INTRODUCTION:

Oral route of drug administration have wide acceptance up to 50-60% of total dosage forms. Solid dosage forms are popular because of ease of administration, accurate dosage, self medication, pain avoidance and most importantly the patient compliance.

The oral route of administration is considered as the most widely accepted route because of its convenience, compaction, ease of manufacturing, safest and economical route.

Migraine is a common chronic headache disorder characterized by recurrent attacks lasting 4–72 hours, of a pulsating quality, moderate or severe intensity aggravated by routine physical activity and associated with nausea, vomiting, photophobia or phonophobia.

The rizatriptan benzoate (RTB) is a potent and selective 5-HT1B/1D receptor agonist. It is used for treating acute migraine with and without aura and minimising migraine symptoms, including pain, nausea, and photophobia or phonophobia. The half life of rizatriptan is 2-3 hrs and absorption is rapid up to 90%, but absolute bioavailability is low, i.e., 47% because of high first pass effect when taken orally.

Superdisintegrants are the agents added to tablet and some encapsulated formulations to promote the breakup of the tablet and capsule “slugs’ into smaller fragments in an aqueous environment thereby increasing the available surface area and promoting a more rapid release of the drug substance. They promote moisture penetration and dispersion of the tablet matrix.

Natural superdisintegrants are safer as compared to synthetic superdisintegrant. They are facilely available in natural regions around the world therefore they are preferred over synthetic superdisintegrants. Various gums and mucilages from different plant species have been widely utilized as superdisintegrants due to their ability to absorb water and swelling attributes. They can swell up to 5 times their original volume and this swelling leads to breakage of tablets into smaller pieces, which in turn improves the dissolution rate. In the present work formulation and development of MDTs was done using Musa paradisiaca variety as a superdisintegrant. Musa paradisiaca L .is a botanical name of banana plant which has different varieties.

MATERIALS AND METHODS:

Materials:

Rizatriptan benzoate was gift sample from Glenmark Pharmaceuticals, Goa. Avicel PH-102 was purchased from Arihant Treding, Mumbai, Pearlitol SD-200 and Magnesium stearate was obtained from S.D Fine Chemicals, Mumbai. All the excipients are of Analytical Grade.

Methods:

UV Absorption Spectroscopy:

𝜆max of the drug was determined by UV spectroscopy. Stock solution of drug was prepared by dissolving rizatriptan benzoate in deaerated water. 100mg of rizatriptan benzoate was accurately weighed and added into 100ml volumetric flask and the volume was made up with the deaerated water to get the concentration of 1000µg/ml. From this 10 ml was withdrawn and diluted to 100ml to get concentration of 100µg/ml. From that aliquots of 0.1ml, 0.2ml, 0.3ml, 0.4ml, 0.5 ml were pippeted out into 10ml volumetric flasks. The volume was made up with deaerated water to get the final concentrations of 1, 2, 3, 4, 5 µg/ml respectively. The absorbance of each concentration was measured at 224.5 nm.

Drug Polymer Compatability Studies:

The drug, polymer and physical mixtures were subjected to Fourier Transform Infrared Studies. The infrared spectra of drug and drug with mixture was shown in fig.2 and fig.3 checked for the drug polymer interaction.

Differential Scanning Calorimetry Study:

DSC analysis of pure drug and drug with miture was carried out. The thermogram are showed in the fig.4 and fig.5

Isolation and Characterization of Dehydrated banana powder:

Method for Isolation:

The collected fresh whole bananas were cleaned from the debris and weighed. The skin peeled bananas were dipped in ethanol in 5 minutes. Then banana was weighed and squashed to paste, this paste was added with citric acid (2-3%) to remove the sticky nature. Then water was separated by centrifugation and processing. The pressed mass was subjected to drying in hot air oven at 50˚C. The dried substances were milled and screened in sieve (#60) to get fine powder. The prepared banana powder can be characterized for various physical, phytochemical and physicochemical tests.

Characterization of Dehydrated Banana Powder:

A. Physical Characterization:

Organoleptic Evaluation: The organoleptic evaluation refers to the evaluation of color, odor, shape, taste and special features which include touch and texture. The majority of information on the identity, purity and quality of the material can be drawn from these observations.

B. Phytochemical Characterization:

Determination of purity of Dehydrated banana powder: To determine the purity of dehydrated banana powder tests for carbohydrates, proteins, oils, glycosides, alkaloids, tannins were carried out.

C. Physicochemical characterization:

1. Swelling Index:

Swelling index of dehydrated banana powder was determined by using reported modified method. One gram of powder was accurately weighed and transferred to 100 ml stopper measuring cylinder. The initial volume of the powder in the measuring cylinder was noted. The volume was made upto 100ml with distilled water. The cylinder was stoppered, shaken gently and set aside for 24 hrs. The volume occupied by the sediment was noted after 24 hrs. Swelling Index (SI) is expressed as a percentage calculated according to the following equation,

Final Volume-Initial Volume

% SI--------------------------------------------

Initial Volume

2. Solubility:

Solubility of powder was checked with different solvents such as water, hot water, acetone, ethanol, methanol, ether, chloroform.

3. Moisture Absorption:

The powder was weighed accurately and placed in a dessicator. After 3 days, the powder was taken out and weighed. The percentage of moisture uptake was calculated as the difference between final weight and initial weight with respect to initial weight.

4. Loss on Drying:

Moisture content of dehydrated banana powder was determined by loss on drying method. Accurately weighed 1g sample was heated at 105˚C to get a constant weight in a hot air oven and percent loss of moisture on drying was calculated using formula given below

Weight of Moisture in Sample

% lod--------------------------------------------------χ 100

Weight of Sample After Drying

5. pH of Dehydrated Banana Powder

The pH of 1%w/v dispersion of the banana powder was determined using a digital pH meter.

Preparation of Mouth Dissolving Tablets by Direct Compression Method:

14.5 mg of rizatriptan benzoate is equivalent to 10mg of rizatriptan

The MDTꞌs of rizatriptan benzoate were prepared by direct compression method. Accurate amount of all the ingredients except magnesium stearate were passed over mesh #40 and mixed homogenously using geometric dilution. At last, magnesium stearate was added to lubricate and mixed well. The blended material was directly compressed by a tablet punching machine with concave faced 9mm of punch and die set. The compression force and mass of all tablets were kept stable with each tablet containing RTB equivalent to 10 mg of rizatriptan. On the basis of results of preliminary batches, final formulation batches were prepared by using 2-factor Central Composite Design using two independent variables X1 and X2 where X1 is the concentration of dehydrated banana powder (X₁), concentration of pore forming agent (X₂). The dependent variables or responses were the % Drug release (Y₁), Disintegration time (Y₂), % Friability (Y₃). All analyses were performed using the Design Expert^® Software. Nine formulation batches of mouth dissolving tablets were prepared and evaluated for precompression and post-compression parameters. The design layout and composition of 2-factor central composite design of rizatriptan benzoate mouth dissolving tablet formulation are given in table-1 and table-2resp.

Precompression parameters:

All formulation batches were evaluated for precompression parameters such as angle of repose, bulk density, tapped density, Carr’s index, and Hausner’s ratio as per the official methods.

Postcompression Parameters:

1. Weight Variation:

The weight variation test is carried out in order to ensure uniformity in the weight of tablets in a batch. The total weight of 20 tablets from each formulation was determined and the average weight was calculated. The individual weight of the tablets was also determined accurately and the weight variation was calculated as specified in IP.

2. Thickness:

Tablet thickness and diameter can be measured using a vernier caliper. The thickness and diameter can be determine by placing the tablet between the two arms of vernier caliper. The test passed if none of the individual diameter and thickness value deviated by ±5 % of average.

3. Hardness:

The hardness of tablet is an indication of its strength. It is the force required to break a tablet by compression in the radial direction. Monsanto hardness tester was used to check the hardness of the tablet. The tablet was placed vertically between the jaws of the tester. The two jaws placed under tension by spring and screw gauge. By turning the screw, the load was increased and at collapse the applied pressure from the spring was measured in kg/cm².

4. Friability:

Friability test was done by placing preweighed sample of tablets with approximately weight of 6.5 g in the Roche type friabilator, which was subjected to 100 revolutions. After rotations, the tablets were dedusted and the percent friability was then calculated by reweighing the tablets.

Initial weight-Final weight

% F---------------------------------------×100

Initial weight

5. Drug Content:

Three tablets were selected randomly and their average weight was determined. Tablets were triturated using mortar and pestle and powder equivalent to 10 mg of rizatriptan was taken and first dissolved in 15 ml deaerated water and volume was made upto 50 ml using deaerated water. Then 1ml of this solution was diluted up to 10 ml using deaerated water. This solution was measured using UV-visible spectrophotometer at 224.5 nm against respective reagent blank.

6. Disintegration Time:

The test was carried out on 6 tablets using the disintegration test apparatus. Distilled water at 37˚C ± 2˚C was used as a disintegration media and the time in second taken for complete disintegration of the tablet with no palatable mass remaining in the apparatus was measured in seconds.

7. Wetting Time:

A double folded tissue paper was placed in a Petri dish.10 ml of water containing a water-soluble dye (methylene blue) was added to the petridish. A tablet (pre- weighed) 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.

8. In-Vitro Dissolution Study:

Dissolution test of rizatriptan benzoate was performed using 900 ml of deaerated water using dissolution type II apparatus at 50 rpm and 37±0.5˚C temperature. Test sample (5ml) was withdrawn at particular time interval and replaced with fresh dissolution medium maintained at 37 ±0.5˚C. The test sample was filtered and sonicated for few minutes, analysed under UV spectrophotometer at 224.5nm.

9. Stability Studies:

Stability testing is an integral part of formulation development. Stability testing ensures that a drug substance will be safe and effective throughout the shelf-life of the product. The stability study of the formulated batches of rizatriptan benzoate tablets were conducted as per ICH guidelines. The tablets were stored at the temperature 40˚C ± 2˚C for 30 days at RH 75 ± 5%. At 15 days intervals, the tablets were evaluated for their physical appearance, hardness, thickness, friability, drug content, disintegration time and drug release studies at specified time interval.

Table: 1 Factor Combinations as Per the Experimental Design

Batch no.	Dehydrated Banana Powder(X₁)	Pearlitol SD –200 (X₂)
RB1	0	0
RB2	+1	+1
RB3	+ɑ	0
RB4	+1	-1
RB5	-ɑ	0
RB6	0	-ɑ
RB7	-1	-1
RB8	0	+ɑ
RB9	0	+1

Table 2: Composition of Optimized Mouth Dissolving Tablets of Rizatriptan Benzoate

Sr No.	Ingredients	Batches
Sr No.	Ingredients	RB1	RB2	RB3	RB4	RB5	RB6	RB7	RB8	RB9
1	Rizatriptan Benzoate	14.5	14.5	14.5	14.5	14.5	14.5	14.5	14.5	14.5
2	Avicel PH-102	110.5	93	103.5	118	132.42	128.5	128	92.9	103
3	Pearlitol SD 200	11	112.5	100	87.5	100	82.3	87.5	117.6	112.5
4	Dehydrated Banana Powder	15	20	22.07	20	7.92	15	10	15	10
5	Aspartame	5	5	5	5	5	5	5	5	5
6	Black Current Flavour	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5
7	Magnesium Stearate	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5
	Average Wt (mg)	250	250	250	250	250	250	250	250	250

*All quantities are in mg

RESULT AND DISCUSSION:

1. Calibration Curve of Rizatriptan Benzoate:

Fig. 1: Standard Calibration Curve of Rizatriptan Benzoate in Deaerated Water

2. FTIR Spectroscopy:

IR spectra of drug and drug + Mixture was shown in fig.2 and fig.3. Presence of all the characteristic peaks of drug in IR spectra of drug polymer mixture indicates no interaction between drug and excipients.

Fig. 2: IR Spectra of Rizatriptan Benzoate

Fig. 3: IR Spectra of Drug + mixture

3. Differential Scanning Calorimetry (DSC) Study:

DSC study of pure drug and drug + mixture was carried out. The thermogram is shown in the fig. 4 and fig.5

Fig.4: DSC of Rizatriptan Benzoate

Fig.5: DSC of Drug + mixture

4. Result of Phytochemical Characterization of Dehydrated Banana Powder:

The test indicated presence of carbohydrate, proteins, saponin glycoside, alkaloids and tannins.

5. Result of Physicochemical characterization of Dehydrated Banana Powder:

The swelling ratio of dehydrated banana powder determined in distilled water was observed to be 59.06 ± 0.832 %. From this it can be concluded that high swelling index indicated that the powder has good water uptake capacity.

Table 3: Result of Physicochemical characterization of Dehydrated Banana Powder

Sr No.	Parameters	Result
1	Swelling Index	59.06 ± 0.832%
2	Solubility study	Slightly soluble in water, sodium hydroxide solution Completely soluble in ethanol
3	Moisture absorption	3.346 ± 0.486%
4	Loss on drying	3.03 ± 0.513 %
5	pH	7.1

From the table 4, the bulk density, tapped density, carrꞌs index, hausnerꞌs ratio and angle of repose were found to be within the limits. The carrꞌs index was the lowest for all the formulations which have excellent flow properties

Table 4: Pre-Compression Parameters of Optimized Batches of Rizatriptan Benzoate

Batch No.	Pre-Compression Parameters
Batch No.	Bulk Density (gm/cc)	Tapped Density (gm/cc)	Carr^,s Index (%)	Hausner’s Ratio	Angle of Repose (˚)
RB1	0.427±0.002	0.476±0.002	10.08±0.025	1.11±0.025	25.17±0.015
RB2	0.425±0.002	0.475±0.002	10.52±0.01	1.12±0.015	26.57±0.036
RB3	0.429±0.001	0.478±0.001	10.25±0.03	1.114±0.03	25.15±0.015
RB4	0.408±0.002	0.468±0.004	12.82±0.015	1.136±0.025	28.81±0.02
RB5	0.423±0.001	0.480±0.002	11.84±0.02	1.126±0.015	29.65±0.020
RB6	0.418±0.002	0.464±0.001	10.52±0.59	1.11±0.01	28.36±0.025
RB7	0.415±0.002	0.480±0.002	13.56±0.02	1.14±0.03	25.17±0.02
RB8	0.415±0.002	0.480±0.001	13.54±0.001	1.18±0.015	23.26±0.02
RB9	0.481±0.002	0.556±0.002	13.47±0.01	1.14±0.02	27.47±0.01

* Where, all quantities are mean± SD

Table 5: Post-Compression Parameters of Optimized Batches of Rizatriptan Benzoate

Batch No.	Post-Compression Parameters
Batch No.	Thickness (mm)	Hardness (kg/cm²)	Friability (%)	Weight variation (%)	Drug content (%)
RB1	4.64±0.01	1.54±0.02	0.316±0.0015	248.16±1.04	99.37±0.36
RB2	4.65±0.01	1.07±0.046	0.318±0.002	244.3±1.52	95.51±0.43
RB3	4.64±0.02	1.59±0.050	0.317±0.001	248.16±1.04	96.74±0.51
RB4	4.67±0.015	1.15±0.025	0.315±0.0005	246.16±1.75	98.22±0.58
RB5	4.62±0.01	1.13±0.052	0.318±0.0015	247.5±1.32	96.60±0.47
RB6	4.62±0.005	1.54±0.03	0.318±0.002	248.5±0.5	98.97±0.52
RB7	4.65±0.020	1.17±0.041	0.318±0.002	247.8±1.60	98.37±0.24
RB8	4.58±0.015	1.63±0.208	0.318±0.0005	245.3±1.15	99.27±0.27
RB9	4.58±0.01	1.53±0.020	0.321±0.003	247.6±1.52	98.87±0.34

*Where, all quantities are mean ± SD

In vitro Dissolution Study of Optimized Batches:

Table 7: Percentage Drug Release of Optimized Batches of Rizatriptan Benzoate

Time (min)	% Drug Release of Optimized Batches of Rizatriptan Benzoate
	RB1	RB2	RB3	RB4	RB5	RB6	RB7	RB8	RB9
0	0	0	0	0	0	0	0	0	0
5	75.21	88.26	66.91	75.83	76.93	62.79	77.89	66.56	71.37
10	80.36	89.63	73.77	80.63	77.89	67.94	78.57	74.80	79.60
15	93.07	95.39	87.84	81.32	86.81	84.06	80.63	84.06	82.69
20	94.44	95.82	91.69	82.69	88.87	95.73	87.84	85.86	85.51
25	98.22	97.53	94.44	88.87	89.90	96.76	95.39	92.90	86.81
30	99.94	100.6	96.76	97.53	97.88	98.82	96.42	99.50	95.39

Table 8: Summary of Results of Analysis of Variance

ANOVA for Y1(% Drug Release)
Source	DF	Sum of Square	Mean Square	F value	P value
Model Residual Cor Total	5 7 12	19.61 6.91 26.52	3.92 0.99 -	3.97 - -	0.0499- significant
ANOVA for Y2(Disintegration Time)
Source	DF	Sum of Square	Mean Square	F value	P value
Model Residual Cor Total	5 7 12	151.51 15.26 166.77	30.30 2.18 -	13.90 - -	0.0016- significant
ANOVA for Y3(Friability)
Source	DF	Sum of Square	Mean Square	F value	P value
Model Residual Cor Total	5 7 12	2.244E – 005 7.254E - 006 2.969E -005	4.488E-006 1.036E-006 -	4.33 - -	0.0408- significant

*Df indicates degree of freedom; F indicates Fischer’s ratio

Fig. 8: Response Surface 3D Contour Graph Showing The Influence of Dehydrated Banana Powder (X1) and Pearlitol SD-200 (X2) on % DR

Fig.9: Response Surface 3D Contour Graph Showing The Influence of Dehydrated Banana Powder (X1) and Pearlitol SD-200 (X2) on Disintegration time

Fig.10: Response Surface 3D Contour Graph Showing the Influence of Dehydrated Banana Powder (X1) and Pearlitol SD-200 (X2) on % Friability

Table 9: Results of stability studies of the optimized batch RB1

Sr No.	Parameters	Condition 40˚C ± 2˚C /75 % ± 5%RH
Sr No.	Parameters	Initial	15 days	30 days
1	Average weight (mg)	248.16	248.18	248.18
2	Hardness (Kg/Cm²)	1.54	1.56	1.56
3	Thickness (mm)	4.64	4.66	4.66
4	Friability (%)	0.316	0.315	0.316
5	Drug content (%)	99.37	99.40	99.40
6	Disintegration time (sec)	15	15	14
7	%Drug release (%)	99.94	99.90	99.90

CONCLUSION:

Mouth dissolving tablets of rizatriptan benzoate were formulated and optimized by using 2-factor central composite design. Two factors i.e. Dehydrated banana powder and pearlitol SD-200 at three levels were selected on the basis of results of preliminary batches. Addition of superdisintegrant dehydrated banana powder leads to significant effect on drug release i.e as the concentration of dehydrated banana powder increases drug release also increases. And the higher concentration of banana powder leads to decrease the disintegration time and % friability. Design-Expert Software was used to optimize and response surface plots and contour plots were drawn, and optimum formulations were selected. Polynomial mathematical models, generated for various response variables using multiple regression analysis, were found to be statistically significant (𝑃< 0.05). Formulation RB1 was selected by the Design-Expert Software which exhibited DT (15.16 sec), Friability (0.316 %), and in vitro drug release (99.94%) within 30 minutes.

ACKNOWLEDGMENT:

Authors specially wish to express their sincere thanks to Glenmark Pharmaceuticals, Goa and also thankful to Department of Pharmaceutics, Shree Sureshdada Jain Institute of Pharmaceutical Education and Research Jamner Dist. Jalgaon Maharashtra for providing the laboratory facilities to carry out this research work.

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Received on 25.06.2019 Modified on 21.07.2019

Asian J. Res. Pharm. Sci. 2019; 9(4):245-252.

DOI: 10.5958/2231-5659.2019.00038.9

Batch No.	Post-Compression Parameters
Batch No.	Disintegration Time (Sec)	Wetting Time (Sec)
RB1	15.16±0.76	37.01±0.66
RB2	7.43±0.60	37.25±1.68
RB3	11.23±0.25	39.33±1.25
RB4	10.5±0.5	39.58±0.67
RB5	20.6±0.28	43.66±1.42
RB6	12.33±0.76	42.60±1.28
RB7	20.5±0.5	42.48±1.21
RB8	11.33±0.15	37.93±2.02
RB9	12.5±0.5	39.96±1.38