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RESEARCH ARTICLE e-ISSN: 2454-7867

Swapna G* et al. Int J Trends in Pharm & Life Sci. 2015: 1(4); 457-470 457

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International Journal of Trends in Pharmacy and Life Sciences Vol. 1, Issue: 4, 2015: 457-470

FORMULATION AND IN-VITRO EVALUATION OF IVABRADINE BUCCAL

TABLETS Garika Swapna*, Sharadha Srikanth, Uma Maheswar Rao

CMR College of Pharmacy, Kandlakoya (V), Medchal Road, Hyderabad – 501401

E.Mail: [email protected]

ABSTRACT

The main objective of the present study was to formulate and evaluate Ivabradine

mucoadhesive buccal tablets by direct compression technique. Ivabradine is a novel medication used for the

symptomatic management of stable angina pectoris and it has short half -life (2 hrs) with a bioavailability of

40% orally. The drug identity was confirmed by UV spectroscopy. The polymers used to sustain the drug

release are Guar gum, Xanthum gum, HPMC K4M and Carbopol934. The compatibility studies between the

drug and the polymer were studied using the FTIR spectroscopy and were found to be compatible.

Preformulation parameters like tapped density, bulk density, Carr’s index, Hausner’s ratio, compressibility

index, angle of repose are studied and the results were found to be within the limits. Using the above

polymers formulations f1 to f12 were manufactured by direct compression technique and the tablets were

evaluated for their thickness, hardness, friability, weight variation and content uniformity test. The in vitro

drug release studies were performed in Phosphate buffer of pH6.8 using USP type-II dissolution apparatus.

From the dissolution studies it was found that f2 formulation containing HPMC K4M was best since it

release minimum amount of drug (9.8%) initially and maximum drug (99.6%) at the end of 8hrs.The f2

formulation was subjected to stability studies for about 3months as per ICH guidelines and found to be

stable.

Key words: Ivabradine, mucoadhesive buccal tablets, direct compression, angina pectoris

*Corresponding Author:

Garika Swapna CMR College of Pharmacy,

Kandlakoya (V), Medchal Road,

Hyderabad – 501401

E.Mail: [email protected]

INTRODUCTION

Buccal delivery refers to drug release which can occur when a dosage form is placed in the outer

vestibule between the buccal mucosa and gingival.

Advantages of mucoadhesive buccal drug delivery:

Drug administration via the oral mucosa offers several advantages.

a. Flexibility in physical state, shape, size and surface.

b. Ease of administration and termination of therapy in emergency.

c. Permits localization of the drug for a prolonged period of time.

d. Administered to unconscious and trauma patients.

e. Offers an excellent route for the systemic delivery of drugs which bypasses first pass metabolism, there

Received: 25/09/2015

Revised: 28/10/2015

Accepted: 31/10/2015



by offering a greater bioavailability.

f. Significant reduction in dose can be achieved, thereby reducing dose dependent side effects.

Disadvantages of buccal drug delivery system:

Drug administration via buccal mucosa has certain limitations,

a) Drugs which irritate the oral mucosa have a bitter or unpleasant taste or odor cannot be administered

by this route.

b) Drugs, which are unstable at buccal pH, cannot be administered by this route.

c) Only drugs with small dose requirements can be administered [1].

Ivabradine is a novel medication used for the symptomatic management of stable angina pectoris. Ivabradine

acts by reducing the heart rate via specific inhibition of the If funny channel, a mechanism different from

beta-blockers and calcium channel blockers, two commonly prescribed anti-angina drugs. Ivabradine is a

cardio tonic agent [2].

MATERIALS AND METHODOLOGY

Materials:

Ivabradine was obtained as a gift sample from Chandra labs, HYD, HPMC K4M, Carbapol Xanthan gum

were obtained from Merck specialties private limited, Guar gum, Mg.sterate, Mannitol, Aspartame , are

purchased from SD Fine Chem [3].

Methodology:

Calibration curve of Ivabradine in pH 6.8 Phosphate buffer:

Ivabradine (100mg) was dissolved in small quantity of phosphate buffer and volume was made up to

100 ml in volumetric flask using Phosphate buffer pH 6.8. From this stock solution 10 ml was withdrawn

and is diluted to 100ml in volumetric flask which gives the concentration of 100µg/ml. From this stock

solution aliquots were withdrawn in volumetric flask to give concentrations 2µg/ml, 4µg/ml, 6µg/ml,

8µg/ml and 10µg/ml. Absorbance of each solution was measured at 286 nm using Shimadzu UV- 1700 UV-

Vis double beam spectrophotometer with Phosphate buffer pH 6.8 as a reference standard [4].

Compatibility Studies:

To investigate any possible interactions between the drug and excipients used, the FT-IR

spectra of pure Ivabradine and its physical mixture with different excipients were carried out using

thermo Electron Corporation (Nicolet IR 200 FTIR) spectrophotometer. The samples were prepared

as KBr (potassium bromide) disks compressed under a pressure of 150 lbs. The wave number range is

selected in between 500 - 3500cm-1.

Method: 1 mg of drug is mixed with the 100 mg of Spectroscopic grade of KBr and triturated for

uniform mixing. The thin and transparent pellet is prepared by applying 150 lbs pressure. The

prepared pellet is exposed to IR beam and spectra are recorded by using FT-IR [5].



Formulation of Mucoadhesive Tablets of Ivabradine:

Direct compression method was employed to prepare buccal tablets of Ivabradine using HPMC

K4M, Carbapol, Xanthan gum and Guar gum as polymers. All the ingredients including drug, polymer and

excipients were weighed accurately according to the batch formula and were passed through #60 to get

uniform particle size. The drug and all the ingredients except lubricants were taken on a butter paper with

the help of a stainless steel spatula and the ingredients were mixed in the order of ascending weights and

blended for 10 min in a porcelain mortar. After uniform mixing of ingredients, lubricant was added and

again mixed for 2 min. The prepared blend (150mg) of each formulation was compressed by using 8mm

punch on a single stroke, multi-station tablet punching machine. The buccal tablets containing 7.5 mg

Ivabradine were prepared using different polymers in varying ratios [6].

Table 1: formulation Of Mucoadhesive Tablets of Ivabradine

Ingredients F-1 F-2 F-3 F-4 F-5 F-6 F-7 F-8 F-9 F-10 F-11 F-12

Ivabradine 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5

HPMC

K4M

5% 10% 15% --- --- --- --- --- --- --- --- ---

Carbopol --- --- --- 5% 10% 15% --- --- --- --- --- ---

Xanthum

gum

--- --- --- --- --- --- 5% 10% 15% --- --- ---

Guar gum --- --- --- --- --- --- --- --- --- 5% 10% 15%

Aspartame 1 1 1 1 1 1 1 1 1 1 1 1

Mannitol q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s

Magnesium

Stearate

4 4 4 4 4 4 4 4 4 4 4 4

Characterization of Tablets:

Thickness: The thickness of the tablets was measured by Vernier calipers. It is expressed in mm [7].

Hardness: Tablets require a certain amount of strength or hardness and resistance to friability, to withstand

mechanical shocks of handling in manufacture, packing and shipping. The hardness of tablet was measured

by Monsanto hardness tester. The tablets from each batch were used for hardness studies and results are

expressed in Kg/cm2

[7].

Weight variation test: Ten tablets were selected at randomly from the lot and weighed individually to

check for weight variation [7].

Friability: It was performed in Roche friabilator where the tablets were subjected to the combined effect of

abrasion and shock by utilizing a plastic chamber that revolves at 25 rpm dropping the tablets at a distance

of six inches with each revolution. Pre weighted samples of 20 tablets were placed in the Friabilator, which



is then operated for 100 revolutions. The tablets are then dusted and reweighed. Conventional compressed

tablets that loose less than 0.5 to 1 % of their weight are generally considered acceptable [7].

Twenty tablets were taken and triturated well. The quantity equivalent to 50mg of Ivabradine was dissolved

in 100ml of phosphate buffer pH 6.8 solutions on rotary shaker overnight. The solution was centrifuged and

supernatant was collected. The absorbance was measured using UV-Visible spectrophotometer at 286nm.

Microenvironment pH study: The microenvironment pH of the tablets were determined by the method

proposed by Battenberg, et al, 1991.The tablets were allowed to swell for 2hours in 2ml of pH 6.8 phosphate

buffer (pH 6.8+0.05) in specially fabricated glass tubes and microenvironment pH was measured by placing

the pH electrode in contact with the surface of the tablet and allowing it to equilibrate for 1 minute [8].

Swelling Study: The swelling properties of the tablets were evaluated by determination of percent of

swelling. Each tablet was weighed (W1) and placed in Petri dish with 5ml of PB PH6.8 and incubated at 37

0c

for predetermined times. After placing the formulation for specified time, the tablets were wiped off to

remove excess of surface water by using filter paper and weighed (W2).

%𝐬𝐰𝐞𝐥𝐥𝐢𝐧𝐠 𝐢𝐧𝐝𝐞𝐱 =(W2) − (W1)

W1× 100

Where, W 1=Initial weight of the tablet. W2= Weight of tablet after swelling time interval [8].

Determination of the Ex-Vivo Residence Time: The ex vivo residence time was found using a locally

modified USP disintegration apparatus. The disintegration medium was composed of 800 ml pH 6.8

phosphate buffer maintained at 37°C. The sheep buccal tissue was tied with thread to the central stand. The

buccal tablet was hydrated with 0.5ml of pH 6.8 phosphate buffer and then the hydrated surface was brought

in contact with the mucosal membrane. The tissue was allowed to run in such way that the tablet completely

immersed in the buffer solution at the lowest point and was out at the highest point. The time taken for

complete erosion or dislodgment of the tablet from the mucosal surface was noted [9].

In Vitro Drug Release Study: In vitro drug release study of mucoadhesive tablets were performed using

standard USP dissolution apparatus type II. The bowls of the dissolution apparatus was filled with 900ml of

phosphate buffer pH 6.8 and maintained at a temperature of 37±0.50C. The protocol of the dissolution

apparatus was settled for automatic 5ml sample withdrawal and replacement of fresh media at predetermined

time interval the dissolution apparatus was covered with the black colour polythene cover to protect the

solution from light. The collected samples were filtered through the 0.45μm 59millipore filter. The samples

were analyzed for drug release using double beam UV spectrophotometer at 286nm [9].

% Friability= (initial weight-final weight/initial weight) x100



Drug Release Kinetics:

To examine the release mechanism of Ivabradine from the prepared buccoadhesive tablets, the results were

analyzed according to the following equation:

𝐌𝐭

𝐌∞ =k.t

n

Where Mt /M∞ is the fractional drug released at time t, k is a kinetic constant incorporating structural and

geometrical characteristics of drug / polymer system [device], and n is the diffusion exponent that

characterizes the mechanism of drug release. It is known that for non-swelling tablets, drug release can be

generally expressed by the Fickian diffusion mechanism, for which n=0.5, whereas for most erodible

matrices, a zero order release rate kinetics is followed, for which n = 1. For non-fickian release, the n value

falls between 0.5 and 1.0 (0.5< n< 0.89) whereas in the case super case II transport n > 0.89.

Data of the in-vitro release was fit in to different equations and kinetic models to explain the release kinetics

of Ivabradine from buccal tablets. The kinetic models used were zero-order equation (eq.1), first order

equation (eq.2), Higuchi equation (eq.3), and Korsmeyer-peppas equation (eq.4).

Zero Order Kinetics: A zero-order release would be predicted by the equation.

At = A0-k0t ------------ (1)

First Order Kinetics: A first-order release would be predicted by equation

Log C = log C0 – Kt/ 2.303 ------------ (2)

Higuchi’s Model: Drug released from the matrix devices by diffusion has been described by

following Higuchi’s classical diffusion equation.

Q = [Dε / τ (2 A - εCs) Cst] 1⁄2 ------------ (3)

Korsmeyer and Peppas Model: The release rates from the controlled release polymeric matrices can be

described by the equation proposed by the Korsemeyer et al [10].

Q = K1tn

Stability studies: Stability studies were performed data temperature of 400

Cat 75% RH, over a

period of three months (90days) for the optimized buccal tablet. Sufficient number of tablets (15)

were packed in amber colored screw capped bottles and kept in stability chamber maintained at

400±1

0C & 75% RH. Samples were taken at monthly intervals for drug content estimation. At the

end of three months period, dissolution test and drug content studies were performed to determine

the drug release profiles and drug content [10].



RESULTS AND DISCUSSION

Preformulation Studies:

These tests were performed as per the procedure and the results are illustrated in the following table no.9

Table 2: Table showing the description of Ivabradine (API)

The results were found as per specifications.

Solubility: It is soluble in water (100 mg/mL), methanol, and ethanol and slightly soluble in hexane.

Melting Point: This test is performed as per procedure and the result was illustrated in the following

table.no10.

Table 3: showing the melting point of API’s

Material Melting Point Melting Point Range

Ivabradine 1370c 135-140

0c

The Result was found to be within limit.

Calibration Curve of Ivabradine:

Table 4: calibration curve data

S.No Concentration (μg/ml) Absorbance(nm)

1 0 0

2 1 0.165

3 2 0.325

4 3 0.471

5 4 0.627

6 5 0.789

Test Description

Colour A white to off white colour crystalline powder

Odour Odourless



Fig.1: Calibration curve plot of Ivabradine in 6.8 phosphate buffer

Compatibility Studies:

Fig.2: Ft-Ir Spectra of Ivabradine Pure Drug

Fig.3: FT-IR Spectra of Ivabradine optimized

Drug-excipient compatibility study indicates that the all used excipients in the optimized formulation are

compatible with the drug based on FT-IR spectra.

y = 0.1565x + 0.005 R² = 0.9997

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

0 1 2 3 4 5 6

abso

rban

ce

concentration μg/ml



Characterization of Blend:

Table 5: Physical Properties of Pre-compression Blend

Formulations Angle of

repose ( ° )

Bulk

Density

(g/mL)

Tapped

Density

(g/mL)

Carr’s

Index

(%)

Hausner’s

ratio

Flow

property

F1 30.250 0.342 0.386 11.39896 1.128655 Good

F2 30.430 0.358 0.412 13.1068 1.150838 Good

F3 22.870 0.326 0.334 2.39521 1.02454 Excellent

F4 22.450 0.334 0.348 4.022989 1.041916 Excellent

F5 24.370 0.442 0.499 11.42285 1.128959 Excellent

F6 29.410 0.321 0.334 3.892216 1.040498 Good

F7 22.880 0.326 0.333 2.39531 1.02464 Excellent

F8 30.130 0.360 0.414 13.1071 1.1509 Good

F9 24.300 0.447 0.500 11.42687 1.1311 Excellent

F10 22.870 0.326 0.334 2.39521 1.02454 Excellent

F11 22.450 0.334 0.348 4.022989 1.041916 Excellent

F12 30.430 0.358 0.412 13.1068 1.150838 Good

Physical Evaluation of Buccoadhesive Tablets:

Table 6: Physical Evaluations of Buccoadhesive Tablets

F.Code Hardness

(kg/cm2)

Thickness

(mm)

Weight

(mg)

Friability

(%)

Drug content

(%)

F1 6.50 ±0.44 2.52±0.17 150.8±1.48 0.36 98.25±1.37

F2 6.60±0.31 2.57±0.25 149.4±0.54 0.39 99.48±0.80

F3 6.72±0.40 2.54±0.80 148.6±0.41 0.43 99.12±2.47

F4 6.86±0.55 2.50±0.20 148.8±1.64 0.12 100.22±0.88

F5 6.34±0.57 2.65±0.66 150.6±1.14 0.54 100.24±1.25

F6 6.49±0.30 2.63±0.25 148.2±0.83 0.58 99.53±1.87

F7 6.51±0.32 2.57±0.81 148.7±0.46 0.36 99.50±0.60

F8 6.53±0.35 2.58±0.80 148.9±0.64 0.39 99.32±0.87

F9 6.52±0.31 2.57±0.82 148.9±0.44 0.43 99.58±0.60

F10 6.76±0.55 2.30±0.20 149.8±1.64 0.12 99.22±0.88

F11 6.44±0.57 2.45±0.66 151.6±1.14 0.18 100.24±1.0

F12 6.59±0.30 2.33±0.25 149.2±0.83 0.26 100.53±1.0

Microenvironment pH study:

Table 7: Results of Microenvironment pH study

F.Code Surface pH

F1 6.4

F2 6.6

F3 6.2

F4 6.6



F5 6.5

F6 6.3

F7 6.5

F8 6.4

F9 6.6

F10 6.3

F11 6.6

F12 6.9

Swelling Index:

Table 8: Results of Percent swelling Index

Time

(min)

Formulation code %

F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12

10 20.8 24.6 30.4 14.8 18.3 20.7 20.1 21.3 18.4 30.4 24.6 20.7

15 48.1 51 56.2 30.1 35.3 38.5 46.2 55.2 56.7 56.2 51 38.5

30 59.6 63.8 67.5 50.4 54.4 60.6 68.5 76.5 67.9 67.5 63.8 60.6

60 76.45 79.4 85.6 65.8 70.7 74.4 88.3 99.6 85.6 85.6 79.4 74.4

Mucoadhesion time:

Table 9: Effects of polymers on Mucoadhesion time

Formulation Code Mucoadhesion time (hr)

F1 6

F2 8

F3 9

F4 5

F5 7

F6 >9

F7 6

F8 7

F9 9

F10 5

F11 6

F12 6



In-Vitro drug Release Study:

Table 10: Cumulative drug release of formulation F1-F12

Fig.4: In-Vitro Drug Release for Formulation F1, F2, F3


0

20

40

60

80

100

120

0 2 4 6 8 10

CU

MU

LATI

VE

% D

RU

G

REL

EASE

TIME IN HRS

F1

F2

F3

0

20

40

60

80

100

0 5 10

CU

MU

LATI

VE

% D

RU

G

REL

EASE

TIME IN HRS

F4

F5

F6

%CDR

Tim

e

(hrs)

F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12

0 0 0 0 0 0 0 0 0 0 0 0 0

1 17.6 9.8 7.2 21.3 20.6 19.8 21.3 20.6 19.8 29.6 30.1 25.4

2 39.8 17.2 15.0 34.9 30.4 25.1 34.9 30.4 25.1 35.9 39.6 35.1

3 52.31 23.80 20.9 48.6 42.6 33.6 48.6 42.6 33.6 59.6 45.8 49.5

4 70.61 45.6 33.8 52.1 54.1 48.2 52.1 54.1 48.2 72.4 61.5 64.5

5 86.3 60.1 58.0 74.8 68.7 56.1 74.8 68.7 56.1 92.1 72.8 79.2

6 98.2 70.8 65.1 98.5 85.9 68.5 97.3 77.4 68.5 100.

5

90.5 88.1

7 -- 89.0 79.3 -- 99.6 74.2 -- 85.9 74.2 -- 99.9 100.

2

8 -- 99.6 86.7 -- -- 90.6 -- 98.6 80.6 -- -- --




Fig.7: In-Vitro Drug Release for Formulation F10, F11, F12 Drug Release Kinetics:

Fig.8: Zero order kinetic graph for formula F2

Fig.9: Higuchi kinetic graph for formula F2

0

20

40

60

80

100

0 5 10

CU

MU

LATI

VE

% D

RU

G

REL

EASE

TIME IN HRS

F7

F8

F9

0

20

40

60

80

100

120

0 5 10

%C

DR

Time in hrs

F10

F11

F12

y = 12.725x - 5.1333 R² = 0.9842

-20

0

20

40

60

80

100

120

0 5 10

%

C

D

R

TIME IN HRS

ZERO ORDER

y = 36.232x - 19.878 R² = 0.8587

-40

-20

0

20

40

60

80

100

120

0 1 2 3

%

C

D

R

SQUARE ROOT OF TIME

HIGUCHI PLOT



Fig.10: Peppas kinetic graph for formula for F2.

Fig.11: First Orders Kinetic Graph for Formula F2

Discussion: In-vitro drug release data of all the buccal tablet formulations was subjected to goodness of

fittest by linear regression analysis according to zero order, first order, Higuchi’s and Korsmeyer-Peppas

models to ascertain the mechanism of drug release. From the above data, it can be seen the formulation,

F2have displayed zero order release kinetics (‘r2 value of 0.9842).From Peppas data; It is evident that the

drug is released by non-Fickian diffusion mechanism. This is because as the proportion of polymers in the

matrix increased the rewash an increase in the amount of water uptake and proportionally greater swelling

leading to a thicker gel layer. Zero-order release from swellable hydrophilic matrices occurs as a result of

constant diffusion path lengths.

Ex-Vivo Drug Permeation Studies for F2:

Table 11: Ex-vivo drug permeation studies for F2

y = 1.6729x + 0.5685 R² = 0.8286

0

0.5

1

1.5

2

2.5

0 0.2 0.4 0.6 0.8 1

L

O

G

%

C

D

R

LOG TIME

PEPPAS

y = -0.1558x + 2.2060 R² = 0.8441

0

0.5

1

1.5

2

2.5

0 2 4 6 8 10

L

O

G

%

D

R

U

G

R

E

M

A

I

N

I

N

G

TIME IN HRS

FIRST ORDER

Time (hr) F2

1 9.03

2 13.8



Fig.12: Graph showing permeation studies of formulation F2

Discussion: The drug permeation was slow and steady, 84.01% of drug could permeate through the

buccal membrane in 8 hours.

Stability Studies:

Table 12: Stability studies of Ivabradine buccoadhesive tablet (F2) at room temperature

Time

Colour

Assay Cumulative % drug

release

Surface PH

25±20c

and

65±5%R

H

40±20c

and

75±5%R

H

25±20c

and

65±5%R

H

40±20c

and

75±5%R

H

25±20c

and

65±5%R

H

40±20c

and

75±5%R

H

First day White 99.48 99.48 97.6 98.6 6.6 6.6

30 days White 99.40 99.30 99.1 97.9 6.6 6.6

60days White 99.31 99.2 97.2 97.1 6.6 6.6

90 days White 98.5 98.0 98 97.8 6.6 6.6

Results from stability studies indicate that the formulated Ivabradine Bucco adhesive tablets are stable for a

period of 3 months under 2 different conditions at 25±20c and65±5%RH and 40±2

0c and 75±5%RH. There

were no remarkable changes were observed during the period of storage.

0

10

20

30

40

50

60

70

80

90

0 5 10% D

RU

G P

ERM

EATE

D

TIME IN HRS

F2

3 26.18

4 35.27

5 44.89

6 58.76

7 70.04

8 84.01



CONCLUSION

It can be concluded that Ivabradine can certainly be administered through the oral mucosa. The

designed Bucco adhesive tablets can overcome the disadvantage of extensive first pass effect and low oral

bioavailability of Ivabradine. This increased and predictable availability of Ivabradine from designed

formulation may result in substantial dose reduction of the dosage form when the drug is administered

through oral mucosa so that it will be economical to the patient. Further work is recommended to support its

efficacy claims by pharmacokinetic and Pharmacodynamics studies in human beings.

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