Up to one-third of people in all age groups have experienced swallowing issues during their lifetime [1]. The increased prevalence of swallowing issues and the development of clinically significant dysphasia (difficulty in swallowing) can be observed with increasing age, intensity of care required, and the number of diseases as well as diseases with dysphasia inducing co-morbidity [2]. ODTs greatly improve patients’ compliance as it is easily taken without the need of water. It provides very rapid onset of action for patients in which it promote pregastric absorption of the drug molecules through buccal, sublingual, oropharyngeal, and esophageal membranes. Moreover, it avoids the first-pass hepatic metabolism leads to elevate bioavailability and reduces drug side effects [3].

Some manufacturing technologies of ODTs include direct compression, wet granulation, and lyophilization [3]. The direct compression method is the easiest and cost-effective method for the production of ODTs [4,5]. Lubrication is a critical element in tablet formulation. Lubricants are used to diminish the friction and adhesion of the powder blend to the punches and die wall [6]. Magnesium stearate is considered as the most common, chemically stable, and metallic salt boundary lubricant with high melting point, but it is hydrophobic [7]. Hence, lubricant concentration has been reported as one of the independent variables for experimental design [5,8,9]. In ODTs, it is important to keep quick disintegration properties of the tablets with adequate hardness [10]. Thus, optimizing the amount of magnesium stearate and mixing time is critical in the manufacturing of ODTs [5].

Optimization is a procedure that exploits available resources to obtain the best possible results. The manner of try and error that was extensively used before is now switched by the optimization system that finds a wide range of application in chemistry and pharmaceutical industry in the meantime [11]. Response surface methodology (RSM) is an assembly of mathematics and statistics procedures that is quite beneficial for the analysis and modelling of problems in which the optimized response of interest is influenced by numerous variables and objectives [12]. Box-Behnken experimental design offers 3 levels for each factor and involves a particular subsection of factorial blends from the 3k factorial design [12,13].

Optimization techniques have been employed by several researchers in the design and development of ODTs [14, 15]. However, some researchers had developed and prepared fluoxetine HCl in ODTs formulation using try and error methodology and they also used either wet granulation or sublimation techniques in order to manufacture the fluoxetine ODTs [16–18]. Consequently, this Box-Behnken experimental design will be the technique of choice to develop and optimize the fluoxetine ODTs. The design helps to develop the work methodology of fluoxetine ODTs. The design can minimize the number of trials, time, money, and gives developed formulation. 

The World Health Organization has listed fluoxetine as an essential medicine [19]. Fluoxetine is a selective serotonin reuptake inhibitor indicated in the treatment of major paediatric depression, adults and children obsessive compulsion disorder, panic, premenstrual dysphoric disease, autism in adult, and trichotillomania [20,21]. The bioavailability of fluoxetine after oral administration has been reported to be up to 72 %, and the elimination of half-life ranged between 1 to 4 days [22]. Fluoxetine HCl is nominated for this work because it is widely used as antidepressant drug.

In the present study, direct compression technique was used to prepare fluoxetine ODTs and Box-Behnken experimental design employed to optimize the variables, including lubricant concentration, mixing time, and compression force through investigating their impact on the tablet weight, thickness, hardness, friability (%), and disintegration time. Moreover, the drug release profile is monitored as well.

Materials

The following chemicals were obtained and used as received. Fluoxetine HCl was purchased from Xi’an Realin Biotechnology Co., Xi’an, China. Microcrystalline cellulose was purchased from JRS Pharma, Aalen, Germany. Lactose spray dried 250 was purchased from DFE pharma, Borculo, Netherland. Croscarmellose sodium was purchased from FMC Biopolymer, Philadelphia, USA. Magnesium stearate was purchased from Fisher Scientific, Pittsburgh, PA, USA. All chemicals and reagents used were of analytical grade.

Flow properties of the powder blend

It is very important to maintain an excellent flowability property of the powder blends to keep the filling of the punches spaces with the required amount of powder during the process of tablet compression. Therefore, after weighting and mixing the powders together before the tablet compression process took place the powder flowability should be monitored. Hausner ratio, Carr’s index, and angle of repose were used to evaluate the flow properties of powders. Hausner ratio and Carr’s index were evaluatedby monitoring both bulk and tapped volume of the powder [23,24]. Bulk density (dB) of the designed powder formulation was calculated according to the method of Martin et al [25], while tapped density (dT) was determined according to Carr [23] and Sheehan [24]. Powder flowability properties were determined using Eqs 1 and 2.

Carr’s index = 100(dT  – dB)/dT …………… (1)

Hausner ratio = dB/dT ……………………….. (2)

Angle of repose was calculated using Eq 3 [24,25].

Tan (α) = height/0.5 base …………………… (3)

All measurements were carried out in triplicate and mean ± standard deviation (SD) computed.

Box–Behnken experimental design

Box–Behnken experimental design (33) of the statistical package, Statgraphics® Centurion XV, version 15.2.05 (Statpoint Technologies Inc, Warrenton, Virginia, USA), was used to assess the effects of selected independent variables on the variables responses to optimize the ODTs formulation procedure. This strategy is used to optimize the procedure using a lesser number of experimental trials by investigating quadratic response surfaces; and for the creation of second order polynomial models. The levels of factor were coded as low, medium, and high settings (−1, 0, and +1) [12,26].

Preliminary experiments revealed that the chosen independent and dependent variables along with their levels and constraints as shown in had a significant effect on the ODTs formulation. The chosen independent variables were the percentage of lubricant concentration (X₁), mixing time (X₂), and compression force (X₃). The observed responses of the dependent variables were the tablets weight (Y₁), thickness (Y₂), hardness (Y₃), % friability (Y₄), and in-vitro disintegration time (Y₅). A total of 15 experimental formulae were planned by Box-Behnken design ().

A (33) Box-Behnken design was employed in this work and extended to optimize the fluoxetine ODTs formulation. Through generating the polynomial equations concerning the dependent and independent variables, the procedure optimized the values of X₁, X₂, and X₃, which gave the best wanted possible values of Y₁, Y₂, Y₃, and Y₄ under controlled circumstances. A new formulation was prepared according to the predicted levels of X₁, X₂, and X₃. Subsequently, the observed responses (Y₁, Y₂, Y₃, Y₄, and Y₅) matched the predicted data and the residual, as well as the residual errors (%) were then calculated.

Preparation of fluoxetine HCL orally disintegrating tablets

Tablets (300 mg) containing fluoxetine HCl were manufactured by direct compression method under standardized conditions, according to the formulation specified in the Box–Behnken design (). Each formulation consisted of fluoxetine HCl (6.67 %), microcrystalline cellulose (30 %), croscarmellose sodium (4 %), and spray dried lactose (to 100 %) and were then mixed together for 15 min. Finally, magnesium stearate (0.5, 1 or 1.5 %) was added and mixed for 2, 13.5 and 25 min. After that 100 g from each formulations powder blends were subjected to the flowability test. Additionally, the remaining formulations powder blends were pressed at 5, 10 and 15 KN using the rotary tablet press (RoTab T, KG Pharma, Berlin, Germany).

Evaluation of ODT thickness, weight variation and hardness

The thickness (mm), uniformity of weight and hardness (20 tablets) were determined using ERWEKA Multi-Check 5.1 (ERWEKA GmbH, Heusensatamm, Germany).

Tablet friability test

Tablet friability (%) was determined using ERWEKA, TA3R friabilator (ERWEKA GmbH, Heusensatamm, Germany). it rotated for 4 min at 25 rpm.

Drug content determination

Drug content (10 Tablets) was determined according to the USP requirements. Tablets were weighed separately, crushed, and the drug was extracted with 0.1 N hydrochloric acid, filtered, and the content (%) determined by Shimadzu UV-1700 spectrophotometer (Shimadzu Corporation, Kyoto, Japan) at a wavelength of 225 nm after suitable dilution [3,16].

Assessment of in vitro disintegration time

The test was carried out in distilled water according to the USP30-NF25 requirements using a disintegration tester (ERWEKA GmbH, Heusensatamm, Germany). The apparatus was maintained at 37 ± 2 °C [27], and the time taken for the ODT to pass through the screen or till no solid residue remains on the screen was recorded as the disintegration time.

In vitro dissolution study

In vitro dissolution was carried out according to the USP30-NF25, using an automated dissolution tester (ERWEKA, Germany) attached to an automated sampler (SP-100 peristaltic pump, Somerset, NJ, USA). Dissolution was done in 900 mL phosphate buffer at pH of 6.8 ± 0.05 and 37 ± 0.5 °C temperature to simulate saliva fluid. The paddle rotated at 50 rpm. The samples were withdrawn automatically after 1, 2, 3, 4, 5, 10, and 15 min and were analyzed at a wavelength of 225 nm [28].

The designed fluoxetine ODTs formulations powder blends were subjected to flowability property testing, before their compression into ODTs through measuring the Hausner ratio, Carr’s index, and angle of repose as displayed in . The 15 formulations powder blends displayed a flowability properties ranged from good to excellent as seen in .

ODT weight, as seen in , ranged between 299.1–319.2 mg with F5 and F7 respectively. All prepared ODTs were around 300 mg ± 7.5 %. Accordingly, all the ODT formulations met the United States pharmacopoeia requirements concerning the homogeneity of weight.

The Pareto chart () showed that variable X₂ only extended after the reference line and the relatively larger coefficient for these terms is shown in the regression equation (Eq 4).

Therefore, only the lubricant mixing time (X₂) had a significant effect on the tablet weight variation (Y₁) with a positive coefficient. So, X₂ displayed a direct proportional effect on Y₁ for all formulations, although the ODT still within the USP requirements (± 7.5 %). Meanwhile X₁ and X₃ had an insignificant effect on Y₁ response.

Y₁ =310.962 – 11.9428X₁ + 1.33677X₂ – 1.96732X₃ + 11.2833X₁² – 0.186957X₁X₂ – 0.55X₁X₃ – 0.0285759X₂² +  0.0178261X₂X₃ + 0.104833 X₃² …………………… (4)

where X₁², quadratic term of lubricant concentration; X₂²,quadratic term of mixing time; X₃², quadratic term of compression force; X₁X₂, interaction between lubricant concentration and mixing time; X₁X₃, interaction between lubricant concentration and compression force; X₂X₃, interaction between mixing time and compression force; Y₁, tablet weight variation (mg); Y₂, tablet thickness (mm); Y_3, tablet hardness (Kp); Y₄, friability (%); and Y₅, in vitro disintegration time (sec).

and Figures 1 – 3 indicate that P_value of X₂ <0.05 and the F_ratio was 73.47 (highest value) so it had a significant effect. The P_values of X₁ and X₃ were >0.05 and the F_ratios were 3.03 and 1.45 (lowest values) so they had an insignificant effect. Moreover, fluoxetine content uniformity within all ODT formulations ranged from 97.72 ± 2.97 to 103.6 ± 1.85 %. Therefore, fluoxetine content distributed homogeneously throughout all suggested prepared formulations.

Tablet thickness (Y₂) measurements were displayed in Tables 2, 4 and Figures 1 – 3. Y₂ ranged from 4.08mm to 4.76mm with F9 and F8, respectively. Pareto chart and estimates calculated showed the priority effect of X₃ over other independent variables, the bars of X₃ and X₂ extended after the reference line accompanied with a negative coefficient of X₃ and positive coefficient of X₂. The relatively larger coefficient of these variables is seen in the regression equation for Y₂ as shown below (Eq. 5):

Y₂ = 5.40669 – 0.355652X₁ + 0.015534X₂ –0.161598X₃ + 0.17X₁² –0.00217391X₁X₂ + 0.001X₁X₃ – 0.000378072X₂² + 0.000173913X₂X₃ + 0.0054X₃² …………………(5)

Calculated p-values were < 0.05, plus the F_ratios were 19.1 and 381.14 for X₂ and X₃ respectively. Therefore, X₃ had the highest priority effect than other independent variables and accompanied by an inverse proportional effect on Y₂ while X₂ was in the second priority effect. Whereas p-value of X₁ was > 0.05 and it accompanied with a very low F_ratio (1.85). Consequently, increasing X₂ and X₃ and led to the decreasing of Y₂.

Tablet hardness responses (Y₃) were displayed in Tables 2, 4 and Figures 1 – 3. The lowest Y₃ was reported with F8 (1.2 Kp) but the highest Y₃ was reported with F9 (8.2 Kp). Additionally, the Pareto chart showed the variables of X₂ and X₃ bars were extended after the reference line and the relatively larger coefficient for these terms is shown in the regression equation as below (Eq 6).

Y₃ = –2.74719 – 0.0923913X₁ – 0.063138X₂ + 1.02967X₃ + 0.35X₁² + 0.00869565X₁X₂ – 0.09X₁X₃ + 0.00274102X₂² – 0.00608696X₂X₃ – 0.0145X₃² ………..(6)

X₃ exhibited positive coefficient while X₂ acquired negative coefficient. The p-values for X₂ and X₃ were < 0.05 while F ratios was 57.3 and 2044.8, respectively, indicating a significant effect of those variables on Y₃ while the calculated P_value of X₁ was >0.05 and the F_ratio was very low (1.94). Therefore, Y₃ was closely related to the increase of X₂ and X₃ [29].

Likewise, tablet friability (%) responses (Y₄) were displayed in Tables 2 and 4 and Figures 1 – 3. It ranged from 0.06–2.5% (F9 and F8 respectively). The X₃ had an inverse effect on Y₄ where its bar extended after the reference line and the relatively larger coefficient for this term is shown in the regression equation as below (Eq. 7):

Y₄ =5.84405 – 2.63685X₁ + 0.0719329X₂ – 0.786978X₃ + 0.975X₁² + 0.00217391X₁X₂ + 0.054X₁X₃ – 0.000727788X₂² – 0.00426087X₂X₃ + 0.03045X₃² ……………………(7)

However, X₁ and X₂ had an insignificant effect on Y₄ response. Furthermore, the P_values were <0.05 and the F_ratio (110.07) were the highest among all other variables effect. On the other hand, the P_values for X₁ and X₂ were >0.05 and the F_ratios were 0.46 and 2.48 respectively, which were lower than the value of X₃ (110.07) reported. This indicated that X₁ and X₂ had insignificant and low priority effect on Y₄. Therefore, the tablets that were prepared at stronger X₃ presented lower Y₄ due to the hardness and thickness [29].

The time of disintegration (Y₅) responses were seen in Tables 2, 4 and Figures 1 – 3. F4 exhibited the lowest Y₅ (11.42 s) but the highest was noticed with F10 (45.45 s) in which the Y₅ regression equation (Eq. 8):

Y₅ =11.0438 – 13.0882X₁ + 0.353025X₂ + 0.0538551X₃ + 1.75833X₁² + 0.0282609X₁X₂ + 1.683X₁X₃ – 0.00068368 X₂² – 0.0472609X₂X₃ + 0.0663833 X₃²    …………………..(8)

The positive coefficient of X₁ and X₃ demonstrated direct proportional effect plus high priority effect of X₃ compared to X₁ on Y₅ as displayed. The P_values of X₁ and X₃ were < 0.05. The P_value of X₂ was > 0.05 which indicated an insignificant effect on Y₅. Additionally, the F_ratios of X₁, X₂, and X₃ were 49.83, 5.44, and 502.69 respectively. These results are in accordance with the findings of other works [29].

All formulations achieved T₅₀ (time of 50 % of fluoxetine release) within the first minute while T₈₀ (time of 80 % of fluoxetine release) was achieved by F4 and F8 within 1 min. The dissolution of the 15 formulations after 5 min ranged from 71.45 - 96.73 %. After 10 min, the values ranged from 78.56 – 100.00 %; while after 15 min, dissolution from almost all formulations approximately 100 %. showed the dissolution profile of selected formulations. This selection is based on the fact that these selected formulations showed the effect of X₁, X₂, and X₃ employed without repeating the results for the remaining formulations that display the effect of independent variables.

The powder blends displayed acceptable flowability property which ranged from good to excellent [23,24]. Magnesium stearate particles formed a thin layer covering the other powder particles that improved the powder flowability properties, especially with higher concentration (1.5 %). The longer mixing time (13.5 and 25 min) enabled the lubricant particles to fill all groves over the powder blend particles surface and form an intact thin layer over the  particles surfaces [9].

Tablet weight variation is closely correlated with the increase of lubricant mixing time due to the presence of lubricant material like magnesium stearate within the powder blend. Besides, the mixing time allowed the lubricant particles to spread efficiently throughout the tablet ingredients particles forming a thin layer over these particles, that leads to minimum particles interaction and friction and consequently improving the flowability properties [7]. The punches spaces of tablet press machine were filled with powder particles without pressure only with the powder flowability effect. Therefore, excellent powder flowability property is considered as a requirement for the successful direct compression technique [9]. Excellent powder flowability property reduced the particle friction so particles moved easily over each other. So, the particle-particle spaces might be reduced to its minimum, leaving more spaces that could be filled with excess particles between the punches spaces instead of air that might explain the tablet weight increase. At the same time the ODTs weight is controlled by the punches spaces that were adjusted before commencing the compression process. Consequently, the ODTs weights were not very noticeable, but they were around 300 mg ± 7.5 % [24].

Tablets thickness is mainly influenced by the increase in compression force and the decrease of mixing time since the decrease of powder flowability property leads to the decrease of particles content. Tablet hardness is also strictly associated with the increase of compression force and the decrease of mixing time as reported by Andries et al [29]. Tablet friability is affected by the compression force employed during tablets pressing in which leads to harder tablets. Disintegration time is thoroughly related to the increase in lubricant concentration and compression force, but it is not influenced by the length of mixing time. It might be due to the decrease of tablets friability % and hardness as reported tby others [29].

Fluoxetine tablet content was uniformly distributed throughout the formulation and the direct compression technique displayed an efficient procedure for the manufacturing of fluoxetine HCl ODTs.

The fluoxetine release (%) was very high within the first minute of dissolution, then T₈₀ was noticed within 5 min of dissolution with those formulations that had the smallest lubricant concentration, shortest mixing time, and lowest compression force (). Consequently, lubricant concentration, mixing time, and compression force influenced the fluoxetine release (%) due to the hydrophobic property of magnesium stearate, since it forms a layer over the particulates and stronger compression force increases the tablets hardness as reported by others [29].

The goal of this work was to prepare an optimized fluoxetine ODTs formula with an average weight of 300 mg ± 7.5%, minimum tablet thickness, friability (%), and disintegration time, but accompanied with maximum tablet hardness. The optimum responses of the variables were gained through graphical and numerical analysis by means of statistical Statgraphics® software and based on the principle of desirability [30]. The Box-Behnken design has suggested an optimized formula as in .

Therefore, the suggested formula was prepared and then characterized as done before. The experimental results were compared to the design predicted results by calculating the residual and residual error (%) in order to validate the Box-Behnken design suggestion. The residual differences were 0.95 mg, –0.02 mm, 0.1 Kp, 0.006 %, and 0.8 s respectively, and the prediction errors (%) were 0.31, –0.4, 2.13, 4.44, and 3.57 %, respectively. The results showed an insignificant difference (t-test, P_value > 0.05) between the predicted and experimental responses (). The suggested optimal formula showed the best-fitted formula amongst other formulae according to the prediction error (%) and/or residual results which were below 5 % and could be considered negligible.

Fluoxetine ODTs have been successfully developed and improved by a Box-Behnken experimental design, and prepared using direct compression technique. Variables including lubricant concentration, mixing time, and compression force have a quantitative effect on the weight variation, thickness, hardness, friability (%), and in vitro disintegration time which could be predicted by Box-Behnken design.

The experimental values of the improved formula were close and in line with the predicted values that verified the integrity of the developed fluoxetine ODTs formulation. Finally, this optimized and developed antidepressant drug, fluoxetine HCl, ODTs formulation will achieve numerous targeted benefits such as rapid onset of action, high bioavailability, ease of administration, and patients’ convenience, especially for those with swallowing difficulties regardless of age.