FORMULATION DESIGN AND IN VITRO CHARACTERIZATION OF...

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Mantry et.al / UJPSR / 2 (1), 2016, 27-34e ISSN: 2454-3764

Print ISSN: 2454-3756

RESEARCH ARTICLEDepartment of Pharmaceutics

FORMULATION DESIGN AND IN VITRO CHARACTERIZATION OF SUSTAINED RELEASE TABLET OF NIFEDIPINE

*Nabin Ghimirey, Sunanda Sharma, Rachna Sharma, Shubhrajit Mantry

Department of Pharmaceutics, Himalayan Pharmacy Institute, Majhitar, Rangpo, E. Sikkim – 737136, INDIA

ARTICLE INFO: Article history: Received: 05 January 2016Received in revised form:09 January 2016Accepted: 02 February 2016Available online: 10 May 2016

Corresponding Author:

Mr. Shubhrajit MantryDepartment of PharmaceuticsHimalayan Pharmacy Institute Majhitar, E. Sikkim, INDIAEmail: [email protected]: +91-7384205300

The aim of the present work was to develop sustained release

formulation of Nifedipine and evaluate the In-vitro Drug release, a poorly

water soluble drug, hydroxy propyl methyl cellulose (HPMC) with

different grade as hydrophilic polymers. Tablets were prepared by wet

granulation and direct compression technique by using various ratio of

different grades of HPMC. Tablets were evaluated for Friability, Hardness,

Weight Variation, Content Uniformity, Thickness and In-vitro drug release.

By observing dissolution profile it was concluded that the formulation

containing HPMC in the ratio of 1:1 showed acceptable dissolution

properties compared to other formulation. This study indicates the

hydrophilic matrix tablet of Nifedipine prepared using HPMC of different

grade can successfully be employed as sustained release matrix tablet in

order to improve patient compliance.

Abstract

Key wordsNifedipine, Sustained release Matrix Tablet,

HPMC K4M, HPMC K100.

INTRODUCTION

Nifedipine is one of a group of compounds

thought to act by blocking the transmembrane inward

movement of calcium [1]. Nifedipine being anti-+hypertensive agent act by blocking ca channel and

+interfere with the working action of ca in blood vessel

constriction and heart muscle contraction and nerve

conduction in the heart [2]. Nifedipine is a yellow

crystalline substance, practically insoluble in water but

soluble in ethanol. Nifedipine is widely used in the

treatment of angina pectoris and systemic hypertension.

It is a poorly soluble drug and its absorption from

gastrointestinal tract is limited by dissolution rate. It has

a short biological half-life (4 hrs.). Absorption of

Nifedipine is poor following administration orally via

immediate release dosage forms. It exhibits 45-65% oral

bioavailability due to hepatic first pass metabolism.

Immediate release formulations of Nifedipine clearly

show fluctuation in drug plasma concentration results in

specific side effects like increase in heart rate.

Sublingual Nifedipine has been used in hypertensive

emergencies, however, was found to be unsafe [3].





Fig. 1: Sustained release Drug profile Fig. 2: Structure of Nifedipine [4]

The design of oral Sustained Drug Delivery

System (DDS) should be primarily aimed to achieve the

more predictability and reproducibility to control the

drug release, drug concentration in the target tissue and

optimization of the therapeutic effect of a drug by

controlling its release in the body with lower and less

frequent dose [5]. The matrix tablet by direct

compression has attracted much attention due to its

technological simplicity in comparison with other

controlled release systems. It require fewer unit

operations, less machinery, reduced number of personnel

and processing time, increased product stability and

production rate [6]. A large array of drug delivery

technologies is available to formulators, but hydrophilic

matrices remain the most commonly used oral Extended

Release (ER) system. These devices are easy to

manufacture, robust, flexible and reliable. Various water-

soluble or water- swellable polymers with high molecular

weight have been used in hydrophilic matrices, such as

HPMC, hydroxyl propyl cellulose (HPC) and

polyethylene oxide (PEO) [7]. HPMC is the dominant

hydrophilic vehicle used for the preparation of oral

controlled drug delivery. While HPMC could potentially

(and therefore control) the release of a soluble drug, it

could also facilitate the release of relatively insoluble

drug (e.g. nifedipine). In the later case, insolubility of the

drug molecule would be the rate limiting step in its

release and HPMC's solubilizing effect would facilitate

the release. The net result is controlled drug delivery for a

prolonged period of time [8]. + Hypertension results due to the rise in Na

concentration in blood. Anti-hypertensive (Nifedipine)

drugs are used to lower B.P in hyper-tension. WHO-ISH

guideline 2003 have defined it to be 140 mm Hg systolic

and 90 mm Hg diastolic, through risk appears to increase

even above 120/80 mm Hg. Epidemiological studies

have confirmed that higher the pressure (systolic and

diastolic or both) greater is the risk of cardiovascular

disease [9].

MATERIALS AND METHOD

Nifedipine was obtained from yarrow chem products,

Mumbai, starch (Finar Chemicals Ltd.), HPMC-K4M

(Yarrow Chem products), HPMC-K100 (Yarrow Chem

products), lactose (S.D. Fine-Chem Ltd.), talc (S.D. Fine-

chem Ltd.), and magnesium stearate (S.D. Fine-chem

Ltd.)





Method

Preparation of sustained release tablet of Nifedipine

Formulation F1 F2 and F3 was prepared by wet granulation method,

ProcedureAccurately weighed amount of drug

(Nifedipine) & the excipients were taken into a mortar.

Slowly the drug along with excipients was triturated & a

wet mass was prepared using ethanol. The wet mass was

then passed through a #120 mesh. The granules were left

for drying. The granules were lubricated with talc (2.5%)

and Magnesium stearate (2.5%) & compressed into tablet

on a 10 station rotary punching machine. Each tablet

contains 30 mg of Nifedipine.

Formulation F4 and F5 was prepared by direct compression method

Procedure

Accurately weighed amount of drug

(Nifedipine) & excipients were taken into a mortar

(except talc & Magnesium stearate) & triturated. Then

the triturated mixture was lubricated with talc (2.5%) &

Magnesium stearate (2.5%). The mixture was then

compressed into tablets on a 10 stationary rotary

punching machine using 5mm concave punches. Each

tablet contains 30 mg of Nifedipine.

Table 1: Composition of Sustained release tablet of Nifedipine

Formulation code

Drug (mg)

Starch (mg)HPMC

K4M (mg)HPMC

K100 (mg)Lactose

(mg)Talc (mg)

Magnesium stearate (mg)

F1

F2

F3

F4

F5

30

30

30

30

30

10

10

10

10

10

40

40

40

30

-

- 110

110

70

80

80

40

40

30

40

5 5

5

5

5

5

5

5

5

5

RESULT AND DISCUSSION

Standard graph

Preparation of Hydrochloric acid pH 1.2 buffers

8.5 ml of HCl was dissolved in little amount of ethanol in

1000 ml volumetric flask.

Then the volume was made up to 1000 ml with the

addition of excess ethanol.

Standard calibration curve of Nifedipine at pH 1.2

100 mg of Nifedipine was taken and dissolved in 1.2 pH

HCl stock solution in 100 ml volumetric flask. The

volume was made up to the mark and marked as A. 10 ml

from above solution (A) was taken into another 100 ml

volumetric flask and volume was made up with stock

solution was marked as B.

From the above stock solution B, 1 ml, 2 ml, 3 ml, 4 ml,

and 5 ml respectively were withdrawn into other 5

volumetric flasks of 10 ml and volume was maintained.

The absorbance of above solution were scanned in UV

region and found that nifedipine showed more

absorbance at 233 nm.





Concentration Absorbance

1 0.161

2 0.316

3 0.483

4 0.633

5 0.790

Table 2: Calibration Curve of Nifedipine at pH 1.2

Fig. 3: Standard Graph of Nifedipine at pH 1.2

Preparation of phosphate pH 7.4 buffer

About 6.8 gm of KH PO and 1.564 gm of sodium 2 4

hydroxide was dissolved in little amount of water.

Volume was made up to 1000 ml of volumetric flask by

addition of ethanol (excess).

Standard calibration curve of Nifedipine at pH 7.4

100 mg of Nifedipine was transferred to 100 ml of

volumetric flask and dissolved with little quantity of

above phosphate pH 7.4 buffer solution. The volume was

made up by adding the buffer solution and marked as “A”.

10 ml of solution from “A” was transferred to another

100 ml volumetric flask and diluted up to the mark adding

buffer stock solution and marked as “B”. From this

solution “B” 1 ml, 2 ml, 3 ml, 4 ml, and 5 ml respectively

transferred into other 10 ml volumetric flask. It was then

diluted and absorbance was found out at 233 nm

Table 3: Calibration Curve of Nifedipine at pH 7.4

Fig. 4: Standard Graph of Nifedipine at pH 7.4

Concentration Absorbance

1 0.083

2 0.242

3 0.405

4 0.552

5 0.736





FOURIER TRANSFORM INFRARED SPECTROSCOPY (FTIR)

The pure drug, physical mixtures and optimized formulations (F3) were subjected for FTIR analysis. The samples were prepared on KBr-press.

The samples were scanned over a range of 4000-400 cm-1 using Fourier transformer infrared spectrophotometer. Spectra were analysed for drug polymer interactions.

Fig. 5: FTIR of Pure Drug (Nifedipine)

Fig. 6: FTIR of HPMC K-100

Fig. 7: FTIR of HPMC K4M

Fig. 8: FTIR of Optimized Formulation (F3)





PRE-COMPRESSION EVALUATIONS [10, 11]

Bulk densityApparent bulk density was determined by pouring a

weighed quantity of tablet blends into graduated cylinder

and measuring the volume and weight.

Bulk Density = Mass of powder / Bulk Volume of the

powder

Tapped density

Take 10 gm of tablet powder and transfer in a measuring

cylinder. Now tap the measuring cylinder 100 times and

check the volume. Repeat the tapping process till the

value of volume does not decrease. The final unchanged

volume is called tapped volume (V ).T

Tapped density = weight of powder/tapped volume (V )T

Hausner's ratio (H)

Hausner's ratio (H) = tapped density/bulk density

The angle of repose of tablet blends was determined by

the funnel method. The blends were allowed to flow

through the funnel freely onto the surface. The diameter

Angle of reposeand height of the powder cone was measured and angle of

repose was calculated using the equation: Tan è = h/r

Where 'h' and 'r' are the height and radius of the powder

cone, respectively.

Table 4: Pre-compression parameters of tablet formulation

Formulation Code BulkDensity

Tapped Density

Hausner's Ratio

Carr's Index

Angle of Repose (è)

F1 0.20 0.23 1.15 13.04 28.93

F2 0.21 0.24 1.14 12.28 29.13

F3 0.20 0.23 1.15 13.04 27.83

F4 0.22 0.26 1.18 15.26 28.62

F5 0.23 0.26 1.13 11.51 28.72

POST-COMPRESSION EVALUATION [12]

Thickness Hardness testThe thicknesses of the tablets were determined using a

Vernier Caliper, 20 tablets from each batch were used and

average values were calculated.

For each formulation, hardness test of 20 tablets each

were determined by using the Pfizer hardness tester.

Weight variation test Friability testEvery individual tablet in a batch should be in uniform

weight and weight variation within the permissible

limits. The weights were determined to within ±1mg by

using digital balance. Weight variation is based on a

sample of 20 tablets.

For each formulation, friability test of 20 tablets each

were determined by using the Electro lab friabilator

tester.

Ten tablets were randomly selected and allowed to

equilibrate with HCl acid buffer of pH 1.2 overnight and

the solution was filtered after 24 hours. Suitable dilutions

were made with HCl acid buffer of pH 1.2 to get the

Drug content uniformityconcentration. Absorbance of the solution was analyzed

spectrophotometrically at 233nm against suitable blank

using UV-visible spectro photometer and drug content

per tablet was calculated.





In-vitro dissolution study

Dissolution study was carried out using USP dissolution

test apparatus type II. The dissolution medium used was o900 ml of 0.1N HCl buffer at 37±0.5 C. The paddle speed

was kept at 50 rpm throughout the study. From the sample

5 ml was withdrawn at predetermined time interval and

equivalent amount of fresh medium was replaced to

maintain a constant volume. After each sampling suitably

diluted with 0.1N HCl buffer and analyzed

spectrophotometrically at 233nm against suitable blank

using UV-visible spectrophotometer.

Stability studies

Stability studies of the optimized formulation did not

reveal any degradation of the drug and there was no

significant change in the physical properties, drug

content, and in vitro release profiles of the optimized

formulation after storage for 3 months.

Table 5: Post compression parameters of tablet formulation

Formulation Code

Hardness 2(kg/cm )

Thickness (mm)

Weight Variation (mg)

Friability (%)

Drug content (%)

F1 2.5±0.47 2.6±0.66 198±0.36 0.85 101.15±1.38

F2 2.5±0.39 2.5±0.25 200±0.23 0.60 97.69±1.88

F3 2.5±0.18 2.4±0.11 200±0.02 0.35 100.01±1.08

F4 2.5±0.54 2.4±0.78 200±0.09 0.49 97.35±1.44

F5 2.5±0.62 2.4±0.38 199±1.12 0.56 99.58±2.32

Table 6: In Vitro Dissolution study of Nifedipine Tablets of all formulations

Time (hours) F1 F2 F3 F4 F5

1 25.47±0.78 35.24±0.82 37.12±0.64 39.83±0.53 36.24±0.77

2 35.63±0.23 45.52±0.73 48.83±0.58 57.52±0.65 49.59±0.74

3 49.74±0.49 56.38±0.55 59.43±0.37 61.82±0.42 59.58±0.53

4 60.09±0.43 69.28±0.78 73.35±0.48 76.89±0.64 68.45±0.53

6 75.26±0.82 82.75±0.66 85.98±0.74 89.52±0.62 82.97±0.69

8 89.57±0.64 96.86±0.54 95.42±0.63 91.76±0.59 93.62±0.52

10 99.86±0.84 98.23±0.23 97.35±0.26 93.42±0.63 96.88±0.83

12 -- -- 99.42±0.63 96.35±0.63 98.23±0.89

www.ujpsr.com 34

Fig. 9: Dissolution Profile of All Formulations (F1- F5)

CONCLUSION

Nifedipine matrix tablet were prepared by using

hydrophilic polymers (HPMC K4M & HPMC K100) in

different ratio. Total Five formulation of matrix tablet of

Nifedipine were prepared. The present study has also

shown constant release for 12 hours and also concluded

that 1:1 ratio of the drug and polymer is required for

constant drug release. By observing dissolution profile of

all formulation we can conclude that the F3 was best

formulation. FTIR studies combined with stability

studies proved the integrity of the developed matrix

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