DEVELOPMENT AND IN VITRO EVALUATION OF PERINDOPRIL FLOATING TABLETS

www.wjpr.net Vol 4, Issue 4, 2015. 1010

DEVELOPMENT AND

IN VITRO

EVALUATION OF PERINDOPRIL

FLOATING TABLETS

Srinivas Martha*

Department of Pharmaceutics, Joginpally B.R Pharmacy College, Yenkapally (v), Moinabad

(M), Hyderabad- 500075, Telangana, India.

ABSTRACT

The purpose of this research was to develop a novel gastro retentive

floating tablets of Perindopril. Perindopril has half life (1-17 hrs) so an

attempt has been made to Sustain the drug release by the incorporation

of hydrophilic swellable polymer such as Hydroxy propyl

methylcellulose and present it in the form of gastro retentive floating

tablets, which after oral administration are designed to provide the

desired controlled and complete release of drug for prolonged period of

time in the treatment of high blood pressure. Floating effervescent

tablets were formulated by using various materials like Hydroxy

propyl methylcellulose, xanthan gum, and gas generating agents like

sodium bicarbonate. The concentration of these agents was also

optimized to get desired controlled release of drug. The floating tablet

formulations were evaluated for physical characterization, hardness,

friability, weight variation, drug content uniformity, swelling index and buoyancy studies.

The results indicated that the floating tablets formulation (F4) prepared by direct compression

with Drug: Xanthan gum (40%) at a ratio of 1: 8 could be suitable for extending the drug

release up to 12 hrs. In-vitro drug release kinetics evaluated using the linear regression

method was found to follow the Higuchi followed by Korsemeyer and Peppas equation.

KEYWORDS: Perindopril, gastro retentive, intragastric floating tablets, buoyancy, Floating

drug delivery, controlled release.

INTRODUCTION

Oral drug delivery has been known for decades as the most widely utilized route of

administration among all the routes that have been employed for the systemic delivery of

drug via various pharmaceutical products of different dosage forms. The reasons that the oral

Volume 4, Issue 4, 1010-1021. Research Article ISSN 2277– 7105

Article Received on 19 Jan 2015,

Revised on 14 Feb 2015, Accepted on 10 Mar 2015

*Correspondence for

Author

Srinivas Martha

Department of

Pharmaceutics,

Joginpally B.R Pharmacy

College, Yenkapally (v),

Moinabad (M),

Hyderabad- 500075,

www.wjpr.net Vol 4, Issue 4, 2015. 1011

route achieved such popularity may be in part attributed to its ease of administration. Oral

sustained drug delivery system is complicated by limited gastric residence times (GRTs).

Rapid GI transit can prevent complete drug release in the absorption zone and reduce the

efficacy of the administered dose since the majority of drugs are absorbed in stomach or the

upper part of small intestine. Dosage forms that can be retained in the stomach are called

gastro retentive drug delivery systems (GRDDS). GRDDS can improve the controlled

delivery of drugs that an absorption window by continuously releasing the drug for a

prolonged period of time before it reaches its absorption site, thus ensuring its optimal

bioavailability. Perindopril is a long-acting ACE inhibitor. It is used to treat high blood

pressure, heart failure or stable coronary artery disease in the form of a Perindopril

arginine (tradenames include Coversyl, Coversum) or Perindopril erbumine (trade name

Aceon). It is actively absorbed from the lower part of the gastro intestinal tract. The drug has

a relatively long acting half life (1-17 hrs) and it undergoes first pass metabolism. Thus, it is a

suitable drug for the development of gastro retentive drug delivery system.

The objective of this work is to design a controlled floating release oral dosage form of

Perindopril to obviate the demerit of the limited residence time of the controlled release

dosage form in the gastro intestinal tract and hence to increase the duration of release.

Floating system has a bulk density less than gastric fluids and so remain buoyant in the

stomach without effecting the gastric emptying rate for a prolonged period of time. While the

system is floating on the gastric contents, the Perindopril released slowely and after release of

drug, the residual system is emptied from the stomach. This results in an increased GRT

(gastric residence time) and better control of fluctuations in plasma drug concentration.

MATERIALS AND METHODS

MATERIALS

Perindopril was received as a gift sample from Aurobindo pharma ltd., Hyderabad. HPMC

K4M, Xanthan gum, Sodium bicarbonate, Micro crystalline cellulose, talc, Magnesium

stearate were purchased from Signet Chemicals, Mumbai.

METHOD

Perindopril tablets were prepared by Direct compression method. All the ingredients were

weighed accurately Perindopil, polymer HPMCK4M, sodium bi-carbonate and diluent were

www.wjpr.net Vol 4, Issue 4, 2015. 1012

magnesium stearate. And then the powder mixture was compressed by employing 10 mm

round shaped die with Lab india 12 station tabletting machine to get tablets.

Formulation design

Table 1: Formulation of Perindopril floating tablets

Ingredients Quantity per tablet (mg)

F1 F2 F3 F4 F5 F6 F7 F8 F9

Perindopril 8 8 8 8 8 8 8 8 8

HPMC K4M 20 25 30 - - - 15 18.7 22.5

Xanthan gum - - - 20 25 30 5 6.5 7.5

NaHCO3 95 95 95 95 95 95 95 95 95

MCC 121 116 111 121 116 111 121 116 111

Magnesium

stearate 4 4 4 4 4 4 4 4 4

Talc 2 2 2 2 2 2 2 2 2

Total weight 250 250 250 250 250 250 250 250 250

Evaluation of Perindopril floating Tablets

The formulated tablets were evaluated for the following physicochemical characteristics.

a) Physical appearance

The general appearance of tablets, its visual identity and overall elegance is essential for

consumer acceptance. The control of general appearance of tablet involves measurement of

number of attributes such as tablet size, shape, color, presence or absence of odor, taste,

surface texture and consistency of any identification marks.

b) Hardness test

Hardness of the tablets was determined by using Monsanto hardness tester. The tablet to be

tested is held in fixed and moving jaw and reading of the indicator adjusted to zero. Then

force to the edge of the tablets was gradually increased by moving the screw knob forward

until the tablet breaks. The reading was noted from the scale which indicates the pressure

required in kg to break the tablet. The hardness of the tablets depends on the weight of the

materials used, space between the upper and lower punches at the time of compression and

pressure applied during compression.

c) Tablet size and Thickness

Control of physical dimensions of the tablets such as size and thickness is essential for

consumer acceptance and tablet-tablet uniformity. The diameter size and punch size of tablets

www.wjpr.net Vol 4, Issue 4, 2015. 1013

measured by Vernier Calipers scale. The thickness of the tablet related to the tablet hardness

and can be used as initial control parameter. Tablet thickness should be controlled within a

±5%. In addition thickness must be controlled to facilitate packaging.

d) Friability

The Roche friability test apparatus was used to determine the friability of the tablets.

Randomly selected twenty pre-weighed tablets were placed in the apparatus and operated for

100 revolutions and then the tablets were reweighed. The acceptable limits of the weight loss

should not be more than 1%. The percentage friability was calculated according to the

following formula.

%friability = (initial weight – final weight) / initial weight * 100

e) Average weight of Tablets

It is desirable that all the tablets of a particular batch should be uniform in weight. If any

weight variation is there, that should fall within the prescribed limits:

±10% for tablets weighing 300mg or less

±7.5% for tablets weighing 300mg to 315mg

±5% for tablets weighing more than 315mg

Twenty tablets were taken randomly and weighed accurately. The average weight is

calculated by

Average weight = weight of 20 tablets

20

f) Floating lag time and Total floating time

Floating characteristics of the prepared formulations were determined using the 0.1N HCL.

The tablets were placed in a 100ml beaker containing 0.1 N HCL at 37 ± 0.50 C. The time

required for the tablet to rise to the surface and float on solution (Floating lag time) and the

time during which dosage form remains buoyant on the solution (Total floating time) was

measured.

g) Drug Content uniformity

Over ten tablets were selected randomly and average weight was calculated. Tablets were

crushed in a mortar and accurately average weighed amount of tablets triturate was taken for

www.wjpr.net Vol 4, Issue 4, 2015. 1014

The content was shaken well and kept for 30 minutes for dissolving the drug and appropriate

dilutions were made. The drug content was estimated by recording the absorbance at 285nm.

h) In-Vitro Dissolution studies

In vitro drug release study of the samples was carried out by using USP – type II dissolution

apparatus (Paddle type). The 0.1 N HCL was used as the dissolution medium. The 900ml of

0.1N HCL was placed into the dissolution flask maintaining the temperature of 37 ± 0.50 C

and 50 RPM. 5 ml of sample was withdrawn after 0.5, 1, 2, 4, 6, 8, 10, and 12 hours and the

same was replaced with fresh dissolution medium (37oC). Collected samples were analyzed

at 285 nm using 0.1 N HCL as blank. The drug release experiments were conducted in

triplicate.

Table 2: In vitro dissolution studies

Drug Name

Dosage Form

Dissolution Apparatus

Speed

(RPMs) Medium

Medium Volume (ml)

Sampling intervals (hrs)

Perindopril Tablets USP-II

Paddle type 50RPM

0.1N

HCL 900

0.5,1,2,4,6, 8,10,12

Stability studies: The purpose of stability testing is to provide evidence on how the quality

of a drug substance or drug product varies with time under the influence of a variety of

environmental factors, such as temperature, humidity etc.

Objective: To generate documented evidence that the tablets manufactured comply with the

finished product specifications under accelerated and long term stability conditions.

Design plan: Accelerated study: The product is subjected to accelerated stability studies at

550C for two weeks and 400C±20C / 75 % ±5% RH for six months. Long term study: The

product is subjected to long term studies at 250C±20C / 60 % ±5% RH for 12 months.

RESULTS AND DISCUSSION

Pre compression parameters

The Pre compression parameters were the primary requirements to determine whether the

specific material was suitable for the targeted formulation or not. The aim was to formulate

the tablet formulation with direct compression method, so it was mandatory to know the bulk

density, tapped density, Carr’s index, Hausner’s ratio and angle of repose as those were the

official requirement while choosing any material for its dosage form formulation. Table 3

www.wjpr.net Vol 4, Issue 4, 2015. 1015

Hausner’s ratio, Angle of Repose for various tablet formulations. The result of evaluation

parameters clearly indicates its suitability to be the material of choice for formulation.

Table 3: Pre compression parameters of Perindopril Powder blend formulated with

different concentrations of HPMC K4M & Xanthan gum

Formulation Bulk Density (gm/cc) Tapped Density (gm/cc) Carr’s Index Hausner’s ratio Angle of repose (0)

F1 0.499 0.531 5.89 1.06 25.11

F2 0.437 0.471 7.14 1.07 26.30

F3 0.508 0.570 10.9 1.12 27.70

F4 0.507 0.530 4.39 1.04 27.56

F5 0.399 0.428 6.76 1.07 28.73

F6 0.433 0.472 8.32 1.14 28.95

F7 0.502 0.533 5.86 1.06 27.49

F8 0.402 0.442 8.96 1.09 28.53

F9 0.481 0.560 13.98 1.16 27.63

Post compression parameters

All the prepared batches were evaluated systematically. The obtained results of the evaluated

post compression parameters were represented in the bellow table i.e. in Table 4. The results

of all the trial batches were compared and found satisfactory, as per the reported

specification. Finally the comparison parameters were keenly observed to finalize for

selection of the optimized batch and formula. Hardness of tablets was found to be in the

range of 3.8 to 4.4 kg/cm2 shown in Table 4. The friability of all tablets was found to be in

the range of 0.58 to 0.75 which is less than 1% that showed good mechanical strength.

Floating lag time and total floating time is increased when xanthan gum is used.

Table 4: post compression parameters of Perindopril floating tablets.

Formulation Average Weight (mg)

Hardness (kg/cm2)

Friability (%) Thickness (mm) Drug content (%) Floating lag time (sec) Total Floating time (hrs)

F1 246 3.8 0.75 3.5 101.0 0.09 >10

F2 243 3.8 0.74 3.8 99.05 0.12 >10

F3 251 3.9 0.72 3.6 98.92 0.89 >10

F4 254 4.0 0.58 4.1 99.85 1.52 >12

F5 239 4.3 0.59 4.0 100 2.14 >12

F6 246 4.3 0.58 3.9 99.06 2.89 >12

F7 252 4.1 0.65 4.2 98.95 1.95 >12

F8 250 4.3 0.66 4.5 98.08 2.80 >12

www.wjpr.net Vol 4, Issue 4, 2015. 1016 FTIR graphs

Drug-excipients interactions play a vital role in the release of drug from formulation. The

pure Perindopril and its mixture with HPMC K4M, xanthan gum, talc, magnecium stearate,

MCC, sodium bicarbonate were mixed separately and were scanned over a range of 400–

4500 cm−1 using FTIR. The drug exhibits peaks due to ketonic group, alcohol group,

secondary amine, terminal CH3 group, and C=O stretching in COOH and CONH. It was

observed that main peaks of Perindopril were present in mixture of drug and polymer, and no

change in main peaks of the drug IR spectra in a mixture of drug and polymers was found in

Fig 1 & 2.

Fig 1: FTIR graph of Perindopril

www.wjpr.net Vol 4, Issue 4, 2015. 1017 Table 5: Cumulative % of Perindopril released from floating tablets.

Formulations

Cumulative percentage drug release Time in hours

00 0.5 1 2 4 6 8 10 12

F1 0.00 46.71 61.83 80.29 101.07 - - - -

F2 0.00 40.56 54.73 71.42 99.00 - - - -

F3 0.00 35.02 42.17 67.11 79.09 84.26 90.06 - -

F4 0.00 24.77 37.22 40.02 58.20 69.81 75.11 89.72 99.98 F5 0.00 22.31 31.72 42.31 54.20 63.21 72.03 84.12 89.15 F6 0.00 16.12 27.63 36.91 48.72 59.32 69.74 78.56 85.23 F7 0.00 28.16 37.37 54.00 69.26 80.41 85.33 90.80 93.44 F8 0.00 24.46 32.09 50.67 67.89 73.50 80.28 80.32 90.39 F9 0.00 16.83 28.57 40.50 54.39 67.96 75.37 80.21 85.64 Marketed

product 0.0 24.22 38.10 40.52 56.42 68.99 74.21 87.02 98.72

The in-vitro drug release profile of tablets from each batch (formulation F1-F9) was carried

in 0.1N HCl having pH 1.2, for 12 hours by using paddle type. The F1,F2,F3 formulations

were done with HPMC K4M which is showing controlled release in which the total drug was

released at the end of below 8 hours. To overcome this problem xanthan gum was used with

forming rate controlling gel within few minutes and F4, F5, F6 formulations were prepared.

F4 was having good controlled release throughout the dissolution period and release 99.98%

of the drug at the end of 12 th hour. F5 & F6 having xanthan gum in more amount was

controlled more and released approximately 87% of drug at the end of 12 th hour.F7, F8, F9

formulations are made in combination of HPMC K4M and xanthan gum. The % cumulative

drug release showed that the release is less when compared to the formulation using only

xanthan gum at the end of 12 th hour. Only 80% of drug is released for F7, F8, F9

formulations at the end of 12 th hour.all the formulations were shown in Fig 3. The

dissolution studies for the optimized formulation F4 and the marketed formulation is

compared. Results showed that % cumulative release of developed optimized formulation

www.wjpr.net Vol 4, Issue 4, 2015. 1018 Fig 3: % Cumulative drug profile of Perindopril tablets formulations (F1-F9)

0 20 40 60 80 100 120

0 5 10 15

%

CD

R

time in hrs

F4

Innovator

Fig 4: Invitro drug release of Perindopril for innovator and optimized F4 formulations

in 0.1N HCl

Kinetics of drug release

Table 6: In vitro drug release kinetic data of Perindopril tablets formulated with

different concentrations

Formulation Zero order (R2)

First order (R2)

Higuchi order(R2)

Peppas (R2)

Hixon crowell (R2)

F1 0.871 0.974 0.994 0.994 0.939

F2 0.912 0.938 0.989 0.978 0.897

F3 0.883 0.960 0.992 0.982 0.933

F4 0.899 0.981 0.997 0.994 0.963

F5 0.963 0.987 0.998 0.996 0.977

F6 0.936 0.989 0.989 0.986 0.988

F7 0.925 0.936 0.997 0.933 0.988

F8 0.966 0.992 0.991 0.988 0.975

www.wjpr.net Vol 4, Issue 4, 2015. 1019 Fig 5: Comparative First order plots of Perindopril floating tablets formulated with

different concentrations of Xanthan gum

Stability studies: It was found that there are no changes in the physical and chemical

parameters of Perindopril tablets of formulation F4 after 1 month at 250C/60% RH ,

400C/75% RH.There is no significant difference in the percentage of drug release of

Perindopril tablets of formulation F4 after 1 month at 250C/60% RH , 400C/75% RH given in

Table 7&8.

Table 7: Dissolution profiles of Perindopril tablets for formulation F4 after one month

at 250c/60% RH

Time interval(min) Percentage of drug release

INITIAL FINAL

0 0 0

0.5 24.77 24.69

1 37.22 37.20

2 40.02 40.00

4 58.20 58.18

6 69.81 69.78

8 75.11 75.06

10 89.72 89.66

12 99.98 99.97

Table 8: Dissolution profiles of Perindopril tablets for formulation F4 after one month

at 400c/75% RH

Time interval(min) Percentage of drug release

INITIAL FINAL

0 0 0

0.5 24.77 24.68

www.wjpr.net Vol 4, Issue 4, 2015. 1020

2 40.02 40.00

4 58.20 58.16

6 69.81 69.76

8 75.11 75.04

10 89.72 89.65

12 99.98 99.96

CONCLUSION

Studies have been carried out to develop Floating tablets of Perindopril with natural polymers

HPMC K4M, xanthan gum and combination of HPMC K4M and xanthan gum. The powder

blend was evaluated for various micromeritic properties. Nine different formulations were

made and the formulations were tested for floating characterization like floating lag time and

floating time, in-vitro dissolution studies. Based on the results of floating and dissolution

studies and marketed with innovators. F4 was found to be the best among trials. The % drug

release was found to be 99.98% the marketed product gave 98.72% of drug release in 12th

hours of dissolution study. The formula F4 with 99.98% of drug release has better control

over release of drug when compared with marketed product.

ACKNOWLEDGEMENT

The authors sincerely express thanks to the Management, Department of pharmaceutics of

joginpally B.R Pharmacy College and Jawaharlal Nehru Technological University,

Hyderabad for providing facilities to carry out this research work. Authors are thankful to

Pharma Train Labs, Hyderabad, India for providing Drug and other Excipients.

REFERENCES

1. Sanjay Dey, Snigdha Dutta, Bhasker Mazumder, “Formulation and in vitro evaluation of

Floating matrix tablets of Atenolol for gastro retentive drug delivery”, International

Journal of Pharmacy and Pharmaceutics, 2012; 4(3): 433-437.

2. M. Mohan Varma and S. Vijaya, "Development and evaluation of gastro retentive

Floating drug delivery system of Atenolol”, International Journal of Pharmaceutical and

Chemical Sciences, 2012; 1(2): 867-876.

3. Mothilal M, Shaik Nelofar, Swati. P. S, Damodharan. N and Manimaran V,

“Development and characterization of floating tablets of Atenolol”, Der Pharmacia Lettr,

2012; 4(2): 571-578.

4. Tushar A, Premchandini, Bakthi B. Barki, “Preparation and statistical optimization of

alginate based stomach specific Floating microspheres of Simavastatin”, Acta Poloniae

www.wjpr.net Vol 4, Issue 4, 2015. 1021

5. A.Pandey, G.Kumar, P.Kothiyal, Y.Barshiliya, “Formulation and Evaluation of Gastro

Retentive Microspheres of Verapamil”, Asian Journal of Pharmacy and Medical Science,

2012; 2(3): 48-54.

6. Abhijeet A. Durgavale, Archana R. Dhole, Shrinivas K.Mohite, Chandrakant S.Magdum,

“Formulation and in vitro evaluation of Floating microspheres of Captropil using

different gas generating agents”, American Journal of PharmTech Research, 2012; 2(2):

565-575.

7. Rakesh Pahwa, Sumit Jindal1, Lovely Chhabra1, Himanshu Dutt1 and Rekha Rao,

“Development and in vitro characterization of effervescent Floating drug delivery system

of Famotidine”, International Journal of Pharmaceutical Sciences and Research, 2012;

3(1): 241-246.

8. Devarajan Krishnarajan, Rangasamy Manivannan, Chandroth Nidhin, Natesan

Senthilkumar, “Design and characterization of floating tablets of Ranozoline”,

International Research Journal of Pharmacy, 3 (4), 268-272Elnawawy T. M, Swailem

A.M, Ghorab D. M, Nour S. A, “Flaoting tablets as a controlled release stomach targeted

drug delivery system Diltiazem Hydrochloride”, Journal Pharmaceutical Research and

Opinion, 2012; 2(11): 173-183.

9. Atul Kumar Sahu, Shailendra Kumar Singh, and Amita Verma, “Formulation and

development of Buoyant controlled release tablets containing Chitosan: Optimization of

in vitro dissolution and release kinetics” International Journal of Pharmacy and

Pharmaceutical Sciences, 2011; 3(2): 81-85.

10.Surrender Varma, Neha Narang, “Development and in vitro evaluation of Floating matrix

tablets of Anti Retroviral drug”, International Journal of Pharmacy and Pharmaceutical

Sciences, 2011; 3(1): 208-211.

11.J. Padmavathy, D. Saravanan, D. Rajesh, “Formulation and in vitro evaluation of

Ofloxacin Floating tablets using HPMC”, International Journal of Pharmacy and

Pharmaceutical Sciences, 2011; 3(1): 170-173.

12.Nirav S Sheth, “Formulation and evaluation of floating drug delivery system”,