ISSN: 0975-766X CODEN: IJPTFI Available Online through … · 2016. 7. 24. · Keywords:...

Polani B Ramesh Babu* et al. /International Journal Of Pharmacy & Technology

IJPT | Jan-2013 | Vol. 4 | Issue No.4 | 4931-4951 Page 4931

ISSN: 0975-766X CODEN: IJPTFI

Available Online through Research Article www.ijptonline.com

FORMULATION AND EVALUATION OF FLOATING BILAYERED TA BLETS OF RIFAMPICIN ISONIAZID AND PYRAZINAMIDE

Hadassah.M*, Swarna Kamala.CH, Prasanthi.D, Sai Karthik.I Prof.J.Vijaya Ratna M.Pharm., Ph.D., F.I.C., D.A.S.

University college of Pharmaceutical Sciences, Andhra University, Visakhapatnam-530003, Andhra Pradesh, India.

Email: [email protected]

Received on 11-11-2012 Accepted on 26-11-2012

Abstract

The purpose of the study is to design bilayer floating tablets of rifampicin, isoniazid and pyrazinamide to give

immediate release of isoniazid and sustained release of rifampicin and pyrazinamide. Isoniazid was formulated in a

separate layer as it triggers the degradation of rifampicin in acidic medium due to the formation of hydrozone and it is

designed to be released in the intestine which can be achieved by preparing isoniazid solid dispersion using different

concentrations of eudragit L 100 as enteric coating polymer. The bilayer tablets consist of sodium starch glycolate as

superdisintegrant for isoniazid in the immediate release layer and hydroxypropyl methylcellulose (HPMC) K100M as

release-retarding agents for rifampicin and pyrazinamide in the sustained release layer. Sodium bicarbonate was used as

the gas generating agent. The direct compression method was employed for preparation of the bilayer tablets. The

tablets were evaluated for the pre and post compression parameters such as weight variation, thickness, friability,

hardness, drug content, in vitro buoyancy studies, and in-vitro dissolution studies and results were within the limits. The

in-vitro dissolution studies were carried out in a USP type-II apparatus in 0.1 N HCl for sustained release layer and in

pH 7.4 phosphate buffer for immediate release layer. Among all SR formulations (FSR1 to FSR5) prepared, batch FSR3

was selected as optimized formulation which showed buoyancy lag time 45 sec and the tablet remained buoyant for >

12h. At all the strengths of the polymer tested HPMC K100M gave relatively slow release of rifampicin over 16h and

pyrazinamide over 12h. Among all IR formulations (FIR1 to FIR4) prepared, FIR2 was selected as optimized

formulation basing on entrapment efficiency (%). The invitro data is fitted in to different kinetic models and the best-fit



was achieved with the Higuchi model for sustained release formulation. The optimized IR formulation followed first

order release kinetics followed by non fickian diffusion.

Keywords: Rifampicin, Isoniazid, Pyrazinamide, Gastroretentive drug delivery system, HPMC K100M, Eudragit L

100, solid dispersion, direct compression method.

1. Introduction

The objective of any drug delivery system is to afford a therapeutic amount of drug to the proper site of action in

the body to attain promptly, and then maintain the desired drug concentration1. An ideal drug delivery system (DDS)

should aid in the optimization of drug therapy by delivering an appropriate amount to the intended site and at a desired

rate. Hence, the DDS should deliver the drug at a rate dictated by the needs of the body over the period of treatment.

Controlled release (modified release) dosage forms are growing in popularity. These more sophisticated systems

can be used as a means of altering the pharmacokinetic behaviour of drugs in order to provide twice or once a day

dosage. The commonly used and most convenient method of drug delivery is oral route of drug administration. Usually,

such once a day or twice a day preparations delivers the drug through GIT2. A number of dosage forms have been

designed to disintegrate or dissolve or release the drug in the stomach, which thereafter get absorbed from the small

intestine. However, gastrointestinal motility, a vigorous and variable phenomenon, presents a major impediment to the

effectiveness of controlled delivery system.

Thus the real issue in the development of oral controlled release dosage forms is not just to prolong the delivery of

drugs for more than 12 hrs but to prolong the residence time of dosage forms in the stomach or somewhere in the upper

small intestine or until all the drug is retained for the desired period of time.

GRDDS are thus beneficial for such drugs by improving their bioavailability, therapeutic efficacy and possible

reduction of the dose and improves the drug solubility that is less soluble in a high pH environment3,4. Apart from these

advantages, these systems offer various pharmacokinetic advantages like maintenance of constant therapeutic levels

over a prolonged period and thus reduction in fluctuation in the therapeutic levels. Gastric retention will provide

advantages such as the delivery of drugs with narrow absorption windows in the small intestinal region. Also prolonged

gastric retention time in the stomach could be advantageous for local action in the upper part of the small intestine.



Multiple compressed tablets are prepared for two reasons: To separate physically or chemically incompatible

ingredients and to produce repeat action/ prolonged action tablet5.

There are three categories under this class6:

I. Layered tablets – two to three component systems.

II. Compression coated tablets – tablet within a tablet.

III. Inlay tablet – coat partially surrounding the core.

The layered tablet is selected over compression coated tablet as the surface contact is less and the production is

simple and more rapid7.

Bilayer Technology Is Preferred For Following Reasons:

• To separate physically or chemically incompatible ingredients and produce repeat action/ prolonged action

tablet.

• The tablet manufacturing machine is generally operated at relatively lower speed than for standard compression

tablet.

• Extension of a conventional technology

• Potential use of single entity feed granules

• Ability to combine different release rates

Tuberculosis, or TB is an infectious bacterial disease caused by Mycobacterium tuberculosis, which most

commonly affects the lungs9.

Most of the commercially available fixed dose TB formulations in the market are based on either 2 drug based

FDC (rifampicin and pyrazinamide) or 4 drug based FDC (rifampicin, isoniazid, pyrazinamide and ethambutol). But 3

drug based FDC (rifampicin, isoniazid and pyrazinamide) which is recommended in the initial phase of short-course

therapy, usually continued for 2 months and can be used for smear negative patients are not available.

Hence the present work was undertaken to develop a floating bilayered tablet of 3 drug based FDC of rifampicin,

isoniazid and pyrazinamide comprising a sustained release layer of rifampicin(120mg) and pyrazinamide(300mg) and an

immediate release layer of isoniazid(50mg).



Isoniazid was formulated in a separate layer as it triggers the degradation of rifampicin in acidic medium due to

the formation of hydrozone and it is designed to be released in the intestine which can be achieved by preparing

isoniazid solid dispersion using eudragit L 100 as enteric coating polymer.

As such, rifampicin and pyrazinamide are released in stomach showing sustained release due to floating

mechanism and isoniazid is intended to be released in intestine showing delayed release as it is enteric coated with

eudragit L 100 through solid dispersion.

Of the available range of cellulosic controlled-release agents, hypromellose (HPMC) is the most widely used.

Hypromellose is a well known excipient with an excellent safety record. Hypromellose polymers are very versatile

release agents8. They are nonionic, so they minimize interaction problems when used in acidic, basic, or other

electrolytic systems. Hypromellose polymers work well with soluble and insoluble drugs and at high and low dosage

levels.

This excipient is nontoxic and have pH-independent hydration and swelling, good compressibility and lubricity,

and versatility due to a wide range of molecular weights. Matrix tablets prepared using HPMC quickly hydrate on the

outer tablet surface to form a gelatinous layer. Once the original protective gel layer is formed, it controls the

penetration of additional water into the tablet. As the outer gel layer fully hydrates and dissolves, a new inner layer must

replace it and be cohesive and continuous enough to retard the influx of water and control drug diffusion. Although gel

strength is controlled by polymer viscosity and concentration, polymer chemistry also plays a significant role.

Therefore in this study, bilayered tablets each containing 120mg of rifampicin & 300mg of pyrazinamide(SR)

and 50mg of isoniazid(IR) were prepared employing HPMC K100M as matrix former in SR layer and sodium starch

glycolate as superdisintegrant and eudragit L-100 as enteric coating polymer in IR layer.

2. Material and Methods

2.1 Materials

Rifampicin, isoniazid and pyrazinamide were obtained as gift samples from Lupin Pharmaceuticals, Ltd. HPMC K100M

and PVP K-30 were obtained as gift samples from ISP, Hyderabad. Sodium bicarbonate was obtained as a gift sample

from Merck Specialties Pvt. Ltd. Microcrystalline cellulose was obtained as a gift sample from Dr. Reddy’s Lab,



Hyderabad. Lactose and Magnesium stearate was obtained as a gift sample from KAPL, Bangalore. Eudragit L 100 was

obtained as a gift sample from Hetero Pharmaceuticals, Hyderabad.

2.2 Preparation of bilayered tablets of rifampicin, isoniazid and pyrazinamide:

2.2.1 Formulation and preparation of immediate release portion (isoniazid)

2.2.1.1 Preparation of isoniazid solid dispersion:

Table-1: Formula for preparing isoniazid solid dispersion.

Ingredients QUANTITY(for 20 tablets) D:P=2:1 D:P=3:1 D:P=5:1 D:P=7:1

Isoniazid 1g 1g 1g 1g Eudragit L 100 0.5g 0.33g 0.2g 0.125g Isopropyl alcohol 1mL 1mL 1mL 1mL Ethanol 2.5mL 2.5mL 2.5mL 2.5mL

D:P=Drug:Polymer

Eudragit L 100 was dissolved in Isopropyl Alcohol. Isoniazid was dissolved in Alcohol and added to the above

solution and mixed for one hour. The solvents were evaporated on a water bath and the residue was passed through a sieve

of mesh size 100. The obtained solid dispersion was compressed into tablets.

2.2.1.2 Determination of entrapment efficiency of isoniazid solid dispersion:

The entrapment efficiency of isoniazid solid dispersion was determined by the centrifugation method. The solid

dispersions (containing an equivalent to 50 mg of drug) were centrifuged at 20000 rpm for one hour in a refrigerated

centrifuge to collect the supernatant liquid. The collected liquid was filtered to measure the free drug concentration after

suitable dilution with a fresh phosphate buffer saline pH 7.4. The absorbance was measured at 263 nm in a UV

spectrophotometer to calculate the entrapment efficiency using the following formula:

Entrapment efficiency = Wt. of drug incorporated/Wt. of drug initially taken × 100

Wt. of drug incorporated = Wt. of drug initially taken - Wt. of free drug

2.2.2 Formulation and preparation of immediate release and sustained release tablets:

All the formulations were prepared by direct compression method using different ratios of diluents(MCC and

Lactose) along with superdisintegrants(sodium starch glycolate).

2.2.2.1 Procedure for preparation of immediate release portion:

1. Isoniazid solid dispersion and all other ingredients were individually passed through sieve ≠ 60.



2. All the ingredients were mixed thoroughly in polythene bag for an hour.

3. The powder mixture was lubricated with magnesium stearate.

4. The tablets were prepared by using direct compression method.

2.2.2.2 Composition of IR layer:

Table-2: Composition Of immediate release portion.

2.2.2.3 Procedure for preparation of sustained release portion:

1. Rifampicin, pyrazinamide and all other ingredients were individually passed through sieve #60.

2. All the ingredients were mixed thoroughly by polythene bag for an hour.

3. The powder mixture was lubricated with magnesium stearate.

4. The tablets were prepared by using direct compression method.

2.2.2.4 Composition of SR layer:

Table-3: Composition Of sustained release portion.

2.3 Evaluation of floating bilayered tablets of rifampicin, isoniazid and pyrazinamide:

2.3.1Pre compression parameters

The flow properties of powder blend (before compression) were characterized in terms of angle of repose, tapped

density, bulk density, Carr’s index and Hausner’s ratio10.

Ingredients QUANTITY(mg/tablet) FIR1 FIR2 FIR3 FIR4

Isoniazid solid dispersion 75 66 60 57.2 Sodium starch glycolate 25 25 25 25 PVP K30 25 25 25 25 MCC 50 50 50 50 Lactose 325 334 340 342.8

Ingredients QUANTITY(mg/tablet)

FSR1 FSR2 FSR3 FSR4 FSR5 Rifampicin 120 120 120 120 120

Pyrazinamide 300 300 300 300 300

HPMC K100M 150 200 250 300 350

Sodium bicarbonate 50 50 50 50 50

PVP 40 40 40 40 40

Magnesium stearate 10 10 10 10 10

MCC 230 180 130 80 30



2.3.2 Post compression parameters

Thickness and diameter

Control of physical dimensions of the tablet such as thickness and diameter is essential for consumer acceptance and

tablet uniformity11. The thickness and diameter of the tablet was measured using vernier callipers. It is expressed in mm.

Five tablets were used and average values were calculated.

Hardness

It indicates the ability of a tablet to withstand mechanical shocks while handling. The hardness of the tablets was

determined using Pfizer hardness tester. The value was noted in kg/cm2.Three tablets were randomly picked and the

hardness of the tablets was determined.

Weight variation

Randomly selected twenty tablets were weighed individually and together in a single pan balance. The average

weight was noted and standard deviation was calculated 12, 13. The tablet passes the test if not more than two tablets fall

outside the percentage limit and none of the tablet differs by more than double percentage limit.

% deviation = (Wavg –Winitial) / Wavg × 100

Where, Wavg - average weight of tablet, Winital - individual weight of tablet.

Friability

Tablet strength was tested by Roche Friabilator. It is expressed in percentage (%). Ten tablets were initially weighed

(W0) and transferred into Friabilator 14. The Friabilator was operated at 25rpm for 4minutes or run up to 100 revolutions.

The tablets were weighed again (W). The % friability was then calculated by

% Friability = (W0-W/ W0) ×100

Where, W0 - initial weight of tablets, W - final weight of tablets

% Friability of tablets less than 1% are considered acceptable.

Drug content

20 tablets of each formulation were weighed and powdered. The quantity of powder equivalent to 120 mg of

Rifampicin/300mg of Pyrazinamide/50mg of Isoniazid was transferred in to a 100 ml volumetric flask and the volume

adjusted to 100ml with 0.1N HCl/0.1N HCl/7.4 Phosphate buffer. Further 1ml of the above solution was diluted to 100



ml with 0.1N HCl/0.1N HCl/7.4 Phosphate buffer and the absorbance of the resulting solution was observed at

475nm/268nm/263nm15.

In-vitro buoyancy studies

The in-vitro buoyancy was determined by floating lag time method. The tablets were placed in 250ml beaker

containing 0.1N HCl 16. The time required for the tablets to rise to the surface and float was determined as floating lag

time (FLT). The time between introduction of dosage form and its buoyancy in 0.1N HCl and the time during which the

dosage form remain buoyant were measured. The total duration of time by which the dosage form remains buoyant is

called total floating time (TFT).

Swelling index

Swelling of tablet excipients particles involves the absorption of a liquid resulting in an increase in weight and

volume. Liquid uptake by the particle may be due to saturation of capillary spaces within the particles or hydration of

macromolecule 17. The liquid enters the particles through pores and bind to large molecule, breaking the hydrogen bond

and resulting in the swelling of particle. The extent of swelling can be measured in terms of % weight gain by the tablet.

For each formulation batch one tablet was weighed and placed in a beaker containing 200ml of 1.2 pH buffer. After each

interval the tablet was removed from beaker, removes excess of buffer by using filter paper and weighed again up to 12

hours. Swelling index was calculated by using the following formula.

Swelling index (SI) = (Wt – W0)/ W0 × 100

Where Wt - weight of tablet at time t

W0 – initial weight of tablet

In-vitro Drug Release

Dissolution parameters for immediate release portion:

Apparatus -- USP-II, Paddle Method

Dissolution Medium -- pH 7.4 phosphate buffer

RPM -- 100

Sampling intervals (hrs) -- 10, 15, 20, 30, 45, 60 min

Temperature -- 37 + 0.5 °C

Dissolution parameters for sustained release portion:

Apparatus -- USP-II, Paddle Method

Dissolution Medium -- 0.1 N HCl



RPM -- 100

Sampling intervals (hrs) -- 30min, 1,2,4,6,8,10,12,14,20,24hrs

Temperature -- 37 + 0.5°C

Dissolution Study:

900ml 0f 0.1 HCl/pH7.4 Phosphate buffer was placed in the vessel and the USP apparatus –II (Paddle Method)

was assembled. The medium was allowed to equilibrate to temp of 37 + 0.5 °C. Tablet was placed in the vessel and the

vessel was covered, the apparatus was operated till 100% release is attained at 100 rpm. At definite time intervals, 5 ml

of the fluid was withdrawn; filtered and again 5ml of the fluid was replaced. Suitable dilutions were done with the

dissolution fluid and the samples were analyzed spectrophotometrically18.

Data Analysis of Release Studies

The release data were analyzed as per Zero order, First order, Higuchi’s and Peppas equation models 19.

3. Results

Preformulation studies:

6.1.1.Sustained release portion:

Table-4: Preformulation studies of sustained release portion blend.

Formulation code or Parameter

Bulk density (mg/cc)

Tapped density(mg/cc)

Angle of repose(o)

Compressibility index (%)

Hausners ratio

FSR1 0.49 0.57 27.40 14.04 1.16

FSR2 0.48 0.55 26.06 12.72 1.14

FSR3 0.46 0.53 24.38 13.20 1.15

FSR4 0.43 0.49 23.72 12.24 1.14

FSR5 0.41 0.47 21.94 12.76 1.14

Immediate release portion:

Table-5: Preformulation studies of immediate release portion blend.

Formula tion code

Bulk density (mg/cc)

Tapped density (mg/cc)

Angle of repose(o)

% Compressibility

Hausners ratio

FIR1 0.53 0.62 26.24 13.120 1.19 FIR2 0.45 0.55 25.42 11.18 1.17 FIR3 0.52 0.62 29.24 12.120 1.13 FIR4 0.47 0.54 27.68 12.96 1.15



Formulation studies:

Sustained release layer:

Table-6: Formulation studies of sustained release layer.

Formulation

code/Parameter

Hardness

(kg/cm2)

Weight

variation

Friability

(%)

Drug Content (%)

Rifampicin Pyrazinamide

F1 6±0.21 900±0.23 0.18 99.17±0.55 98.89±0.18

F2 6±0.36 900±0.14 0.22 99.23±0.48 99.15±0.26

F3 6±0.48 900±0.52 0.20 99.72±0.21 99.42±0.14

F4 6±0.65 900±0.84 0.38 100.53±0.36 98.56±0.54

F5 6±0.55 900±0.93 0.12 99.89±0.65 99.23±0.36

Immediate release portion:

Table-7: Formulation studies of immediate release portion.

Formulation code

Weight variation

Hardness (kg/cm2)

Friability (%)

Drug Content (%)

Disintegration Time (sec)

FIR1 500±0.36 7±0.45 0.12 99.59±0.24 30 FIR2 500±0.16 7±0.28 0.52 99.48±0.48 35 FIR3 500±0.78 7±0.23 0.11 99.61±0.54 48 FIR4 500±0.69 7±0.57 0.63 98.67±0.65 51

Entrappment efficiency of isoniazid solid dispersions:

Table-8: Entrappment efficiency of isoniazid solid dispersions.

Formulation code

Polymer %w/w Entrappment efficiency (%±S.D)

FIR1 Eudragit L-100 33.33 92.57±0.44 FIR2 Eudragit L-100 24.81 88.63±0.24 FIR3 Eudragit L-100 16.66 79.35±0.58 FIR4 Eudragit L-100 11.11 76.14±0.95

Dissolution profiles:

Immediate release formulations:

Table-9: Dissolution profile of immediate release portion.

Time

(min)

%CUMMILATIVE DRUG RELEASE

FIR1 FIR2 FIR3 FIR4

10 56.73 78.87 55.60 63.43



15 69.17 81.65 72.32 71.67

20 81.80 88.15 83.14 84.46

30 92.78 91.39 90.81 92.63

45 96.56 98.07 94.89 95.17

60 98.16 99.56 97.46 98.82

Development of sustained release formulations:

Floating lag time:

Table-10: Floating lag time of sustained release portion.

Amount of sodium bicarbonate(mg)

Floating lag time(sec) Floating time(hrs)

40 310 >12

50 40 >12

60 35 >12

Table-11: Invitro swelling indices of prepared floating tablets.

Formulation

code

Time (hr)

1 2 3 4 5

FSR1

FSR2

FSR3

FSR4

FSR5

28.15

32.46

36.95

38.91

39.28

42.62

50.57

56.34

57.87

58.19

61.68

69.23

74.59

77.52

76.79

73.64

80.35

84.77

89.14

87.92

81.78

90.61

95.43

97.62

98.57

Dissolution profiles of sustained release portion:

Table-12: Dissolution profile of rifampicin based sustained release portion.

TIME (hrs)

%CUMULATIVE DRUG RELEASE FSR1 FSR2 FSR3 FSR4 FSR5

0 0 0 0 0 0 0.5 13.913 10.167 8.849 6.515 5.836 1 25.365 21.124 17.33 14.207 12.258 2 39.18 35.254 28.367 23.656 20.981 4 52.233 48.661 43.165 37.214 33.927

6 65.874 61.451 58.571 51.592 46.457 8 83.724 78.854 70.233 6.052 57.039 12 99.377 97.856 84.693 78.377 73.754 16 97.564 85.317 81.526 24 98.325 92.545



Table-13: Dissolution profile of pyrazinamide based sustained release portion.

TIME (hrs)

%CUMULATIVE DRUG RELEASE

FSR1 FSR2 FSR3 FSR4 FSR5

0 0 0 0 0 0

0.5 16.265 14.024 10.61 8.442 7.124

1 28.098 25.496 21.985 17.247 15.926

2 46.132 42.075 35.573 28.972 25.914

4 65.026 61.25 48.326 43.244 40.316

6 81.072 79.37 61.159 58.349 54.132

8 96.216 94.186 79.193 70.59 65.396

12 98.978 81.678 79.949

16 96.732 94.744

Kinetics of sustained release formulations:

Table-14: Release kinetics for rifampicin based sustained release portions.

Formula tion

Zero order (K 0)

Regression

coefficient (r)

First order (K 1)

Higuchi (KH)

Korsemeyers-peppas n r2

FSR1 7.9006 0.9390 0.381 0.9929 0.5981 0.9888

FSR2 7.8855 0.9568 0.293 0.9875 0.6808 0.9839

FSR3 5.9921 0.9395 0.210 0.9918 0.6828 0.9903

FSR4 4.1736 0.8889 0.158 0.9845 0.6978 0.9783

FSR5 3.9849 0.8995 0.107 0.9543 0.7177 0.9828

Table-15: Release kinetics for pyrazinamide based sustained release portions.

Formula tion

Zero order (K0)

Regression

coefficient (r)

First order (K 1)

Higuchi (KH)

Korsemeyers-peppas n r2

FSR1 11.221 0.9605 0.374 0.9938 0.6276 0.9918 FSR2 11.275 0.9463 0.332 0.9896 0.6722 0.9929 FSR3 7.9217 0.9588 0.344 0.9865 0.6672 0.9835 FSR4 5.888 0.9337 0.192 0.9912 0.6861 0.9857 FSR5 5.8095 0.9512 0.168 0.9904 0.7206 0.9857

Kinetics of immediate release formulations:



Table-16: Release kinetics for immediate release portions.

Formulation Zero order (K 0)

Regression coefficient (r)

First order (K 1)

FIR1 1.3448 0.6558 0.064 FIR2 1.1744 0.4995 0.077 FIR3 1.3111 0.6356 0.054 FIR4 1.2868 0.6119 0.065

Figure-1: Zero order plot for immediate release portion of isoniazid.

Figure 2: Swelling indices of prepared floating tablets.

Figure 3: Zero order plot for rifampicin based sustained release portion.

0

20

40

60

80

100

120

0 20 40 60 80

F1

F2

F3

F4

Time

% c

umul

ativ

e d

rug

rel

ease

0

20

40

60

80

100

120

0 2 4 6

F1

F2

F3

F4

F5% S

we

llin

gin

de

x

Time(hrs)

0

20

40

60

80

100

120

0 10 20 30

F1

F2

F3

F4

F5

% c

um

ula

tive

Time(hr)



Figure 4: Zero order plot for pyrazinamide based sustained release portion.

First order plots:

Figure 5: Comparative first order plots for immediate release tablets of isoniazid.

Figure 6: Comparative first order plots for sustained release tablets of rifampicin.

0

20

40

60

80

100

120

0 5 10 15 20

F1

F2

F3

F4

F5% c

um

ula

tive

dru

g

Time(hr)

-0.5

0

0.5

1

1.5

2

2.5

0 20 40 60 80

log

% d

rug

re

ma

inin

g

Time(sec)

F1

F2

F3

F4

Linear (F1)

Linear (F2)

Linear (F3)

Linear (F4)

-2

-1.5

-1

-0.5

0

0.5

1

1.5

2

2.5

0 10 20 30

log

% d

rug

re

ma

inin

g

Time(min)

F1

F2

F3

F4

F5

Linear (F1)

Linear (F2)

Linear (F3)

Linear (F4)



Figure 7: Comparative first order plots for sustained release tablets of pyrazinamide.

Higuchi plots:

Figure 8: Higuchi plot for optimized formulation(FSR3) of rifampicin

Figure 9: Higuchi plot for optimized formulation(FSR3) of pyrazinamide.

Peppas plots:

Figure 10: Peppas plot for optimized formulation(FSR3) of rifampicin.

-1

-0.5

0

0.5

1

1.5

2

2.5

0 5 10 15 20

log

% d

rug

re

ma

inin

g

Time(min)

F1

F2

F3

F4

y = 25.951x - 6.0846

R² = 0.9918

-20

0

20

40

60

80

100

120

0 2 4 6

% d

rug

square root of

y = 29.182x - 6.0871

R² = 0.9865

-20

0

20

40

60

80

100

120

0 1 2 3 4

% d

rug

square root of time

y = 0.6828x + 1.2103

R² = 0.9903

0

0.5

1

1.5

2

2.5

-1 0 1 2

log

% d

rug

re

lea

se

log time



Figure 11: Peppas plot for optimized formulation(FSR3) of pyrazinamide.

Optimized formula of bilayered tablet: Table 17: Optimized formula of bilayered tablet:

S.NO SR LAYER(800mg) IR LAYER(100mg)

Ingredients Quantity

(mg/tablet)

Ingredients Quantity

(mg/tablet)

1 Rifampicin 120 Isoniazid solid dispersion 66

2 Pyrazinamide 300 Sodium starch glycolate 5

3 HPMC K100M 250 PVP K30 5

4 Sodium bicarbonate 50 MCC 10

5 PVP 40 Lactose 14

6 Magnesium stearate 10 - -

7 MCC 30 - -

DISSOLUTION PROFILE OF BILAYERED TABLETS

Table 18: Dissolution profile of bilayered tablets.

TIME (hrs) %CUMULATIVE DRUG RELEASE

In 0.1N HCl In 7.4 Phos phate buffer

Rifampicin Pyrazinamide Isoniazid Isoniazid

0 0 0 0 0

0.16 - - 0 78.87

0.25 - - 0 81.65

0.33 - - 0 88.15

0.5 8.849 10.61 0 91.39

0.75 - - 0 98.07

y = 0.6672x + 1.2911

R² = 0.9835

0

0.5

1

1.5

2

2.5

-0.5 0 0.5 1 1.5lo

g %

dru

g

log time



1 17.33 21.985 0 99.56

2 28.367 35.573 0 -

4 43.165 48.326 0 -

6 58.571 61.159 - -

8 70.233 79.193 - -

12 84.693 98.978 - -

16 97.564 - - -

Table 19: Physico chemical characteristics of bilayered tablets.

Formula tion

Weight Variation (mg)

Hardness (kg/cm2)

Friability (%)

Drug Content (%) Disintegration Time (sec) of IR layer

BL32 900±0.36 7±0.45

0.33

R 99.59±0.24 H 98.13±0.17 Z 98.52±0.33

35±3

4. Discussion

Pre compression parameters

All the pre-compressional parameters like bulk density, tapped density, angle of repose, Carr’s index, Hausner’s

ratio etc were evaluated (table 4 & 5) and were found to be within the limits, indicating the power blend has the required

flow property for compression. The tablets were prepared by direct compression method.

Post compression parameters

Hardness of the tablet was in the range 6±0.14 to 10±0.24 kg/cm2. Weight loss in the friability test was in the range

0.33±0.09 to 0.37±0.05% (table 6 & 7). All the floating tablets prepared contained rifampicin within 99±1.65%,

pyrazinamide within 98±0.35% and isoniazid within 99±0.52% of the labeled claim.

In-vitro buoyancy studies

Buoyancy studies were performed using 0.1 N HCL solution (pH 1.2 buffer) at 370C (table 10); the tablets floated

and remained without disintegration.

Swelling study

Swelling study was performed for all the formulations FSR1-FSR5 for 5hrs (table 11). Swelling increases as the

time passes because the polymer gradually absorbs water due to hydrophilicity of polymer.



In-vitro drug release study and drug release kinetics:

Drug release profiles of the SR and IR layer tablets are given in tables 6.9, 6.11 & 6.12 and shown in figures 6.6,

6.8 & 6.9.The drug release parameters of all the tablets prepared are summarized in table no 6.14, 6.15 and 6.16. As

there is no marketed SR product available, comparison was not done.

Rifampicin and pyrazinamide release from the floating SR tablets prepared was slow and spread over a period of

12-20hrs and dependent on the polymer used and its concentration in the tablet. The release data were analyzed as per

zero order ,first order, Higuchi and Peppas models .The correlation coefficient (r) values obtained in different models

are shown in Table 6.14 and 6.15.

Isoniazid release from the IR tablets prepared was fast within 60 min and dependent on superdisintegrant used in

the tablet. The release data were analyzed as per zero order, first order. The correlation coefficient (r) values obtained in

different models are shown in Table 6.16.

Analysis of release data of SR tablets as per zero order and first order indicated that the drug release from the SR

layer followed first order kinetics which is indicated by the higher correlation coefficient (r) values for first order

model.

Analysis of release data of IR tablets as per zero order and first order indicated that the drug release from the IR

layer followed first order kinetics which is indicated by the higher correlation coefficient (r) values for first order

model.

When the release data of SR tablets were analyzed as per korsemeyer-peppas equation the release exponent ‘n’

was found in the range 0.45-0.89 indicating non-fickian(anomalous) diffusion as the release mechanism from these

tablets.

Plots of % drug released vs √T were found to be linear (r>0.94)with all the SR formulations prepared, indicating

that the drug release from these tablets was diffusion controlled.

With the polymer (HPMC K100M), as the polymer concentration was increased ,the release rate constant

(K0)was decreased. A good relationship was observed between the polymer and release rate(K0).

At all the strengths of the polymers tested, HPMC K100M gave relatively slow release. The optimized SR

formulation should be selected based on the properties of both rifampicin and pyrazinamide. Although FSR4 and FSR5



showed drug release over a period of 24hrs in case of rifampicin and 16hrs in case of pyrazinamide, but in case of

rifampicin MEC cannot be achieved within 1hr. Hence FSR3 is selected as optimized formulation as it showed drug

release over a period of 16hrs in case of rifampicin(t1/2=3 to 4 hrs) and 12hrs in case of pyrazinamide (t1/2=9 to 10hrs).

So, FSR3 was considered as the best sustained release formulation. IR formulations made using showed almost similar

drug release profile. Hence entrapment efficiency(%) is considered in selecting the optimized IR formulation. FIR 2 has

an entrapment efficiency(%) of 88.63±0.24 and thus it is considered as optimized IR formulation.

5. Conclusion

Floating matrix tablets each containing 120mg of rifampicin and 300mg of pyrazinamide were formulated

employing HPMC K100M each in 5 different strengths(16.66, 22.22, 27.77, 33.33, 38.88%). Immediate release tablets

each containing 50mg of isoniazid were formulated employing sodium starch glycolate in 5% concentration. Among all

SR formulations , FSR 3 provided slow and optimum release of rifampicin over 16 hrs and that of pyrazinamide over

12hrs and is considered as a good sustained release formulation. Among all IR formulations FIR 2 provided rapid

release of isoniazid within 60 min and is considered as a good immediate release formulation basing on entrapment

efficiency(%).

Rifampicin and pyrazinamide release from the floating SR matrix layer was diffusion controlled and followed

first order kinetics. Isoniazid release from the IR layer was rapid and within 60min and dependent on the

superdisintegrant used and followed first order kinetics. Among all formulations BL32 provided slow release of

rifampicin over 16 hrs and pyrazinamide over 12hrs and rapid release of isoniazid within 60min, hence it is considered

as an optimum bilayerd formulation.

6. Acknowledgements

The authors are thankful to Prof.J.Vijaya Ratna for her meticulous guidance, transcendant suggestions, constructive

critisicm and constant encouragement. The authors are also thankful to Andhra University, Visakhapatnam for

allowing us to carry out the research work in their labs. The authors are also thankful to one and all whose support

and co-operation lead to the successful completion of this project.

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Corresponding Author:

Hadassah.M*,

Email: [email protected]

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