INTRODUCTION:

Despite of tremendous innovations in drug delivery, the oral route remains the preferred route for administration of therapeutic agents because of accurate dosage, low cost therapy, self-medication, non-invasive method and ease of administration leading to high level of patient compliance¹. The most popular dosage forms are being conventional tablets and hard gelatin capsules. One important drawback of such dosage forms is “Dysphagia” or difficulty in swallowing for many patients; almost 50% of the population is affected by such problem. Hence they do not comply with prescription, which results in high incidence of non-compliance and ineffective therapy². In some cases such as motion sickness, sudden episodes of allergic attacks or coughing and unavailability of water, swallowing conventional tablets may be difficult. Particularly the difficulty is experienced by paediatric and geriatric patients. To overcome such problems of swallowing and patient non-compliance, Fast Disintegrating Tablets have emerged as an alternative dosage form.

Recently, fast disintegrating drug delivery systems have started gaining popularity and acceptance as new drug delivery systems, because they are easy to administer and lead to better patient compliance³. Fast disintegrating tablets (FDT) are those solid dosage forms when placed on tongue, disintegrate or dissolve instantaneously, releasing the drug, within a few seconds without the need of water. When this type of tablet is placed into the mouth, the saliva will serve to rapidly disintegrate the tablet^{4, 5}. The faster the drug into solution, quicker the absorption and onset of clinical effect. Pharmaceutical technologists have put in their best efforts to develop a fast dissolving/disintegrating drug delivery system (FDDTs)⁶. Fast disintegrating tablets (FDT) are also known as “fast dissolving”, “mouth dissolving”, “rapid-dissolve”, “quick disintegrating”, “orally disintegrating”, “rapimelt”, “fast melts”, “orodispersible”, “melt-in–mouth”, “quick dissolving”, “porous tablets”, “EFVDAS” or “Effervescent Drug Absorption System”^{7, 8}.The Center for Drug Evaluation and Research(CDER), US FDA defined Fast-dissolving/disintegrating tablets (FDDTs) are “A solid dosage form containing medicinal substances, which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue”. Recently European Pharmacopoeia also adopted the term “Oro Dispersible Tablet” defined as “uncovered tablet for buccal cavity, where it disperses before ingestion” ^{9, 10}.

MATERIALS AND METHODS:

MATERIALS:

Eletriptan Hydrobromide was received as a gift sample from Micro Lab Pharmaceuticals Mumbai, India. Sodium starch glycolate, Croscarmellose sodium were received as gift samples from Micro Lab Pharmaceuticals Mumbai. D-Mannitol, Microcrystalline cellulose, Talc, magnesium stearate were procured from Micro Lab Pharmaceuticals Mumbai, India. All other chemicals were of analytical grade.

Evaluation of Powder Blend of tablets ^8,
9

The flow properties of powder blend were characterized in terms of angle of repose, Carr’s index and Hausner's ratio. The bulk density and tapped density were determined and from this data Carr's index and Hausner's ratio were calculated.

Angle of repose:

The angle of repose of powder blend was determined by the funnel method. The accurately weighed powder blends were taken in the funnel. The height of the funnel was adjusted in such a way the tip of the funnel just touched the apex of the powder blend. The powder blend was allowed to flow through the funnel freely on to the surface. The diameter ofthe powder cone was measured and angle of repose was calculated using the following equation.

Tan^-1= h/r

Were, h and r are the height and radius of the powder cone.

Bulk density (BD):

Apparent bulk density was determined by pouring presieved drug excipient blend into a graduated cylinder and measuring the volume and weight “as it is”. It is expressed in g/ml and is given by

BD = M / V0

Where, M is the mass of powder and V0 is the Bulk volume of the powder.

Tapped density (TD):

It was determined by placing a graduated cylinder, containing a known mass of drug- excipient blend, on mechanical tapping apparatus. The tapped volume was measured by tapping the powder to constant volume. It is expressed in g/ml and is given by eq.

TD = M / Vt

Where, M is the mass of powder and Vt is the tapped volume of the powder.

Compressibility Index:

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 packed down. The formula for Carr’s index is as below:

Carr’s index (%) = [(TD-BD) ×100] / TD.

Hausner’s Ratio:

Hausner’s Ratio is a number that is correlated to the flow ability of a powder.

Husner’s Ratio = TD / BD.

Preparation of Eletriptan Hydrobromide Tablets

Eletriptan Hydrobromide was mixed thoroughly with Sodium starch glycolate, Crosscarmellose sodium, D-Mannitol , Microcrystalline cellulose and Talc as per the quantities mention in formulaTable-1, by geometric mixing. The blend was then passed through #40 mesh. Magnesium stearate was weighed and then mixed with above blend and final blend was compressed into tablets using 7 ± 0.1 mm round concave punches and corresponding dies on rotary tablet compression machine (10stationas, Shiv Machinary, India).

Evaluation of prepared tablets^8-12

The prepared Eletriptan Hydrobromide Fast Disintegrating tablets were evaluated for thickness, hardness, friability, uniformity of weight and drug content.

Thickness:

The thickness of tablet was determined using Vernier caliper. Six tablets from each batch of formulation were used and mean thickness value and standard deviation were calculated for each formulation.

Hardness:

For each formulation, the hardness of six tablets was measured using the Monsanto hardness tester and mean value and standard deviation was calculated.

Weight variation:

To study the weight variation, 20 tablets of each formulation were weighed using an electronic digital balance. The average weight of each tablet was calculated and the percentage deviation in weight was calculated.

Drug Content:

As per IP twenty tablets were weighed accurately and powdered. Powder equivalent to 150 mg of Eletriptan Hydrobromide was weighed and was shaken with 100 ml of distilled water in 100 ml volumetric flask. It was filtered and from this filtrate 10 ml was pipetted out and diluted up to 100 ml with distilled water. From this solution again 10 ml was pipetted out and diluted up to 100 ml in 100 ml volumetric flask. Absorbance was measured at 219 nm and content of Eletriptan Hydrobromide was calculated using distilled water as blank.

Wetting Time^7,8:-

The wetting time of the tablets was measured using as per following procedure. 5 circular tissue papers of 10 cm diameter were placed in a Petri dish with a 10-cm diameter. 10 ml of water containing a water-soluble dye (potassium permanganate) was added to the petri dish. A tablet was carefully placed on the surface of tissue paper. The time required for water to reach the upper surface of the tablet was noted as the wetting time

Water absorption Ratio^10,11:

A piece of tissue paper folded twice was placed in a small Petri dish containing 6 ml of water. A tablet was put on the paper and the time required for complete wetting was measured. The wetted tablet was then weighed. Water absorption ratio, R, was determined using following equation:

R=100(wa/wb)

Where, ‘Wb’ is weight of tablet before water absorption and ‘Wa’ is weight of tablet after water absorption.

In vitro Disintegration Time^10-12:

Disintegration time for FDTs was determined using USP disintegration apparatus with phosphate buffer of pH 6.8. The volume of medium was 900 ml and temp was 37± 0.2 °C. The time in seconds taken for complete disintegration of the tablet with no palatable mass remaining on the mesh was measured. To comply the test all tablets should disintegrate within 3 minutes.

In–vitro drug release^1,12:

To study the drug release from the tablet, the USP Type II (paddle) apparatus was employed. In this method, 900 ml of phosphate buffer pH 6.8 was used as the dissolution media and the paddle was rotated at constant speed of 50 RPM. The temperature of the media was maintained at 37 ± 0.5⁰C. Sample of 5 ml was removed at a time interval of one minute for 7 minutes. The samples were filtered and the concentration in each sample was determined by UV spectrophotometer at 260 nm and reported as average of three determinations.

Accelerated Stability study^{7, 8}:

In any rational design and evaluation of dosage forms for drugs, the stability of the active component is the major criteria in determining their acceptance or rejection. Stability studies were carried out as per ICH Q₁A(R) guidelines. The optimized formulation F9was wrapped in aluminum foil and subjected to 40 ±2°C temperature in stability chamber for the period of six months. The formulation was analyzed for organoleptic characteristics, hardness, drug content and dissolution.

RESULTS AND DISCUSSION:

The powder blend for all formulation containing various concentration of Croscarmellose sodium and sodium starch glycolate as mentioned in Table-1as superdisintegrant was prepared and then the FTIR studies were done, which suggests incompatibility (Fig.2 3), the study suggests that the drug and excipients are compatible to each other. The diluents such as, microcrystalline cellulose mannitol were selected because of its advantages in terms of easy availability and negative heat of dissolution. The wetting time (Fig 4) of the tablets were also considerably reduced in tablets. The drug content of all the formulations was found to be between 95.0-101 % The porous structure is responsible for faster water uptake; hence it facilitates wicking action of superdisintegrants in bringing about faster disintegration. Tablets with lower friability (0.5%) may not break during handling on machines. Batches F1 to F9 showed good mechanical integrity, but the disintegration time was found to be less than 40 seconds. In vitro release studies were carried out using USP XXIII tablet dissolution test apparatus paddle method at 37±0.5 °C, taking 900 ml of pH-6.8 dissolution medium. Speed of rotation of the paddle was set at 50 rpm. Aliquots of 5 ml were withdrawn after 0, 1, 2, 3,4,5 min and analyzed spectrophotometrically at 219 nm. The in vitro dissolution profile (Fig.1) indicated faster and maximum drug release from formulation F9. Formulation F9 prepared by direct Compression from final tablets showed release 99% drug at the end of 5min.

Table 1: Composition of Fast Disintegrating Tablet Batches as per 3² Full Factorial Design

Ingredients	F1	F2	F3	F4	F5	F6	F7	F8	F9
EletriptanHydrobromide	20	20	20	20	20	20	20	20	20
Croscarmellose Sodium	1.5	1.5	1.5	3	3	3	5	5	5
Sodium starch Glycolate	2.4	4.2	7.6	2.4	4.2	7.6	2.4	4.2	7.6
D-Mannitol	50	50	50	50	50	50	50	50	50
Magnesium stearate	2.4	2.4	2.4	2.4	2.4	2.4	2.4	2.4	2.4
Talc	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5
Microcrystalline Cellulose	72.2	70.4	67	70.7	68.9	65.5	68.7	66.9	63.5
Total	150	150	150	150	150	150	150	150	150

(All the quantities given in Table 1 are in mg.)

Figure 1: FTIR spectra of Eletriptan HBr

Figure 2 : FTIR spectra of drug and drug + Croscarmellose sodium

Table 2: Evaluation of Powder Blend for Flow Properties

Batch	Angle of repose (θ)	Bulk density (gm/ml)	Tapped density (gm/ml)	Compressibility index (%)	Hausner’s Ratio
F1	16.22±1.070	0.424±0.0047	0.511±0.010	19±1.07	1.10
F2	30.5±0.56	0.424±0.0011	0.525±0.017	18.4±0.660	1.23
F3	28.44±15.24	0.536±0.0095	0.611±0.005	12.50±0.427	1.13
F4	29.13±1.105	0.411±0.0105	0.512±0.012	19.5±0.5	1.22
F5	27.1±0.95	0.525±0.0141	0.574±0.0037	10.45±0.905	1.10
F6	23.1±0.6075	0.523±0.0075	0.62±0.0264	12.57±0.590	1.13
F7	29.81±0.707	0.514±0.0058	0.632±0.0026	12.41±0.512	1.13
F8	22.57±0.57	0.430±0.0176	0.522±0.0037	19.23±0.76	1.23
F9	24.28±0.625	0.526±0.004	0.614±0.0058	15.42±0.961	1.17

Figure 3 FTIR spectra of drug and drug+ SS g

Table 3 :Characterization of prepared Fast Disintegrating Tablet

Batch	Thickness (mm)	Hardness (kg/cm²)	% Friability (%)	Average weight (mg)	Water absorption ratio
F1	3.38±0.072	3.1±0.124	0.641±0.015	145.12±0.722	88.14±1.64
F2	3.40±0.094	3.1±0.08	0.77±0.015	146±1.6	87.1±1.63
F3	2.42+0.026	3.4±0.169	0.83±0.030	146.9±1.9	87.39±1.39
F4	2.88±0.077	3.2±0.081	0.33±0.032	145.12±0.722	82.66±1.24
F5	2.6±0.01	2.8±0.124	0.73±0.026	146±0.5	94±1.63
F6	3.51±0.12	3.2±0.081	0.64±0.02	147.1±1.07	86±0.81
F7	3.35±0.01	3.2±0.20	0.46±0.025	142±1.5	92.66±1.24
F8	3.22±0.026	2.8±0.124	0.85±0.041	146±0.88	96.66±1.24
F9	3.51±0.025	3.1±0.124	0.93±0.01	150.6±1.82s	92.43±1.05

Figure 4: Determination of wetting time

Table 4: % drug release of Fast Disintegrating Tablet

Time in min.

70.9±

0.76

65..05±

0.97

60.3±

0.77

63.7±

1.6

70±

1.02

67.95±

1.30

82.2±

1.21

61.15±

1.32

71.6±

1.52

77.25±

1.23

74.05±

1.20

72.4±

1.6

68.5±

1.41

74.75±

1.0

74.6±

1.0

85±

0.86

70.7±

1.4

82.25±

1.50

79.6±

1.88

84.5±

1.22

84.55±

0.65

83.5±

1.8

84.22±

1.5

90±1

.25

91.6±

1.2

80.7±

1.1.

88±

1.36

82±

1.51

94±

1.11

93.8±

0.79

94.6±

1.60

87.65±

1.2

94±

2.0

93±

0.92

93.5±

0.70

94±

1.42

91.4±

0.75

95±

0.74

98±

0.10

96.9±

1.0

94.9±

1.50

96.25±

1.5

94.6±

1.30

91±

1.0

99±

1.72

Figure 5 : Graph of % drug release of Fast Disintegrating Tablet