Formulation and Evaluation of Sertraline HCl ...

RESEARCH ARTICLE

Formulation and Evaluation of Sertraline HCl Sublingual Oral Disintegrating Tablets Using Factorial Design A Abd El-Bary1, S H Shalaby2, M A El Nabarawi1, D M N Abouhussein2* Abstract: Sertraline HCl (SRT) oral disintegrating tablets (ODTs) were formulated using direct compression technique through a 3 x 22 factorial design. Since disintegration time is an essential pharmacopoeial test for ODTs and tablet hardness testing is important for product development, this study aimed to develop an optimized formula with adequate disintegration time and hardness. The effect of different types of sugar based diluents (Xylitol and Maltitol), disintegrating agent (Ac-Di-Sol, crospovidone (CP) and co-processed mixture of Ac-Di-Sol and crospovidone) and disintegrating agent concentration (5%, 10%) were studied. Upon evaluation of the prepared ODTs, tablets containing Xylitol with 10% CP (F4) and Maltitol with 10% CP (F10) and Maltitol with 10% co-processed mixture (F12) appeared to have superior properties as ODTs.

INTRODUCTION SRT is a selective serotonin reuptake inhibitor (SSRI) that is widely used as antidepressant and antianxiety drug that is slightly soluble in water. [1] The physicochemical characteristics of SRT molecule restrict its oral absorption leading to a low drug bioavailability. [2] SRT absorption from the gastrointestinal tract is almost complete, but rather slow, with a time to reach the maximum plasma concentrations (Cmax) of 4.5–8.4 hr after ingestion which may be contributed to extensive first-pass metabolism in the liver that leads to decreasing the bioavailability by 44%. [3-4] The SRT daily dose usually ranges between 50 and 200 mg and the drug is slowly absorbed with an elimination half-life ranging from 22 to 36 hours with a reported average of 26 hours. [5] Dysphasia or general difficulties in swallowing of tablets may be a problem for geriatric, pediatric, or passengers, if they do not have access to water. Sublingual oral disintegrating dosage forms can solve this problem where they rapidly disintegrates in the mouth where the drug is dissolved in the saliva allowing high drug loading which in turn facilitates rapid absorption and provide the advantages of liquid medication in the form of solid preparation. [6-10] In addition, sublingual medications overcome the disadvantage of first pass metabolism in the liver as the drug goes directly to the blood stream. Co-processing is a newly explored utilized method for the preparation of directly compressible excipients. Coprocessing is defined as combining two or more established excipients using the suitable process. Coprocessing of adjuvants could lead to the formation of excipients with superior properties compared to the simple physical mixtures of their components. [11] Two disintegrating (DS) agents, namely; croscarmellose sodium (Ac-Di-Sol), CP and a co-processed mixture of both DS agents were used in this study each in two concentrations namely 5% and 10%. Also, the effect of different types of sugar based diluents was studied through the use of Xylitol

(low compressible diluent) and Maltitol (high compressible diluent). MATERIALS AND METHODS Materials Sertraline HCl, kindly supplied by the Egyptian Company for Chemicals and Pharmaceuticals (ADWIA), El-Obour City 1st Industrial area, Egypt. Ac-Di-Sol was obtained from Gujarat Overs Las Inc, Bodakdev, Ahmedabad, India. CP and Maltitol, was obtained from ACRŌS Organics, New Jersey, USA. Xylitol, magnesium stearate and ethanol absolute 99.8% was obtained from Sigama Aldrich, Saint Louis, MO 63103, USA. Stevia extract was obtained from NuNatural Inc., Eugene, OR 97402, USA. Avicel PH 102, FMC Biopolymer, Brussels, Belgium. Potassium dihydrogen orthophosphate, Di-sodium hydrogen orthophosphate and sodium chloride was obtained from El-Nasr Company, Cairo, Egypt. Preparation of Co-processing Mixture Blends of CP and Ac-Di-Sol were prepared in the ratio of 1:1. Suspensions of each DS agent in ethanol were added in a beaker and stirred on a magnetic stirrer till most of ethanol was evaporated. The coherent mass was left to dry in oven at 40°C, then was triturated in glass mortar and pestle, passed through sieve 250 μm and stored in airtight container till further use. This blend will be used as disintegrating agent in the prepared SRT ODTs. Preparation of Sublingual SRT ODTs Oral disintegrating tablets (ODTs) containing Sertraline Hydrochloride equivalent to 50 mg Sertraline were prepared by direct compression method using a 10 mm diameter die on a single punch tablet press. Tablets were prepared using 3 x 22 full factorial design at 95% confidence level as showed in Table 1.

1Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt.

Preformulation Studies on the Prepared Powder for Tabletting Each mixture powder of each formula in Table 1 was subjected to the following examination:

2Department of Pharmaceutics, National Organization for Drug Control and Research (NODCAR), Egypt. E-mail: [email protected] *Corresponding author

1. Bulk Density [12-13] Bulk density was measured by pouring 5 gram of powder into 100 ml cylinder using the formula:

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RESEARCH ARTICLE Table 1: Composition of SRT Sublingual ODTs Using Different Sugar Based Diluents and Different Disintegrating Agent in Different Concentration Ingredients Sertraline HCl* Ac-Di-Sol CP Co-processed Avicel pH 102 Xylitol Maltitol Mg Stearate Stevia Extract

F1 56 10 50 79.5 2 2.5

F2 56 20 50 69.5 2 2.5

F3 56 10 50 79.5 2 2.5

F4 56 20 50 69.5 2 2.5

F5 56 10 50 79.5 2 2.5

F6 56 20 50 69.5 2 2.5

F7 56 10 50 79.5 2 2.5

F8 56 20 50 69.5 2 2.5

F9 56 10 50 79.5 2 2.5

F10 56 20 50 69.5 2 2.5

F11 56 10 50 79.5 2 2.5

F12 56 20 50 69.5 2 2.5

*equivalent to 50 mg sertraline

Table 2: Powder Characteristics Compressibility Index (%) ≤10 11-15 16-20 21-25 26-31 32-37 >38

Hausner Ratio 1.00-1.11 1.12-1.18 1.19-1.25 1.26-1.34 1.35-1.45 1.45-1.59 >1.6

Flow Character Excellent Good Fair Passable Poor Very poor Very, very poor

Figure 1: Main effect plot of different factors on hardness of SRT ODT using different sugar based diluents and different DS agents in different concentration

ρb = M / V Where: ρb: bulk density, M: weight of powder, V: volume of powder.

This test is the easiest way for measurement of the flowability of powder. % C.I. = ρt - ρb /ρt ൈ 100 Where: ρt = tapped density, ρb = bulk density.

2. Tapped Density [9-14] 5 g of powder was placed in a measuring cylinder and tapped for 100 times where the minimum volume (Vt) occupied was recorded. The tapped density was calculated using following formula:

4. Hausner Ratio [9 and 14] Hausner ratio is an indirect index of ease of powder flowability. It is the ratio of tapped density to bulk density. It is calculated by following formula:

ρt = M / Vt

ρt / ρ b

3. Compressibility Index [9]


Where: ρt = tapped density, ρb = bulk density.


RESEARCH ARTICLE Table 3: Preformulation Studies on the Prepared Powder of Sertraline ODTs Formula No. Formula 1 Formula 2 Formula 3 Formula 4 Formula 5 Formula 6 Formula 7 Formula 8 Formula 9 Formula 10 Formula 11 Formula 12

Bulk Density (pb) g/ml 0.56 0.56 0.57 0.555 0.5 0.5 0.555 0.588 0.574 0.549 0.588 0.555

Tapped Density (Pt) g/ml 0.795 0.8 0.69 0.7 0.61 0.588 0.714 0.666 0.714 0.675 0.66 0.625

Carr´s Compressibility Index (Pt- pb/ Pt)*100 29.55% 30% 20.71% 17.39% 18.03% 14.96% 22.26% 18.66% 19.6% 11.71% 11.71% 11.2%

Hausner Ratio (Pt/ pb) 1.42 1.42 1.26 1.21 1.22 1.176 1.28 1.22 1.24 1.13 1.12 1.12

Angle of Repose (Degrees) 33 29.68 24.22 19.79 25 19.8 23.96 24.22 23.96 19.8 19.57 15.64

Table 4: Physical Properties of Sublingual SRT ODT Formula No. F# 1 F# 2 F# 3 F#4 F#5 F# 6 F#7 F#8 F#9 F# 10 F# 11 F#12

Average Weight (mg) 196.2±2.14 198±2.48 197±3.3 199.45±2.93 200.21±3.12 198.9±3.92 196.9±3.67 199±2.52 199±1.66 200.5±2.6 196.3±2.89 198.4±2.96

Thickness (mm)

Hardness (Kg)

Friability (%)

2.2±0.022 2.23±0.015 2.2±0.011 2.13±0.011 2.2±1.014 2.15±0.01 2.2±0.008 2.19±0.011 2.1±0.008 2.13±0.011 2.18±0.011 2.17±0.006

0.67±0.037 0.76±0.054 0.9±0.084 2.96±0.143 3.5±0.52 3.5±0.22 2.7±0.13 3±0.194 2.76±0.113 3.3±0.126 3.5±0.138 3.8±0.105

Broken Broken Broken 0.71 0.55 0.56 0.6 0.59 0.51 0.52 0.52 0.41

5. Angle of Repose [9-14] Funnel method was used to determine the angle of repose. Funnel is fitted vertically at 6.3 cm height where opening end of funnel is closed with thumb until the powder is poured then the thumb is removed and the maximum cone height (h) and radius of heap (r) were measured. The angle of repose (ϴ) was calculated using the formula: ϴ = Tan-1 (h/r) Evaluation of the Prepared SRT Sublingual ODTs 1. Average Weight Twenty tablets were randomly chosen, weighed individually and then the average weight was determined according to the limits of BP 2013. [15] 2. Tablet Thickness The thickness was measured for ten randomly selected tablets and the average thickness was determined. [16] 3. Tablet Hardness For each formulation, 10 randomly selected tablets were examined for their hardness using Pharma test hardness apparatus tester. [17-18] 4. Tablet Friability Ten tablets were weighed (Wi) and rotated at 25 rpm/min for 4 minutes using Erweka fibrilator. The tablets were


Wetting Water Time Absorption (sec) Ratio 13±2 37.1±2.16 22±1.732 60.2±2.78 8±1 53.6±1.08 6±1 81.7±0.98 29±4.358 59.03±2.08 57±3.46 83.12±1.97 50±1.73 56.65±2.32 21±2 45.54±2.54 17±2.645 44.5±2.36 10±1.732 78.7±1.94 16±1 78.52±1.29 18±2.645 85.3±1.45

Disintegration (sec) 6±1.82 19±2.3 7±1.41 3±1.05 16±2.28 22±2.28 60±4.71 51±3.83 13±1.41 3±0.82 20±2 13±1.41

Content Uniformity (%) 98±0.919 97.4±0.418 92.4±0.827 98.3±0.943 94±0.836 93.2±0.663 92.3±0.751 92.3±0.533 107.3±1.04 102.64±1.55 94.4±1.17 104.9±0.565

In-vitro Dispersion (sec) 9.11±0.348 13.85±0.589 13.14±0.286 11.52±0.516 12.22±0.47 10.5±0.917 19.45±0.492 17.1±0.567 15.14±0.332 9.42±0.544 16.1±0.567 12.2±1

then weighed (Wf) and friability percentage (F %) was calculated according the following equation: [19] F % = Wi – Wf / Wi X 100 Where: Wi is initial weight of tablets before rotation, Wf is final weight of tablets after rotation. 5. Content Uniformity Five tablets were powdered and a quantity of powder equivalent to 50 mg sertraline was accurately weighed, extracted with methanol, filtered using Millipore filter 0.45 μm and measured spectrophotometrically at Omax 273 nm. The drug content was calculated using standard calibration curve. 6. In-vitro Disintegration The disintegration test was performed using USP disintegration apparatus in simulated saliva solution (SSS) of pH 6.8 (2.38 g sodium phosphate dibasic, 0.19 g potassium phosphate monobasic and 8g sodium chloride adjusted to pH 6.8) [20] at 37Ԩ. Average time taken was calculated for six tablets for each formulation. [21- 23] 7. Wetting Time The tablet was placed on a piece of Whatman filter paper disc in a Petri dish (internal diameter 6.5cm) containing 6 ml of purified water and is allowed to complete wetting.


4

4

3.5

3.5

3

3

2.5

2.5

Maltitol

2

Xylitol

1.5

Cell Mean

1

.5

.5 10%

Xylitol

1.5

1

0

Maltitol

2

0

5%

Ac-Di-Sol

Coprocessed Cell

Cell

Figure 2: Interaction bar plot of hardness for diluent and disintegrating agent concentration effect SRT sublingual ODTs

4

4

3.5

3.5

1

0

1 .5 0 10%

5% Cell

Figure 4: Interaction bar plot of hardness for disintegrating agent and disintegrating agent concentration effect SRT sublingual ODTs

The time required for the tablet to be completely wetted was then recorded. [24] All experiments were done in triplicate and the mean result was taken. 8. Water Absorption Ratio The tablet was placed on a piece of Whatman filter paper disc in a Petri dish (internal diameter 6.5 cm) containing 6 ml of purified water and allowed to wet completely. The tablet was weighed before and after complete wetting. All experiments were done in triplicate and the mean result was taken. Water absorption ratio, R was determined according to the following equation: R = 100 (Wa – Wb)/Wb Where, Wb: weight before water absorption, Wa: weight after water absorption. 9. In-vitro Dispersion Test This test was performed to ensure disintegration of tablets in the salivary fluid, if it is used as a fast dissolving tablet. One tablet was placed in a measuring cylinder containing 10 ml of pH 6.8 phosphate buffer at 37±0.5ºC and the time required for complete dispersion was determined. [25] All experiments were done in triplicate and the mean result was taken. 10. In-vitro Release The drug release was determined using Hanson Research device apparatus II (paddle). The test was performed at 50


CP, 5%

.5

CP, 10%

CP

1.5

Xylitol

1.5

Coprocessed, 5%

Coprocessed

2

Maltitol

2

Ac-Di-Sol, 5%

Ac-Di-Sol

2.5

Ac-Di-Sol, 10%

2.5

Cell Mean

3

3 Cell Mean

CP

Figure 3: Interaction bar plot of hardness for diluent and disintegrating agent effect SRT sublingual ODTs

Coprocessed, 10%

Cell Mean

RESEARCH ARTICLE

Cell

Figure 5: Interaction bar plot of hardness for diluent, disintegrating agent and disintegrating agent concentration effect SRT sublingual ODTs

rpm using 500 ml simulated saliva solution pH 6.8 equilibrated at 37°C±0.5°C. Aliquot samples of 2 ml were withdrawn from the vessels at the specified time intervals, filtered using syringe fitted with 0.45 μm Millipore filter and measured spectrophotometrically at Omax 273 and replaced with fresh medium in the vessels. Measurements were done at different time intervals for 30 minutes. All experiments were done in triplicate and the mean result was taken. RESULTS AND DISCUSSION Preformulation Studies on the Prepared Powder for Tabletting Table 2 reveals that increasing carr´s compressibility Index and Hausner ratio indicates poorer flowability characteristics of the tested powder. Table 3 shows the results of the preformulation studies on the prepared powder. Powder of ODTs containing Xylitol showed lower flowability properties than those containing Maltitol as the former revealed higher values of carr´s compressibility index (30-14.96%), Hausner ratio (1.42-1.176) and angle of repose (33-19.79) than those prepared from Maltitol which showed carr´s compressibility index (22.26-11.2%), Hausner ratio (1.28- 1.12) and angle of repose (23.96-15.64). This may be due to the fact of Xylitol being low compressible diluent and that Maltitol is high compressible one. Together with, the used type of disintegrating agent affected the powder flowability. The flowability was enhanced in the order of Co-processed mixture > CP > AcDi-Sol. This may be due high compressibility properties of


RESEARCH ARTICLE

Figure 6: Main effect plot of different factors on disintegration time of SRT sublingual ODTs using different sugar based diluents and different DS agents in different concentration

CP. [26] Together with, the co-process of both disintegrating agents led to enhancement of the properties of the new obtained excipient leading to increased flow properties, compressibility and show better dilution potential (the ability of the excipient to retain its compressibility even when diluted with another material). [11] Evaluation of the Prepared SRT Sublingual ODTs 1. Average Weight Average weight of prepared ODTs ranged from 196.16 mg to 200.38 mg as shown in Table 4 which showed acceptable weight variation ranges. The relative standard deviation ranged from 1.09-1.97% for all formulae. 2. Tablet Thickness Thickness of the prepared tablets ranged from 2.1 mm to 2.23 mm as shown in Table 4. All formulae had acceptable variation ranges showing RSD from 0.31 to 1%. 3. Tablet Hardness Hardness of the prepared tablets were measured and ranged from 0.67 kg to 3.8 kg as shown in Table 4. All Formulae gave acceptable results except F 1, F2 and F3 that resulted in low values 0.67, 0.76, 0.9 kg respectively. ANOVA result for all the studied factors and interaction of these factors showed p < 0.05, so we can conclude that all the studied factors have significant effect on the hardness of the prepared SRT ODTs. Figure 1, Figure 5 and Table 4 reveal that formulae prepared using Maltitol as diluent showed higher hardness than those prepared using Xylitol indicating that former SRT ODTs have better mechanical strength with more ability to withstand physical and mechanical stress conditions upon handling than ODTs containing Xylitol. This may be returned to the fact of the high compressibility of Maltitol in comparison to Xylitol. [27] For the effect of disintegrating agent on hardness of the prepared SRT ODTs, it is revealed from Figure 1 that


hardness increases in the order of Ac-Di-Sol