INTRODUCTION:

The tablet is the most widely used dosage form existing today because of its convenience in terms of self-administration, compactness and ease in manufacturing. However, geriatric, pediatric and mentally ill patients experiences dfficulty in swallowing conventional tablets, which leads to poor patient compliance. To overcome these problems, scientists have developed innovative drug delivery system known as mouth dissolving/disintegrating tablets⁽¹⁾. United States Food and Drug Administration (FDA) defined ODT as “a solid dosage form containing medicinal substance or active ingredient which disintegrates rapidly usually within a matter of seconds when placed upon the tongue⁽²⁾.

Naratriptan is a triptan drug used for the treatment of migraine headaches. It is a selective 5-hydroxytryptamine1 receptor subtype agonist (5-HT1B/1D). Chemically it is N-methyl-2-[3-(1methylpiperidin-4-yl)-1H-indol-5-yl] ethane-1-sulfonamide monohydrochloride. It is well absorbed (70% oral bioavailability); absorption is rapid with peak plasma concentrations after 2-5 hours. As migraine sufferers have markedly reduced functional ability, they would be benefited from acute treatment that helps them to resume their functional activities as quickly as possible⁽³⁾.

In the present study mouth dissolving tablet of naratriptan was developed so as to achieve rapid disintegration in mouth systemic absorption and maximum peak concentration in less time. As tablet disintegrates in mouth this could enhance the clinical effect of the drug through pre-gastric absorption from the mouth, pharynx and oesophagus this leads to an increase in bioavailability by avoiding first pass liver metabolism. Three distinct pharmacological actions have been implicated in the antimigraine effect of the triptans: (1) stimulation of presynaptic 5-HT1D receptors, which serves to inhibit both dural vasodilation and inflammation; (2) direct inhibition of trigeminal nuclei cell excitability via 5- HT1B/1D receptor agonism in the brain stem and (3) vasoconstriction of meningeal, dural, cerebral or pial vessels as a result of vascular 5-HT1B receptor agonism. Bioavailability - Well absorbed, with oral bioavailability of about 70% Peak plasma concentrations attained within 2–3 hours after oral administration. Absorption may be slower during a migraine attack, with peak plasma concentrations attained in 3–4 hours. Food does not affect pharmacokinetics of naratriptan HCl, so used in vascular headaches, acute treatment of migraine attacks with or without aura, not recommended for management of hemiplegic or basilar migraine or for the prophylaxis of migraine⁽⁴⁾.

MATERIALS AND METHOD:

Naratriptan HCl was obtained as gift sample from Glaxosmithkline Mumbai, Croscarmellose sodium, Microcrystalline cellulose PH101 was obtained from Haffkine Ajintha Pharmaceutical Ltd, Jalgaon. All other ingredients and reagent used of either pharmaceutical or analytical grade.

Method of preparation:

Weigh all the ingredients properly. Naratriptan HCl was passed through the sieve # 60, MCC PH 101, Pearlitol SD-200 were passed through sieve #22, croscarmellose sodium, crospovidone, aspartame, flavour, magnesium stearate, talc & aerosil was passed through sieve # 60. After sifting geometrical mixing of MCC PH101, Pearlitol SD-200 with naratriptan HCl. Then mixed all remaining ingredients. The blend was compressed on 250 mg weight of tablets using 9 mm S/C punch on CIP Lab Press tablet punching machine.

Table 1: Composition of orally disintegrating tablet of naratriptan hydrochloride

Ingredient	F1	F2	F3	F4	F5	F6	F7
Naratriptan HCl	2.5	2.5	2.5	2.5	2.5	2.5	2.5
MCC PH 101	120	126	118.5	130	125	115.25	112
Pearlitol SD- 200	105	95.25	104	97.5	100	111	110.50
Croscarmellose sodium	_	_	_	2.5	5	3.75	2.5
Crospovidone	5	8.75	7.5	_	_	_	5
Aspartame	7.5	7.5	7.5	7.5	7.5	7.5	7.5
Vanilla	5.0	5.0	5.0	5.0	5.0	5.0	5.0
Mg. stearate	1.25	1.25	1.25	1.25	1.25	1.25	1.25
Talc	2.5	2.5	2.5	2.5	2.5	2.5	2.5
Aerosil	1.25	1.25	1.25	1.25	1.25	1.25	1.25
Average wt.(mg)	250	250	250	250	250	250	250

*All ingredients were in mg

Evaluation of Precompression Parameters of Granules

1) Density:

I) Bulk Density (BD):

Apparent bulk density was determined by pouring blend into a graduated cylinder. The bulk volume and weight of powder was determined. The bulk density was calculated using the formula⁽⁵⁾

BD = Weight of powder / Bulk of powder

II) Tapped Density (TD):

The measuring cylinder containing known mass of blend was tapped for a fixed time. The minimum volume occupied in the cylinder and weight of powder blend as measured. The tapped density was calculated using the formula⁽⁵⁾

TD= Weight of powder/ Tapped volume of powder

2) Flow properties:

I) Compressibility index and hausner ratio:

The compressibility index was calculated using the formula ⁽⁶⁾.

Carr’s index = TD - BD/TD Х 100

Where,

TD = Tapped density

BD = Bulk Density

II) Hausner Ratio:

Hausner ratio of each batch of tablet blend was also calculated by following formula ⁽⁷⁾

Hausner ratio = Tapped density/ Bulk density

III) Angle of repose ⁽⁸⁾

tan θ = h/r

Where,

θ = Angle of repose,

h = Height of pile,

r = Radius of the circle

Evaluation of ODT: -

1) Weight Variation Test

Weigh individually 20 units selected at random or, for single dose preparation in individual containers, the contents of 20 units, and calculate the average weight. Not more than two of the individual weights deviate from the average weight by more than the percentage shown in the table and none deviates by more than twice the percentage ^{(9, 10)}.

2) Thickness:

Tablet thickness is important characteristic in reproducing appearance and also in counting by using filling equipment. Some filling equipment utilizes the uniform thickness of the tablets as a counting mechanism. 10 tablets were taken and their thickness was recorded using micrometer. The test passed if none of the individual diameter & thickness value deviated by ± 5% of the average ⁽¹¹⁾.

3) Hardness:

The hardness of core tablets was measured using Monsanto hardness tester. A total of five tablets from each formulation were taken for the study and the average of the three is reported ^(12).

4) Friability:

For a tablet with an average weight of 0.65 g or less sample of whole tablets corresponding to about 6.5 g and tablet for an average weight of more than 0.65 g take a sample of 10 whole tablets. Dedust the tablets carefully and weigh accurately the required number of tablets. Place the tablets in the drum and rotate it 100 times. Remove the tablets, remove any loose dust from them and weigh them accurately. The test is run only once unless the result are difficult to interpret or if the weight loss is greater than the targeted value, in which case, the test is repeated twice and mean of the three test is determined. A maximum loss of weight (from a single test or from the mean of the three tests) is not greater than 1.0% is acceptable for most tablets⁽¹³⁾.

%F = Initial weight – Final weight/ Initial weight Х100

5) Drug Content:

Three FDTs were selected randomly and their average weight was determined. Tablets were triturated using mortar and pestle and tablet powder equivalent to 2.5 mg of naratriptan was taken and first dissolved in 15 ml distilled water and volume was made up to 50 ml using distilled water. Then 1ml of this solution was diluted up to 10 ml using distilled water. This solution was measured using UV-visible spectrophotometer at 223 nm against respective reagent blank⁽¹³⁾.

Drug content = Abs. of test sample/ Abs. of standard Х 100

6) Wetting Time and Water Absorption Ratio

The wetting time of the tablet can be measured using a simple procedure. Five 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 was added to the petri dish. A tablet was carefully placed on the surface of tissue paper in the petri dish at room temperature. The time required for water to reach the upper surface of the tablets and completely wet them was noted as the wetting time.

The weight of the tablet before keeping in the petri dish was noted (Wb). The wetted tablet from the petri dish was taken and reweighed (W a). The water absorption ratio, R was determined according to following equation⁽²⁾

R = Wa –Wb/ Wb

Where,

Wb and Wa are the weight before and after water absorption respectively.

Fig: Before water to reach the upper surface of the tablet

Fig: Water to reach the upper surface of the tablet

7) Uniformity of Dispersion (Dispersibility test):

Place 2 tablets in 100ml of water and stir gently until completely dispersed. A smooth dispersion is obtained was passes through a sieve screen with nominal mesh aperture of 710 μm (sieve # 22) ⁽¹³⁾

8) Disintegration Test:

The time for disintegration of ODT is generally less than 1 min and actual disintegration time that patient can experience range from 5 to 30 seconds. The disintegration test for ODT should mimic disintegration in mouth within the saliva ⁽⁹⁾.

9) In-Vitro Dissolution Study:

The release rate of naratriptan hydrochloride from mouth dissolving tablets was determined using USP dissolution test apparatus II (paddle method). The dissolution test was performed using 900 ml of phosphate buffer pH 6.8 at 37°C ± 0.5°C and 50 rpm. Sample solution of 5 ml was withdrawn from the dissolution apparatus at intervals (2, 4, 6, 8, 10, 12 and 15 min). The withdrawn samples were replaced with fresh dissolution medium of same quantity. The withdrawn samples were filtered through whatman filter paper and analyzed spectrophotometrically at 223 nm ^{(2, 13)}.

%DR = Sample abs/ Std.abs Х Std. dilution Х Test dilution Х purity/ Label claim

RESULT

Fig: Standard calibration curve of naratriptan HCl in phosphate buffer pH 6.8

Drug Polymer Compatibility Study: -

1) Fourier Transform Infra Red Study:

The FTIR spectrum of pure drug (naratriptan hydrochloride), croscarmellose sodium, pure drug + croscarmellose (1:1), pure drug + crospovidone (1:1)

Fig: FTIR spectra of naratriptan HCl

Fig: FTIR spectra of croscarmellose sodium

Fig: FTIR spectrum of naratriptan HCl: croscarmellose sodium

Fig: FTIR spectrum of naratriptan HCl: crospovidone

2) DSC Thermogram:

Fig: DSC thermogram of naratriptan HCl

Fig: DSC thermogram of naratriptan HCl: croscarmellose sodium (1:1)

Table 2: Evaluation of pre-compression parameters of orodispersible tablet of naratriptan hydrochloride

Parameters

Bulk Density (g/ml) ±SD

0.63±

0.025

0.68±

0.024

0.68±

0.018

0.67±

0.028

0.71±

0.026

0.64±

0.015

0.64±

0.018

Tapped Density (g/ml) ± SD

0.80±

0.021

0.82±

0.018

0.84±

0.014

0.80±

0.012

0.86±

0.08

0.78±

0.012

0.82±

0.014

Hausner Ratio

± SD

1.26±

0.008

1.20±

0.010

1.23±

0.008

1.34±

0.015

1.16±

0.008

1.28±

0.012

1.35±

0.012

Carr’s Index (%) ± SD

21.25±

0.54

17.07±

0.52

19.04±

0.48

15.29±

0.38

14.23±

0.24

21.87±

0.42

15.00±

0.47

Angle of Repose(degree) ± SD

28.75±

0.52

31.8±

0.48

34.4±

0.41

36.2±

0.47

29.50±

0.42

30.6±

0.47

28.8±

0.52

Table 3: Evaluation of post-compression parameter of orodispersible tablets of naratriptan HCl

Evaluation parameter	F1	F2	F3	F4	F5	F6	F7
Weight variation (mg)	247 ± 1.34	248 ± 1.37	250 ± 1.34	249± 1.36	250± 1.32	249 ± 1.35	251 ± 1.33
Thickness (mm)	4.72 ± 0.01	4.69 ± 0.02	4.70 ± 0.02	4.70 ± 0.02	4.68 ± 0.01	4.66 ± 0.01	4.65 ± 0.02
Hardness (kg/cm²)	2.20 ± 0.20	1.80 ±0.25	1.70 ± 0.15	2.00 ± 0.24	1.50 ± 0.26	1.80± 0.28	2.10 ±0.30
Friability (%)	0.83 ± 0.02	0.82 ± 0.02	0.82 ± 0.03	0.87 ± 0.02	0.78 ± 0.01	0.84 ± 0.01	0.90 ±0.03
Content uniformity (%)	97.2 ± 1.47	98.4 ±1.32	98.6 ±1.22	98.3 ± 1.27	98.7 ± 1.24	6.6 ± 1.34	96.8 ± 1.52
Wetting time (sec)	29	30	32	26	24	29	24
Water absorption ratio (%)	72.2	68.4	69.5	72.2	70.4	67.8	69
Disintegration time (sec)	36	32	34	30	26	29	24

*Where, all values was mean ± SD, n = 3

Table 4: Result of in-vitro drug release study of orodispersible tablet of naratriptan HCl

Time (min)	% Drug Release
Time (min)	F1	F2	F3	F4	F5	F6	F7	Marketed formulation
0	0	0	0	0	0	0	0	0
2	60.70	62.57	61.70	65.50	68.80	67.20	68.50	66.80
4	68.80	75.50	73.40	77.60	80.20	78.50	80.40	77.80
6	72.20	80.00	77.20	81.20	86.20	83.10	85.30	84.90
8	75.30	84.00	82.10	85.80	92.20	86.60	91.20	89.70
10	78.80	88.00	86.00	88.90	96.40	89.20	96.60	92.50
12	84.00	90.00	88.30	90.70	99.29	92.30	99.40	94.60
15	88.10	94.00	92.70	92.20	99.99	94.80	100	97.80

Fig: In-vitro drug release study of F5 and marketed orodispersible tablet of naratriptan HCl

CONCLUSION:

Precompression parameters were evaluated angle of repose, compressibility index, and hausner ratio. Among these formulations F5 indicated that good flow property.

Post-compression study was also performed. Various parameters such as weight variation, thickness, hardness, friability, disintegration time and in-vitro drug release were determined. Among these formulation F5 showed best result.

In-vitro disintegration time and wetting time revealed that croscarmellose sodium acts as superdisintegrants when compared to crospovidone.

Post compression study was performed successful batch F5 which gives better result as compare to marketed tablet.

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Received on 07.06.2018 Accepted on 02.08.2018

Asian J. Pharm. Tech. 2018; 8 (3):139-144 .

DOI: 10.5958/2231-5713.2018.00022.3