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4.1. MATERIALS USED:

The following raw materials were used for the formulation of fast dissolving tablets:

Table No. 2: List of raw materials used.

S.N. Raw Materials Manufactures

1. Montelukast Sodium Recipharm Pharmaservices Pvt. Ltd.,Tumkur

2. Sodium starch glycolate Karnataka fine chemicals

3. Crospovidone Karnataka fine chemicals

4. Guar gum Himalaya drug company, Bangalore

5. Gellan gum Indian Fine Chemicals, Mumbai

6. Sterculia gum Indian Fine Chemicals, Mumbai

7. Mannitol Indian Fine Chemicals, Mumbai

8. Magnesium stearate SDFCL T.V industrial eastate mumbai

9. Stevia leaf powder Himalayan Pvt. Ltd, Bangalore

10. Microcrystalline Cellulose PH Indian Fine Chemicals, Mumbai

101

The distilled water was used in all experiments.

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The following chemicals were used for the experimental purposes:

4.1.1 EQUIPMENTS AND INSTRUMENTS USED:

Equipments and instruments used for the preparation of Fast dissolving tablets are given in
table below:

Table No. 3: List of equipment and instruments used.

S.N. Name of Equipment/instruments Model /Manufacturer

1. Electronic analytical balance BL 110 S/Sartorius

2. FT-IR Spectrophotometer Jasco/ FTIR 460 PLUS

3. UV/Visible Spectrophotometer Systronics/ UV-117

4. USP dissolution apparatus Labindia/ DS 8000

5. Digital pH meter Servewell Instruments Pvt, ltd

6. Bulk density apparatus Singhla Lab

7. Rotary tablet compression machine Servewell Instruments Pvt, ltd

8. Tablet hardness tester Mansanto, India

9. Vernier Caliper Mitutoyo/SXR629

10. Roche Friability Apparatus Electro Lab

11. Disintegration Apparatus Singhla Lab

12. Stability chamber REMI/SC-19 PLUS

4.2 METHOD
4.2.1 PRE-FORMULATION STUDIES:
Pre-formulation study is the first step in the development of dosage form of a drug

substance. It is defined as a phase of research and development, where the biopharmaceutical

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principles are applied to determine the physicochemical parameters of a new drug substance

with a goal to design optimum drug delivery system.

Objective of pre-formulation studies:

 To generate useful information about the drug to the formulator to design an optimum

drug delivery system.

 To establish necessary physicochemical parameters of a new drug substance.

 To determine kinetic rate profile.

 To establish physical characteristics of drug.

 To find out compatibility of a drug with commonly used excipients.

Identification of pure drug by IR Spectroscopy

The FTIR spectrum of the sample of the drug was compared with the standard FTIR spectra

of the pure drug.

Determination of melting point

Melting point of Montelukast Sodium was determined by open capillary method.

Solubility Analysis

Solubility analysis is carried out for Montelukast Sodium samples in various solvents. 10

mg pure drug was dissolved in 10ml of different solvents i.e. water, ethanol and dimethyl

formamide solubility was determined.44

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Determination of Absorption Maxima (λmax)

Standard stock solution of Montelukast Sodium was prepared in 0.5% SLS working standard

solution of Montelukast Sodium was prepared by taking suitable aliquots of standard drug

solution (1000µg/ml) and volume was made up to 10ml with 0.5% SLS. The resulting

solutions were then scanned in the UV range (200-400) using UV double beam

spectrophotometer using blank. The spectrum of absorbance versus wavelength was recorded

and analyzed for the absorbance maximum (λmax). 45

Preparation of Standard calibration curve for Montelukast Sodium

Accurately weighed 100mg of Montelukast Sodium was dissolved with 0.5% SLS in 100ml

volumetric flask. From this stock-I, 10ml was pipette in 100ml volumetric flask and volume

was made with 0.5% SLS to make second solution. From the second stock solution different

aliquots were prepare solution in the range 5-30µg/ml. The standard curve was obtained by

plotting absorbance vs concentration.45,46

Method of preparation

Fast dissolving tablets each containing Montelukast Sodium equivalent to 10mg of

Montelukast Sodium, were prepared using superdisintegrants, sodium starch glycolate,

crospovidone, gellan gum, guar gum and sterculia gum according to the formulae given in

Table 4. The average weight of the tablet was taken to be 180mg. The ingredients were

seived through a 60# mesh and then the required quantities weighed. All the ingredients

except magnesium stearate. After mixing the drug and the excipients for 20 min, magnesium

stearate were added and further mixed for additional 2 min. The tablet mixture was then

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compressed (8 mm diameter, concave punches) using a single punch tablet compression

machine (Cadmach). 3

Table No. 4: Formulation Development of Fast Dissolving Tablet of Montelukast

Sodium by Direct Compression

Name of Quantity (mg/ tablet)

Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9

Montelukast 10 10 10 10 10 10 10 10 10

Sodium

Crospovidone 20 30 40 - - - 20 30 20

SSG - - - 20 30 40 - - -

Guar gum - - - - - - 20 10 -

Gellan gum - - - - - - - - 20

Sterculia gum - - - - - - - - -

Stevia leaf 9 9 9 9 9 9 9 9 9

powder

Mannitol 15 15 15 15 15 15 15 15 15

Magnesium 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6

stearate

MCC pH 101 122.4 112.4 102.41 122.4 112.4 102.4 102.4 102.4 102.4

Total 180 180 180 180 180 180 180 180 180

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Table No. 5 : Formulation Development of Fast Dissolving Tablet of Montelukast

Sodium by Direct Compression

Name of Quantity (mg/ tablet)

Ingredients F10 F11 F12 F13 F14 F15 F16 F17 F18

Montelukast 10 10 10 10 10 10 10 10 10

Sodium

Crospovidone 30 20 30 - - - - - -

SSG - - - 20 30 20 30 20 30

Guar gum - - - 20 10 - - - -

Gellan gum 10 - - - - 20 10 - -

Sterculia gum - 20 10 - - - - 20 10

Stevia leaf 9 9 9 9 9 9 9 9 9

powder

Mannitol 15 15 15 15 15 15 15 15 15

Magnesium 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6

stearate

MCC pH 101 102.4 102.4 102.4 102.4 102.4 102.4 102.4 102.4 102.4

Total 180 180 180 180 180 180 180 180 180

Note: weight per tablet is 180mg containing montelukast equivalent to 10mg montelukast.

SSG: Sodium starch glycolate

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Evaluation of Pre-compression studies.

Bulk Density:

a) Bulk Density: Accurately weighed of powder from each formulation previously passed

through 20-mesh sieve, was transferred into a graduated cylinder via a large funnel. The

powder in the cylinder was leveled without compacting, and the unsettled apparent volume

(V0) was noted. The apparent bulk density (g/ml) was calculated by the following

formula;

Bulk density (BD) = Weight of powder / Bulk volume (V0 )

b) Tapped density: Accurately weighed of powder from each formulation, which was

previously passed through 20-mesh sieve, was transferred into a graduated cylinder.

Then the cylinder containing the sample was mechanically tapped by raising the cylinder

and allowing it to drop under its own weight using Bulk density apparatus. The density

apparatus was set for 100 taps and after that, the volume (Vf) was measured and continued

operation till the two consecutive readings were equal. The tapped bulk density in gm/ml

was calculated by the following formula:

Tapped Density (TD) = Weight of powder / Tapped volume (Vf)

c) Carr’s Index

The Compressibility Index of the powder blend was determined by Carr’s

compressibility index. It is a simple test to evaluate the BD and TD of a powder and the

rate at which it is packed down. The formula for Carr’s Index is as below:

Carr’s Index (%) = [(TD-BD) x 100] / TD

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d) Hausner’s Ratio

The Hausner’s ratio is a number that is correlated to the flowability of a powder or granular

material. The formula for Hausner’s Ratio is as below:

Hausner’s Ratio = TD / BD

Table No. 6 : Effect of Carr’s Index and Hausner’s Ratio on flow property.

Carr’s Index (%) Flow Character Hausner’s Ratio

< 10 Excellent 1.00-1.11
11-15 Good 1.12-1.18
16-20 Fair 1.19-1.25
21-25 Passable 1.26-1.34
26-31 Poor 1.35-1.45
32-37 Very poor 1.46-1.59
>38 Very, very poor >1.60

e) Angle of repose

The angle of repose of powder was determined by the fixed funnel method. Powder was

taken in the funnel. The height of the funnel was adjusted in such a way that the tip of

the funnel just touched the apex of the conical pile of the blend. The blend was allowed

to flow through the funnel freely on to the graph paper that is placed on a flat

horizontal surface. The diameter of the base of the powder cone was measured and angle

of repose was calculated using the following equation.

θ = tan-1( h /r)
Where, ‘θ’ = angle of repose

‘h’ = height of the powder cone

‘r’ = radius of the powder cone

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Table No. 7 : Effect of Angle of repose (θ) on Flow property.

Angle of Repose (θ) Type of Flow

< 20 Excellent

20-30 Good

30-34 Passable

>35 Very poor

f) Drug - Excipients Compatibility Studies

A successful formulation of a stable and effective solid dosage form depends on careful

selection of excipients that are added to facilitate administration, promote the consistent

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

Compatibility studies of pure drug Montelukast Sodium with polymers and other

excipients were carried out prior to the preparation of tablets. Compatibility of Montelukast

Sodium with the polymers used in the formulation and the physical mixture of final

formulation were established by FT-IR spectroscopy. Any changes in the chemical

composition after combining with the excipients were investigated by comparing FTIR

spectra of the sample mixture with that of the pure drug. 47,48

Evaluation of post-compression methods.

a) Shape and appearance:

The formulated tablets were visually observed for its shape and colour

b) Weight variation test:

Weight variation of tablet was determined by analytical weighing balance. Twenty tablets

were selected randomly from each batch and weighed individually. The average and standard

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deviation were then calculated. The specifications for weight variation and percentage

deviation mentioned in Indian Pharmacopoeia are given in following table:

Table No. 8: Limits for Weight Variation (IP)

Average weight of tablets Percentage deviation (%)

80 mg or less 10

More than 80 mg but less than 250 mg 7.5

250mg or more 5

b) Uniformity of thickness:

Thicknesses of uncoated tablets were measured using a calibrated Vernier caliper.

Three tablets of each formulation were picked randomly and dimensions were measured

in mm and standard deviation was also calculated.

c) Hardness test:

Hardness of uncoated tablets were determined using a Monsanto hardness tester.

Three tablets were randomly picked from each batch and hardness is expressed in kg/cm2.

The mean and standard deviation were also calculated.

d) Friability test:

Roche friabilator was used for friability test. Ten uncoated tablets from each

formulation were weighed (Winitial) accurately, placed in the friabilator and rotated at 25 rpm

for a period of 4 min. Tablets were again weighed (Wfinal) and the percentage weight loss in

tablet was determined using formula:

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F= %

% friability of the tablets less than 1% is considered acceptable.

e) Drug content uniformity:

10 uncoated tablets from each formulation were crushed and powder equivalent to 10

mg Montelukast Sodium was dissolved in 100 ml volumetric flask with water 100µg/ml of

the drug concentration was made. Then solution was filtered and further dilutes 1ml solution

in 10 ml volumetric flask and diluted with water. The solution was analyzed UV

spectrophotometrically at 240 nm. The amount of Montelukast Sodium was estimated by

using standard calibration curve of the drug. Drug content was studied in triplets for each

batch of formulation.

f) In-vitro Disintegration test:

Disintegration test for uncoated tablets was carried by placing one tablet in each

tube of the basket and top portion of the each tube was closed with disc. The

disintegrating apparatus was run using 0.5% SLS maintained at 37±20C. The assembly

was raised and lowered between 30 cycles per minute. The time taken for complete

disintegration of the tablet with no palpable mass remaining in the apparatus was measured

and recorded. The experiments was carried out in triplicate from each formulation.

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g) In-vitro drug release studies of tablets:

Drug release studies of 6 uncoated tablets from each formulation were carried

out using a USP XXIII dissolution rate test apparatus (Apparatus 2, 50 rpm, 37 °C) for 5

minutes in 0.5% SLS (900 ml). The samples were withdrawn at time intervals 1, 2, 3, 4, 5,

6 and 5 minutes and directly analyzed for Montelukast Sodium content using UV

spectrophotometer at 240 nm. Suitable volume of the dissolution media was added after

each sample withdrawal to compensate loss. 47,49

h) Drug kinetic release.

The cumulative amount of Montelukast release at different time intervals from the different

formulation of tablets were fitted to zero order kinetics, first order kinetics, Hixson-Crowell

Kinetics, Higuchi’s model and korsmeyer-Peppas model to characterize mechanism of drug

release.

Zero order release: Zero order release kinetics refers to the process of constant drug

release from a drug delivery device. It describes the system in which the release rate is

independent of its concentration. In its simplest form, zero order release can be represented

as: Q = Q0 + K 0 t

Where, ‘Q’ is the amount of drug dissolved in time ‘t’,

‘Q0’ is the initial amount of drug in solution, and

‘K0’ is the zero order release constant.

If the zero order drug release kinetic is obeyed, the plot of cumulative % drug release [Q] vs.

time[t] will be straight line with a slope of K0 and an intercept at Q0.

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First order release: This model has also been used to study absorption and/or

elimination of drugs. It describes the drug release from the system in which the release rate is

concentration dependant. The release of the drug which followed first order kinetics can be

expressed by the equation:

= - K 1C

The above equation can also be expressed as:

Log C = log C0 -

Where, ‘C’ is the amount of drug dissolved in time‘t’,

‘C0’ is the initial amount of drug in the solution,

‘K1’ is the first order release constant

If the release pattern of drug follows first order kinetics, then a plot of log of cumulative

drug remaining [ log (C0 - C)] vs. time[t] will be straight line with a slope of K1/2.303 and an

intercept at t= 0 of logC0.

Hixson-Crowell Kinetics: Hixson and Crowell (1931) recognized that the

particles’ regular area is proportional to the cube root of its volume. They derived the

equation: W0 1/3 - Wt 1/3 = KHC . t

Where; ‘W0’ is the initial amount of drug,

‘Wt’ is the amount of drug released at time ‘t’, and

‘KHC’ is Hixson-Crowell rate constant.

If the Hixson-Crowell drug release kinetic is obeyed, the plot of cube root of drug amount to
1/3 1/3
be released [W0 - Wt ] vs. time[t] will be straight line with a slope of KHC and an

intercept at W0 1/3.

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Higuchi Model: Higuchi tried to relate the drug release rate to the physical constants

based on simple laws of diffusion. Higuchi derived an equation to describe the release of a

drug from an insoluble matrix as the square root of a time-dependent process based on

Fickian diffusion. The Fickion diffusion equation is:

Mt/M∞= [2DSε (A - 0.5Sε)] 1/2 * t1/2

Where, Mt and M∞ = cumulative amount of drug release at time ‘t’ and infinite

time respectively.

‘D’ is Diffusion coefficient,

‘S’ is Solubility,

‘ε’ is Porosity, and

‘A’ is Drug content per cubic centimeter of matrix tablet.

Simplifying the equation;

Mt/M∞= KH * t ½

Where, ‘KH’ is Higuchi release constant.

If the Higuchi model of drug release is obeyed, then a plot of Mt/M∞ versus t1/2 will be

straight line with slope of KH.

Krosmeyer-Peppas Model: Korsmeyer et al. (1983) derived a simple relationship

which describes the fractional drug release is exponentially related to the release time. It

adequately describes the release of drug from a polymeric system of slabs, cylinders and

spheres, as expressed in following equation.

M t/ M ∞ = K t n

or, Log (Mt / M∞) = log K + n log t

Where, ‘Mt / M∞’ is fraction of drug released at time ‘t’,

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‘k’ is the rate constant, and

‘n’ is the diffusion exponent.

If the Krosmeyer-Peppas model of drug release is obeyed, then a plot of log cumulative %

drug release [Log (Mt / M∞)] vs. log time [log t] will be straight line. By incorporating the

first 60% of release data, mechanism of release can be indicated according to Korsmeyer

where ‘n’ is the release exponent, indicative of mechanism of drug release.50,51

Table No. 9: Different Drug Release Mechanisms as per Korsmeyer-Peppas Model.

Diffusion exponent (n) Overall solute diffusion mechanism

0.45 Fickian diffusion

0.45 < n < 0.89 Anomalous (non-Fickian) diffusion

0.89 Case-II transport

n > 0.89 Super case-II transport

i) Stability Studies

Stability studies were 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.

Tablet formulation was subjected for stability studies over a period of 3 months as per

. The tablets were wrapped with aluminium foil and packed in amber colored screw capped

and kept in a stability chamber maintained at 40±2˚C. Samples were taken after 3 month

analyzed for the tablet parameters: colour, thickness, hardness, drug content and in-vitro

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dissolution profile. In-vitro drug release at 0 month and after 3 months of stability study was

compared.

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