ¼Final weight of matrix tablet after 24 h

� initial weight of matrix tablet=

final weight of matrix tablet after 24 h ð3Þ

Invitro drug release

Invitro dissolution studies of MPS formulation was carried

out as per specified in USP 30 using USP dissolution

apparatus type II at 50 rpm for total period of 20 h using

500 ml of phosphate buffer of pH 6.8. Aliquot of 5 ml was

withdrawn at time intervals of 1, 4, 8, 20 h and same

amount was replaced with fresh dissolution medium. For

CBZ formulation, dissolution was performed in USP dis-

solution apparatus II (Veego, India). Dissolution vessel

consists of 900 ml water maintained at 37 ± 0.5 �C at

100 rpm. Aliquots of 10 ml were withdrawn at 3, 6, 12,

24 h and replaced with equal volumes of fresh dissolution

medium. Samples were analyzed by UV spectroscopy

method at 223 nm for MPS and 285 nm for CBZ. The

optimized drug release profiles for both the drugs were

fitted into different mathematical models to investigate the

drug release mechanism from dosage form. Dissolution

was performed in triplicate.

Results and discussion

Synthesis of OSFG

Esterification of polysaccharides generally carried out in

presence of strong base catalyst such as NaOH, KOH,

pyridine or triethylamine at elevated temperature. Use of

these strong alkali at elevated temperature are associated

with some disadvantages like alkali degradation of poly-

saccharides and other reagents that may lead to reduced

molecular weight, incomplete derivatization or derivative

with undesired functionalities. In this work, esterification

of FG was carried out with NaHCO3 as a mild catalyst in

anhydrous condition to avoid such undesired results.

Mechanism involves initial formation of alkali–polysac-

charides complex (polycarbanion) followed by reaction

with reagent to form esters of different degree of substi-

tution depending on reaction condition (temperature, time,

substrate/reagent ratio) (Fig. 1). The reactivity of branched

A. K. Sav et al.

123

macromolecules to forms a polycarbanion varies, the pri-

mary –OH at C6 being most reactive followed by sec-

ondary –OH at C2 and C3. Results for reaction carried out

at two different gum: catalyst: reagent ratio (namely, 1:2:2

and 1.5:3:5) were tabulated in Table 1. It was found that

increase in substrate concentration showed increase in DS

due to availability of more hydroxyl group in substrate for

substitution. Reaction carried out at different temperature

gives varying degree of substitution for e.g. DS at 40 �C

was found to be low with moderate retention of viscosity

about 60 % but as the reaction was carried out at higher

temperature (98 �C), degree of substitution increased but at

the same time viscosity also reduced significantly. This was

probably due to pH-induced alkaline degradation and these

results are in agreement with earlier report stating that at

higher temperature, molecular weight decreases. DS was

decreased as the reaction duration was further increased

from 2 to 4 h. This reduction can be explained as follows;

as the reaction progresses, the concentration of OSA in

reaction is depleted due to esterification and hydrolysis of

OSA as well as the derivatized product.

Varying the reagent concentration also has profound

effect on DS and viscosity. The DS increases with presence

of more concentration of reagent but viscosity was also

reduced significantly. Thus for further studies, reaction

condition gum:catalyst:reagent ratio 1.5:3:5, reaction time

2 h and temperature 98 �C was selected as it gives high

degree substituted FG with moderate retention of viscosity.

The product was characterized for physicochemical prop-

erties and evaluated for its release retarding property in

extended release formulation.

Physicochemical characterizations of FG and OSFG

Table 2 indicates that derivatized gum has similar physical

characteristics to that of gum. Slight decrease in galacto-

mannan content was observed which might be due to its

alkaline degradation. All other parameters like %LOD,

acid insoluble matter, and total ash was found to be in limit

range as led by quality standards of Indian medicinal

plants. Viscosity of gum was found to be 600 cps. Angle of

repose value was less in case OSFG as compared to FG

Fig. 1 Substitution reaction mechanism

Table 1 Effect of reaction

parameters on degree of

substitution and viscosity

(n = 3, mean ± SD)

a Gum:catalyst:reagent

G:C:Ra Temperature (�C) Time (h) DS Viscosity (cPs)

1:2:2 40 2 0.085 ± 0.005 340

40 4 0.044 ± 0.007 325

60 2 0.093 ± 0.008 320

60 4 0.088 ± 0.003 300

98 2 0.115 ± 0.018 300

98 4 0.105 ± 0.015 250

1.5:3:5 40 2 0.098 ± 0.005 320

40 4 0.102 ± 0.017 300

60 2 0.118 ± 0.022 300

60 4 0.115 ± 0.013 280

98 2 0.133 ± 0.015 280

98 4 0.131 ± 0.012 250

Table 2 Physicochemical properties of FG and OSFG

Constituents FG (%) OSFG (%)

Acid insoluble matters 2.5 3 %

% Loss on drying (LOD) 0.3 0.32

Protein 8.3 7.88

Soluble galactomannan (dietary fiber) 78.3 73.12

Total ash 0.5 1

Angle of repose(h) (flow property) 20.67 14.69

Bulk density (g cc-1) 0.588 0.666

Tapped density (g cc-1) 0.714 0.769

Hausner’s ratio 1.21 1.15

Moisture content (%) 13.27 15.21

Microbial count for bacteria (cfu g-1) 9 7

For fungi (cfu g-1) 2 1

pH 6.6 7

Particle size (mesh) 80–150 60–150

Synthesis and evaluation of octenyl succinate anhydride derivative of fenugreek gum

123

which indicated good flow property of modified FG.

Microbial limit was found to be in acceptable limits as

specified by Herbal Pharmacopeia of India.

Swelling behavior of FG and OSFG

Swelling property of gum and OSFG were evaluated in

different aqueous medias such as water, pH 1.2 buffer

(0.1 N HCl) and pH 6.8 buffer to check the effect of sub-

stitution on FG. Studies revealed that OSFG has slightly

decreased swelling property as compared to the FG due to

presence of hydrophobic substituent (Fig. 2). The swelling

capacity was found to be higher in pH 1.2 media indicates

suitability for gastro retentive modified drug release system.

FTIR

An FTIR spectrum provides a rapid and reliable analytical tool

for evaluating substitution in modified gum. Introduction of

substituent groups in esterified FG clearly indicated by presence

of –C=O absorption around 1,336 cm-1 (1,730–1,750 cm-1)

which is absent in FG. A peak at 1,570 cm-1 ascribing the

asymmetry stretching of RCOO- indicates that derivative

product was synthesized as FG sodium octenyl succinate. There

was an increment in the absorption due to carbon–hydrogen

bending (C–H) at 1,384 cm-1 in the acetyl group compared to

those of FG (Fig. 3). The absorption band at 1,019 cm-1 (guar)

got shifted to 1,034 cm-1 (succinylated gum) due to C–O

stretching in C–O–C linkage. Absence of peaks in the region

1,850–1,750 cm-1 indicated that the product is free of unre-

acted anhydrides and their byproducts (respective acids).

Solid state CPMAS 13C-NMR

Structure of esterified FG was further characterized by

CPMAS 13C-NMR spectroscopy (Fig. 4). Spectrum of FG

showed C1 (mannose) around 101.08 ppm and 95.24 ppm

for C1 (galactose). Signals between 60 and 85 ppm were

assigned to different carbon chains of the mannose back-

bone as well as galactose side chains. At 81.72 ppm C4, C5

and C6 of branched mannose unit was seen overlapping.

The 63.29 ppm signal was due to C6 (mannose and gal-

actose). A strong signal at 23.35 ppm was characteristic of

methyl of an acetyl group, at 178.80 and 183.72 ppm

indicates presence of carbonyl group (R–CO–O) which

confirms the modification in gum. Signal around

129–134 ppm showed presence aliphatic carbon side chain

of octenyl group (RC=CH2). Similarly presence of several

peaks around 14–37 ppm and 40–70 ppm indicated octenyl

derivatization of FG.

DSC

FG showed a broad endothermic peak around 50–100 �C,

indicates loss of associated moisture content. A sharp

endothermic peak at 180–182 �C was observed in OSA

substituted FG whereas it was absent in gum (Fig. 5). This

endothermic peak was due to decarboxylation of succinic

acid anhydride group present in octenyl succinate substi-

tuted FG. Succinic acid anhydride gets decarboxylated at

185–187 �C which confirms the introduction of hydro-

phobic group in hydrophilic FG.

X-ray diffraction study

X-ray diffractogram study was performed to predict the

physical state of and modified gum. Absence of X-ray

diffraction peak in gum indicated that gum was present as

amorphous state whereas octenyl succinated FG showed

presence of several intense peaks at two theta values (2h)

of 6.876, 10.335, 18.178, 19.379, 20.766, 22.718, 24.12,

and 27.617 confirms the change in physical state to crys-

talline (Fig. 6). This observation is agreement with the

earlier results obtained by researcher who mentioned that

the esterification occurred primarily in the amorphous

regions.

SEM

Change in morphological characteristic of succinylated FG

as compared to FG shown in Fig. 7. FG particles present as

irregular size and shape with smooth surface whereas

OSFG particles also present as irregular shape but surface

was found to be rough as compared FG indicates surface

modification during derivatization process.

Formulation development

Drug–excipients interaction

Pure MPS showed C–O stretching (primary alcohol) at 1,049,

C–O stretching in C–O–C 1,114 cm-1, at 1,240 cm-1 C–O

0102030405060708090

FG OSFG

% Swelling

Water

pH 1.2

pH 6.8

Fig. 2 Swelling behavior of FG and OSFG

A. K. Sav et al.

123

stretching in C=C–O–C, C=C aromatic ring stretching

1,563 cm-1, N–C major peaks at 3,147 cm-1. CBZ pure drug

showed characteristic absorption bands at 3,465 cm-1 (NH

stretching of CO–NH2), 3,020 cm-1 (aromatic CH stretch-

ing), 1,677 cm-1 (C=O stretching of CO–NH2), 1,604 cm-1;

1,488 cm-1 (C=C ring stretching). FTIR spectra of pure drug

and drug with tablet excipients mixture revealed retention of

the all the majors peaks at their respective absorption band

position (figure not shown). These results indicate absence of

chemical interaction between drug and OSFG.

Fig. 3 FTIR spectra of a OSFG and b FG

Synthesis and evaluation of octenyl succinate anhydride derivative of fenugreek gum

123

Formulation of extended release matrix tablet

Formulation compositions for MPS and CBZ formulation

compositions are shown in Tables 3 and 4. Before formu-

lating matrix tablets, granulated powder blends containing

respective drug and excipients mixture were evaluated for

preformulation parameters like flow property, loose bulk

density (LBD), tapped (TBD) density and they were found

to have excellent flow property (data not shown). After

formulation parameters like tablet hardness (Monsanto

Hardness Tester), thickness, diameter (Vernier Caliper),

friability testing (Roche Friabilator) and tablet weight

variation were also studied. Results depicted in Table 5 for

MPS formulation and Table 6 for CBZ formulation showed

that all the physical parameters are in acceptable pharma-

copoeial limit and showing good uniformity. Drug content

analysis showed that both the formulations contains more

than 98 % drug.

Swelling property of matrix tablet

Swelling study for matrix tablet formulations were carried

out to investigate the extent of swelling variation with

different formulation compositions. Matrix tablets when

come in contact with water, it starts wetting at surface and

slowly leads to swelling of polymer. Swelling property is

mainly dependant on nature of polymer for e.g. hydrophilic

polymer has better swelling property than hydrophobic

polymer. It was also seen from the study that matrix table

prepared with FG has higher swellability as compared to

OSFG containing tablet formulation due more hydrophilic

nature of FG.

Invitro drug release

Synthesized OSFG has both hydrophobic and hydrophilic

property which can be used to modify the drug release.

Initially batches were taken with FG at different levels of

loading (batches F1–F4). Invitro drug release studies

indicated that matrix tablets prepared with gum were

unable to control the drug release in all ratios and MPS

formulation showed more than 70 % drug release in first

1 h. High water solubility nature of MPS causes rapid

diffusion of the dissolved drug through the hydrophilic gel

layer whereas CBZ formulations shows retarded drug

release as the level of gum increases because it did not

dissolve in dissolution medium and diffusion through

hydrophilic gel barrier was also slow. Release profile

obtained for both the drugs were not as per desired speci-

fication, thus it indicated the need for polymer having

Fig. 4 Solid state CPMAS 13C-

NMR of a FG and b OSFG

A. K. Sav et al.

123

hydrophobic property in addition to hydrophilic property to

control the drug release for the extended period. Further

MPS batched were taken with OSFG alone(F5–F7), F5 and

F6 showed about 50 % drug release in first hour whereas

F7 releases 25 % drug release in same time but in all the

cases release was not sustained for 20 h (data not shown).

Combination of FG and OSFG were also investigated due

to undesirable release profile obtained from earlier batches.

F8–F10 batches prepared with combination of FG and

OSFG showed slow drug release sustained for 20 h

(Fig. 8a). This effect might be due to presence of hydro-

phobic group which restrict the penetration of dissolution

medium inside the matrix and prevents the diffusion of

drug through hydrophilic gel barrier of FG. F10 exhibited

similar drug release profile as marketed formulation Selo-

ken� XL 50 mg. Figure 8b, CBZ formulation F6–F7 pre-

pared with OSFG alone showed highly retarded drug

release. This can be explained as follows; the presence of

hydrophobic group in OSFG facilitated the drug release

and it was sustained for 24 h by slow diffusion through

Fig. 5 DSC thermogram of

a FG and b OSFG

Synthesis and evaluation of octenyl succinate anhydride derivative of fenugreek gum

123

hydrophilic gel barrier of OSFG. F7 exhibits similar drug

release profile as marketed formulation Tegretal� 200 CR.

Studies suggested that drug release behavior depends on

nature of drug, polymer type and concentration of polymer

which is in agreement with earlier work. It was also

observed that water soluble drug release is faster than water

insoluble drug. This study also suggested that polymer

containing both property can act as better modulating agent

for drug release as compared to polymer with single

property (Ganesh et al. 2008). Similarity factor (f2) was

found 79.19 for MPS formulation (F10) and CBZ (F5)

showed 50.74 indicating the extent of similarity in drug

release profile between developed and marketed

formulation.

Release kinetic study

The n (diffusion exponent) and r2 values for zero order,

first order, Higuchi, Peppas and Hixson Crowell models for

both the optimized batches are given in Table 7. The

kinetic model that best fitted the Invitro release data was

selected based on the correlation coefficient value (r2)

obtained from various kinetic equations. Invitro drug

release data was best fitted to Korsmeyer–Peppas equation

followed by first order release. Literature also reported that

natural polymer containing matrix tablet formulation

exhibits such type of release mechanism (Chandrasekhar

et al. 2011; Kumar et al. 2012). It suggest that drug release

mainly took place through combination mechanism of

diffusion and erosion of polymer whereas as per n value

(diffusion exponent, [0.89), it follows super case trans-

port-2 or case-2 relaxation mechanism suggesting erosion

mechanism.

Fig. 6 X ray diffractogram of

a FG and b OSFG

Fig. 7 Scanning electron micrograph of a FG and b OSFG

A. K. Sav et al.

123

Table 3 Formulation compositions of metoprolol succinate extended release tablet

Ingredients F1 F2 F3 F4 F5 F6 FV7 FV8 F9 F10

MPS 50 50 50 50 50 50 50 50 50 50

FG 50 100 150 200 100 150 100

OSFG 50 100 200 100 150 200

Avicel PH 101 122.5 72.5 22.5 3.65 122.5 72.5 3.65 3.65 3.65 3.65

Povidone K90 25 25 25 28.5 25 25 28.5 28.5 28.5 28.5

Magnesium stearate 2.5 2.5 2.5 2.85 2.5 2.5 2.85 2.85 2.85 2.85

Total (mg) 250 250 250 285 250 250 285 285 385 385

Table 4 Formulation composition of CBZ extended release tablets

Ingredients F1 F2 F3 F4 F5 F6 F7

CBZ 200 200 200 200 200 200 200

FG 100 200 300 400 200

OSFG 200 400 200

Avicel PH 101 21.5 20.5 19.5 18.5 21.5 18.5 18.5

Povidone K90 25 25 25 25 25 25 25

Magnesium stearate 3.5 4.5 5.5 6.5 4.5 6.5 6.5

Total (mg) 350 450 550 650 450 650 650

Table 5 Physical characteristics of MPS tablet formulations (mean ± SD, n = 3)

Formulation Average weight (mg) Thickness (mm) Diameter (mm) Hardness (kg cm-2) Friability (%) Drug content (%)

F1 246.5 ± 0.2 3.55 ± 0.03 9.27 4–5 0.88 ± 0.22 98.15 ± 0.5

F2 248.5 ± 0.3 3.46 ± 0.04 9.38 4–5 0.78 ± 0.25 99.35 ± 0.75

F3 249.5 ± 0.18 3.34 ± 0.05 9.30 4–5 0.85 ± 0.14 98.33 ± 1.5

F4 282.1 ± 0.23 3.36 ± 0.04 9.27 5–6 0.67 ± 0.05 99.45 ± 1

F5 248.2 ± 0.24 2.67 ± 0.05 9.18 4–5 0.93 ± 0.13 98.27 ± 0.5

F6 247.0 ± 0.16 2.65 ± 0.04 9.18 4–5 0.87 ± 0.14 99.22 ± 1.5

F7 284.3 ± 0.24 3.48 ± 0.03 9.57 5–6 0.67 ± 0.22 97.89 ± 1.3

F8 283.6 ± 0.19 3.39 ± 0.06 9.37 6–7 0.57 ± 0.14 98.35 ± 0.8

F9 384.6 ± 0.20 3.98 ± 0.07 10.47 6–7 0.65 ± 0.24 99.45 ± 0.8

F10 384.5 ± 0.24 3.88 ± 0.03 10.57 6–7 0.62 ± 0.24 98.34 ± 1

Table 6 Physical characteristics of CBZ tablet formulation (mean ± SD, n = 3)

Formulation Average weight (mg) Thickness (mm) Diameter (mm) Hardness (kg cm-2) Friability (%) Drug content (%)

F1 347.2 ± 0.2 4.62 ± 0.03 10.42 5.6 0.68 ± 0.12 98.35 ± 0.40

F2 448.0 ± 0.3 4.91 ± 0.04 10.50 5–6 0.58 ± 0.25 99.15 ± 0.55

F3 549.5 ± 0.1 5.09 ± 0.03 10.40 5–6 0.65 ± 0.14 99.40 ± 0.45

F4 649.1 ± 0.2 5.40 ± 0.04 12.57 5–6 0.60 ± 0.05 97.25 ± 0.45

F5 448. ± 0.14 4.87 ± 0.4 10.47 5–6 0.67 ± 0.13 97.17 ± 0.70

F6 648.0 ± 0.1 6.05 ± 0.04 12.60 5–6 0.77 ± 0.14 99.32 ± 0.75

F7 648.0 ± 0.2 6.08 ± 0.05 11.28 6–7 0.68 ± 0.23 99.15 ± 0.80

Synthesis and evaluation of octenyl succinate anhydride derivative of fenugreek gum

123

Conclusion

FG being a polysaccharide can be used after chemical or

enzymatic modification to alter physicochemical properties

to vary its application in drug delivery system. In this study,

OSA derivative of FG was synthesized using NaHCO3 a

mild catalyst in anhydrous condition. The highest degree of

substitution achieved was 0.133 with reduced viscosity to

half of the gum due to introduction of hydrophobic group.

XRD and DSC studied indicated change in physical state of

gum amorphous to crystalline. The developed hydrophobic

derivative of FG has good release retarding property. Invitro

drug release study also suggested that depending upon type

of drug and judicious selection of combination polymer

with both hydrophilic and hydrophobic property can pro-

vide desired drug release profile.

Acknowledgments This article does not contain any studies with

human and animal subjects performed by any of the authors. And all

authors (AK Sav, RA Fule, MT Ali and P Amin) declare that they have no

conflict of interest. Authors are thankful to Department of Biotechnology,

India for fellowship during work. Amit hydrocolloids for generous

gift sample of octenyl succinic anhydride. Dr. Ramesh Joshi and

Dr. P.R. Rajamohanan from National Chemical Laboratory (N.C.L.),

Pune, India for their kind help in performing 13C NMR analysis.

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20

40

60

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% D

rug

Rel

ease

Time (h)

Seloken® XL 50mg

F10

F9

0

20

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0 10 20 0 10 20 30

% D

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Rel

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Time (h)

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