ORIGINAL PAPER

Development of hollow/porous floating beads of metoprololfor pulsatile drug delivery

Sangmesh S. Taranalli • Panchaxari M. Dandagi •

Vinayak S. Mastiholimath

Received: 24 April 2013 / Accepted: 25 March 2014

� Springer International Publishing Switzerland 2014

Abstract The purpose of this work was to develop hol-

low calcium pectinate beads for floating pulsatile release of

metoprolol tartrate intended for chronopharmacotherapy.

Floating pulsatile concept was applied to increase the

gastric residence of the dosage form having lag phase

followed by a burst release. To overcome limitations of

various approaches for imparting buoyancy, hollow/porous

beads were prepared by simple process of acid-base reac-

tion during ionotropic cross-linking using low methoxy

pectin, xanthan gum, sodium carboxy methyl cellulose,

guar gum, locust bean, gellan gum and calcium chloride as

a cross-linking agent. Based on the preliminary studies

optimized polymers were selected for formulation design

with different polymers ratio concentrations. The obtained

floating beads were studied for entrapment efficiency,

buoyancy study, swelling index, surface morphology,

in vitro release, stability studies and in vivo floating study.

The floating beads obtained were porous, float up to

12–24 h. The radiological studies (X-rays) pointed out the

capability of the system to release drug in lower parts of

GIT after a programmed lag time for hypertension. The

floating beads provided expected two-phase release pattern

with initial lag time during floating in acidic medium fol-

lowed by rapid pulse release in phosphate buffer. From the

accelerated stability studies, it was observed that the for-

mulations are quite stable. All formulations followed first-

order release kinetics by diffusion mechanism. This

approach suggested the use of hollow calcium pectinate

microparticles as promising floating pulsatile drug delivery

system for site- and time-specific release of drugs acting as

per chronotherapy of diseases.

Keywords Hollow beads � Calcium pectinate beads �Floating pulsatile drug delivery � Metoprolol tartrate �Chronotherapy � Radiology

1 Introduction

A delivery system with a release profile that is character-

ized by a time period of no release (lag time) followed by a

rapid and complete drug release (pulse release) can be

called as an ideal pulsatile drug delivery system. Pulsatile

delivery system provides one or more rapid release pulses

at predetermined lag times or at specific sites resulting in

better absorption of the drug, and there by providing more

effective plasma concentration time profile (Venkatesh

2005). Natural biodegradable polysaccharides like pectin,

locust bean, guar gum, chitosan, sodium alginate and gellan

gum have been used in controlled drug delivery. Various

approaches to induce buoyancy in cross-linked beads have

been used (Whitehead et al. 2000; Iannuccelli et al. 1998;

Sriamornsak and Nunthanid 1999). The use of sodium

bicarbonate as buoyancy imparting agent to produce

floating beads is simplest among the various approaches

and has been attempted successfully by many workers

(Bussmer et al. 2003). Their floating property was based on

the evolution of CO2 when in contact with acidic envi-

ronment followed by the ability of polymer gel to entrap it,

which decreases their density below one. These beads have

been used to achieve prolonged gastric residence time, for

sustained release/stomach-specific drug delivery providing

S. S. Taranalli (&) � P. M. Dandagi

Department of Pharmaceutics, KLEU’s College of Pharmacy,

Belgaum 590010, Karnataka, India

e-mail: sangamesh369@yahoo.com

V. S. Mastiholimath

Department of Quality Assurance, KLEU’s College

of Pharmacy, Belgaum, India

Eur J Drug Metab Pharmacokinet

DOI 10.1007/s13318-014-0194-9

an opportunity for both local and systemic drug action

(Rajnikanth et al. 2007).

In cardiovascular disease, capillary resistance and vas-

cular reactivity are higher in the morning and decreases

latter in the day. Platelet agreeability is increased and

fibrinolytic activity decreased in the morning, leading to a

state of relative hypercoagulability of the blood. Therefore,

the frequencies of myocardial infarction (MI) and of sud-

den cardiac death are more prone from morning to noon.

Ambulatory blood pressure measurements show a signifi-

cant circadian variation to characterize blood pressure.

Increased heart rate, blood pressure, imbalanced autonomic

tone, and circulating level of catecholamines controlling

the cardiac arrhythmias show important circadian variation

and trigger the genesis of the circadian pattern of cardiac

arrhythmias. Atrial arrhythmias appear to exhibit circadian

pattern usually with a higher frequency in the daytime and

lower frequency in the night time with the abnormal foci

under the same long-term autonomic regulation as normal

pacemaker tissue. According to study, ventricular tach-

yarrhythmias show late morning peak in the patients with

MI sometime in the distant past morning peak and after-

noon peak in patients with recent MI. Both pharmacoki-

netics and pharmacodynamics of some oral nitrates,

calcium channel blocker and b-adrenoceptor antagonist

medications have been shown to be influenced by the cir-

cadian time of their administration (Mandal et al. 2010).

Metoprolol is a cardioselective b1-adrenergic blocking

agent used for acute MI, heart failure, angina pectoris and

mild to moderate hypertension. It may also be used for

supraventricular and tachyarrhythmias and prophylaxis for

migraine headaches. Metoprolol competes with adrenergic

neurotransmitters such as catecholamines for binding at

beta (1)-adrenergic receptors in the heart. Beta (1)-receptor

blockade results in a decrease in heart rate, cardiac output,

and blood pressure (Metoprolol tartrate (internet) 2012).

All beta blockers are nearly equally effective in decreasing

frequency and severity of attacks and in increasing exercise

tolerance in classical Angina, but cardioselective agents.

Long-term b-blocker therapy lowers risk of sudden cardiac

death among ischemic heart disease patients. In angina

pectoris, beta blockers are to be taken on a regular schedule

not on as and when required basis (Tripathi 2008).

It is moderately lipophilic drug belonging to class I of

BCS classification having high solubility and high perme-

ability. Since the half-life of metoprolol tartrate is 3–4 h,

two multiple doses are needed to maintain a constant

plasma concentration for a good therapeutic response and

improved patient compliance (Metoprolol tartrate (internet)

2012). Although it is well absorbed in the gastrointestinal

tract, its bioavailability is 40–60 % as a result of extensive

first pass metabolism (Metoprolol (internet) 2012). Thus,

there is a strong clinical need and market potential for a

dosage form that will deliver metoprolol tartrate in a

controlled manner to a patient needing this therapy, thereby

resulting in a better patient compliance.

Multi-particulate or multiple unit systems offer various

advantages over single-unit systems. These include no risk

of dose dumping, flexibility of blending units with different

release patterns, relative merits of bioavailability more

consistent blood levels, reproducible and avoid all or none

effect. The aim of the study was to design and characterize

hollow/porous floating beads of metoprolol tartrate for

pulsatile drug delivery for the treatment of hypertension.

2 Materials and method

2.1 Materials

Low methoxy pectin (LMP) was obtained as generous gift

sample from Krishna Pectins Pvt. Ltd., Jalgaon, Maha-

rashtra, India. Metoprolol tartrate was obtained as generous

gift sample from Astrazeneca Pharmaceuticals Pvt. Ltd.,

Bangalore (India). Xanthan gum, Sodium CMC, Guar gum

Locust bean, Gellan gum and Sodium bicarbonate from Hi-

media Laboratories Pvt. Ltd., Mumbai, and Calcium

Chloride from Loba Chem Pvt. Ltd., Mumbai. All other

chemicals used were of analytical grade.

2.2 Method

2.2.1 Formulation of metoprolol tartrate beads

2.2.1.1 Preliminary studies for selection of polymer com-

bination Four formulations were prepared using different

polymers as shown in Table 1.

Evaluation parameters such as drug entrapment effi-

ciency, buoyancy study of the beads and in vitro drug

release for the formulated beads were done and the

promising batch was selected on the basis of above

parameters for the further study.

2.2.1.2 Ionotropic gelation/bead formation A polymeric

solution was prepared by dissolving various amounts of

polymers in 15 ml of deionized water. Then, gas-forming

agent, such as sodium bicarbonate and metoprolol tartrate

(100 mg), was added into the solution (Table 2). The dis-

persion was sonicated for 30 min to break the lumps and to

remove air bubbles. The resultant dispersion was dropped

via a 21-gauge syringe needle into 3 % w/v calcium

chloride (CaCl2) solution containing 10 % (v/v) acetic

acid. The distance between the tip of the needle and the

surface of the CaCl2 medium was about 6 cm. The beads

formed were stirred at 150 ± 5 rpm using magnetic stirrer

for 15 min for curing. The beads were separated by

Eur J Drug Metab Pharmacokinet

filtration, washed three times with distilled water and

subsequently oven dried at 45 �C for 6 h (Dupuis et al.

2006).

2.2.2 Characterization of beads

2.2.2.1 Particle size analysis and surface morphol-

ogy 100 beads were analyzed for their size distribution by

optical microscopy. The mean diameter was determined by

measuring the number of divisions covered by beads using

ocular micrometer previously calibrated using stage

micrometer. The surface Morphology was analyzed with a

scanning electron microscope (JEOL JSM-6360 SEM)

operated at an acceleration voltage of 5 kV (Pornsak et al.

2005; Gadad et al. 2009).

2.2.2.2 Determination of drug entrapment effi-

ciency Accurately weighed quantities (50 mg) of beads

from each batch were placed in 100 ml phosphate buffer, pH

7.4 and mechanically agitated on shaker at 200 rpm for 24 h.

The resultant dispersions were filtered and analyzed spectro-

scopically at 224 nm. The percentage entrapment efficiency

was calculated using following equation (Claire et al. 2011).

Drug entrapment efficiency %

¼ Actual drug content in the beadsð=theoretical drug contentÞ � 100:

2.2.2.3 Bead porosity and bulk density The bead porosity

was assessed using mercury porosimetry (Autoscan 60

Porosimeter, Quantachrome software, USA). The pressure

was applied from 0 to 6,000 psi. The mercury intrusion

data were recorded and plotted against pressure. Standard

values for the contact angle and surface tension of mercury

were used for calculations. The bulk densities of the beads

were also measured using same mercury porosimeter

(Bulgarelli et al. 2002).

2.2.2.4 Buoyancy study Floating property of beads was

evaluated using USP XXIII type II dissolution test apparatus

(Electrolab TDT-06P, Mumbai, India) filled with 900 ml in

pH 1.2 containing 0.02 % w/v Tween 80, using paddle at a

rotation speed of 100 rpm. The temperature of medium was

maintained at 37 ± 2 �C. 100 beads of each batch were

placed in the media. Floating ability was observed visually

(Huimin et al. 2012; Mastiholimath et al. 2008).

2.2.2.5 Determination of swelling index The swelling

behavior of the beads was studied in pH 7.4 phosphate

buffer solution. Approximately 100 mg of beads was taken

in a dissolution basket and weighed; the baskets along with

the beads were immersed in 7.4 phosphate buffer solution.

The weight of the basket along with the beads was deter-

mined after 1 h, and then every hour. The swelling index

(SI) of each formulation was calculated using the following

equation (Sandolo et al. 2011; Patel et al. 2011):

%SI ¼ W2 �W1

W1

� 100

where, W1 is weight of the dry beads and basket and W2 is

weight of the swollen beads and basket.

2.2.2.6 In vitro drug release The dissolution study of

beads equivalent to 100 mg of metoprolol tartrate was

performed using a USP XXIII type 2 dissolution test

apparatus. The drug release study was performed in 900 ml

for 6 h in pH 1.2. Then the dissolution medium was

replaced with phosphate buffer of pH 6.8 for 3 h, the

average small intestinal transit time is about 3 h. After 9 h,

the dissolution medium was replaced with phosphate buffer

Table 1 Preliminary studies for selection of polymer combination

Batch

no.

Drug

(mg)

Low methoxy

pectin (mg)

Xanthan

gum (mg)

Sodium CMC

cellulose (mg)

Guar

gum (mg)

Locust

bean (mg)

Gellan

gum (mg)

Sodium

bicarbonate (mg)

FA 100 300 50 100 – – – 150

FB 100 300 50 – 100 – – 150

FC 100 300 50 – – 100 – 150

FD 100 300 50 – – – 100 150

Table 2 Formulation code for metoprolol tartrate floating beads

Batch

no.

Metoprolol

tartrate (mg)

Low methoxy

Pectin (mg)

Xanthan

gum (mg)

Locust

bean (mg)

Sodium

bicarbonate (mg)

Deionized

water (ml)

FCE 100 300 30 120 150 15

FCF 100 300 60 90 150 15

FCG 100 300 120 30 150 15

Eur J Drug Metab Pharmacokinet

of pH 7.4 maintained at 37.0 ± 0.5 �C at 100 rpm for 18 h.

Periodically 5 ml of sample was withdrawn and replaced

by dissolution media in order to maintain sink condition.

The withdrawn samples were filtered through a Wattman

filter paper 41 and the concentration of metoprolol tartrate

was measured spectrophotometrically at 221.5 and 224 nm

for acidic and basic media, respectively, after suitable

dilutions (Patel et al. 2011).

2.2.3 In vivo study

2.2.3.1 Radiology (X-rays) The optimized batch was

chosen for the preparation of the barium sulfate-loaded

beads. The barium sulfate beads were prepared as of

optimized batch but the drug was replaced with barium

sulfate (100 mg). Healthy rabbit weighing approximately

2.3 kg was used to assess in vivo floating behavior. Ethical

clearance for the handling of experimental animals was

obtained (CPCSEA). The animal was fasted for 12 h and

the first X-ray photographed to ensure the absence of radio

opaque material in the stomach. The rabbits were made to

swallow barium sulfate-loaded beads with 30 ml of water.

During the experiment, rabbits were not allowed to eat but

water was provided. At predetermined time intervals, the

radiograph of abdomen was taken using an X-ray machine

(Gangadharappa et al. 2011).

2.2.3.2 Stability study Stability study has become an

integral part of formulation development. It generates

information on which proposal for nature of drug or dosage

and their recommended storage conditions are based. The

accelerated stability study was conducted for selected for-

mulation as per the ICH guidelines.

Accelerated testing 40 ± 2 �C/75 ± 5 % RH for

6 months.

As per ICH guidelines, beads of promising formulation

were selected and subjected to accelerated stability study.

Weighed quantity of the samples was kept in glass vials,

sealed with rubber plugs and exposed to controlled tem-

perature (40 ± 2 �C) and relative humidity (75 ± 5 %) for

a period of 6 months in humidity control oven (Lab Con-

trol, Ajinkya IM 3500 Series, India).

2.2.3.3 Photo-stability study A light source that is

designed to produce an artificial daylight fluorescent lamp

combining visible and ultraviolet (UV) outputs, xenon, or

metal halide lamp is used. D65 is the internationally rec-

ognized standard for outdoor daylight as defined in ISO

10977 (1993). ID65 is the equivalent indoor indirect day-

light standard. For a light source emitting significant

radiation below 320 nm, an appropriate filter may be fitted

to eliminate such radiation. After 1, 2, 3 and 6 months, the

samples were taken out and analyzed for drug entrapment

efficiency, buoyancy study, and in vitro release (Gadad

et al. 2009; Amrutkar et al. 2012).

2.2.3.4 Release kinetics One of the most important and

challenging areas in the drug delivery field is to predict the

release of the active agent as a function of time using both

simple and sophisticated mathematical models. The impor-

tance of such models lies in their utility during both the

design stage of a pharmaceutical formulation and the

experimental verification of a release mechanism. In order to

identify a particular release mechanism, experimental data of

statistical significance are compared to a solution of the

theoretical model. To analyze the mechanism for the drug

release and drug release rate kinetics of the dosage form, the

data obtained was fitted into Zero order, First order, Higuchi

matrix and Korsmeyer-Peppas. In this study by comparing

the R2 values obtained, the best-fit model was selected.

Drug release kinetics can be analyzed by various

mathematical models, which are applied considering the

amounts of drug released from 0 to 24 h. The following

plots were made: Cumulative percentage drug release

versus time (zero-order kinetic model); log cumula-

tive percentage drug remaining versus time (first-order

kinetic model); cumulative percentage drug release versus

square root of time (Higuchi model); and log cumula-

tive percentage drug remaining versus log time (Kors-

meyer’s Peppas model) (Lin and Kawashima 1987).

3 Result and discussion

3.1 Pre-formulation study

3.1.1 Compatibility study

The FT-IR spectra of pure metoprolol tartrate and the

combination of metoprolol tartrate with the polymer show

similar characteristic functional peak. The similarity in the

peaks indicates the compatibility of metoprolol tartrate

with polymers as shown in Fig. 1.

3.1.2 Formulation of floating calcium pectinate beads

Based upon the results of preliminary study, FC formula-

tion was selected for further studies because it showed

highest entrapment efficiency of 70.89 %, produced float-

ing beads buoyancy for 24 h and highest in vitro drug

release of 96.04 %.

Three formulations (FCE, FCF and FCG) of metoprolol

tartrate beads were made. The formulations were prepared

by varying polymer ratio and keeping the concentration of

drug and other ingredients same as showed in table: the

method used to prepare the calcium pectinate beads by

Eur J Drug Metab Pharmacokinet

dripping method using 21-gauge needle into the 3 % cal-

cium chloride solution containing 10 % v/v acetic acid.

The beads were formed due to the cross-linking of the

pectin with divalent calcium ions of the calcium chloride

solution. The reaction between sodium bicarbonate and

acetic acid was occurred liberating carbon dioxide as gas

bubbles which are responsible for floating of beads.

3.1.3 Characterization of beads

3.1.3.1 Particle size analysis and surface morphol-

ogy The mean surface diameter of all three formulations

was between 1.134 ± 0.018 and 1.198 ± 0.008 (mm),

tabulated in Table 3; this indicates that size of beads

increased significantly with increase in viscosity there by

subsequent increase in interfacial tension, resulting in the

formation of larger particles.

Surface morphology of beads batch no FCF was

observed. It was shown that beads were spherical in

shape, with slightly rougher surface/shrinkage and dis-

crete as shown in Fig. 2. The surface topography reveals

that the beads were highly porous because of rapid

escape of the carbon dioxide during formulation. The

cross section of beads from batch FCF showed a hollow

core in the matrix, which may be because of the pre-

sence of gas generating agent. The thick matrix

Fig. 1 FTIR spectra

Table 3 Characterization of floating beads

Batch

code

Particle

size (mm)*

Drug entrapment

efficiency (%)*

Swelling

index (%)*

Bulk density

(g/cm3)*

Porosity

(%)

Floating ability

in pH 1.2 (h)

FCE 1.134 ± 0.02 68.44 ± 3.81 1.51 ± 0.15 1.35 ± 0.05 28.94 [12

FCF 1.176 ± 0.01 76.84 ± 6.37 1.95 ± 0.13 1.13 ± 0.19 32.73 [24

FCG 1.198 ± 0.01 72.72 ± 4.23 1.83 ± 0.13 0.87 ± 0.13 34.08 [24

* Values expressed are mean ± SD (n = 3)

Eur J Drug Metab Pharmacokinet

boundaries around the hollow core observed may be due

to the coalescence of the gas bubbles formed in the wet

beads.

3.1.3.2 Drug entrapment efficiency Drug entrapment in

the beads includes drug entrapped within the polymer

matrices. The values of total % entrapment efficiency of

the drug were in the range of 53.78–76.84 % for dried

beads as shown in Table 3.

The actual drug content and drug entrapment efficiency

was found to be more for the batch FCF with respect to

other batch; this may be due to greater extent of cross-

linking and thereby greater entrapment efficiency.

3.1.3.3 Bead porosity and bulk density The bulk density

of the beads (Batch no FCG) was less as compared with the

batch no FCE and FCF. As bulk density increases it was

observed that size and porosity decreases (Table 3).

3.1.3.4 Determination of buoyancy of beads Only beads

of batch no FD had a buoyancy lag time of 3 min. Batches

FA, FD and FCE produced floating beads remained floating

for more than 12 h and FC, FB, FCF and FCG for more

than 24 h. The floating property of hollow/porous beads

may be attributed to the low bulk density and the porosity

of the beads, implying that the beads will have the pro-

pensity to exhibit an excellent buoyancy effect in vivo.

Fig. 2 SEM photographs of

metoprolol tartrate formulation

beads

Eur J Drug Metab Pharmacokinet

Batches FA, FD and FCE floating beads remained floating

for \24 h. This may be attributed because these batches

could not maintain matrix integrity for more than 12 h.

3.1.3.5 Determination of swelling index The swelling

behavior of the polymer is also an important factor con-

trolling the release of the drugs from the bead systems. The

extent of swelling of the formulated beads showed that the

swelling was related to different polymer ratio with

swelling being more significant for beads with increased

gel formation this may be due greater extent of cross-

linking between the polymers. The SI was found to be in

the range of 1.51–1.95 % as shown in Table 3.

3.1.3.6 Drug release study The dissolution study of all

the formulations of metoprolol tartrate beads was carried

out in different media namely pH 1.2 and pH 6.8, 7.4

phosphate buffer. All these beads released 6.32–14.02 % of

the drug in acidic medium irrespective of time.

Batch FCE, FCF and FCG showed 14.02, 8.72 and

6.32 % drug release within 6 h in acidic medium, respec-

tively. There was a slow release for 6 h. After 6 h there

was burst release in phosphate buffer and the drug release

observed for about 18 h. The drug release profile in

phosphate buffer is shown in Fig. 3.

The porous beads showed excellent lag time in drug

release profile in acidic pH, this may be due to insolubility

of pectin. At acidic pH, calcium pectinate and locust bean

remained protonated into insoluble form with reduced

swelling. The second phase of pulsed release in pH 6.8 and

7.4 can be attributed to rapid swelling and gel relaxation of

calcium pectinate, locust bean at alkaline pH.

3.1.3.7 In vivo study The in vivo gastric residence of the

batch FCF was studied by radiological study (X-ray) of

radio-labeled beads using rabbit as animal model. In

stomach, the insoluble beads were acted as indigestible

food particle. Radiographic image 1–6 (Fig. 4) shows

X-ray scans taken on the rabbit during radiological study. It

can be interpreted from the images that the beads were

clumped together intact and remained floating for 8 h of

the study.

3.1.3.8 Stability study In view of potential utility of the

formulation, stability study was carried out on batch FCF

for 6 months according to ICH guidelines. Formulations

were subjected to drug entrapment, floating behavior and

in vitro release study after 30, 60, 90 and 180 days.

On comparing the optimized formulation with initial

data of % entrapment efficiency is 70.03 and cumulative %

drug release is 88.79. Result showed (Table 4) that there

were no significant changes observed in the appearance,

drug entrapment efficiency, buoyancy study and in vitro

release analysis of formulation. It confirms that formulation

FCF was stable at a temperature of 40 ± 2 �C/75 ± 5 %

and photo stable at the end of 180 days.

Fig. 3 In vitro release profile for formulations

Eur J Drug Metab Pharmacokinet

3.1.3.9 Drug release kinetics Based on regression coef-

ficient values (R2), all the formulations followed first-order

drug release kinetics. From Peppas model, it was found that

batch no FA, FB, FC, FCE, FCF and FCG showed anom-

alous transport kinetics, i.e., a combined mechanism of

pure diffusion and Case II transport and batch no FD

showed non-Fickian diffusion (Table 5).

4 Conclusion

The hollow beads containing metoprolol tartrate showed

excellent buoyancy in acidic environment of stomach.

The enhanced buoyancy of porous beads makes them

excellent candidate for intragastric floating drug delivery,

by slowing down the gastric emptying. The pulsatile drug

delivery was characterized by rapid and complete drug

release from the drug loaded porous beads due to the fast

disintegration in the basic medium after a lag time in

acidic environment. The release from porous beads was

due to faster entry of the gastrointestinal fluid through the

weak matrix of the bead in the buffer. Overall, the

buoyant beads provided a lag phase while showing gastro

Fig. 4 Radiographic images

taken on the rabbit during

radiological studies

Table 4 Stability study

Time

(days)

Drug entrapment

efficiency (%)*

Floating

duration

(h)

Percent cumulative

drug release at

the end of 24 h*

0 75.24 ± 6.33 [24 95.28 ± 0.81

30 74.55 ± 6.13 [24 95.54 ± 0.73

60 74.25 ± 6.06 [24 93.11 ± 1.48

90 73.71 ± 5.70 [24 91.83 ± 0.94

180 70.03 ± 5.40 [24 88.79 ± 0.90

* Values expressed are mean ± SD (n = 3)

Eur J Drug Metab Pharmacokinet

retention followed by a pulsatile drug release that would

be beneficial for hypertension.

Acknowledgments The authors are highly thankful to Dr. A. D.

Taranalli, Principal KLEU’s college of pharmacy, Belgaum for pro-

viding all the facilities required for the project. Authors wish to

thanks Low methoxy pectin (LMP), was obtained as generous gift

sample from Krishna Pectins Pvt. Ltd, Jalgaon (India). Metoprolol

tartrate was obtained as generous gift sample from Astrazeneca

Pharmaceuticals Pvt Ltd, Bangalore, Karnataka, India. Xanthan gum,

Sodium CMC, Guar gum, Locust bean, Gellan gum, Sodium bicar-

bonate from Hi-media Laboratories Pvt Ltd. Mumbai for providing

drug and polymers as a gift sample.

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Table 5 Model fitting

Batch no. Zero order First order Higuchi model Korsmeyer-peppas model

R2 n R2 n R2 n R2 n

FA 0.7968 4.433 0.9034 -0.040 0.7771 22.24 0.7356 1.164

FB 0.8572 4.624 0.9492 -0.051 0.8124 22.87 0.8049 1.143

FC 0.8299 4.856 0.9462 -0.061 0.8010 24.24 0.7853 1.139

FD 0.7431 4.810 0.9065 -0.055 0.7777 24.99 0.7542 0.987

FCE 0.7902 4.580 0.8987 -0.048 0.8033 23.46 0.8072 0.968

FCF 0.7865 5.083 0.9372 -0.067 0.7707 25.56 0.7585 1.186

FCG 0.8430 4.341 0.9428 -0.039 0.7958 21.42 0.7396 1.200

R2 regression coefficient, n slope

Eur J Drug Metab Pharmacokinet