FORMULATION AND EVALUATION OF GASTRO...

RESEARCH ARTICLE e-ISSN: 2454-7867

M.Gayathri & .N.Srinivas. Int J Trends in Pharm & Life Sci. 2015: 1(2); 142-153. 142

Available online at www.ijtpls.com

International Journal of Trends in Pharmacy and Life Sciences Vol. 1, Issue: 2, 2015: 142-153

FORMULATION AND EVALUATION OF GASTRO RETENTIVE RAFT

FORMING APPROACH FOR NISOLDIPINE

M.Gayathri*& S. Sujatha

Malla Reddy Institute of Pharmaceutical Scienses Maisammaguda,Dulapally,

Secunderabad- 500014

E.Mail:[email protected]

ABSTRACT

Nisoldipine (INN) is a calcium channel blocker of the dihydropyridine class. The half-life of drug is

relatively approximately 7-12 hours and in normal course of therapy drug administration is required every

3-7 hours, Controlled release dosage forms have been demonstrated to improve therapeutic efficiency by

maintenance of a steady drug plasma concentration. In the present study different polymers like Ethyl

cellulose and Carbapol were used to prepare Gastro- retentive matrix tablet of Nisoldipine using raft forming

approach. Pre-formulation study was carried out for powder blends and it was evaluated to determine the

flow characteristics by bulk density, tapped density, Hausner‟s ratio, Carr‟s index and angle of repose. Drug

and polymers were subjected for compatibility study using FTIR studies, which suggested that there

was no interaction between drug and polymers. Controlled release can be achieved by formulating

drugs as matrix devices using Carbapol. The formulated tablets were evaluated for physical characterization

like thickness, hardness, friability, weight variation and drug content, Acid neutralization, Raft strength, and

dissolution. All the physical parameters of prepared Gastro- retentive matrix tablet of Nisoldipine using raft

forming approach tablets comply with IP specifications.

Key Words: Nisoldipine, calcium channel blocker, Carbapol, controlled release tablets.

*Corresponding Author:

M.Gayathri

Malla Reddy Institute of Pharmaceutical Scienses,

Maisammaguda,Dulapally,

Secunderabad- 500014

E.Mail:[email protected]

INTRODUCTION

Controlled release drug delivery systems that retain in the stomach for a long time have many

advantages over sustained release formulations [1]. Such retention systems (i.e. GRDDS) are important for

the drugs that are degraded in intestine or for drugs like antacids or certain enzymes that should act locally

in the stomach [2-3]. Gastric retention may increase solubility for the drugs which are poorly soluble

in intestine due to alkaline pH before they are emptied, resulting in improved bioavailability [4].

Nisoldipine Mechanism of action is by deforming the channel, inhibiting ion-control gating mechanisms,

and/or interfering with the release of calcium from the sarcoplasmic reticulum, Nisoldipine inhibits the

influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes [5-6]. The

decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells,

causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue,

decreased total peripheral resistance, decreased systemic blood pressure, and decreased after load. The

Received: 15/07/2015

Revised: 26/08/2015

Accepted: 28/08/2015



Gastro-retentive Raft approach controlled matrix tablets of Nisoldipine were prepared through direct

compression method (without granules making step) [7].

MATERIALS AND METHODS

MATERIALS:

Table 1: List of materials

S.No Ingredients CompanyName

1 Nisoldipine Natco chemicals, Hyderabad

2 Ethyl cellulose Colorcon Asia pvt limited, India.

\

3 Carbapol 934p Colorcon Asia pvt limited, India.

4 MCC Krystal colloid Ltd,Mumbai

5 Sodium alginate LobachemiePvt. Ltd, Mumbai

6 Sodium –bi-carbonate Krystal colloid Ltd,Mumbai

Mumbai, 7 Talc LobachemiePvt. Ltd, Mumbai

8 Lactose LobachemiePvt. Ltd, Mumbai

9 Magnesium stearate LobachemiePvt. Ltd, Mumbai

METHODOLOGY:

Nisoldipine Tablets Preparation [11]:

All the tablets, each containing 17 mg of Nisoldipine, were prepared by direct compression method

and some of the formulations were prepared by using Ethyl cellulose, Carbapol 934p to study the effect of

Polymer on the drug release. Nisoldipine and polymers such as Ethyl cellulose, Carbapol 934p were

accurately weighed, geometrically mixed and passed through #40 mesh and then diluents such as lactose and

micro crystalline cellulose were accurately weighed and passed through #40 meshes. Both mixtures were

mixed for 5 minutes as a dry mixing. Then, the lubricant magnesium stearate was passed through #60 mesh

added to the mixture and mixed for 2 minutes. Then finally mg.sterate was added to free flow of granules.

Then the mixtures were compressed into tablets using 16 station rotary compressed machines with punch

size 9mm.

Evaluation of Nisoldipine Tablets:

Thickness [12]:

Twenty tablets from the representative sample were randomly taken and individual tablet thickness was

measured by using digital vernier caliper. Average thickness was calculated.

Hardness [13]:

Tablet hardness was measured by using Monsanto hardness tester. From each batch six tablets were

measured for the hardness and average of six values was noted.



Table 2: Composition of Different formulations from F1 to F9

Friability Test [13]:

From each batch, ten tablets were accurately weighed and placed in the friability test apparatus (Roche

friabilator). Apparatus was operated at 25 rpm for 4 minutes and tablets were observed while rotating. The

tablets were then taken after 100 rotations, dedusted and reweighed. The friability was calculated as the

percentage weight loss.

Weight Variation Test [14-15]:

To study weight variation individual weights (WI) of 20 tablets from each formulation were noted using

electronic balance. Their average weight (WA) was calculated. Percent weight variation was calculated as

follows. Average weights of the tablets were calculated.

% weight variation = (WA–WI) x 100/ WA

Assay[16]:

Five tablets were weighed and triturate, from that transfer an accurately weighed portion of the powder

equivalent to about 8mg of Nisoldipine to a100ml volumetric flask containing buffer solution and then

concentration is measured at λmax i.e.206nm.

Raft strength measurement by in-house method [17-20]:

A tablet powder equivalent to unit dose was transferred to 150 ml of 0.1 N HCl and maintained at 37°C in a

250 ml glass beaker. Each raft was allowed to form around an L-shaped wire probe (diameter: 1.2 mm) held

upright in the beaker throughout the whole period (30 min) of raft development. Raft strength was estimated

using the modified balance method. Water was added drop wise to the pan and the weight of water required

to break the raft was recorded.

INGREDENTS F1 F2 F3 F4 F5 F6 F7 F8 F9

Nisoldipine 17 17 17 17 17 17 17 17 17

M.C.C 56.5 46.5 36.5 41.5 56.5 46.5 36.5 41.5 46.5

Lactose 56.5 46.5 36.5 41.5 56.5 46.5 36.5 41.5 46.5

Sodium alginate 50 50 50 60 50 50 50 60 50

Ethyl cellulose 40 60 80 60 - - - - 30

Carbapol 934 p - - - - 40 60 80 60 30

NaHCO3 25 25 25 25 25 25 25 25 25

Talc 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5

Mg.sterate 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5

Total weight 250mg 250mg 250mg 250mg 250mg 250mg 250mg 250mg 250mg



In-Vitro Dissolution Studies [21]:

The in-vitro dissolution studies were performed using the USP II (Paddle)dissolution apparatus at

50rpm.The dissolution medium consisted of 900ml of phosphate buffer 0.1N Hcl, maintained at 37±0.5ºC.

Analiquot (5ml) was withd rawn at specific time intervals and drug content was determined by UV-visible

spectrometer at236 nm.

Kinetic Analysis of Dissolution Data [22-24]:

To analyze the in vitro release data various kinetic models were used to describe the release kinetics. The

zero order rate Eq. (1) describes the systems where the drug release rate is independent of its concentration

(Hadjiioannouet al., 1993). The first order Eq. (2) describes the release from system where release rate is

concentration dependent (Bourne, 2002). Higuchi (1963) described the release of drugs from insoluble

matrix as a square root of time dependent process based on Fickian diffusion Eq. (3). The Hixson-Crowell

cube root law Eq. (4) describes the release from systems where there is a change in surface area and

diameter of particles or tablets (Hixson and Crowell, 1931).

C = K0 t (1)

Log C = LogC0 - K1 t / 2.303 (2)

Q = KHt1/2

(3)

Q01/3

– Qt1/3

= KHC t (4)

Mechanism of Drug Release [25]:

Korsmeyer‟set al (1983) derived a simple relationship which described drug release from a polymeric

system Eq. (5). To find out the mechanism of drug release, first 60% drug release data was fitted in

Korsmeyer‟s–Peppas model.

Mt / M∞ = Ktn(5)

RESULTS AND DISCUSSION

Standard Curve of Nisoldipine:

The absorbance was measured in a UV spectrophotometer at 236nm against phosphate buffer solution of

0.1 HCl The absorbance so obtained was tabulated as in Table . 3. Calibration curve was plotted and

shown in Figure .1.

Table3: Spectrophotometric data for the estimation of Nisoldipine

SL.NO CONCENTRATI

ON (µg/ml)

ABSORBANCE(2

36nm) 1 0 0

2 2 0.0691

3 4 0.1409

4 6 0.2209



5 8 0.2908

6 10 0.3629

Fig. 1: Standard curve of Nisoldipine in 0.1 N HCl phosphate buffer.

Calibration curve of the pure drug Nisoldipine was prepared in the concentration range of 2 to

10µg/ml at the wavelength of 206nm. The calibration curve showed good linearity and regression

coefficient was 0.999(r2).

FTIR:

The possible interaction between the Nisoldipineand the polymers such as Ethyl cellulose, Carbapol 934 p,

was studied by IR spectroscopy. The IR spectra for Nisoldipine, Ethyl cellulose, Carbapol 934 p, and its

physical mixtures are shown in figures 2 to 4.

Fig. 2: IR spectra of Nisoldipine pure drug

Fig. 3: IR spectra of Nisoldipine with HPMC K15M

0

0.0691

0.1409

0.2209

0.2908

0.3629

y = 0.0036x R² = 0.9996

0

0.1

0.2

0.3

0.4

0 50 100 150%

of

dru

g re

leas

e

Concentration µg/ml



Fig. 4: IR spectra of Nisoldipinewith Guar gum

The results revealed no considerable changes in the IR peaks of Nisoldipine when mixed with excipients

compared to pure Nisoldipine. These observations indicated the compatibility of Ethyl cellulose, Carbapol

with Nisoldipine. The FTIR studies revealed that there is no interaction between drug and polymers.

Physical Evaluation of Pre-compression Blend:

Table4: Physical evaluation of Pre-compression Blend

FORM

ULATI

ON

BULK

DENS

ITYG/

CC

TAPPD

DENSIT

YG/C

HAUSN

ER

RATIO

COMPRESSIBI

LITY

INDEX%

ANGLE

OF

REPOSE(

Ɵ)

F1 0.49±0.04 0.57±0.02 1.17±0.03 14.04±0.04 27.40±0.05

F2 0.48±0.06 0.55±0.03 1.14±0.02 12.72±0.02 26.06±0.02

F3 0.46±0.01 0.53±0.01 1.15±0.05 13.20±0.04 24.38±0.01

F4 0.43±0.02 0.49±0.02 1.14±0.04 12.24±0.03 23.72±0.06

F5 0.41±0.02 0.47±0.03 1.13±0.01 12.76±0.05 21.94±0.03

F6 0.45±0.03 0.48±0.05 1.12±0.05 11.36±0.02 20.48±0.04

F7 0.51±0.05 0.57±0.03 1.18±0.01 13.85±0.06 24.54±0.04

F8 0.55±0.01 0.56±0.02 1.15±0.03 13.11±0.03 25.74±0.02

F9 0.48±0.01 0.55±0.02 1.14±0.03 12.72±0.03 24.4±0.02

Note: *All values are mean ± S.D,n=3

The bulk densities of the powder blends of all the formulations ranged from 0.41 to 0.55 gm/cc. The Tapped

densities of the powder blends of all the formulations ranged from 0.47 to 0.59 gm/cc. The Hausner‟s ratio

values ranged from 1.12 to 1.18.Evaluated values of Hausner‟s ratio obtained were less than 1.25 indicating

good flow. It means that the powder flow properties were within the pharmacopoeial limits. The Carr‟s

index was within the pharmacopoeial specifications and the values ranged from 11.36 to 14.04%. 12-16

Carr‟s index value indicates good flow, 18-21 Carr‟s index value indicates fair.The angle of repose of the

powder blends of all the formulations were determined and the values ranged from 20.48 0

to 27.400

and it



was observed to within the pharmacopoeial limits. The results of angle of repose (< 25) indicate excellent

flow properties of granules, and it was observed to be within the pharmacopoeial limits.

Table5: Physical Evaluation of tablets

Note: *All values are mean ± S.D, n=20

Table 6: Physical Evaluation of Acid neutralization & Raft strength of Raft tablets

Formulation code Acid Neutralization capacity (mEq) Raft Strength

F1 6.32±0.2 3.4±0.15

F2 8.4±0.5 3.7±0.12

F3 9.3±0.15 3.9±0.21

F4 5.7±0.18 4.4±0.12

F5 8.32±0.2 4.53±0.24

F6 10.4±0.3 4.94±0.10

F7 5.6±0.12 5.6±0.21

F8 7.3±0.23 5.4±0.05

F9 10.4±0.17 5.8±0.5

Note: *All values are mean ± S.D, n=6

The hardness of all the formulations ranged from 4.1 to 5.1 kg/cm2. The pharmacopoeial limit for hardness

is 3-5 kg/cm2. Hence all the formulations passed the test for hardness. Thickness of all the formulations was

between 4.12 to 4.42 mm which was according to the pharmacopoeial specifications. The weight variation

test was performed and the weights of the tablets were between 247.2 to 252.9 mg. The pharmacopoeial

specification for weight variation limit is ±7.5.4. Hence all the formulations passed the weight variation test

Formula

Code

Hardness

(kg/cm2)

Thickness

(mm)

Weight

Variation

(mg)

Friability

(%)

Assay

(%)

F1 4.4±0.15 4.12±0.17 247.2±0.13 0.18±0.15 99±0.13

F2 4.2±0.11 4.25±0.15 248.3±0.12 0.22±0.16 99±0.12

F3 4.6±0.13 4.21±0.12 250.5±0.15 0.20±0.12 97±0.15

F4 4.1±0.15 4.42±0.15 252.9±0.14 0.19±0.17 98±0.14

F5 4.3±0.12 4.10±0.13 250.3±0.11 0.16±0.11 100±0.12

F6 4.7±0.13 4.37±0.15 247.8±.13 0.14±0.12 98.±0.11

F7 4.8±0.13 4.14±0.12 249.2±0.13 0.21±0.14 99±0.14

F8 4.9±0.12 4.13±0.11 252.2±0.11 0.17±0.15 99.±0.13

F9 4.6±0.13 4.18±0.12 250.2±0.13 0.11±0.14 99±0.24



and the % weight variation was within the pharmacopoeial specifications. Friability of the tablets was

determined by using Roche friabilator. The friability of all the formulations was determined, and the values

were in the range from 0.14 to 0.22 %. Friability values below 1% were an indication of good mechanical

resistance of the tablets. Hence all the formulations were within the pharmacopoeial limits. The percentage

drug content of all the tablets was found to be in the range of 97.98 to 100.24 %. This was within the

acceptable limits. The preparation complies with the test if each individual content is 85 to 115% of the

average content. Hence all the formulations were passes the test and the values are within the

pharmacopoeial limits. Acid neutralization capacity and satisfactory. According to data batch F9 was having

maximum raft strength. So it was selected as an optimized batch.

Raft Strength Measurement by Texture Analyzer:

Raft strength of the most satisfactory formulation was determined by Texture Analyzer (Brookfield QTS).

The graph of load vs. time is shown below.

Fig.5: Graph of load vs. time for Batch F9

Initially load was increased with time, it showed maximum load when raft was broken and then it decreased

sharply. The maximum raft strength observed at the breaking (rupture) point of the raft was found to be 5.0

gm.

In-Vitro Drug Release Studies:

Table7: In-vitro drug Release data of Nisoldipine from formulations F1 to F9

Time in hrs F1 F2 F3 F4 F5 F6 F7 F8 F9

0 0 0 0 0 0 0 0 0 0

2 24±0.14 26±0.13 24±0.12 25±0.25 26±0.24 23±0.18 23±0.12 25±0.01 23±0.23

4 46±0.52 40±0.17 37±0.04 39±0.42 42±0.17 36±0.12 41±0.32 46±0.25 42±0.12

6 53±0.36 50±0.21 44±0.1 49±0.01 64±0.82 59±0.21 54±0.62 58±0.014 63±0.26

8 65±0.21 61±0.24 58±0.25 63±0.05 76±1.2 72±0.32 63±0.02 66±0.23 70±0.18

10 74±0.13 72±0.38 66±0.32 71±0.08 88±0.26 84±0.45 74±0.32 79±0.15 83±0.28



Note: *All values are mean ± % RS.D, n=6

Fig.6: In-vitro drug Release data of Nisoldipine from formulations F1 to F9

The results of release studies of formulations F1 to F9 are shown in Table 7. And Figure 6.Here the matrix

tablets were formulated using polymers such as F1 to F8 Ethyl cellulose, Carbapol, and F9 both combined

polymers were used in different proportions and these tablets were done in vitro dissolution studies from

F1 to F9. The release of drug depends not only on the nature of matrix but also upon the drug polymer

ratio. As the percentage of polymer decreased, the kinetics of release increased. In above performed eight

formulations F5 was best drug release. Compared with F9 Formulation release was satisfactory.

Drug Release Kinetics:

Table 8: Dissolution Kinetics of optimized batch F5

0

20

40

60

80

100

0 5 10 15%

of

dru

g re

leas

e

Time in hrs

F1

F2

F3

F4

F5

F6

R² = 0.968

0

20

40

60

80

100

120

0 5 10 15

% d

rug r

elea

se

time(hrs)

Zero order plot

12 84±0.62 74±0.32 69±0.14 72±0.06 95±0.15 90±0.21 87±0.21 89±0.61 92±0.34

Time Square

root Log time

% drug

released

log % drug

released

% drug

remaining

log % d

remaining

0 0

0

100 2

2 1.414214 0.30103 26 1.4149733 74 1.86923172

4 2 0.60206 42 1.6232493 58 1.763427994

6 2.44949 0.778151 64 1.80618 36 1.556302501

8 2.828427 0.90309 76 1.8808136 24 1.380211242

10 3.162278 1 88 1.9444827 12 1.079181246

12 3.464102 1.079181 95 1.9777236 5 0.698970004



Fig.7: Zero Order kinetics Plot of Optimized formulation F5

Fig.8: First Order kinetics Plot of Optimized formulation F5

Fig.9: Peppas Koresmeyer„s Order kinetics Plot of Optimized formulation

The drug release data obtained were extrapolated by zero order, Highuchi, First order, Korsemeyer

peppas to know the mechanism of drug release from the formulations. The release rate kinetic data for all

the formulations was shown in Table.8. The release kinetics shows that the release of drug followed zero

order release in all the formulations. As the drug release was best fitted in zero order kinetics, indicating

that the rate of drug release is concentration in-dependent.

CONCLUSION

Nisoldipine was chosen as the model candidate for this study since it possesses near ideal

characteristics that a drug must have in formulating a sustained drug delivery system, high lipid solubility,

effective in low plasma concentration, high degree of first-pass metabolism. Optimized formulation F5 has

successfully Gastro- retentive matrix tablet of Nisoldipine using raft forming approach for 12 hours and the

drug release pattern was good. The results of the study demonstrate that hydrophilic polymer Carbapol can

effectively control the release of Nisoldipine for 12 hrs. Direct compression is feasible for development of

once a day Controlled release tablet of Nisoldipine provided careful selection of optimum concentration of

Carbapol is followed. Many of patients are suffering from severe acidity and heart burning and gastro

R² = 0.9538

0

0.5

1

1.5

2

0 5 10 15

Log %

dru

g

rem

eain

ing

Time (hrs)

First order plot

R² = 0.992

020406080

100120

0 1 2 3 4

% d

rug r

elea

se

Square root time

Higuchi plot



easophagul reflux disease problem which can be overcame by formulating raft forming controlled release

matrix tablet .containing antacid and proton pump inhibitor. It was conclude that Raft matrix tablet was

prepared by sodium alginate (raft forming agent) and sodium bicarbonate and Citric acid (antacid) which

can form a floating raft in the presence of 0.1 N HCl .Raft strength is directly proportional to amount of

sodium alginate. A F5 was used for optimization. An optimized batch shows good raft strength, acid

neutralization capacity and satisfactory in vitro drug release in 12 hr. The drug was also compatible with

other ingredients used in formulation. It can be conclusively stated that development of extended release

formulation of hydrophilic drugs does not necessitate the inclusion of the hydrophobic polymers to

hydrophilic polymers and the desired extended release of hydrophilic drugs is also viable with hydrophilic

polymer alone. The release kinetics shows that the release of drug followed Zero order release in all the

formulations and controlled by diffusion mechanism, Non-Fickian diffusion.

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