FORMULATION AND EVALUATION OF PULSINCAP DRUG …

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Sambasivarao et al. World Journal of Pharmacy and Pharmaceutical Sciences

FORMULATION AND EVALUATION OF PULSINCAP DRUG

DELIVERY SYSTEM OF NICORANDIL

*A. Sambasivarao, M.S, Ph.D, T. Jyotshna, S. K. Nishma, P. Lakshmi, Y. Shashank

Professor, A.S.N College of Pharmacy, Burripalem Road, Tenali, A.P India.

ABSTRACT

The present study was aimed to develop the formulation of pulsincap

drug delivery system of Nicorandil. In this study Nicorandil immediate

release granules were prepared by wet granulation method. F9 was

selected as a better formulation to do the further process. In this study

100mg of hydrogel plug was prepared using HPMC K200M by wet

granulation method using 5%w/v PVP K30 solution. Plug 3 was

selected as a better formulation when compared to other formulations.

FTIR studies has shown no interaction between polymer and drug.

Cross-linked gelatine capsule were evaluated and confirmed that 24 hrs

formaldehyde treatment was sufficient. 100mg hydrogel plug was optimized. The results

indicated that drug content was uniform. In-vitro release studies revealed that increasing the

polymer content resulted in sustained release. Value of n in Korsmeyer-Peppas Equation is

greater than 0.89 hence, formulation were follows swelling controlled super case II transport.

KEYWORDS: Pulsincap, Nicorandil, HPMC K200M.

INTRODUCTION

Nicorandil is an orally efficacious vasodilatory drug and antianginal agent. It is a niacinamide

derivative that induces vasodilation of arterioles and large coronary arteries by activating

potassium channels. It is often used for patients with angina who remain symptomatic despite

optimal treatment ith other antianginal drugs.[1]

Nicorandil is a dual-action potassium channel

opener that relaxes vascular smooth muscle through membrane hyperpolarization via

increased transmembrane potassium conductance and increased intracellular concentration of

cyclic GMP. It is shown to dilate normal and stenotic coronary arteries and reduces both

ventricular preload and afterload.[2]

Pulsatile drug delivery systems are time-controlled drug

delivery system. These systems are design to achieve time specific and site specific delivery

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.632

Volume 9, Issue 4, 561-581 Research Article ISSN 2278 – 4357

*Corresponding Author

Dr. A. Sambasivarao

Professor, A.S.N College of

Pharmacy, Burripalem Road,

Tenali, A.P India.

Article Received on

22 Jan. 2020,

Revised on 12 Feb. 2020,

Accepted on 04 March 2020

DOI: 10.20959/wjpps20204-15734


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of drugs according to the circadian rhythm of the body. Pulsatile release pattern has gained

most popular form of controlled drug delivery system because conventional systems with a

continuous release are not ideal. Pulsatile systems are beneficial for the drugs having

chronopharmacological behaviour.[3,4]

The potential benefits of pulsatile drug delivery have

been demonstrated in the management of a number of diseases. PDDS is likely to be

successful for diseases such as asthma, myocardial infarction, angina pectoris, peptic ulcer,

arthritis, hypertension, hypercholesterolemia as in these diseases particular rhythms in the

onset and extent of symptoms are observed.[5]

Cardiovascular diseases such as hypertension

and angina, or chest pain, also follow a definite circadian rhythm. Hypertension is increased

in the early morning hours. Systolic blood pressure rises approximately 3 mm Hg/hr for the

first 4-6 hours post-awakening, while the rate of rise of diastolic blood pressure is

approximately 2 mm Hg/hr. The silent ischemic events showed a circadian pattern with a

high density of 34% events occurring between 6 a.m. and noon.[6]

The causes for these

findings have been suggested to be release of catecholamine, cortisol increase in the platelet

aggregation and vascular tone.

MATERIAL AND METHODS

Materials

Nicorandil, SSG, CCS and CP were obtained as a gift sample from Pharmatrain, Hyderabad,

India. HPMC K200M, MCC, Mannitol, Talc and Mg.Stearate was gift sample from Sunlife

sciences, Hyderabad. All other reagents and solvents used were of analytical grade satisfying

pharmacopoeias specifications.

I. Standard Calibration Curve of Nicorandil 0.1N Hcl buffer

Working standard: 50mg of Nicorandil was weighed and dissolved in 5ml methanol and

then make up to a volume of 50ml with water it gives 1000µg/ml concentrated stock solution.

Dilution 1: From the working standard solution 1ml was diluted to 10ml with 0.1N HCL it

will give 100µg/ml concentrated solution.

From dilution-1, take 0.2, 0.4, 0.6, 0.8 and 1.0ml of solution and was diluted up to mark in

10ml volumetric flask to obtain 2, 4, 6, 8 and 10µg/ml concentrated solutions. The

absorbance was measured in the UV-Visible spectrophotometer at 262 nm using 0.1N Hcl

buffer as blank and graph of concentration versus absorbance was plotted.


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II. Standard Calibration Curve of Nicorandil in 6.8phosphate buffer

Working standard: 50mg of Nicorandil was weighed and dissolved in 5ml methanol and

then make up to a volume of 50ml with water it gives 1000µg/ml concentrated stock solution.

Dilution 1: From the working standard solution 1ml was diluted to 10ml with 6.8 phosphate

buffer it will give 100µg/ml concentrated solution.

From dilution-1, take 0.2, 0.4, 0.6, 0.8 and 1.0ml of solution and was diluted up to mark in

10ml volumetric flask to obtain 2, 4, 6, 8 and 10µg/ml concentrated solutions. The

absorbance was measured in the UV-Visible spectrophotometer at 262 nm using

6.8phosphate buffer as blank and graph of concentration versus absorbance was plotted.

III. Preparation of Cross-Linked Gelatine Capsules

Formalin treatment has been employed to modify the solubility of gelatine capsules.

Exposure to formalin vapours results in an unpredictable decreases in solubility of gelatine

owing to the crosslinkage of the amino group in the gelatine molecular chain aldehyde group

of formaldehyde by Schiff’s base condensation.

Method

Hard gelatine capsule of size 0 was taken. Bodies were separated from cap, 25 ml of 15%

(v/v) formaldehyde was taken into desiccators and a pinch of potassium permanganate was

added to it, to generate formalin vapours. The wire mesh containing the empty bodies of

capsule was then exposed to formaldehyde vapours. The caps were not exposed leaving them

water-soluble. The desiccators were tightly closed. The reaction was carried out for 12 h after

which the bodies were removed and dried at 500C for 30 min to ensure completion of reaction

between gelatine and formaldehyde vapours. The bodies were then dried at room temperature

to facilitate removal of residual formaldehyde. These capsule bodies were capped with

untreated caps and stored in a polythene bag.

Preparation of hydrogel plug

Hydrogel plug was prepared by wet granulation method by using 5% w/v PVP K30 solution.

Preparation of binder solution: Accurately weigh 5gms of PVP K30 and dissolve in 100ml

of water.


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Ingredients Plug 1 Plug 2 Plug 3

HPMC K200M 20 40 60

MCC 80 60 40

Total weight 100 100 100

The formulation of pulsincap hydrogel plug was prepared by using wet granulation method

with PVP K30 solution in different proportions of HPMC K200M using 6mm punches and

dies on rotary tablet press keeping variation in thickness and hardness values of tablet plug.

This plug was then fitted into the body of hard gelatin capsule (containing equivalent to 10mg

of Nicorandil granules) which was cross linked by exposing the capsule bodies to

formaldehyde vapour in desiccator for 12 hours.

IV. Preparation of Immediate release Nicorandil granules

All the excipients except Magnesium stearate & Aerosil were cosifted through # 40 sieve

& blended in a poly bag for 10 min

Preparing the dump mass using 5% w/v PVP K30 solution

Wet screening the dampened powder into granules using # 20 sieve

To the above mixture # 60 sieve passed Magnesium stearate & Aerosil were added &

lubricated by blending in a poly bag for 5 min

Table 1: Formulation for Nicorandil Immediate release granules.

Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9

Nicorandil 10 10 10 10 10 10 10 10 10

SSG 1 2 3 -- -- -- -- -- --

CCS -- -- -- 1 2 3 -- -- --

Crospovidone -- -- -- -- -- -- 1 2 3

MCC 52 51 50 52 51 50 52 51 50

Mannitol 35 35 35 35 35 35 35 35 35

Mg.stearate 1 1 1 1 1 1 1 1 1

Talc 1 1 1 1 1 1 1 1 1

Total weight 100 100 100 100 100 100 100 100 100

III. EVALUATION OF GRANULES

The formulated granules were evaluated for the following quality control studies and

dissolution studies.

1. Density

a) Bulk density (BD): It is the ratio of total mass of powder to the bulk volume of powder

Weigh accurately 25 g of granules, which was previously passed through 22sieve and


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transferred in 100 ml graduated cylinder. Carefully level the powder without compacting, and

read the unsettled apparent volume. Calculate the apparent bulk density in gm/ml by the

following formula.

Bulk density = weight of powder/ Bulk volume.

Db =

0V

M

M = mass of the powder, V0 = bulk volume of the powder.

b) Tapped density (TD): It is the ratio of total mass of powder to the tapped volume of

powder.

Weigh accurately 25 g of granules, which was previously passed through 22# sieve and

transferred in 100 ml graduated cylinder of tap density tester which was operated for fixed

number of taps until the powder bed volume has reached a minimum, thus was calculated by

formula.

Tapped density = Weigh of powder / Tapped volume

Dt = (M) / (V f).

M = mass of the powder, V f = tapped volume of the powder.

2. Carr‟s Index

Compressibility index of the powder blend was determined by Carr’s compressibility index.

It is a simple test to evaluate the BD and TD of a powder and the rate at which it packed

down.[19]

The formula for Carr’s index is as below:

Compressibility index = 100 x density Tapped

density Bulk -density Tapped

3. Hausner‟s Ratio

Hausner’s Ratio is a number that is correlated to the flow ability of a powder.

Hausner‟s Ratio = DensityBulk

Density Tapped


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Table 2: Compressibility index limits.

Scale of Flow ability (USP29-NF34)

Compressibility Index (%) Flow Character Hausner‟s Ratio

≤ 10 Excellent 1.00-1.11

11-15 Good 1.12-1.18

16-20 Fair 1.19-1.25

21-25 Passable 1.26-1.34

26-31 Poor 1.35-1.45

32-37 Very Poor 1.46-1.59

> 38 Very, very Poor > 1.60

4. Angle of Repose: It is defined as the maximum angle possible between the surface of a

pile of powder and the horizontal plane.

Angle of Repose of granules was determined by the funnel method. Accurately weighed

powder blend was taken in the funnel. Height of the funnel was adjusted in such a way the tip

of the funnel just touched the apex of the powder blend. Powder blend was allowed to flow

through the funnel freely on to the surface. Diameter of the powder cone was measured and

angle of repose was calculated using the following equation.

= tan-1

(h/r)

Where: = angle of repose, h = height in cms, r = radius in cms.

The angle of repose has been used to characterize the flow properties of solids. It is a

characteristic related to inter particulate friction or resistance to movement between particles.

Table 3: Angle of repose limits.

Flow Properties and Corresponding Angles of Repose

Flow Property Angle of Repose (degrees)

Excellent 25–30

Good 31–35

Fair—aid not needed 36–40

Passable—may hang up 41–45

Poor—must agitate, vibrate 46–55

Very poor 56–65

Very, very poor >66

B) Post compression studies

1. Average weight/Weight Variation: 20 tablets were selected and weighed collectively and

individually. From the collective weight, average weight was calculated. Each tablet weight


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was then compared with average weight to assure whether it was within permissible limits or

not. Not more than two of the individual weights deviated from the average weight by more

than 7.5% for 300 mg tablets and none by more than double that percentage.

Average weight = weight of 20 tablets

20

%weight variation = average weight - weight of each tablet ×100

Average weight

Table 4: Weight variation tolerance for uncoated tablets.

Acceptance criteria for tablet weight variation (USP 29-NF 34)

Average weight of tablet(mg) % difference allowed

130 or Less than ± 10

130-324 ± 7.5

More than 324 ± 5

2. Thickness: Thickness of the tablets (n=3) was determined using a Vernier calipers.

3. Hardness test: Hardness of the tablet was determined by using the Monsanto hardness

tester (n=3) the lower plunger was placed in contact with the tablet and a zero reading was

taken. The plunger was then forced against a spring by turning a threaded bolt until the tablet

fractured. As the spring was compressed a pointer rides along a gauge in the barrel to indicate

the force.

4. Friability test: This test is performed to evaluate the ability of tablets to withstand

abrasion in packing, handling and transporting.

Initial weight of 20 tablets is taken and these are placed in the Friabilator, rotating at 25rpm

for 4min.

The difference in the weight is noted and expressed as percentage.

It should be preferably between 0.5 to 1.0%.

%Friability = [(W1-W2)/W1] X 100

Where, W1= weight of tablets before test,

W2 = weight of tablets after test


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5. Assay Procedure

Accurately weigh and dissolve equivalent to 25 mg of drug in methanol and than make up to

the volume of 25ml with water it gives 1000µg/ml concentrated solution.

From above that solution 1ml was diluted to 10ml with water it will give 100µg/ml

concentrated solution.

From above that solution 1ml was diluted to 10ml with water it will give 10µg/ml

concentrated solution.

And take absorbance from UV visible spectroscopy apply in below formula

Assay = test absorbance/standard absorbance*standard concentration/sample

concentration*purity of drug/100*100

6. In vitro Dissolution Study for Immediate release granules

900 ml of 0.1N HCl (or) 6.8 phosphate buffer was placed in the vessel and the USP-II

apparatus (Paddle method) was assembled. The medium was allowed to equilibrate to

temperature of 370C±0.5

0C. A tablet was placed in the vessel and was covered; the apparatus

was operated up to 60minutes at 75 rpm. At definite time intervals, 5 ml of dissolution

medium was withdrawn; filtered and again replaced with 5 ml of fresh medium to maintain

sink conditions. Suitable dilutions were done with dissolution medium and were analyzed

spectrophotometrically at max =262 nm using a UV-spectrophotometer (Lab India).

Table 5: Dissolution parameters for Immediate release granules.

Parameter Details

Dissolution apparatus USP -Type II (paddle)

Medium 0.1N HCl (or) 6.8 phosphate buffer

Volume 900 ml

Speed 75 rpm

Temperature 37± 0.5 ºC

Sample volume withdrawn 5ml

Time points 5, 10, 15, 30, 45 and 60 min

Analytical method Ultraviolet Visible Spectroscopy

λ max 262 nm

7. In vitro Dissolution Study for pulsincap DDS

900 ml of 0.1N HCl was placed in the vessel and the USP-II apparatus (Paddle method) was

assembled. The medium was allowed to equilibrate to temperature of 370C±0.5

0C. A tablet

was placed in the vessel and was covered; the apparatus was operated up to 120 minutes at 75


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rpm. At definite time intervals, 5 ml of dissolution medium was withdrawn; filtered and again

replaced with 5 ml of fresh medium to maintain sink conditions. Suitable dilutions were done

with dissolution medium and were analyzed spectrophotometrically at max =262 nm using a

UV-spectrophotometer (Lab India). Then remove the 0.1N Hcl and replace with 6.8

phosphate buffer and continue the dissolution with the above procedure from 120 minutes.

Table 6: Dissolution parameters for Pulsincap DDS.

Parameter Details

Dissolution apparatus USP -Type II (paddle)

Medium

0.1N HCl upto 120min

And

6.8 phosphate buffer from 120min-540min

Volume 900 ml

Speed 75 rpm

Temperature 37± 0.5 ºC

Sample volume withdrawn 5ml

Time points 5, 10, 15, 30, 45, 60, 120, 180, 240, 300, 360. 420,

480 and 540 min

Analytical method Ultraviolet Visible Spectroscopy

λ max 262 nm

In vitro Release Kinetics Studies: The analysis of drug release mechanism from a

pharmaceutical dosage form is important but complicated process and is practically evident in

the case of matrix systems. The order of drug release from Pulsincap drug delivery was

described by using zero order kinetics or first order kinetics. The mechanism of drug release

from Pulsincap drug delivery was studied by using Higuchi equation and the Peppa’s-

Korsemeyer equation.

1. Zero Order Release Kinetics

It defines a linear relationship between the fractions of drug released versus time.

Q=k0t.

Where, Q is the fraction of drug released at time t and ko is the zero order release rate

constant. A plot of the fraction of drug released against time will be linear if the release obeys

zero order release kinetics.

2. First Order Release Kinetics: Wagner assuming that the exposed surface area of a tablet

decreased exponentially with time during dissolution process suggested that the drug release


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from most of the slow release tablets could be described adequately by the first-order

kinetics. The equation that describes first order kinetics is

Log C= Log Co-kt/2.262

Where C is the amount of drug dissolved at time t,

Co is the amount of drug dissolved at t=0 and

k is the first order rate constant.

A graph of log cumulative of log % drug remaining Vs time yields a straight line. Will be

linear if the release obeys the first order release kinetics.

3. Higuchi equation: It defines a linear dependence of the active fraction released per unit of

surface (Q) and the square root of time.

Q=K2t1/2

Where K2 is release rate constant. A plot of the fraction of drug released against square root

of time will be linear if the release obeys Higuchi equation. This equation describes drug

release as a diffusion process based on the Fick’s law, square root time dependent.

4. Peppa‟s-Korsemeyer equation (Power Law): In order to define a model, which would

represent a better fit for the formulation, dissolution data was further analysed by Peppa’s-

Korsemeyer equation (Power Law).

Mt/ M∞ =K.tn

Where, Mt is the amount of drug released at time t

Mα is the amount released at time α,

Mt/Mα is the fraction of drug released at time t,

K is the kinetic constant and n is the diffusion exponent.

To characterize the mechanism for both solvent penetration and drug release n can be used as

abstracted. A plot between log drug release up to 60% against log of time will be linear if the

release obeys Peppa’s-Korsemeyer equation and the slope of this plot represents ―n‖ value.

The kinetic data of the formulations were included.


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Nature of release of the drug from the designed tablets was inferred based on the correlation

coefficients obtained from the plots of the kinetic models. The data were processed for

regression analysis using MS EXCEL.

Table 7: Drug release kinetics mechanism.

Diffusion exponent(n) Mechanism

0.45 Fickian diffusion

0.45 < n <0.89 Anomalous(Non- Fickian) diffusion

0.89 Case II transport

n > 0.89 Super Case II transport

RESULTS AND DISCUSSION

1. Construction of Standard calibration curve of Nicorandil in 0.1N HCl

The absorbance of the solution was measured at 262nm, using UV spectrometer with 0.1N

HCl as blank. The values are shown in table. A graph of absorbance Vs Concentration was

plotted which indicated in compliance to Beer’s law in the concentration range 2 to 10 µg/ml.

Table 8: Standard calibration curve values.

Concentration (µg/ml) Absorbance

0 0

2 0.129

4 0.263

6 0.395

8 0.512

10 0.642

Figure 1: Nicorandil Standard calibration curve in 0.1 N Hcl.


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2. Construction of Standard calibration curve of Nicorandil in 6.8 phosphate buffer

The absorbance of the solution was measured at 262nm, using UV spectrometer with 6.8

phosphatebuffer as blank. The values are shown in table no 20. A graph of absorbance Vs

Concentration was plotted which indicated in compliance to Beer’s law in the concentration

range 2 to 10 µg/ml.

Table 9: Standard calibration curve values.

Concentration (µg/ml) Absorbance

0 0

2 0.138

4 0.281

6 0.413

8 0.556

10 0.698

Figure 2: Nicorandil Standard calibration curve in 6.8 phosphate buffer.

Evaluation studies

Table 10: Pre compression studies of Nicorandil Hydrogel plug.

Formulation

Code

Bulk density

(Kg/cm3)

Tapped

density

(Kg/cm3)

Cars index Hausners

ratio

ng e of

repose

Plug 1 0.44 0.50 12 1.1 27.92

Plug 2 0.40 0.48 16 1.2 32.73

Plug 3 0.50 0.58 13 1.16 28.58


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Inference

The blends prepared for direct compression of tablets were evaluated for their flow

properties; the results for the blends of compression tablets were shown in Table:

The bulk density and the tapped density for all formulations were found to be almost

similar.

The Carr’s index and Hausner’s ratio were found to be in the range of ≤ 18 and 1.1 to

1.23 respectively, indicating good flow and compressibility of the blends.

The angle of repose for all the formulations was found to be in the range of 27.92-34.96˚

which indicating passable flow (i.e. incorporation of glidant will enhance its flow).

Table 11: Post compression studies of Nicorandil Hydrogel plug.

Formulatio

n Code

% weight

variation

Thickness

(mm)

Hardness

(Kg/cm2)

% Friability

Plug 1 2.37 3.41 7.51 0.31

Plug 2 3.16 3.61 7.49 0.42

Plug 3 0.47 3.28 7.47 0.35

Inference

The variation in weight was within the range of ±10% complying with pharmacopoeia

specifications of USP.

The thickness of tablets was found to be between 3.28-3.61 mm.

The hardness for different formulations was found to be between 7.47 to 7.51 kg/cm2,

indicating satisfactory mechanical strength

The % Friability was within limit

Table 12: Evaluation studies of Nicorandil immediate release granules.

Formulation

Code Bulk density Tapped density Cars index

Hausners

ratio

Angle of repose

(degrees)

F1 0.325 0.375 13.33 1.15 4.7

F2 0.281 0.317 11.35 1.12 5.5

F3 0.333 0.357 6.722 1.07 6.1

F4 0.270 0.307 12.05 1.13 6.8

F5 0.25 0.289 13.49 1.15 6.7

F6 0.285 0.312 8.65 1.09 6.8

F7 0.285 0.322 11.49 1.12 6.1

F8 0.313 0.338 7.39 1.07 5.6

F9 0.312 0.338 7.69 1.08 4.5


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Inference

The prepared tablets were evaluated for their flow properties; the results for the blends of

compression tablets were shown in Table.

The bulk density and the tapped density for all formulations were found to be almost

similar.

The Carr’s index and Hausner’s ratio were found to be in the range of ≤ 18 and 1.0

respectively, indicating good flow and compressibility of the blends.

The angle of repose for all the formulations was found to be 4.5-6.8 which indicating

passable flow (i.e. incorporation of glidant will enhance its flow).

Table 13: Dissolution data of Nicorandil immediate release granules.

Time (Min) F1 F2 F3 F4 F5 F6 F7 F8 F9

0 0 0 0 0 0 0 0 0 0

5 15.47 19.52 23.45 21.21 32.46 46.98 51.34 57.28 45.33

10 19.58 23.49 31.43 28.36 43.28 54.73 69.26 73.26 77.86

15 23.42 27.44 39.32 39.13 55.23 68.76 85.31 91.32 99.54

30 51.26 57.32 78.26 51.29 69.56 81.23 98.26 99.26 97.37

45 59.38 63.25 85.33 63.16 75.37 89.38 99.98 98.05 94.23

60 72.14 78.21 97.28 79.34 93.24 99.27 99.10 95.32 89.37

Figure 3: Comparative dissolution profile for F1, F2 and F3 formulations.


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Figure 6: First order plot for F1, F2 and F3 formulations.


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Table 14: R2 and „n‟ resu t tab e.

Formulation

Code

R2 Value

Zero order First order

F1 0.984 0.998

F2 0.971 0.992

F3 0.963 0.979

F4 0.967 0.990

F5 0.916 0.967

F6 0.861 0.949

F7 0.773 0.885

F8 0.704 0.736

F9 0.642 0.356


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Inference

Among the different polymers Crospovidone was showing better drug release

F9 was showing the satisfactory results

When we plot the release rate kinetics for best formulation F9 was following zero order

because correlation coefficient value of zero order is more than first order value.

Table 15: Dissolution data of Nicorandil Pulsincap DDS.

Time (Min) Plug 1 Plug 2 Plug 3

0 0 0 0

5 37.51 39.44 41.19

10 69.85 71.49 73.36

15 99.19 98.42 99.10

30 97.43 95.35 98.39

45 90.49 92.46 93.94

60 84.42 89.41 89.72

120 0.32 0.25 0.14

180 0.05 4.36 0.26

240 17.43 8.62 0.47

300 45.35 21.53 0.49

360 98.97 79.41 1.52

420 2.52 99.45 3.29

480 0.45 5.63 5.48

540 0.33 0.26 99.49

Figure 9: Comparative dissolution profile for Plug 1, Plug 2 and Plug 3 formulations.


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Figure 10: First order for Plug 1, Plug 2 and Plug 3 formulations.

Figure 11: Higuchi plots for Plug 1, Plug 2 and Plug 3 formulations.

Figure 12: Peppas plots for Plug 1, Plug 2 and Plug 3 formulations.


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Table 16: R2 and „n‟ resu t tab e.

Formulation

Code

R2 Value

“N” Va ue Zero order First order Higuchi Peppas

Plug 1 0.456 0.305 0.397 0.531 0.959

Plug 2 0.308 0.137 0.275 0.443 0.617

Plug 3 0.334 0.126 0.365 0.558 0.929

Inference

Plug 3 was showing the satisfactory results

When we plot the release rate kinetics for best formulation Plug 3 was following zero

order because correlation coefficient value of zero order is more than first order value.

FT-IR spectroscopy for Nicorandil

The FTIR spectra‟s, observed that the characteristic absorption peaks of pure Nicorandil

were obtained. The spectral data suggests that the major peaks for drugs are obtained as

nearer value and there were no considerable changes in IR peaks in all physical mixtures of

drug and polymers. This indicates that the drugs were molecularly dispersed in the polymers

or in drug loaded formulations thus thereby indicating the absence of any interactions.

Figure 13: IR graph for Nicorandil.


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Figure 14: IR graph for Crospovidone.

Figure 15: IR graph for HPMC K200M.

Figure 16: IR graph for Nicorandil + Crospovidone.


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SUMMARY AND CONCLUSION

1. Suitable analytical method based on UV-Visible spectrophotometer was developed for

Nicorandil. λmax of 262 nm was identified in phosphate buffer solution, pH 6.8.

2. HPMC K200M polymer was used in different ratios for hydrogel plug preparation. And

HPMC K200M was respectively showed better pulsatile drug release of Nicorandil.

3. When polymer concentration increases the release rate decreases this is because of reason

when the concentration of polymer increases the diffusion path length increases

4. Hydrogel plug granules was showed satisfactory results for all pre and post compression

studies.

5. Nicorandil immediate release granules were prepared by wet granulation method using

Sodium starch glycolate, Croscarmellose sodium and Crospovidone.

6. Crospovidone was given better release when compared with other polymers.

7. Formulation F9 was selected for puls in cap drug release.

8. Formulation F9 was tried with all 3 plugs for puls in cap drug delivery system.

9. Plug-3 gave better-pulsatile drug release when compared with other 2 plugs.

10. The most probable mechanism for the drug release pattern from the formulation was

Super Case II transport.

BIBLIOGRAPHY

1. In Rang and Dale’s Pharmacology (7th

ed., pp. 261). Edinburgh: Elsevier/Churchill

Livingstone. [ISBN: 978-0-7020-3471-8]

2. Goldschmidt M, Landzberg BR, Frishman WH: Nicorandil: a potassium channel opening

drug for treatment of ischemic heart disease. J Clin Pharmacol, 1996 Jul; 36(7): 559-72.

[PubMed:8844437]

3. Shah S, Gandhi S, Tank D Pulsatile drug delivery system: drug delivery in symphony

with circadian rhythm. Dec Pharm J Series, 2010; 1(5): 18-41.

4. Sharma GS, Srikanth MV, Uhumwangho MU, Phani Kumar KS and Ramana Murthy KV

Recent trends in pulsatile drug delivery systems - A review. Int J Pharm Pharm Sci.,

2010; 2(4): 200-212.

5. Lemmer B, Chronopharmacokinetics: implications for drug treatment, J Pharmacy

Pharmacol, 1999; 51(8): 887-890.

6. Deedwania PC, Nelson JR, Pathophysiology of silent myocardial ischemia during daily

life hemodynamic: Evaluation by simultaneous electrocardiographic and blood pressure

monitoring, Circ., 1990; 82(4): 1296-1304.

http://www.ncbi.nlm.nih.gov/pubmed/8844437

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