Formulation and Evaluation of Fast Dissolving Tablets of Aripiprazole

 

Peenal Gangotia, Shweta Nehate, Hitesh Jain*, D. B. Meshram

Pioneer Pharmacy Degree College, Vadodara, Gujarat, 390019, India

 

ABSTRACT:

Objective: Aim of present work is to formulate and evaluate fast dissolving tablets of Aripiprazole. Experimental work: Initially complexes of drug were made with β- cyclodextrin in the molar ratio of 1:1 to 1:4 by kneading method to mask the bitter taste of drug and fast dissolving tablets were prepared by direct compression method using 3² factorial design. Evaluation of taste masking was done by Electronic Tongue. The optimized batch was subjected for short term stability study at 40ºC with RH of 75% for a period one month. Drug release mechanism was determined by fitting drug release data of S5 to various kinetic models. Result and Discussion: Drug β- cyclodextrin complex in the ratio of 1:4 efficiently masked the bitter taste of drug. Fast dissolving tablets were evaluated for their post compression properties. The optimized batch S5 released the drug upto 98.8 within 30 min. By comparing the correlation coefficient values from the applied models, the Koresmayer Peppas was shown the most appropriate to describe the kinetics of S5 formulation. Conclusion:  Complexes of drug were made with β-cyclodextrin in the molar ratio of 1:1 to 1:4 by kneading method. Among all the formulation, it was conclude that S5 optimized batch which shows the higher drug release up to 98.8 % and disintegration time 18 sec so, S5 is the best optimized batch. Drug release mechanisms were determined by fitting drug release data of S5 to various kinetic models. By comparing the correlation coefficient values from the applied models, the Koresmayer peppas was shown the most appropriate to describe the kinetics of S5 formulation.

 

 

 

INTRODUCTION:

Oral routes 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 most popular solid dosage forms are being tablets and capsules; one important drawback of this dosage forms for some patients, is the difficulty to swallow. Drinking water plays an important role in the swallowing of oral dosage forms. Often times people experience inconvenience in swallowing conventional dosage forms such as tablet when water is not available, in the case of the motion sickness and sudden episodes of coughing during the common cold, allergic condition and bronchitis¹.

 

 

 

Fast dissolving tablets are also called as mouth-dissolving tablets, melt-in mouth tablets, orodispersible tablets, rapid melts, porous tablets, quick dissolving etc. Fast dissolving tablets are those when put on tongue disintegrate instantaneously releasing the drug which dissolve or disperses in the saliva.²

 

MATERIAL AND METHODS:

Aripiprazole was obtained as a gift sample from Alembic Pharmaceuticals Ltd., Vadodara. All other excipients were used of analytical grade.

 

Preparation of complex of drug with β-Cyclodextrin:

The drug and β‐cyclodextrin complexes were prepared in the molar ratio of 1:1 to 1:4 by kneading technique. The required amount of drug and β‐cyclodextrin (β-CD) was taken and transferred to a mortar pestle. The size of mixture was reduced by continuous stirring with pestle. Water-methanol mixture (3:1) ratio was added to the above physical mixture and continuously stirred until the slurry mass was formed. Slurry mass was collected and dried in a hot air oven for hrs at 50 °C, dried mass was collected and further dried in desiccators over silica gel for 24 hrs to remove all the excess residual solvents. The dried mass was collected and passed through 60# mesh, then stored in desiccators at room temperature.^3-4

 

Phase Solubility Studies:

Solubility measurements were performed according to method reported by Higuchi and Connors. An excess amount of the drug was added to 10 ml volumetric flask containing 1%, 2%, 3%, 4% of β-CD as carriers. The samples were allowed to shake for 24 hours at 37 ±0.5°C. The solutions were filtered through membrane filter (0.45μ). After 24 hours, the Aripiprazole concentration was determined spectrophotometrically at 219 nm. The apparent stability constant (Kc) of the complexes was calculated from the slope of the phase-solubility diagrams using the equation. The slope is obtained from the initial straight-line portion of the plot of Aripiprazole concentration against β-CD concentration, and S0 is the solubility of Aripiprazole in water, in the absence of carrier. The apparent stability constants (Ks) were estimated from the straight line of the phase solubility diagrams according to the following equation of Higuchi and Connors

 

Ks = slope / S0 (1-slope)

 

Where So represents the drug solubility in absence of cyclodextrins (the intercept of the phase solubility diagram).

 

The complexation efficiency (CE), which represents the solubilizing efficiency of the cyclodextrins for the drug, was also calculated from the slope of the phase solubility profile as the ratio of the complex to free cyclodextrin concentration, according to the following equation. ^5-6

 

CE = slope / 1-slope

 

Evaluation of taste masking by E-Tongue Test:

All samples were weighed using an analytical balance (±0.5 mg precision) and completely dissolved in appropriate volumes of non de-ionized distilled water at 25°C to obtain the desired concentrations and taste attributes. Each of the e-Tongue testing beakers was loaded with 25 ml of the appropriate, particle free solution. The reference electrode and the seven-sensor assembly were immersed into each testing beaker for an acquisition time of 120 s. This was followed by sequential immersion into two rinsing beakers containing fresh non de-ionized distilled water for 10 s each to prevent any cross contamination or carry-over residues from previous samples. This series of tests was repeated six times in rotation. The first two replicate measurements of the test solution were for sensor training purposes and the readings from the last four replicates were used for data analysis. The potentiometric difference created between each individual sensor and the reference electrode was measured and recorded by the e-Tongue BPM software. All samples were analyzed at room temperature. ⁷

 

Preparation of Tablet:

Fast dissolving tablets were prepared by direct compression method. Drug and excipients were accurately weighed and passed through no. 20# mesh sieve separately. Then mixture was blended for 20 min. The uniform blend was compressed to form the tablets by compression machine. The total weight of tablets was kept constant at 300 mg. The tablet press setting was kept constant across all formulation.

 

Evaluations of Fast Dissolving Tablet:

Hardness:

To perform this test, a tablet was placed between two anvils, force was applied to the anvils and the crushing strength that just caused the tablet to break was recorded. The hardness was measured using Monsanto hardness tester. ⁸

 

Friability Test:

The friability of the tablets was determined using Sent win friabilator. Approximately 6.5 g (Wo) of dedusted tablets were subjected to 100 free falls of 6 inches in a rotating drum and are then reweighed (W). The friability was given by

 

F= 100 × (1 – Wo/W)

 

Weight Variation Test:

Twenty tablets were to be weighed individually; average weight was calculated & individual tablet weight was compared to the average weight. The tablets met the USP test if no more than two tablets were outside the percentage limit & if no tablet differs by more than two times the percentage limit. ⁹

 

Disintegration time:

Six tablets were placed individually in each tube of disintegration test apparatus and discs were placed. The water bath was maintained at 37 0C ± 0.5 ºC and the times taken for all tablets to disintegrate completely were noted.

 

Wetting Time:

Five circular tissue papers of 10 cm diameter are placed in a Petri dish with a 10 cm diameter. 10 ml of water containing Eosin, a water soluble dye is added to Petri dish. A tablet is carefully placed on the surface of the tissue paper. The time required for water to reach upper surface of the tablet is noted as wetting time. ¹⁰

 

In Vitro Drug Release:

In vitro drug release of the samples was carried out using USP-type II dissolution apparatus (paddle type). The dissolution medium, 900 ml of pH 6.8 phosphate buffer maintaining the temperature of 37 + 0.5 ^oC and rpm of 50. One Aripiprazole tablet was placed in each paddle of dissolution apparatus. The apparatus was allowed to run for 30 min. Samples measuring 5 ml were withdrawn after every 5 min. The fresh dissolution medium was replaced every time with the same quantity of the sample. Collected samples were suitably diluted with dissolution medium and analyzed at 219 nm using dissolution medium as blank. The cumulative percentage drug release was calculated. ^11-12

 

RESULTS:

Potential Difference by E-Tongue:

 

Table 1: Data of Potential Difference of complex by E-tongue

Sr. No.	Sample code	Potential difference
1	Pure drug	0.143
2	1:1	0.106
3	1:2	0.071
4	1:3	0.070
5	1:4	0.060

 

 

Figure 1: Phase solubility study β-Cyclodextrin

 

 

Figure 2: Differential Scanning Calorimetry thermo grams of pure Aripiprazole, β-CD, Drug: β-CD (1:4)

 

Figure 3: In-vitro drug release of batches S1-S3

 

 

Figure 4: In-vitro drug release of batches S4-S6

 

 

Figure 5: In-vitro drug release of batches S7-S9

 

 

Table 2: Post compression parameters of batches S1-S9

Batch	Hardness (kg/cm2) Mean (n=3)	Friability (%)	Weight variation (mg) (n=20)	Disintegration Time (Sec) (±SD) n=6	Wetting Time (Sec) (±SD)	Drug Content (%) (n=10)
S1	3.5±0.3	0.45	298.75±0.19	48±1.31	93.00±1.00	98.59±0.23
S2	3.6±0.4	0.43	300.23±0.35	40±1.56	105.11±1.05	100.45±0.62
S3	3.2±0.3	0.39	299.75±0.47	25±0.75	120.40±1.12	98.54±0.79
S4	3.3±0.2	0.42	301.25±0.28	39±0.36	104.33±0.98	97.69±0.14
S5	3.1±0.1	0.36	300.65±0.37	18±0.85	74.62±1.00	97.37±0.97
S6	3.1±0.4	0.37	299.45±0.25	21±0.85	75.00±0.86	97.54±0.34
S7	3.3±0.2	0.38	301.75±0.36	28 ±0.10	83.00±0.63	101.45±0.67
S8	3.7±0.3	0.37	300.15±0.65	30±0.56	78.00±0.50	99.56±0.56
S9	3.9±0.2	0.40	300.15±0.57	22±0.85	89.33±0.78	100.43±0.29

 

 

 

 

Figure 6: Contour plot showing the effect of (X1) Concentration of cross carmellose (%) and (X2) Concentration of Cross povidone on response Y1 Disintegration time (sec)

 

 

Figure 7: Response surface plot of Disintegration time (sec)

 

 

Figure 8: Contour plot showing the effect of (X1) Concentration of cross carmellose (%) and (X2) Concentration of Cross povidone on response Y2 Drug release (%) Response surface plot of Drug release (%)

 

 

Figure 9: Response surface plot of Drug release (%)

Stability Study:

 

Figure 10: In vitro drug release of S5 after stability study

 

CONCLUSION:

In the present study, an attempt was made to formulate the Fast Dissolving tablet of Aripiprazole and to evaluate the formulated dosage form for various physico-chemical parameters like hardness, friability, weight variation, drug content as well as drug release. Complexes of drug were made with β-cyclodextrin in the molar ratio of 1:1 to 1:4 by kneading method. Bitter taste of drug was efficiently masked by the 1:4 ratio of drug and β-cyclodextrin. Fast dissolving tablets were prepared by direct compression method using 3² factorial design. All the prepared batches were evaluated for their post compression properties. Among all the formulation, it was conclude that S5 optimized batch which shows the higher drug release up to 98.8 % and disintegration time 18 sec so, S5 is the best optimized batch. Drug release mechanisms were determined by fitting drug release data of S5 to various kinetic models. By comparing the correlation coefficient values from the applied models, the Koresmayer Peppas was shown the most appropriate to describe the kinetics of S5 formulation.

 

REFERENCES:

1.      Mash A, et al. Fast dissolving tablet: a review. International Journal of Current pharmaceutical research. 2017: 0975-7066.

2.      Mangal M, et al. Fast dissolving tablet: an approach for emergency treatment. International Journal of Research. 2012: 377-380.

3.      Singh R, et al. Characterization of cyclodextrin inclusion complexes – a review. Journal of Pharmaceutical Science and Technology. 2(3); 2010: 171-183.

4.      Uekama K, et al. Cyclodextrin drug carrier systems. Chemical Review. 1998: 2045 -2076.

5.      Rawat S, et al. Rofecoxib-β-cyclodextrin inclusion complex for solubility enhancement. Pharmazie. 2003: 639 641.

6.      Rawat S, et al. Solubility enhancement of celecoxib using β-cyclodextrin inclusion complexes. European Journal of Pharmaceutics and Biopharmaceutics. 2004: 263–267.

7.      Rachid O, et al. An Electronic tongue: evaluation of the masking efficiency of sweetening and Flavoring agents on the bitter taste of Epinephrine. American Association of Pharmaceutical Scientists. 2010: 550-557.

8.      Mohapatra A, et al. Formulation, development and evaluation of patient friendly dosage forms of metformin. Part-I: Orally disintegrating tablets. American Association of Pharmaceutical Scientists. 2009: 167-171.

9.      Jagdale S, et al. Formulation and in vitro evaluation of taste-masked orodispersible dosage form of diltiazem hydrochloride. Brazilian Journal of pharmaceutical Sciences. 2011: 908-916.

10.   Prabhakar S, et al. Formulation and evaluation of fast dissolving tablets of cyclodextrin inclusion complexes water insoluble drug: glimepiride. International Journal of Research in Ayurveda and Pharmacy. 3(3); 2012:  465-470.

11.   Jagdale S, et al. Formulation and in vitro evaluation of taste-masked orodispersible dosage form of diltiazem hydrochloride. Brazilian Journal of pharmaceutical Sciences. 2011: 908-916.

12.   Gunda R. Formulation development and evaluation of rosiglitazone maleate sustained tablets using 3² factorial designs. International Journal of Pharmatech Research. 2015: 713-724.

 

 

 

 

Received on 06.10.2018         Modified on 05.11.2018

Accepted on 27.12.2018         © RJPT All right reserved