FORMULATION AND EVALUATION OF FLOATING DRUG DELIVERY SYSTEM OF ENALAPRIL MALEATEijtpls.com/wp-content/uploads/2016/03/IJTPLS-2015-Vol … · · 2016-03-09FORMULATION AND EVALUATION

RESEARCH ARTICLE e-ISSN: 2454-7867

Vamsi Krishna LV et al. Int J Trends in Pharm & Life Sci. 2015: 2(2); .801-812 801

Available online at www.ijtpls.com

International Journal of Trends in Pharmacy and Life Sciences Vol. 2, Issue: 2, 2016: 801-812.

FORMULATION AND EVALUATION OF FLOATING DRUG DELIVERY

SYSTEM OF ENALAPRIL MALEATE L. V. Vamsi Krishna*, P. Jaya Chandra, T. Ragatarangini, B. Rama Lakshmi, E. Satheesh Kumar.

Hindusthan Abdul Ahad & V. Sreedhar

Department of Pharmaceutics, Balaji College of Pharmacy, Anantapuramu, Andhra Pradesh.

E.Mail: [email protected]

ABSTRACT

The aim of this study is to develop floating tablets of ACE inhibitor drug of Enalapril maleate which

after oral administration prolongs the gastric residence time and increases bioavailability of the drug, which

are predominantly absorbed. Floating drug delivery system is formulated by using excipients like Hydroxy

propyl methyl cellulose (HPMC) K15, Xanthan gum, sodium alginate, poly vinyl pyrrolidine, Sodium

bicarbonate, Citric acid, Microcrystalline cellulose, Magnesium stearate and Talc. The drug-polymer

interactions were evaluated by using FTIR studies shows that there are no interactions. Tablets were

prepared by direct compression. The prepared tablets evaluated for physical properties like weight variation,

hardness, friability, floating lag time, floating duration time, swelling index, in vitro dissolution studies. 6

formulations were prepared by using various concentrations of polymers among that F1 shows that highest

drug release 85.95% which contains HPMC K 15 and xanthan gum.

Key words: Enalapril maleate, floating tablets, gastric residence time, floating lag time.

*Corresponding Author:

Mr. L. V. Vamsi Krishna

Department of Pharmaceutics,

Balaji college of Pharmacy, Rudrampeta bypass,

Ananthapuramu-515002

INTRODUCTION

Floating systems or Hydrodynamically balanced systems are low-density systems that have sufficient

buoyancy to float over the gastric contents and remain buoyant in the stomach without affecting the gastric

emptying rate for a prolonged period of time. While the system is floating on the gastric contents, the drug is

released slowly at the desired rate from the system. After release of drug, the residual system is emptied

from the stomach [1-2].

Enalapril maleate is a white to off-white crystalline powder and it’s IUPAC Name :(2S)-1-[(2S)-2-

[[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl]pyrrolidine-2-carboxylic acid (Z)-butenedioate.

It is sparingly soluble in water, soluble in ethanol, and freely soluble in methanol. Enalapril maleate is

rapidly absorbed from stomach, which makes its suitable candidate for floating drug delivery system. It is

used to treat essential or renovascular hypertension and symptomatic congestive heart failure [3].

Received: 06/02/2016

Revised: 20/02/2016

Accepted: 26/02/2016



MATERIALS AND METHODS

Table1: Materials used in the Formulation and Evaluation.

S.NO Materials Suppliers / Manufactures

1 Enalapril maleate Gift sample from DR.REDDY’S LAB

2 HPMC K15 S.D. Fine chemicals Pvt Ltd, Mumbai

3 Xanthum Gum S.D. Fine chemicals Pvt Ltd, Mumbai

4 Sodium alginate MOLY CHEMICALS., Mumbai

5 Poly vinyl pyrolidine MOLY CHEMICALS., Mumbai

6 Sodium bicarbonate NOVA FINE CHEMICALS., Hyderabad.

7 Citric acid Qualigens Fine chemicals., Mumbai

8 Microcrystalline cellulose S.D. Fine chemicals Pvt Ltd, Mumbai

9 Magnesium sterate S.D. Fine chemicals Pvt Ltd, Mumbai

10 Talc S.D. Fine chemicals Pvt Ltd, Mumbai

FORMULATION DEVELOPMENT

All ingredients were selected for formulation based on preformulation studies and literature Research.

Brief Manufacturing procedure of Preparation of Tablets by Direct Compression Method

weighed all ingredients separately

API and other excipients are passed through the 60 # sieve and blended for 15 minutes.

Magnesium stearate was passed through the 40 # sieve and added to the above blend and blended

for 2-3 minutes.

Compressed the blend into tablet by 5 mm concave punches. BB tooling on eight station rotary tablet

compression machine.

Table2: General composition of formulations prepared by direct compression method

INGREDIENTS F1 F2 F3 F4 F5 F6

Enalapril maleate 20mg 20mg 20mg 20mg 20mg 20mg

HPMC K15 5mg - 5mg - 5mg -

Xanthum Gum 10mg - - 5mg - 5mg

Sodium alginate - 5mg 10mg - - 10mg

Poly vinyl pyrolidine - 10mg - 10mg 10mg -

Sodium bicarbonate 5mg 5mg 5mg 5mg 5mg 5mg

Citric acid - - 1mg 1mg 2mg 2mg

Microcrystalline

cellulose

8.5mg 8.5mg 7.5mg 7.5mg 6.5mg 6.5mg

Magnesium sterate 0.5mg 0.5mg 0.5mg 0.5mg 0.5mg 0.5mg

Talc 1mg 1mg 1mg 1mg 1mg 1mg

Total wt of tablet

(mg)

50mg 50mg 50mg 50mg 50mg 50mg



Table3: Equipment used in the Formulation and Evaluation.

S. No Instruments/ Equipment Model and Manufacturer/ supplier

1 Electronic balance AX-200, Shimadzu Corporation, Japan.

2 UV-visible

spectrophotometer T60, PG Instruments., UK.

3 Hot air oven Parekh Scientifics [INDIA],Mumbai.

4 Tap density apparatus

(USP) DBK Instruments, Mumbai.

5 Rotary compression

machine Ceemach Minipress, Gujarat.

6 Friabilator EF-2 Friabilator, Electrolab, Mumbai.

7 Hardness tester Pfizer, Servewell Instruments and

Equipments Pvt Ltd, Bangalore.

8 Dissolution apparatus DBK Instruments, Mumbai.

9 Digital pH meter 7007, Digisun Electronics, Hyderabad.

10 Vernier calipers RK Industries, Mumbai.

11 FTIR Bruker .

12 Stability Chamber Parekh Scientifics(INDIA), Mumbai.

PREFORMULATION STUDIES

Drug polymer compatibility [FTIR studies]:

A physical mixture containing pure drug and pure polymers with ratio of 1:1was transferred into a

screw capped bottle and stored at 40 2o C RH 75% for a period of 1 month. After the study period, the

samples were subjected for FTIR analysis. The study was performed on Fourier transformer infrared

spectrophotometer Bruker. The samples (drug, polymers and physical mixtures) were prepared on KBr-

press. The samples were scanned over wave number range of 4000 to 400 cm -1

. Spectra were analyzed for

drug polymer interactions and functional groups.

Angle of Repose

The angle of repose was measured by passing the prepared granules through a sintered glass funnel of

internal diameter 27 mm on the horizontal surface. The height (h) of the heap formed was measured with a

cathetometer, and the radius (r) of the cone base was also determined. The angle of repose (Ɵ) was

calculated from equation [4-5].

Angle of repose (Ɵ) = tan-1

h/r

Bulk density

The term bulk density refers to a measure used to describe a packing of particles. It is expressed in

gm/ml and was determined using a balance and measuring cylinder. Initially the weight of the measuring

cylinder was tarred. Then, 4 gm presieved (40#) bulk drug were poured into the measuring cylinder using a



funnel and weighed (M). Then volume of the powder (Vb) was taken. Bulk density of the granules was

calculated using following formula [4-5].

Bulk density = M/Vb

Tapped density

Blend was tapped for a fixed number of taps. The minimum volume (Vt) occupied in the cylinder and the

weight (M) of the blend was measured. The tapped density was calculated using following formula[4-5].

Tapped density = M/ Vt

Compressibility (Carr’s) Index:

An accurate weight of granules was poured into a volumetric cylinder to occupy a volume (V0) and then

subjected to a standard tapping procedure onto a solid surface until a constant volume was achieved (Vf).

The Carr’s index was calculated using equation[4-5].

Compressiblity index = V0 - Vf *100

V0

Hausner’s ratio = tapped density / bulk density.

EVALUATION OF TABLETS

Weight variation test

Weight variation test was carried out as per IP. Twenty tablets were randomly selected and

individually weighed. The average weight and standard deviation was calculated [4-5].

Percentage deviation = [X-X*/ X] × 100

X -Actual weight of the tablet

X٭-Average weight of the tablet

Hardness:

The tablet hardness, which is the force required to break a tablet in a diametric compression force.

The hardness tester used in the study was Monsanto hardness tester, which applies force to the tablet

diametrically with the help of an inbuilt spring. It is expressed in Kg / cm2

[4-5].

Friability:

Friability of the tablets was determined using Roche friability (Electrolab, Mumbai). This device

subjects the tablets to the combined effect of abrasions and shock in a plastic chamber revolving at 25 rpm

and dropping the tablets at a height of 6 inches in each revolution. Preweighed sample of tablets was placed

in the friabilator and were subjected to 100 revolutions. Tablets were dedusted using a soft muslin cloth and

reweighed.

The friability (f) is given by the formula: f = (1- W0 / W) × 100

Where, W0 is weight of the tablets before the test and W is the weight of the tablet after the test [4-5].

Swelling index

The studies were carried out gravimetrically. Swelling media used for these studies were distilled

water and simulated gastric fluid (pH 1.2). The prepared tablets were introduced into the swelling media. At



predetermined time intervals the tablets were removed from medium, excess water was blotted with tissue

paper and immediately weighed. This procedure was repeated until the tablet reached constant weight. The

swelling index was calculated using following formula

Wb – Wa

Swelling Index = ---------------- x 100

Wa

Where, Wa=Weight of dry tablet, Wb= Weight of swollen tablet [4-5].

Floating Properties of Tablets:

The In vitro buoyancy was determined by floating lag time. The tablets were placed in a 100 ml glass beaker

containing 0.1 N HCl.

1. Floating Lag Time: The time required for the tablet to rise to the surface of the medium and float was

determined as floating lag time.

2. Floating Duration Time: The time for which the tablet remained floating on the surface of medium was

determined as floating duration time[4-5].

In vitro dissolution Methodology:

In-vitro drug release study was performed at 37±0.5°C using eight station USP type-II apparatus with paddle

rotating at 50 rpm. The drug release study was carried out in 0.1N HCL by taking about 900ml of the

dissolution medium. The drug release study was performed in 0.1N HCL to demonstrate the availability of

Enalapril maleate. About 5 ml of sample was withdrawn at specified time intervals from the dissolution

medium and replaced with equal volume of fresh medium. Samples were filtered through whattmann filter

paper and analyzed using UV spectrophotometer (T60, PG Instruments) at 210.0 nm [4-5].

RESULTS AND DISCUSSION

Table 4: Observation for physical compatibility test.

S. No Name of the Excipient Category Ratio

API: Excipient At 40 2

0C / 75%RH

(30 days)

1. Enalapril maleate-API Drug 1 NCC

2. API+HPMC K15 Polymer 1 : 1 NCC

3. API+ Xanthan agum Polymer 1 : 1 NCC

4. API+ Sodium alginate Polymer 1 : 1 NCC

5. API+PVP Binder 1 : 1 NCC

6. API+ Sodium

bicarbonate

Gas generating

agent 1 : 1 NCC



7. API+ Citric acid

Gas generating

agent 1 : 1 NCC

8. API+ Magnesium sterate Lubricant 1 : 1 NCC

9. API +Talc Glidant 1 : 1 NCC

10. API + Micro crystalline

Cellulose

Diluent and

Disintegrant 1 : 1 NCC

Fig. 1: FTIR of enalapril maleate pure drug

Fig. 2: FTIR of enalapril maleate +HPMC K15



Fig. 3: FTIR of enalapril maleate +xanthan gum

Fig. 4: FTIR of enalapril maleate +sodium aliginate



Fig. 5: FTIR of enalapril maleate + PVP

Fig. 6: FTIR of enalapril maleate + sodium bicarbonate



Table 5: Calibration curve for Enalapril maleate

Fig. 7: Calibration curve for Enalapril maleate

Table 6: Determination flow properties of powder.

The bulk density, tapped density, compressibility index and Hausner’s Ratio were observed reveals that all

formulations blend has excellent flow characteristics and flow rate than the raw material. The angle of

repose was found to be in the range of 17.80° to 32.88°, which indicate excellent flow properties of the

powder mixture. The Carr’s index was found to be in the range of 10 to 20, which indicates excellent to

good compressibility of the powder mixture. Hausner’s ratio was found in the range of 1.09 to 1.26, which

indicates good flow properties as reported in table.

y = 0.018x + 0.0682 R² = 0.9924

0

0.02

0.04

0.06

0.08

0.1

0.12

0.14

0.16

0.18

0 1 2 3 4 5 6

Ab

sorb

ance

Concnetration (μg/ml)

Calibration curve of Enalapril Maleate

Concentration

(mcg/ml)

Absorbance

0 0

1 0.087

2 0.102

3 0.122

4 0.145

5 0.156

Code Bulk density g/cm3 Tapped

density g/cm3

Angle of

repose (Ɵ)

Carr’s

index %

Hausner’s

ratio

F1 0.44 ±0.01 0.48 ±0.02 26.83 ±0.8 8.33±1 1.09 ±0.02

F2 0.32 ±0.02 0.40 ±0.01 30.2 ±1.01 20 ±1.2 1.25 ±0.01

F3 0.34 ±0.01 0.42 ±0.01 32.88 ±1 19.04±1 1.23 ±0.01

F4 0.45 ±0.02 0.5 ±0.02 17.80 ±1.1 10±1.01 1.11 ±0.03

F5 0.40 ±0.02 0.50 ±0.03 18.2 ±0.8 20 ±0.8 1.25 ±0.02

F6 0.38 ±0.03 0.48 ±0.03 32.56 ±1 20 ±1.2 1.26 ±0.01

Pure Drug 0.41 ±0.02 0.55 ± 0.01 26.19 ±0.03 23.54 ±0.01 1.34 ±0.01



Table 7: Floating and Swelling Properties

Formulation Floating Lag Time

(sec)

Floating Time (hrs) Swelling index

(%)

F1 1.16 min 8 120%

F2 3.25 min 6 70%

F3 1.10 min 7.30 110%

F4 3.11 min 4 78%

F5 4.00 min 8 99%

F6 5.15 min 4 89%

Fig. 8: floating of tablets



Table 8: In-Vitro drug Release data of all the formulations [F1-F6]

Fig. 9: In-vitro drug release data of all the formulations [F1-F6]

SUMMARY

Systematic studies were conducted by using four different polymers in different concentrations to

prepare Enalapril maleate floating tablets by direct compression method. All the prepared systems

were evaluated for the different properties.

By performing compatibility studies by FTIR spectroscopy, no interaction was confirmed.

Formulated tablets gave satisfactory results for various evaluation parameters like tablet hardness,

friability, weight variation, Thickness.

0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10

F1

F2

F3

F4

F5

F6

Time (Hrs)

% D

rug r

elea

se

Time (hrs) F1 F2 F3 F4 F5

F6

0 0 0 0 0 0

0

1 21.24± 1.2 20.74 ±0.8 23.49± 1.1 16.2 ±1.2 23.49± 1

48.45±1.1

2 23.49 ±1.6 33.21 ±0.6 36 ±0.98 26.45 ±1.1 34.74 ±0.9

80.7±1.1

3 38.97 ±1.4 41.71± 1.1 45.7± 0.87 32.95 ±1 41.98 ±1

85.95±1.2

6 63 ±1.3 60.75 ±0.9 67.5 ±0.8 49.7 ±1.2 63.7 ±0.89

86.2±1.1

7 75.95±1.2 73.45 ±1 78.2 ±0.7 64.2 ±1 78.75 ±0.9

86.2±0.098

8 85.95± 1.2 75.95 ±0.6 83.7 ±0.65 82.95±1.1 80.2 ±1

86.2±0.098



Floating lag time was found to be in the range of 1.10 min to 5.15 min, F3 was found to be 1.10 min,

F1 was found to be 1.16 min.

Floating duration time was found to be in the range of 4 to 8 hrs ,F1 and f5 was found to be 8 hrs and

F3 was found to be 7.30 hrs

In vitro drug release was carried out by using 0.1 N Hcl. Formulation F1 containing HPMC K15 and

Xanthane gum showed drug release of 85.95% up to 8 hours, but the drug release from the

formulation F2 containing sodium alginate and Poly vinyl Pyrolidine shows 75.95%.in 8 hours

Formulation F3 containing HPMC K15 and Sodium alginate showed 83.70% but in formulation F4

containing Xanthane gum and polyvinyl pyrolidine , was observed that the drug release was 82.95%

in 8 hours.

Formulation F5 containing HPMC K15 and polyvinyl pyrolidine showed drug release of 80.20% but

the formulation F6 containing xanthane gum and sodium alginate 85.95% within 4 hours.

4.2 CONCLUSION

Floating drug delivery system of Enalapril maleate is prepared to increase the bioavailability of the

drug by direct compression method using polymers like Hydroxy propyl methyl cellulose (HPMC) K15,

Xanthan gum, sodium alginate, poly vinyl pyrrolidine. From the results obtained it can be concluded that

among all the formulations with HPMC K15 and Xanthan gum, showed control release.

Hence, Floating drug delivery system of Enalapril maleate is prepared to increase the bioavailability

of the drug and prolonged therapeutic effect for the better management of used to treat essential or

Renovascular hypertension and symptomatic congestive heart failure.

ACKNOWLEDGEMENTS

The authors are grateful to Management and Principal Dr. Hindustan Abdul Ahad for providing all the

necessary facilities to complete this project work.

REFERENCES

1. Kawashima Y, Niwa H, Takeuchi H, Hino T, Itoh Y. Hollow microspheres for use as a floating controlled

drug dlivery system in the stomach. Journal of Pharmaceutical Sciences. 1992: 81; 135-40.

2. Garg R, Gupta. Progress in controlled gastroretentive delivery systems, review article. Tropoical Journal

Pharmaceutical research. 2008:7(3); 1055-1066.

3. www.drugbank/drugs DB00584 browsed on 03rd

october 2015.

4. Natasha S, Dilip A, Gupta MK and Mahaveer PK. A Comprehensive review on Floating Drug delivery

system- Review. International Journal Research in Pharmaceutical and Biomedical Sciences. 2011: 428-441.

5. Anil Kumar AP, Felix JV, Vishwanath BA. Formulation and evaluation of Bilayer Floating tablets of

Enalapril maleate. International Journal of Pharma. 2014:1-12.

http://www.drugbank/drugs%20DB00584

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FORMULATION AND EVALUATION OF FLOATING DRUG DELIVERY SYSTEM OF ENALAPRIL MALEATEijtpls.com/wp-content/uploads/2016/03/IJTPLS-2015-Vol … · · 2016-03-09FORMULATION AND EVALUATION