INTRODUCTION:

The oral route is the most favorable route due to a rich list of advantages related to patients' convenience. However, there are numerous drawbacks for this route, starting from the swallowing problem. Mouth dissolving drug delivery systems are a novel generation of oral drug delivery system. They provides the convenience of a tablet formulation and also, allow the ease of swallowing provided by a liquid¹. Orodispersible tablets (ODT) can be defined as a solid dosage form containing medicinal substances, upon placed into the oral cavity, rapidly disintegrates into smaller granules or melt in the mouth within a few seconds.

The basic approach in the development of orodispersible tablets is the use of super disintegrants, which provide instance disintegration of tablets in the saliva without the need of water or chewing thereafter, the drug rapidly release facilitating the oromucosal and gastric absorption as a result directly reaches to the systemic circulation². The only limitation to this technology rises from the nature of the selected drug, as a matter of solubility, permeability and stability. Solid dispersion is an efficient method of magnifying the solubility of the drugs via the dispersion of one or more active ingredients in an inert hydrophilic carrier or matrix at solid state, which enhance the wettability and solubility of the drug^3,4

Ketotifen Fumarate is histamine H1 receptor antagonist, it stabilizes the mast cells by blocking the release of mediators. Accordingly, it considered as effective management in asthma and allergic condition. The lipophilic nature of the drug is quite challenging as it exhibits a rapid absorption through the GIT, yet extensively undergoes a first pass effect^5,6. This research aims to increase the solubility and dissolution rate of Ketotifen Fumarate by incorporation into solid dispersion, then selecting the optimal formulation to develop orodispersible tablets of the selected drug.

MATERIALS AND METHODS:

MATERIALS:

Ketotifen fumarate, croscarmelose sodium (CCS), microcrystalline cellulose (Avicel PH 102), sodium saccharine, talc, magnesium stearate, sodium bicarbonate, citric acid were supplied from Samara Drug Industries (SDI) Iraq, crospovidone (CP) (poly plasdone XL), sodium starch glycolate (SSG) were supplied from Aladdin Chemistry Co Ltd, China, poloxamer 407, mannitol, purchased from Riedel-De-Haen, Germany. All other chemicals, reagents and solutions used were of analytical grade.

Preparation of Ketotifen Fumarate Solid Dispersion:

Two methods of preparations were employed to prepare three different formulations for each method, every formulation consist of a certain drug- carrier ratio as demonstrated in Table 1. The methods of preparations are:

Solvent evaporation method:

Preparations of three formulations were established using different drug: carrier ratios (1:2, 1:4, 1:6). The physical mixture of the drug and carrier is dissolved in common solvent (methanol), which left over one to two nights until a clear, solvent-free film is left. The resultant film was scratched and grinded via mortar and pestle, followed by sieving to gain homogenized particle size and uniform distribution of the drug within the formulation⁷.

Fusion method:

Ketotifen Fumarate was dispersed into poloxamer 407 as a carrier using three different ratios (1:2, 1:4 and 1:6). This method carried out by melting the polymer alone on a water bath at 60°C, and then the drug is added to the melted polymer with continuous mixing for 15 min. The mixture is left to cool and congealed, so the mixture is scratched and grinded then sieved⁸.

Table 1: Composition of Ketotifen Fumarate Solid Dispersion.

Batch code	Ratio of preparation (drug: polymer)	Method of preparation	Content
Batch code	Ratio of preparation (drug: polymer)	Method of preparation	Drug (mg)	Polymer (mg)
Fsd 1	1:2	Fusion method	100	200
Fsd 2	1:4		100	400
Fsd 3	1:6		100	600
Fsd 4	1:2	Solvent evaporation method	100	200
Fsd 5	1:4		100	400
Fsd 6	1:6		100	600

Determination of Saturated Solubility:

The solubility of ketotifen fumarate pure drug and its solid dispersion formulations was determined at pH 6.8 phosphate buffer by shake-flask method. Excess amount of the powder was shaken in a rotary flask shaker at room temperature at 25±0.1°C for 24 hours. The samples were filtered and evaluated by a UV-spectrophotometer at λmax 300nm⁸.

In-Vitro Dissolution Test:

In vitro dissolution studies were performed for the optimum solid dispersion formulation and the pure drug. The test was conducted by weighing 20mg of pure drug and an equivalent amount of the optimum formulation, each was tested via employing dissolution apparatus type two according to the USP guidelines, by using 900mL of pH 6.8 phosphate buffer solution as the dissolution medium, with a rotation speed of 50rpm in a controlled temperature at 37±0.5°C. Five milliliters sample was withdrawn and replaced with equal volume of fresh media at the following timing: 1, 2, 3, 4, 5, 10, 15, 20, 25 and 30 min. Each sample was filtered and examined with UV-spectrophotometer at 300nm⁹.

Characterization by Powder X- Ray Diffraction:

The extent of crystallinity was determined for pure ketotifen fumarate, polymer and optimized formulation using Powder X-ray Diffraction (PXRD) system equipped with Cu radiation (at 1.54060 Å wave length) at a voltage of (40 Kv) and a current of (30mA). The instrument was operated in the continuous scan mode and samples were analyzed in the range (5 - 80^◦) with a step size of (0.05^◦) at scanning speed of (5^◦/min) and (2θ) axis.

Scanning Electron Microscopy (SEM):

The morphological behavior of the drug alone and the solid dispersed system were detected by SEM (S-50 model, FEI company-Netherland), the sample was mounted on round brass stub using double backed adhesive tape and then sputter coated for 30 seconds with gold palladium under an argon atmosphere. The stub containing the coated sample was placed in the scanning electron microscope chamber, the disappearance of the crystals in the solid dispersed mixture assures complete solubility of the drug⁷.

Fourier Transform Infrared Spectroscopy (FT-IR):

The test was performed to check the possible interaction of excipient along with the drug was assessed for the optimum formulation. Samples were grinded, mix with potassium bromide, the disc was prepared by compressing the powder at a pressure in a hydraulic press and analyze using FTIR spectroscopy in the range of 4000-400 cm^-19.

Determination of Flow Properties:

The flow properties of the powder blend were evaluated by the angle of repose via the fixed height cone technique, the pre weighted powder is poured through the funnel kept on a stand at a fixed height from petridish until the apex of the conical pile just reaches the tip of the funnel. The diameter of powder cone was measured and the angle of repose was calculated. Moreover, the compressibility index of the powder blends was determined by Carr’s compressibility index or Carr’s index (CI) Hausner’s ratios were carried for each powder blend. Bulk density (dB) of the powder formulation was calculated according to the method of Martin et al, while tapped density (dT) was determined according to Carr and Sheehan. Three determinations were done for each formula¹⁰.

Formulation of Oral Dispersible Tablet:

All the tablets formulations were prepared by direct compression method except formulation (F10), which was prepared as the same composition of formulation (F1) yet the method of preparation was via wet granulation method. Table 2 shows the components of each formulation using different types or different concentration of super disintegrants or combination of two super disintegrants.

Accurate weighing for each component of each formulation were performed, which homogenized via screening through 0.36mm sieve, the components all together except the lubricant (Magnesium stearate ) were mixed for 5 min. thereafter the lubricant was added with a mixing time did not exceed 2 minutes in order to prevent the sticking of tablet to the die during compression face, the tablets were compressed by using 8 mm punch, using single bunch tablet machine, the resultant tablets were evaluated eventually¹¹.

Table 2: Composition of the Dispersed Ketotifen Fumarate Orodispersible Tablets.

Composition	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10
Drug	7	7	7	7	7	7	7	7	7	7
MCC	20	20	20	20	20	20	20	20	20	20
Mg stearate	3	3	3	3	3	3	3	3	3	3
Talc powder	1	1	1	1	1	1	1	1	1	1
Mannitol	51	58.5	51	58.5	51	58.5	51	33.5	48.5	51
Sodium saccharine	3	3	3	3	3	3	3	3	3	3
CP superdisintegrant	15	7.5	-	-	-	-	-	15	-	15
CCS superdisintegrant	-	-	15	7.5	-	-	-	-	-	-
CCS: CP (1:1)	-	-	-	-	-	-	15	-	-	-
SSG	-	-	-	-	15	7.5	-	-	-	-
Sodium bicarbonate	-	-	-	-	-	-	-	12.5	12.5	-
Citric acid	-	-	-	-	-	-	-	5	5	-
Total weight	100	100	100	100	100	100	100	100	100	100

*Abbreviation: MCC: microcrystalline cellulose, Mg stearate: magnesium stearate, CP: crospovidone, CCS: crosscarmellose sodium, SSG: sodium starch glycollate * All the ingredients are expressed in mg.

Determination of Physicochemical Parameters:

The thickness of tablets prepared was determined via Vernier caliper instrument by placing a tablet between two arms of the vernier calipers., while the hardness of the prepared tablets was determined to study the ability of the tablets to withstand breakage during transportation, using (Guoming electrical hardness tester) in which the harness is expressed as Kg/cm² required crushing the tablets. The hardness test was performed with five tablets from each batch were tested randomly and the average reading ± SD was recorded¹². On the other hand, the friability test was conducted by operating (Roch friabilator). Twenty tablets of known weight were placed in friabilator, which operated to revolve at 25rpm for 4 min, post testing the tablets were brushed to remove the dust then reweighed. Percentage friability was calculated from loss of weight. Those tablets with weight lose percent below 1% are generally considered acceptable. The weight variation was determined by individually weighing twenty random tablets and calculating the average weight, then comparing the individual weight to the average. The percentage deviation was determined for weight variation¹³.

Content Uniformity:

It was performed by crashing and dissolving 20 tablets individually in pH 6.8 phosphate buffer followed by measuring the amount of ketotifen fumarate in each tablet by UV-spectrophotometer at 300nm¹³.

In- Vitro Disintegration Test:

Disintegration time (DT) of the prepared tablets was determined using disintegration apparatus in pH 6.8 phosphate buffer at 37±0.5°C as disintegration medium. The time in seconds taken for complete disintegration of the tablet with no solid residue remains on the screen was recorded, the test was done for three tablets for each formulation¹⁴.

In-Vivo Disintegration Test:

All the in vivo evaluation tests were approved by the Ethics Committee of the college of pharmacy, Mustansiriyah University, Baghdad, Iraq. The test has been performed following the ethical standards laid down in the 1964 Declaration of Helsinki. Healthy six male volunteers (aged 22-25 years of age) were participated in testing the formula. Appropriate subjects were informed of the aim of the test, before participating in the test.

The mouth was first rinsed with purified water, one tablet was placed inside the buccal cavity. Afterward, the time for complete tablet disintegration without chewing was recorded per second.

Dissolution Test:

The test was performed using USP type II apparatus (50 rpm) at 37±0.5°C, by placing 3 tablets individually in 900mL pH 6.8 phosphate buffer for 30 min. Samples were periodically withdrawn and analyzed spectrophotometrically at 300nm and the percent drug release of the three tablets after 30 min was calculated, along with time of 80% drug dissolution (T80%) and percent drug dissolved in 2 min (D2 %) ¹⁴.

Statistical Analysis:

The results of the experiments were given as a mean of triplicate samples± standard deviation (SD) and were analyzed according to one-way analysis of variance (ANOVA single factor) at which significant results if (P˂0.05) and non-significant (p˃0.05).

RESULTS:

Saturated Solubility:

The saturated solubility of all prepared solid dispersion was evaluated as shown in Table 3. The solubility of pure ketotifen fumarate is 10mg/mL in pH 6.8. As shown in Table 3, formulation (Fsd3), which was prepared using the fusion method, showed increased the solubility of the drug as ~2-fold compared with pure drug solubility in the same buffer. The solubility studies revealed that there is a significant increase (p < 0.05) in drug solubility by using the two solubility methods mentioned earlier.

Table 3: Solubility of Ketotifen Fumarate.

Batch code	Method of preparation	Solubility (mg/mL)
Fsd1	Fusion method	12.3 ± 0.25
Fsd 2		15.6 ± 0.40
Fsd 3		20.7 ± 0.33
Fsd 4	Solvent evaporation method	10.5 ± 0.28
Fsd 5		11.3 ± 0.32
Fsd 6		12 ± 0.24

*Results are expressed as mean ± SD, n = 3

Optimized Solid Dispersion Formulation:

Formulation (Fsd 3) with ratio 1:6 was chosen as the best method and formulation since it showed higher drug solubility than other method and other prepared ratios, therefore, further characterization of this formulation was performed.

In Vitro Evaluation of Solid Dispersion:

The results of the in vitro drug release of pure drug versus selected solid dispersion formulation (fsd 3) was shown in Fig. 1. There was a significant increase (p < 0.05) in the percentage drug release from the solid dispersion mixture during the first minute of release compared to the pure drug as the percent drug release was close to 99% after 10 min of release from the solid dispersion. However, the maximum percent of drug release from the raw drug could not exceed 60% at the same interval.

Fig. 1: Release Profile of Pure Drug Powder vs. Solid Dispersion of Drug.

Compatibility and interactions:

The selected formulation (Fsd 3) was free from chemical interaction as was proven by a set of tests including the x- ray diffraction XDR, scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy FTIR. The XDR of the drug- polymer solid dispersion mixture is shown in Fig.2.

Fig. 2: X- Ray Diffraction (XRD) Patterns of Pure Drug, Polymer (Poloxmer 407) and the Optimum Solid Dispersion Formulation (Fsd 3).

The solid-state characterization of the drug, poloxamer 407 and solid dispersion formulation (Fsd3) was examined via XRD to investigate the crystalline nature of the three components. The diffraction spectrum of pure ketotifen fumarate confirmed the crystalline structure of the drug as it was demonstrated by sharp peaks. As shown in Fig. 2, however, slightly changes in the peak positions of ketotifen fumarate were observed in solid dispersion, peak intensity was also decreased in solid dispersion. The relative reduction of diffraction intensity of drug in solid dispersion at these angles suggests that the size of the crystals was reduced. Moreover there is no appearance of new diffraction peaks which rule out any chemical interaction between the components or the existence of any other type of crystals¹⁵

Another test accomplished was the SEM test that showed the conversion of drug while dispersed into the polymer from a crystalline form to the amorphous state (Fig. 3), which proved the complete solubilization or dispersion of the drug in the polymer system that enhances the dissolution of the ketotifen fumarate¹⁶.

On the other hand, FTIR spectra for the raw material (the drug, poloxamer407 and the selected solid dispersion formulation Fsd3) as shown in Figure 4 shows no chemical interactions as the peaks remain in their exact positions, yet the intensity was changed as the drug was dispersed through the solid bed¹⁷.

Fig. 3: SEM Results of the Drug after Incorporation into Solid Dispersion.

Fig. 4: FTIR Spectra of the Drug, Optimum Solid Dispersion Formulation (Fsd 3) and polymer (poloxamir 407).

Physicochemical Properties of the Tablets:

Table 4: Pre Compression and Post Compression Characteristics of Each Formulation.

Post Compression Properties					Pre Compression Properties			Batch code
weight variation *n=20	drug content *n=20	Friability (%)	hardness (kg/cm2) *n=5	thickness (mm) *n=3	Carr’s index	Angle of repose (degree)	Bulk density (gm/mL)	Batch code
99.9 ± 0.83	100.6±0.8	0.15	3.68 ± 0.17	3 ± 0.17	14.1	33.5	0.58	F1
100 ± 0.28	99.5±0.7	0.2	3.7 ±0.01	3.46±0.15	13.5	30.5	0.58	F2
99 ± 0.77	100.2±0.07	0.12	4 ±0.05	3.25±0.05	21.7	35	0.56	F3
100 ± 0.80	99.2±0.4	0.18	4.11 ±0.02	3.51±0.03	21	34	0.53	F4
98.2± 0.45	99.3±0.6	0.12	3.66 ±0.7	3.11±0.057	21.5	36	0.53	F5
98.91 ± 0.80	99.8±0.05	0.21	3.8 ±0.1	3.39±0.11	20	31	0.50	F6
98 ± 0.83	98±0.17	0.43	3.89 ±0.2	3.37±0.07	14.2	26	0.55	F7
99 ± 0.77	99±0.08	0.14	4 ±0.5	3.32 ±0.12	16.8	31	0.53	F8
99 ± 0.61	98±0.05	0.15	4 ±0.07	3.2 ±0.1	17.5	34.5	0.52	F9
98.98 ± 0.56	101.3±0.05	0.66	3.9±0.1	3.29±0.07	18.3	39	0.59	F10

*Results for hardness, thickness, weight variation and dry contents are expressed as mean ± SD

Table 4 shows the results of thickness, hardness, friability, drug content and the weight variations for the formulated tablets. The mean thickness was almost uniform in all the formulations and values ranged from 3mm to 3.51mm. The hardness of all the tablets prepared was maintained within the 3.66Kg/cm2 to 4.11Kg/cm2. The friability was found in all developed formulations in the range 0.12% to 0.66% to be well within the approved range (<1%). Weight variations test shows none of the formulations exceeded the limits of 7.5%. On the other hand, for the dry contents, all the batches gave acceptable results as none of them was outside the range of 92.5 - 107.5%¹⁸.

Disintegration Time (DT):

Table 5 shows the disintegration time in seconds for tablets produced from each formulation. Both in vitro and in vivo studies were conducted to test the DT for each formulation.

Tablet being directly compressed, as CP was in the exact concentration was used in both F1 and F10, yet F10 was produced via wet granulation method, which requires prolonged time for disintegration, as the binder effect¹⁹.

Release Profile:

Concerning drug release, table 5 illustrates the effect of polymer type and concentration on drug release rate, Formulations (F1-F7) contain different type or concentration of disintegrants, or combination of both, formulation (F1) has the least T 80% value (1.2 min) compared to the others. Moreover, it has the highest D2 min (90.04%) than other formulations. Nevertheless, F1 can be considered as a promising formula to prepare ketotifen fumarate as ODT.

Table 5: In Vivo - In Vitro Disintegration Time and T80%, D2% for each Formulation.

Batch code	DT in vivo	DT in vitro	T 80% min	D2 min (%)
F1	15 ±0.03	17±0.2	1.2	90.04
F2	27±0.1	27±0.05	1.8	87.2
F3	23.5±0.1	25±1	8	63.2
F4	36.5±0.15	38±.05	11.5	60.66
F5	47±0.32	48 ±0.1	12	59.9
F6	56.5±0.33	57±0.2	16	54.3
F7	18±0.02	19±0.1	9	72.6
F8	25.5±0.02	26±0.03	16	44.3
F9	44±0.01	47±0.07	20	15.6
F10	59.2±0.22	60.3 ±0.5	27.6	9.5

*Results are expressed as mean ± SD, n = 3, (T80%): time of 80% drug dissolution. D2%: percent drug dissolved in 2 minutes.

Table 5 also showed a significant decrease in percent drug release (p < 0.05) of F9 (sodium bicarbonate 12.5 % w/w) regarding F1(CP15% w/w) and F8(CP15% w/w and sodium bicarbonate 12.5% w/w), where F9 was prepared by replacing the super disintegrants with only effervescent disintegrants. The effervescent base can be considered as a disintegrant in the ODT formulation but it is less efficient than using a combination of super disintigrant and effervescent base and both are less efficient regarding using super disintigrant alone, this agreed with reported data.

The effect of method of compression was also investigated as shown in table 5 which shows a significant increase in the percent drug release (p < 0.05) for tablet prepared via direct compression (F1) rather than wet granulation method (F10) as the percent release was 90.04% after 2 min. On the other hand, the maximum percent drug release achieved from F10 prepared by wet granulation method was 9.5% after 2 min.²⁰.

DISCUSSION:

Solid dispersions of ketotifen fumarate have been successfully prepared by fusion and solvent evaporation methods. The fusion method has more impact on solubility than solvent evaporation. This increase in solubility is due to uniform dispersion between hydrophilic carrier and drug as hydrophilic carriers are known to interact with drug molecules mainly by electrostatic forces or by intermolecular hydrogen bonds leading to enhance the wettability and solubility of the drug. The addition of poloxamer 407 in higher concentrations enhances the solubility of the drug due to better wettability with increased drug carrier ratio. The dispersions prepared by the solvent evaporation method also show enhanced solubility of the drug but it was lower than the dispersion prepared by the fusion method. Since fusion method showed remarkable conversion of the drug particles from crystalline to fine amorphous form, result in increases the interfacial area of contact between the drug particles and dissolution medium, because of high energy input. Hence, batch Fsd 3 (solid dispersion prepared by fusion method) showed the highest solubility enhancement²¹.

For the prepared orodispersiple tablets, there was a significant effect of super disintegrants on the post compression evaluations of the formulation. The results showed that the formulation with a higher concentration of CP (F1) has shorter disintegration time, as CP act as a wicking agent that absorbs saliva quickly into the tablet, generating large volume inside the tablet, which causes expansion and hydrostatic pressure that rapidly burst the tablet into small fragments, while the SG, and CCS act as disintegrants by a swelling mechanism with gel formation, which in turn shown some delay as the gelling formation that acts as a viscous barrier hindering the water contact with the tablet, therefore delay the disintegration time²². While, the combination of CP with other disintegrants (effervescent) showed delayed disintegration as the combination competes over the small volume of saliva available for disintegration, as the rate of saliva secretion in normal conditions is 0.3 - 0.1 mL/min. Therefore, the formulation with a higher concentration of CP alone showed the shortest disintegration time. Furthermore, the tablet formulated via direct compression not only disintegrates faster but dissolves better as well. CP is a promising fast disintegrant but further studies on the other excipient are required. Therefore, formulation F1 prepared via direct compression method showed optimum orodispersible tablets characteristics as the shortest disintegration time and rapid drug release.

ACKNOWLEDGMENT:

The author would like to appreciate the support of College of Pharmacy, Mustansiriyah University, Baghdad, Iraq for support.

CONFLICT OF INTEREST:

No conflict of interest is associated with this work.

REFERENCES:

1. Sajid A, Sarfaraz A, Sarfaraz A, Nawazish A, Intakhab A. Trend in fast dissolving tablets: an overview. Research Journal of Pharmacy and Technology.2016; 9(1): 69-78.

2. Vishali T, Damodharan N. Orodispersible tablets: a review. Research Journal of Pharmacy and Technology. 2020; 13(5): 2522-2529.

3. Punitha S, Srinivasa RG, Srikrishna T, Lakshman KM. Solid dispersions: a review. Research Journal of Pharmacy and Technology.2011; 4 (3): 331-334.

4. Godge G, Labade SP. Preparation of solid dispersion of poorly water soluble drug formulation and consideration. International Journal of Pharma Sciences and Research. 2015; 6: 0975-9492.

5. Kharshoum RM, Salem HF. Formulation and evaluation of ketotifen fumarate fast disintegrating sublingual tablets. International Journal of Drug Delivery. 2011; 3(4): 619-632.

6. Fahmy R, Badr-Eldin SM. Novel delivery approach for ketotifen fumarate: dissofilms formulation using 3² experimental design: in vitro/in vivo evaluation. Pharmaceutical Development and Technology. 2014; 19(5): 521-530.

7. Jadhav YL, Bharat P, Ostwal PP, Jain MS. Solid dispersion: solubility enhancement for poorly water soluble drug. Research Journal of Pharmacy and Technology.2012; 5(2); 190-197.

8. Silverstein RM, Webster FX, Kiemle D. editors. Infrared spectrometry. New York: Wiley publishing; 2005.

9. Gilbert SB, Neil RA. The Theory and Practice of Industrial Pharmacy. In: Lachman L, Lieberman HA. editors. Tablets. India: CBS Publishing; 2009. p. 293-4.

10. Elkhodiary KA, Hassan MA, Afifi SA. Formulation and optimization of orodispersible tablets of flutamide. Saudi Pharmaceutical Journal. 2014; 22: 53-61.

11. Avinash B et al. Formulation and evaluation of mouth dissolving tablets of domperidone. Research Journal of Pharmacy and Technology.2010; 3(3): 821-824

12. Mahapatra AK, Swain RP, Revathi B, Nirisha N, Murthy PN. Orodispersible tablets: a review on formulation development technologies and strategies. Research Journal of Pharmacy and Technology. 2013; 9(6): 941-953.

13. Patil PR, et al. Formulation and evaluation of orally disintegrating tablet of atenolol by using ion exchange resin. Research Journal of Pharmacy and Technology.2013; 6(7): 753-760.

14. Meher DA. Novel fast disintegrating tablet: a review. Research Journal of Pharmacy and Technology. 2012; 5(2): 143-151.

15. Paul P, Shahriar M, Dewan I, Islam A. Comparative in vitro dissolution study of spironolactone from binary and tertiary solid dispersion: model dependent and independent approaches. Journal of Drug Delivery and Therapeutics.2012; 2(4): 73-80.

16. Bala R, Khanna S, Pawar PK. Formulation and optimization of fast dissolving intraoral drug delivery system for clobazam using response surface methodology. Journal of Advanced Pharmaceutical Technology and Research. 2013; 4(3): 151–159.

17. Sahu SK, et al. Formulation and evaluation of orodispersible tablet of montelukast sodium. Research Journal of Pharmacy and Technology. 2018; 11(3): 1112-1118.

18. SravanthiN, Alekhya, Vikram RI. Formulation and evaluation of mouth dissolving tablets of clozapine by direct compression method. Research Journal of Pharmacy and Technology. 2017;10(8); 2543-2550.

19. Kantharao CH, Swarna K, Leelakrishna J, Anusha J, Asha B, Bhavani B. Diclofenac orodispersible tablets: formulation and In vitro evaluation. Annal of Clinical and Laboratory Research. 2019; 7; 1-8.

20. Shirsand SB, Swamy PV, Kusum DV, Sarasija S. Formulation design and optimization of fast dissolving effervescent tablets of clonazepam. RGUHS Journal of Pharmaceutical Sciences. 2011; 1(3): 202-208.

21. Bibi R, Naqvi BS, Shoaib MH, Rahim N. Design and evaluation of new formulation of enalpril maleate tablet. Pakistan Journal of Pharmaceutical Sciences. 2011; 24(2): 211-215.

22. Salman ZD, Maraie NK, Alabbassi MG, Ghareeb MM. In Vitro/In Vivo Evaluation and bioavailability study of amitriptyline hydrochloride from the optimized oral fast dissolving films. UK Journal of Pharmaceutical and Biosciences.2014; 2(6): 32-42.

Received on 24.07.2020 Modified on 19.09.2020

Research J. Pharm. and Tech. 2021; 14(7):3610-3616.

DOI: 10.52711/0974-360X.2021.00624