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Gottumukkala et al. World Journal of Pharmaceutical Research

AN APPROACH TO FORMULATE AND EVALUATE LABETALOL AS

FAST DISSOLVING TABLETS

Manoj Varma Gottumukkala *, Senthil Kumar K , Dr. Mohammed Gulzar Ahmed

and

Krishna K

Department Of Pharmaceutics, S.A.C.College of Pharmacy, B.G.Nagara, Karnataka-571448

India.

ABSTRACT

Delivery of drugs is always been a challenge and is the most important

aspect in formulation. Drugs are usually delivered via different

delivery systems and selection of the system depends on drug

solubility, bio availability, half life, site of action, etc. Oral delivery is

usually the most preferred route of drug administration, and there have

been many advances in controlling the release rate of a drug and its

bioavailability. Increased patient compliance is important for any Drug

delivery system. Many patients do not adhere to a regime of prescribed

drugs because of difficulty in administration or the taste of a drug. So it

is vital to ensure the convenient administration of a drug. In the present

work, fast dissolving tablets of Labetalol were prepared using novel

co-processed superdisintegrants and physical mixtures consisting of crospovidone and

sodium starch glycolate in the different ratios 1:1, 1:2, 1:3 and in vice versa. Labetalol is a

drug of choice which is used in treatment of Hypertension and Angina. Drug compatibility

with excipients was checked by FTIR studies. After examining the flow properties of the

powder blends the results are found to be with in prescribed limits and indicated good flow

properties. It was then subjected to tablet compression. All the formulations were subjected to

post compression parameters like hardness and friability and they showed good mechanical

strength and resistance. The wetting time is an important criteria for understanding the

capacity of disintegrants to swell in the presence of little amount of water and were found to

be in the range of 21 to 55 sec. Among all the designed formulations, formulation F5 was

found to be promising and it showed an in-vitro disintegration time of 21 sec, which

facilitates its faster disintegration in the mouth. The formulation F5containing co-processed

World Journal of Pharmaceutical Research SJIF Impact Factor 5.045

Volume 3, Issue 6, 735-754. Research Article ISSN 2277 – 7105

Article Received on

20 May 2014,

Revised on 20 June 2014,

Accepted on 31 July 2014

*Correspondence for

Author

Manoj Varma

Gottumukkala

Department Of Pharmaceutics,

S.A.C.College Of Pharmacy,

B.G.Nagara, Karnataka India

[email protected]

mailto:[email protected]


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superdisintegrant(3:1 mixture of crospovidone and sodium starch glycolate) emerged as the

overall best formulation based on drug release characteristics with 6.8 pH Phosphate buffer as

dissolution medium. Short-term stability studies on promising formulation F5 indicating no

significant changes in hardness, drug content and in-vitro drug release. From this study, it can

be concluded that dissolution rate of Labetalol FDTs can be enhanced by the use of co-

processed superdisintegrants.

Keywords: Co-processed superdisintegrants, Labetalol, Crospovidone, sodium starch

glycolate and direct compression.

INTRODUCTION

Drug delivery systems are strategic tools for expanding markets, extending product life

cycles and generating opportunities. DDS make a significant contribution to global

pharmaceutical sales through market segmentation and are moving rapidly. A report by

Global Business Intelligence (GBI) predicts the DDS market will grow by 10.3% annually in

the years leading up to 2016. According to GBI, research has resulted in significant growth in

DDS market which is expected to rise from $101 billion in 2009 to $199 billion by 2016. Of

this oral delivery market constitutes about 52% of market share and expected to reach $92

billion by 2016 up by 11.3% each year [1]

.

Fast dissolving drug delivery system

United States Food and drug administration (FDA) defined fast dissolving tablet (FDT) as “a

solid dosage form containing medicinal substance or active ingredient which disintegrate

rapidly usually within a matter of seconds when placed up on the tongue”. Fast dissolving

tablets are also known as mouth dissolving tablets, melt-in-mouth tablets, Oro-dispersible

tablets, rapid melts, porous tablets and quick dissolving tablets.

Fast dissolving tablets dissolve or disintegrate in the oral cavity without the need of water.

Their characteristic advantages such as administration without water, anywhere, anytime lead

to their suitability to geriatric and pediatric patients. They are also suitable for the mentally

ill, the bedridden, and patients who do not have easy access to water. The benefits, in terms

of patient compliance, rapid onset of action, increased bioavailability and good stability make

these tablets popular as a dosage form of choice in the current market [2]

.


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Limitations

1.The tablets usually have insufficient mechanical strength. Hence, careful handling is

required

2.The tablets may leave unpleasant taste and/or grittiness in mouth if not formulated properly

[3].

3.Drugs with relatively larger doses are difficult to formulate into MDT e.g. antibiotics like

ciprofloxacin with adult dose tablet containing about 500 mg of the drug.

4.Patients who concurrently take anticholinergics medications may not be the best candidates

for MDT [4]

.

5.MDT requires special packaging for proper storage and safety of product [5]

.

Mechanism

Disintegrants are important excipients of the tablet formulation they are always added to

tablet to induce breakup of tablet when they are in contact with aqueous fluid and this process

of deaggregation of constituent particles before the drug dissolution occurs, is known as

disintegration process and excipients which induce this process are known as disintegrants.

The objectives behind addition of disintegrants are to increase surface area of the tablet

fragments and to overcome cohesive forces that keep particles together [6]

.

Co-processed super disintegrants: Co-processing is defined as process of combining 2 or

more established excipients by an appropriate method. Co-processing of excipient could lead

to formation of excipients with superior properties compared with the simple physical

mixture of their components or with individual components. A large number of co processed

diluents are commercially available. The representative examples are Ludipress, Cellactose,

and Starlac. The use of co-processing is a totally unexplored avenue in disintegrants. The

widely used superdisintegrants are sodium starch glycolate, crospovidone, and

crosscarmellose sodium. Like diluents, each superdisintegrant has strengths and weaknesses.

In the present investigation, the preparation and evaluation of co processed disintegrant

containing crospovidone and sodium starch glycolate was explored.

The reasons for the selection of crospovidone and sodium starch glycolate are:

Crospovidone has better compressibility compared with other superdisintegrants, high

capillary activity, pronounced hydration capacity, and little tendency to form gels. Sodium

starch glycolate was chosen because of its high swelling capacity. Moreover, the disintegrant

efficiency of sodium starch glycolate is unimpaired by the presence of hydrophobic


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excipients such as lubricants. Sodium starch glycolate exhibits good flow property (angle of

repose G36º). The bulk density of crospovidone and sodium starch glycolate is 0.4 and 0.756

g/cm3, respectively. Hence, if a physical mixture of superdisintegrants is used in high-speed

tabletting, the problem of segregation of the disintegrants may be encountered.A blend of

swelling and wicking types of excipient may also prove to be efficient because the medium

(usually water) required for swelling will be brought into the tablet more easily if a wicking

(hydrophilic) type of superdisintegrant is also present [7]

.

HYPERTENSION

Hypertension is the state of increase in blood pressure than normal tension of 120/80 mm Hg.

The WHO -ICH guidelines (2003) have defined it to be 140 mm Hg systolic and 90 mm Hg

diastolic pressure. Epidemiological studies have confirmed that higher the pressure greater is

the risk of cardio vascular disease. Hypertension is a very common disorder particularly past

middle age. It is not a disease in itself, but is an important risk factor for cardio-vascular

mortality and morbidity. Worldwide, raised blood pressure is estimated to cause 7.5 million

deaths, about 12.8% of the total of all deaths. This accounts for 57 million disability adjusted

life years (DALYS) or 3.7% of total DALYS. Globally, the overall prevalence of raised

blood pressure in adults aged 25 and over was around 40% in 2008. The proportion of the

world‟s population with high blood pressure, or uncontrolled hypertension, fell modestly

between 1980 and 2008. However, because of population growth and ageing, the number of

people with uncontrolled hypertension rose from 600 million in 1980 to nearly 1 billion in

2008.

ANTI HYPERTENSIVE’S

Anti-Hypertensive‟s are the agents that tend to lower the Blood pressure. Antihypertensive

drugs have been remarkably improved in the last 50 years. Different classes of drugs have

received prominence with passage of time in this period. Before 1950 hardly any effective

and tolerated antihypertensive was available. Veratrum and Sodium thiocynate could lower

blood pressure but were toxic and difficult to use. The ganglion blockers developed in 1950‟s

were effective but inconvenient. Reserpine was a breakthrough, but produced mental

depression. The therapeutic potential of hydralazine could not be tapped fully because of

marked side effects when it was used alone. Guanethidine introduced in 1961 was an

improvement on ganglion blockers. The antihypertensives of 1960-70s were Methyldopa, β

blockers, thiazide and high ceiling diuretics and clonidine. The status of β blockers and

diuretics was consolidated in the 1970s and selective α1 blocker prazosin broke new grounds.


739


The antihypertensives of the 1980-90s are ACE inhibitors and calcium channel blockers.

Angiotensin receptor blockers are the latest antihypertensives. With the development of many

types of drugs delineation of their long-term benefits, complications and understanding of the

principels on which to combine them, hypertension can now be controlled in most cases with

minimum discomfort [8]

.

LABETALOL

Labetalol is a white or off-white crystalline powder, soluble in water. It a selective alpha-1

and non selective beta adrenergic antagonist which is used in the treatment of high blood

pressure. It has particular indication in pregnancy induced hypertension which is commonly

associated with pre-eclampsia. It is also used to treat chronic and acute hypertension of

pheochromocytoma and hypertension crisis. It has a half life of 6-8 hrs, bioavailability of

~25% and most of the drug is eliminated via urine [9]

. In the present investigation, the

preparation and evaluation of fast dissolving tablets by using co-processed superdisintegrants

containing crospovidone and sodium starch glycolate was studied. The reasons for selection

of crospovidone are high capillary activity, pronounced hydration capacity and little tendency

to form gels. Sodium starch glycolate was chosen because of its high swelling capacity. The

concept of formulating fast dissolving tablets (FDT) of Labetalol using co-processed

superdisintegrants helps to increase the water uptake with shortest wetting time and there by

decrease the disintegration time of the tablets by simple and cost effective direct compression

technique [10]

. These systems may offer superior profile with potential mucosal absorption,

thus increase the drug bioavailability [11]

.

MATERIALS AND METHODS

Table no I: List of chemicals

SI.NO MATERIALS SUPPLIERS

1 Labetalol Yarrow chemicals limited, Mumbai

2 Crospovidone S.D fine chem limited, Mumbai

3 Sodium starch glycolate S.D fine chem limited, Mumbai

4 Micro crystalline cellulose S.D fine chem limited, Mumbai

5 Mannitol S.D fine chem limited, Mumbai

6 Magnesium stearate S.D fine chem limited, Mumbai

7 Ethanol S.D fine chem limited, Mumbai

8 Potassium di hydrogen

phosphate S.D fine chem limited, Mumbai

9 Sodium hydroxide S.D fine chem limited, Mumbai

10 Talc S.D fine chem limited, Mumbai

11 Sodium saccharin S.D fine chem limited, Mumbai

12 Flavour S.D fine chem limited, Mumbai


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EQUIPMENTS USED

Table no II: List of equipments used

METHODOLOGY

Preparation of co-processed superdisintegrants

The co-processed superdisintegrants were prepared by solvent evaporation method. A blend

of crospovidone and sodium starch glycolate (in the ratio of 1:1, 1:2 & 1:3) was added to 10

ml of ethanol. The contents of the beaker (250 ml capacity) were mixed thoroughly and

stirring was continued till most of ethanol evaporated. The wet coherent mass was granulated

through no 44 sieve. The wet granules were dried in a hot air oven at 60º C for 20 minutes.

The dried granules were sifted through no 44 sieve and stored in airtight container till further

use.

Table no III: Preparation of co-processed superdisintegrants different ratios

Code Crospovidone+ Sodium starch glycolate Sodium starch glycolate+ Crospovidone

CPSD-1 1:1 -

CPSD-2 1:2 1:2

CPSD-3 1:3 1:3

SL.NO EQUIPMENT MODEL/COMPANY

1 Electronic analytical balances and precision

scales Acculab Sartorius group

2 UV-Visible spectrophotometer Spectrophotometer UV-1700,

Shimadzu.

3 Fourier Transform Infrared

spectrophotometer Thermo Nicolet

4 pH meter Techno scientific products

5 Hot air oven Kemi

6 Multi tablet Punching machine LAB PRESS, Cip Machinaries

Ltd. Ahmedabad

7 Roche friabilator PSM Industries, Benguluru

8 Hardness tester Monsanto hardness tester

9 Electrical weighing balance Essae-Teraoka

10 Disintegration test apparatus Sii Serwell Instruments INC.,

11 Dissolution test apparatus Lab India

12 Stability chamber (106 Model) LABTOP, SKY Lab

Instruments & Eng Pvt.Ltd.


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Preparation of fast dissolving tablets by direct compression method

Fast dissolving tablets of Labetalol were prepared by direct compression method by using co-

processed superdisintegrants like Crospovidone, Sodium Starch Glycolate. Mannitol,

Microcrystalline Cellulose as a diluent, Sodium saccharin as a sweetening agent, Mint as a

flavor, Magnesium Stearate, Talc used as a lubricant and glident. All the ingredients (except

granular directly compressible excipients) were passed through # 60-mesh separately. Then

the ingredients were weighed and mixed in geometrical order after sufficient mixing of drug

as well as other components and compressed into tablets of 200mg using 8mm round flat

punches on 12 station rotary tablet machine. The formulations are shown

Table no IV : Selected excipients for prototype formulation

SL.NO EXICIPIENT FUNCTION

1 Crospovidone Superdisintegrant

2 Sodium starch glycolate Superdisintegrant

3 Micro crystalline cellulose Diluent & Disintegrant

4 Mannitol Diluent

5 Magnesium stearate Lubricant

6 Talc Glident

7 Sodium saccharin Sweetening agent

8 Mint Flavor

Table no V : FORMULATION DEVELOPMENT OF LABETALOL FAST

DISSOLVING TABLETS

CPSD PHYSICAL MIXTURE

FORMULA CODE

F0

(C

F)

F1 F2 F3 F4 F5 F6 F7 F8 F9 F10

(1:

1)

(1:

2)

(1:

3)

(2:

1)

(3:

1)

(1:

1)

(1:

2)

(1:

3)

(2:

1)

(3:

1)

LABETALOL 100 100 100 100 100 100 100 100 100 100 100

CO-PROCESSED

SUPERDISINTEGR

ANTS

- 10 10 10 10 10 10 10 10 10 10

MCC 50 40 40 40 40 40 40 40 40 40 40

MANNITOL 30 30 30 30 30 30 30 30 30 30 30

SODIUM

SACCHARIN 8 8 8 8 8 8 8 8 8 8 8

FLAVOUR 2 2 2 2 2 2 2 2 2 2 2

MAGNESIUM

STEARATE 5 5 5 5 5 5 5 5 5 5 5

TALC 5 5 5 5 5 5 5 5 5 5 5

TOTAL WEIGHT 200 200 200 200 200 200 200 200 200 200 200

*All quantities are in milligrams (mg) only.


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Table no VI : Full-forms of formulation codes

FORMULATION CODE ABBREVIATION

F0 (CF) Control formulation without superdisintegrants.

F1 (1:1) Co-processed superdisintegrants of crospovidone:sodium starch

glycolate (1:1) ratio.









F6 (1:1) Physical mixture of crospovidone:sodium starch glycolate (1:1)

ratio.


ratio.


ratio.


ratio.


ratio.

PRE-FORMULATION STUDIES

Pre-formulation testing is the first step in the rationale development of dosage forms of a

drug substance. It can be defined as an investigation of physical and chemical properties of a

drug substance alone and when combined with excipients. The overall objective of pre-

formulation testing is to generate information useful in developing stable and bioavailable

dosage forms which can be mass produced.

Analytical Method used in the Determination of Labetalol.

Melting point:

Melting point was determined by open capillary method.

Identification of pure drug:

Identification of Labetalol was carried out by Infra Red Absorption Spectrophotometer.

Determination of λmax [12]

The first step in Pre-formulation is to establish a simple analytical method so that all future

measurements can be quantitative. Most drugs absorb light in the ultraviolet wavelength

(190-390 nm) region, since they are generally aromatic and contain double bonds.


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100 mg of Labetalol was accurately weighed on Electronic balance and dissolved in 100 ml

of 6.8 pH phosphate buffer which gives-1000 μg/ml conc. Labetalol is soluble in water. 1 ml

of this solution was diluted with 100 ml of 6.8 pH phosphate buffer which gives -10 μg/ml

conc. in separate volumetric flask and scanned on a UV-visible spectrophotometer

(Shimandzu 1700) between 190 to 390 nm. The λmax of the drug was found to be 303 nm.

Standard calibration curve of Labetalol in 6.8 pH

Phosphate buffer.

Labetalol (100 mg) was dissolved in small amount of 6.8 pH Phosphate buffer and volume

was made up to 100 ml using the same which is called as stock-I solution. 10 ml of the above

solution is diluted to 100 ml in another volumetric flask which is called as Stock-II solution.

From this stock-II solution serial dilutions were made by pipetting out 1 ml, 2 ml, 4 ml, 6 ml,

8 ml and 10 ml to obtain solutions of the drug in the concentration ranging from 10, 20, 40,

60, 80, 100 μg/ml respectively. The absorbance of the solutions was measured at 303 nm

using UV-visible spectrophotometer. A graph of concentration Vs absorbance was plotted.

The results obtained are shown in Table no VIII.

Solubility studies: Labetalol is soluble in Ethanol, Methanol, Water, 0.1 N HCL and in

different basic pH buffers of 6.8, 7.2, 7.4, and 7.8.

Compatibility study: A successful formulation of a stable and effective solid dosage form

depends on careful selection of the excipients that are added to facilitate administration that

promote the consistent release and bioavailability of the drug and protect it from degradation.

If the excipients are new and have not been used in formulations containing the active

substance, the compatibility studies are of paramount importance. Compatibility of the drug

with the excipients is determined by subjecting the physical mixture of the drug and the

polymers of the main formulation to infrared absorption spectral analysis (FTIR). Any

changes in chemical composition of the drug after combining it with the polymers were

investigated with I.R. spectral analysis.

Procedure: Weighed amount of drug (3 mg) was mixed with 100mg of potassium bromide

(dried at 40-50oC). The mixture was taken and compressed under 10-ton pressure in a

hydraulic press to form a transparent pellet. The pellet was scanned by IR spectrophotometer.

Similar procedure is followed for all relevant excipients used.


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Pre-compression and post compression parameters are studied according to the standard

procedures and results are shown in Table no X and XI.

In-vitro dissolution studies[12]

Dissolution testing of Labetalol fast dissolving tablets was carried out with paddle type in

USP dissolution apparatus at rpm 50 and temperature 37±0.5°C in 6.8 pH phospate buffer. At

each specified intervals of time 5 ml sample was withdrawn and replaced by fresh media. The

samples were analytically tested to determine the concentration by UV spectroscopy method

at wavelength of 303 nm. The results obtained are shown in Table no XII.

Details of dissolution test

Dissolution test apparatus : USP type II

Speed : 50 rpm

Stirrer : Paddle type

Volume of medium : 500 ml

Volume withdrawn : 5 ml

Medium used : 6.8 pH phosphate buffer.

Temperature : 37±0.5ºC

Stability Studies[13]

Stability can be defined as the capacity of drug product to remain within specifications

established to ensure its identity, strength, quality, and purity.

Importance of stability studies

Stability studies are important for the following reasons.

1.This is an assurance given by the manufacturer that the patient would receive a uniform

dose throughout the shelf life.

2.The drug control administration insists on manufacturers on conducting the stability

studies, identity, strength, purity and quality of the drug for an extended period of time in the

conditions of normal storage.

3.Stability testing prevents the possibility of marketing an unstable product. Both physical

and chemical degradation of drug can result in unstable product.


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Purpose of stability studies: Stability studies are done to understand how to design a

product and its packaging such that product has appropriate physical, chemical and

microbiological properties during a defined shelf life when stored and used.

Storage conditions

Table no VII : Drug substances intended for normal storage

Study Storage conditions Minimum period of time

Long term

Intermediate

Accelerated

25ºC ±2 ºC/60%RH±5%RH

30 ºC±2 ºC/65%RH±5%RH

30 ºC±2 ºC/65%RH±5%RH

40 ºC±2 ºC/65%RH±5%RH

12 Months

6 Months

6 Months

The optimized formulation was subjected for two months stability study according to ICH

guidelines. The selected formulations were packed in aluminium foil in tightly closed

container. They were then stored at 40ºC / 75% RH for two months and evaluated for their

permeation study [14]

.

RESULTS AND DISCUSSION

Melting point: Melting point of Labetalol was determined by capillary method and its

melting point was found to be 188˚C.

Solubility studies: Labetalol is soluble in Ethanol, Methanol, Water, 0.1N HCl and in

different basic pH buffers of 6.8,7.2,7.4,7.8.

In the present study, a total of 10 formulations of fast dissolving tablets labetalol were

prepared using co-processed super disintegrants by direct compression method. In order to

select the best formulation, various parameters were checked and subjected to in-vitro

dissolution studies, release profile was observed and compared. Evaluation for general

appearance, physical parameters, drug content and release studies were performed according

to official method and also with modified official methods. All the above tests are described

in methodology section. Stability studies were performed for a two month and parameters

like physical appearance; hardness, drug content and in-vitro dissolution studies of the best

formulations were evaluated.

Determination of λmax and preparation of standard curve: The solvent medium was

selected on the basis of solubility and it was found that labetalol is soluble in 6.8 pH

phosphate buffer. Standard stock solution was prepared and scanned by UV


746


spectrophotometer according to procedure mentioned in methodology section. The λmax was

found to be 303 nm against 6.8 pH phosphate buffer as blank.

Table no VIII : Standard calibration curve for Labetalol in 6.8 pH phosphate buffer.

Fig.1: Standard graph of Labetalol.

The standard curve and data was obtained by the procedure described in methodology

section. The results were shown in Table no VIII and Fig. 1. The linear plot between

concentrations versus absorbance showed that Beer-Lambert‟s law was obeyed in

concentration range of 10-100 µg/ml.

IR of Labetalol.

I R of the Labetalol was determined by FTIR spectra as mentioned in the Fig. 2

Concentration

(µg/ml)

Absorbance

I II III IV Average

0 0 0 0 0 0

10 0.111 0.089 0.089 0.099 0.097

20 0.200 0.179 0.176 0.186 0.185

40 0.392 0.355 0.354 0.370 0.368

60 0.579 0.543 0.553 0.554 0.557

80 0.746 0.720 0.750 0.752 0.742

100 0.895 0.898 0.910 0.886 0.897


747


Fig. 2: IR spectrum of Labetalol

Table no IX: FTIR characteristic peak of Labetalol

Fig.3: IR spectrum of drug with crospovidone,sodium starch glycolate, and

microcrystalline cellulose.

FUNCTIONAL STANDARD OBSERVED

GROUPS PEAKS PEAKS

OH-Streching 3100-3600 3356

NH-Streching 3100-3500 3188

Aromatic –CH 2900-3100 2982

Aliphatic-CH 2850-2960 2810

C=O Streching 1650-1700 1673

C=C Streching 1620-1680 1640


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Compatibility study of drug with polymers

Physical mixture of drug and polymer was characterized by FTIR spectral analysis for any

physical as well as chemical alteration of the drug characteristics. From the results, it was

concluded that there was no interference of the functional group as the principle peaks of the

Labetalol were found to be unaltered in the drug- polymer physical mixtures, indicating they

were compatible chemically.

Table no X: Pre-Compression Parameter results

Code Bulk density g/cc Tapped density g/cc Carr’s index% Hausner’s ratio Angle of

repose(°)

F0 0.475±0.091 0.607±0.114 21.7±0.03 1.27 29.61±0.0

4

F1 0.502±0.104 0.612±0.031 18.04±0.094 1.22 25.19±0.0

67

F2 0.518±0.067 0.615±0.064 15.77±0.061 1.18 25.89±0.0

51

F3 0.56±0.081 0.672±0.089 16.6±0.074 1.2 24.21±0.0

79

F4 0.538±0.093 0.677±0.107 20.5±0.087 1.25 24.17±0.0

84

F5 0.534±0.075 0.672±0.102 20.53±0.034 1.25 27.51±0.0

39

F6 0.493±0.102 0.629±0.07 21.6±0.105 1.26 24.52±0.0

21

F7 0.524±0.089 0.666±0.078 20.06±0.089 1.26 26.86±0.0

44

F8 0.506±0.084 0.617±0.041 17.9±0.102 1.21 25.12±0.0

42

F9 0.519±0.067 0.637±0.021 18.5±0.071 1.22 26.61±0.0

39

F10 0.487±0.079 0.617±0.08 21.06±0.067 1.26 24.86±0.0

42

Pre-formulation studies

For each type of formulation blends of API and excipients were prepared and evaluated for

various parameters as explained earlier. Bulk density was found in the range of 0.475-0.560

g/cm3 and the tapped density between 0.607 - 0.677 g/cm

3. Using the above two density data,

Carr‟s compressibility index were calculated. The compressibility index was found between

15.7-21.7% and the compressibility and flowability data indicated good flow properties of all

powder blends. The better flow property of all powder blends was also evident from angle of

repose. The angle of repose was range of 24.17°-29.61°. Angle of repose below 30º indicates


749


good flow property. In the present study all powder blends showed good flow property. The

results are shown in

Table no X .

Tabletting

The uniform blends of tablet composition were directly compressed by keeping tablet press

setting constant across all formulations. Proper lubrication of powder blends was essential for

ease of ejection of compressed tablets as well for the free movement of lower punch during

compression cycle to eliminate any possible influence of these factors on the study.

POST- COMPRESSION EVALUATION PARAMETERS

Various standard and quality control test carried out on compressed tablets and they are

demonstrated Table no XI.

General appearance

All the FDT formulations were evaluated for their general appearance like taste, colour and

odour. All FDT formulation are sweet taste, white colour and Mint odour.

Fig.4: IN-VITRO DRUG RELEASE STUDIES OF LABETALOL FDT's

In-vitro drug release studies

As there is no specific dissolution test available for FDTs dissolution rate is studied as per

USP specifications for conventional tablets with little modification. All the FDT formulations

were evaluated for their in-vitro drug release according to the procedure described in


750


methodology section and the results are shown in Table no XII. The maximum drug release

of 90.88% was obtained from formulation F5, and minimum drug release of 73.66% shown

by F6. The average drug release immediately after dispersion for all the formulations was in

the range of 73.66% to 90.88%. The control formulation F0 drug release was found to be

15.81%.

Table no XI: Post- compression parameter results

Code

Weight

variation

(mg)

Hardness

kg/cm2 Thickness

Friability

(%)

Disintegra

tion

Time (sec)

Wettin

g time

Water

absorption

ratio

%CDR

F0 199.81±0.26 2.71±0.10 3.12±0.01 0.37±0.15 245 55 39.95 15.81

F1 199.92±0.32 3.31±0.09 3.14±0.03 0.31±0.11 38 31 61.8 78.23

F2 200.05±0.41 3.12±0.04 3.14±0.03 0.37±0.09 27 28 63.8 81.49

F3 199.92±0.49 3.31±0.007 3.15±0.02 0.26±0.62 31 30 50.84 83.56

F4 199.91±0.31 3.14±0.05 3.14±0.01 0.32±0.44 29 28 59.65 87.20

F5 200.03±0.89 3.11±0.03 3.15±0.04 0.19±0.53 26 21 63.42 90.88

F6 199.95±0.92 3.19±0.10 3.13±0.01 0.37±0.20 39 31 50.18 73.66

F7 200.04±0.66 2.97±0.14 3.15±0.02 0.42 ±0.32 41 35 52.08 80.10

F8 199.9±0.56 3.15±0.05 3.14±0.01 0.57±0.06 48 34 54.58 78.61

F9 200.01±1.04 3.22±0.06 3.15±0.01 0.74±0.09 52 36 50.75 81.1

F10 200.03±0.52 3.14±0.04 3.14±0.01 0.71±0.09 32 32 55.45 79.81

Table no XII: In-vitro drug release studies of Labetalol FDTs

S.no

Time

in

mins

% CUMULATIVE DRUG RELEASE

FORMULATION CODES

F0 F1 F2 F3 F4 F5 F6 F7 F8 F9 F10

1 0.5 4.98 33.35 38.64 41.18 40.2 42.06 37.27 38.54 39.03 40.1 38.34

2 1 6.78 47.90 54.2 53.41 57.25 50.36 41.5 48.39 48.88 50.16 50.36

3 1.5 7.02 54.26 61.78 68.56 68.28 69.62 48.3 55.45 50.43 54.57 54.77

4 2 7.31 62.17 68.5 70.21 71.59 72.29 50.6 63.45 53.88 61.38 58.43

5 3 8.5 68.31 73.26 73.27 75.64 74.66 55.7 68.51 59.12 67.32 61.4

6 4 10.08 71.6 76.04 76.63 77.24 78.31 58.04 70.41 68.16 70.31 67.13

7 6 10.87 75.25 77.24 77.64 78.62 84.43 63.37 73.4 70.31 74.5 71.29

8 8 13.83 77.5 79.21 80.10 81.19 87.91 68.61 78.21 74.55 78.2 77.71

9 10 15.81 78.23 81.49 83.56 87.20 90.88 73.66 80.1 78.61 81.1 79.81

Discussion about kinetic models

Different kinetic equations (Zero order, First order, Higuchi‟s, Hixson-Crowell and

Koresmeyer-Peppas equation) were applied to interpret the release rate. The release obeyed

first order kinetics and the results of this investigation showed high correlation coefficient

among the formulation for first order release and the probable release mechanism was initial


751


diffusion and the value of release exponent (n) was found to be a function of the polymer

used and the physicochemical properties of the drug molecule itself and the n values was

found to be in the range of 0.113 to 0.348 followed with Fickian (case I) release.

Mathematical modeling of drug release profile:

Table no XIII: Release exponent values and release rate constant values for different

formulations

R2=Regression coefficient, n= Exponential value

STABILITY STUDIES

Stability study was conducted for two best formulations selected based on in-vitro

disintegration time and in-vitro drug release. The stability studies for best formulations were

carried out as per procedure in methodology section 4.There was no significant change in

taste, colour and odour. The results are found to be satisfactory. There was no significant

variation in the in-vitro dissolution profiles after two months stability study for best

formulation F5.The results of the stability are given in the following Table no XIV.

Table no XIV: Stability studies for best formulations stored at 40ºC/75% RH

FORMULA

CODE

KORESMEYAR

AND PEPPAS HIGUCHI

HIXON

CROWEL

FIRST

ORDER

ZERO

ORDER

R2

n

R2 R

2 R

2 R

2

F0 0.9743 0.388 0.9683 0.9829 0.9832 0.9821

F1 0.8914 0.1562 0.8411 0.7813 0.8183 0.7001

F2 0.8524 0.1275 0.7825 0.7279 0.7722 0.6353

F3 0.8349 0.1186 0.761 0.7264 0.779 0.6216

F4 0.825 0.1211 0.7707 0.765 0.821 0.6374

F5 0.8883 0.1374 0.8468 0.8659 0.9222 0.7255

F6 0.9925 0.1315 0.9854 0.9641 0.9764 0.9285

F7 0.9346 0.1351 0.8854 0.8433 0.8794 0.7625

F8 0.9815 0.1313 0.9636 0.9343 0.9527 0.8872

F9 0.9657 0.1302 0.9277 0.8922 0.9234 0.8183

F10 0.9671 0.1309 0.9521 0.9314 0.9553 0.8657

TIME Hardness kg/cm

2 In-vitro drug release (%CDR)

F4 F5 F4 F5

15 days 3.14 3.11 87.2 90.88

30 days 3.12 3.09 87.14 90.72

45 days 3.13 3.10 87.04 90.55

60 days 3.1 3.09 86.80 90.00


752


TIME IN MIN

Fig.4 : Comparison of in-vitro drug release before stability with after stability of

best formulation F5 and F4.

TIME IN MIN

Fig.5: Comparison of in-vitro drug release before stability with after stability of best

formulation F4

100

90

80

70

% 60

C 50

D

R 40

30

20

10

0

0 2 4 6 8 10 12

100

90

80

70

% 60

C 50 D

R 40 30

20

10

0 0 2 4 6 8 10 12


753


CONCLUSION

Fast dissolving tablets of Labetalol were prepared using co-processed superdisintegrants

ofcrospovidone and sodium starch glycolate with different ratio‟s (1:1, 1:2 and 1:3) and vice

versa by direct compression method. A total of ten formulations were prepared along with

control formulation.

The following conclusions can be drawn from the results obtained.

FTIR studies revealed no chemical incompatability of drug with excipients.

The tabletting properties like Angle of repose, Bulk density, tapped density; Hausner‟s

ratio and Carr‟s index of all the formulations were found to be with in the standard limits.

All the physical characteristics of the formulations like thickness, hardness, friability,

wetting time, drug content, water absorption ratio, in-vitro disintegration time and in-vitro

dissolution studies were found to be well with in the limits of official standards.

All the formulations get disintegrated within a time period of 65 seconds when tested for

in-vitro disintegration time.

The F5 formulation containing crospovidone and sodium starch glycolate in 3:1 ratio as

co-processed superdisintegrants was found to have the higher percentage of drug release

compared with other formulations.

The F6 formulation containing crospovidone and sodium starch glycolate in 1:1 ratio as

physical mixture was found to have the lesser percentage of drug release compared with other

formulations.

All the formulations are found to follow First order drug release and „n‟ value indicates

that release mechanism follows Fickian release. Stability studies of the tablets in normal

humidity conditions were checked and observed that FDT preparations require specialized

packing and storage conditions.

It can be concluded from the present work that co-processed superdisintegrants of

crospovidone and sodium starch glycolate are superior than its physical mixture and they

enhanced the dissolution rate of Fast Dissolving Tablets.

REFERENCES

1. www.gbiresearch.com, [email protected], titled “Drug delivery market to reach

$199 bn by 2016”, says GBI Research 15-Nov-2010.

2. Gohel M, Patel M, Amin A, Agrawal R, Dave R, Bariya N. Formulation Design and

Optimization of Mouth Dissolve Tablets of Nimesulide Using Vacuum Drying

Technique.AAPS PharmSciTech, 2004;5(3):36.

mailto:[email protected]


754


3. Susijit S, B Mishra, PK Biswal, Omprakash P, Santosh KM and Goutam KJ. Fast

Dissolving Tablet as a Potential Drug Delivery System. DIT, 2010;2(2):130-33.

4. Hitesh J, Ravi P, Pratik U, Jitendra B, Satish K. Fast Dissolving Tablets Present and

Future Prospectus. JAPHR, 2011;2(1):57-70.

5. VN Deshmukh. Mouth Dissolving Drug Delivery System A Review. IJPTR,

2012;4(1):412-21.

6. Rajkumar G, Satyendra SB, Ashish P, K Sharma, G Tiwari and Rituraj S. A Review on

Formulation and Evaluation of Orodispersible Tablets (Fast Dissolving Tablet).

WJPR,2012;1(3):576-90.

7. Raghavendra Rao NG and Upendra K. Formulation and Design of Fast Dissolving

Tablets Of Felodipine Using Novel Co-Processed Superdisintegrants. IJPRD,

2010;2(9):113-121.

8. KD Tripathi. Essentials of Medical Pharmacology. 6th

ed. New Delhi; Jaypee: p. 539.

9. www.drugbank.com/Labetalol.

10. S B Shirsand, R G Ramani, P V Swamy.Novel Co-Processed Superdisintegrants

in the Design of Fast Dissolving Tablets.IJPBS,2010;1(1):1-11.

11. AK Patil, T Aman, Nithin BB, Abhilash P, Madhuri T, Supriya K. Formulation

and evaluation of mouth dissolving tablets of montelukast sodium. RJPBCS,

2011;2(3):268-74.

12. J Ramesh, VP Reddy, GC Rao. Formulation and evaluation of oral disintegrating tablets

of Labetalol Hydrochloride. IJPS, 2010;2(2):488-495.

13. Dr.Shyamala Bhaskaran. Industrial pharmacy. 1st ed. New Delhi: Birla Publications Pvt.

Ltd; 2010. p. 46-69

14. ICH Q1A (R2) Stability testing guidelines: Stability Testing of new drug substances and

products.[online]. [Cited 2008 Nov 10]; Available from

URL:http://www.tga.health.gov.au/docs/pdf/euguide/inch/273699r2en.pdf.

http://www.drugbank.com/Labetalol

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