1. INTRODUCTION:

The most commonly approved method is oral administration due to its simplicity, convenience, safety, and, most importantly, high patient adherence¹.

Recently, several new technologies have been available to improve compliance with oral drug dosage, such as preparing orally disintegrating tablets (ODTs)². The literature employs various terms to describe orally disintegrating tablets (ODTs), including fast dissolving, rapidly disintegrating, fast dispersing, fast melting tablets, and rapid melting³. The products dissolve or disintegrate quickly when in contact with saliva, thereby eliminating chewing, swallowing, or taking tablets with liquids⁴. As both solids and liquids, ODTs offer the advantage of quick disintegration and dissolution, as a result of their high pore structure, leaving no residue in the mouth, requiring no water for administration, offering a pleasant flavour, facilitating high drug loads normally less than 500 mg, and accurate dosing⁵. As a result, they are preferred over conventional tablets among the elderly, young, paralyzed, and patients who have difficulty swallowing^6-7. Different methods are used for producing orally disintegrating tablets (ODTs) like freeze-drying, granulation, molding, direct compression, spray drying, cotton candy process, sublimation, phase transition and mass extrusion techniques. The process of freeze-drying provides better solubility, precise dosing, and is ideal for low-dose formulations and powders that do not flow well. The direct compression method allows for basic conventional equipment to be used, resulting in lower costs and fewer processing steps⁸. Furthermore, freeze-drying can be used to prepare high-dose drugs that are sensitive to moisture and heat⁹. Erectile dysfunction (ED) and premature ejaculation (PE) are two common male sexual disorders encountered by clinicians daily¹⁰. ED refers to the inability to achieve or maintain a satisfactory erection for an extended period. ED is common and becomes more prevalent with age¹¹. The research from the Massachusetts Male Aging Study discovered that 52% of men between the ages of 40 and 70 experience erectile dysfunction, while over 70% of men over the age of 70 are affected. The first-line recommended treatment for ED is the use of phosphodiesterase type 5 (PDE5) inhibitors. Which include sildenafil, vardenafil, tadalafil, and avanafil, are prescribed to treat ED in men. Tadalafil (TADA) is classified as a class II drug according to the Biopharmaceutics Classification System (BCS), characterized by low solubility and high permeability. It acts as a highly selective inhibitor of PDE5¹². Inhibition this enzyme leads to smooth muscle relaxation in the corpus cavernosum, boosting blood flow and causing an erection¹³. The characteristics of tadalafil make it the most versatile drug available on the market. PDE5 inhibitors are available worldwide. As a treatment for ED, Tadalafil was approved in 2003. It has an 18-hour elimination half-life¹⁴. Premature ejaculation in men with PE is defined by IELT (intervaginal ejaculatory latency time) and problems with ejaculatory control. PE is defined by the American Urological Association as ejaculation that occurs earlier than intended, either before or shortly after penetration, causing distress to one or both partners¹⁵. The International Society for Sexual Medicine recommended revised evidence-based definitions of acquired premature ejaculation (APE) and lifelong premature ejaculation (LPE) in 2014¹⁶. Taking selective serotonin reuptake inhibitors off-label is the first line. In both acquired and lifelong PE, it is an important strategy for managing both. In initial studies of these drugs for the treatment of depression, these drugs were associated with delays in ejaculation and orgasms, which have been exploited for the treatment of PE¹⁷. In many countries, Dapoxetine (DAPO) has been approved as an on-demand treatment for PE due to its very short half-life of 19 h¹⁸. Most of Dapoxetine's inactive metabolites are processed in the liver and kidneys, leading to reduced bioavailability. In addition, the bitter flavor of oral Dapoxetine formulations is a commonly experienced issue¹⁹. The risk of PE-related ED increases with the proportion of acquired ejaculatory problems²⁰. When treating men with PE and comorbid ED with PDE5 inhibitors, Dapoxetine demonstrated significant treatment benefits and was generally well tolerated^21-22. In terms of sales, TADA and DAPO are offered in traditional tablet forms for oral consumption under the brand name TADAPOX. To the best of our knowledge, there are currently no ODTs containing TADA and DAPO available for purchase. There are only two studies on TADA formulations in the literature. Liquisolid formulations were prepared in one study by incorporating TADA into liqui-solid tablets through direct compression²³. In a different study, TADA orodispersible tablets were developed using the direct compression technique and incorporating sodium starch glycolate (SSG) as a superdisintegrant²⁴. Thus, the goal of this research was to create and assess orodispersible tablets (ODTs) with TADA and DAPO through direct compression and freeze-drying methods to achieve quicker dissolution, faster effects, reduced liver processing, rapid release, and enhanced patient adherence by camouflaging Dapoxetine flavor with Eudragit E100 coating via spray drying. ODT excipients (Mannitol, Cross PVP, Mg Stearate, Aerosil, and Aspartame) were utilized in making ODTs through direct compression, while (Xanthan Gum, Mannitol, and Aspartame) were employed in making ODTs through freeze-drying. Quality control parameters for the developed ODTs included tests for content uniformity, hardness, friability, water absorption, disintegration time, and dissolution.

2. MATERIALS AND METHODS:

2.1. Materials:

The working standard of TADA was kindly supplied by Ibn-Alhaytham pharmaceutical industries, Aleppo-SyriaThe certificate of analysis stated that the purity percentage was 99.35%. The working standard of DAPO was kindly supplied by Unipharma pharmaceutical industries, Damascus -Syria. As per the analysis certificate, the purity level was documented at 99.87% (Jawaharlal Nehru Pharma City, India). Mannitol, Aerosil, Aspartame, Eudragit E100 and Mg Stearate was kindly supplied by Rama Pharma pharmaceutical industries, Aleppo-Syria. Xanthan gum, and Cross PVP was kindly supplied by Asia pharmaceutical industries, Aleppo-Syria. The study utilized analytical grade reagents: methanol with a purity of 99.7% was provided by (Scharlau- Spain), while double distilled water was used in all experiments.

2.2. Instrumentation:

In this study, Bruker ATR-FTIR spectrum analyzer (Massachusetts, USA) was used for all measurements. Pilot Press (Sallius mini SXt44, India) was used for the compression of tablet. Epsilon 2-6D LSC Freeze Dryer (Germany) was used for freeze-drying. YC-015 mini spray dryer (Pilotech, Shanghai) was used for the encapsulation of Dapoxetine HCl. A model DRS Dissolution tester (Prabhadevi, Mumbai, India) was used for the dissolution test of tablets. DSC- PT10 (Linseis, Thailand) was used for all measurments. Tapped density tester (Model TDA-2, Mumbai). Convection oven (HERAEUS D-6450 HANAU, India). Erweka (TA20, Germany) was used for the friability test. A disintegration tester (Copley, USA). The pH meter (GLP21, Crison, Spain) was used to adjust the pH of the phosphatic buffer to pH 6.8. The compound's solubility was increased by using sonication with an ultrasonic processor (Power Sonic 405, Hwashin, Korea). The UV/Vis Spectrophotometer Instrument Ltd (T80+, UK) is the ultraviolet spectrophotometric device and it has a computer connection. Digital Tablet-Hardness Tester (Cyprus) tested ODTs for hardness.

2.3. Preparation of ODT formulations:

2.3.1. Selection of excipients:

The ODT formulation was prepared using direct compression excipients mannitol as a filler, cross povidone, as a super disintegrating agent, aerosil as a glider, magnesium stearate as a lubricant, and aspartame as a sweetening agent. An ODT formulation was made by freeze-drying xanthan gum as a binder, mannitol as a filler, and aspartame as a sweetener. Tadalafil, Dapoxetine HCl containing ODT prepared by direct compression technique (TADA, DAPO, DC-ODT). A homogeneous physical mixture of Tadalafil and Dapoxetine HCl with excipient was prepared by geometric extension. The compressibility index, Hausner ratio, angle of repose, bulk/tapped density, and moisture content were used to assess the physical characteristics of the powder mixture. The ODTs weighing 280 mg, were produced using direct compression via Pilot Press (Sallius mini SXt44, India) its rotative compression machine, and it has 12 presses, with a production capacity of 4,000 tablets/hour. Tadalafil, Dapoxetine HCl containing ODT by the freeze-drying technique (TADA, DAPO, LYO-ODT). Following a 30-minute swelling period in pre-heated distilled water (20–25 °C), xanthan gum was mixed with the other excipients individually using a magnetic stirrer until thoroughly combined. Tadalafil and Dapoxetine HCl were added and blended until a uniform mixture was formed. The ultimate outcome was divided into circular Aluminium packages (1 mL) and the freeze-drying process was detailed in Table (1). Lyophilized using Epsilon 2-6D LSC Freeze Dryer (Germany).

Table 1. Lyophilization cycle of (TADA, DAPO, LYO-ODT).

Lyophilization cycle	Cooling rate (°C\min)	Temperature (°C)	Time (min)	Pressure (micro bar)
Freezing stage	1	-45	180	-
Primary drying	1	-20	480	100
Secondary drying	1	20	300	50

2.3.2. Taste masking of Dapoxetine Hydrochloride:

One of the most common taste masking techniques is microencapsulation. Various methods can be used, including coacervation, solvent evaporation, extrusion, and spray drying^25-26-27-28. Dapoxetine HCl, a bitter-tasting SSRI, is available worldwide in conventional tablets. A drug-polymer solution was prepared using Eudragit E100 as a taste-masking polymer. The copolymer has a solubility that depends on pH and is made up of poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) in a ratio of 1:2:1. It cannot be dissolved in saliva with a pH of 6.8-7.2 but dissolves quickly at pH levels lower than 5, giving good protection in the mouth and fast drug release in the stomach. In addition to masking taste, this polymer also protects against moisture. Spray drying is a relatively simple and convenient technology for the preparation of microparticles. Microencapsulation of Dapoxetine HCl using Eudragit E100 was performed using a YC-015 mini spray dryer (Pilotech, Shanghai). Dapoxetine HCl and Eudragit E100 were accurately weighed and simultaneously dissolved by magnetic stirring in a solvent of purified water to obtain a clear solution with the addition of (0.1N) hydrochloric acid as a polymer to adjust the pH (pH=4). Drug/polymer ratios (1:5) and polymer concentration (7.5%) were used for microparticles. Solid microparticles were formed from the drops. A cyclone separated the particles and a collector collected them. Experiments were carried out under the following conditions: inlet temperature 105 °C, outlet temperature 80 °C, and pump rate 8 RPM. The prepared microparticles of Dapoxetine HCl were used for the freeze-drying method only, because the direct compression method requires a large amount of the prepared microparticles of Dapoxetine HCl, which we don't have due to the small quantity of Dapoxetine HCl.

2.3.3. In-vivo taste evaluation:

We evaluated the taste in six healthy male humans (aged 18-55) who provided informed consent. In this experiment, the pure drug, prepared microparticles, and final ODTs (TADA, DAPO, LYO-ODT) was placed on the tongue for 30 seconds and allowed to dissolve completely. For judging the bitterness of the taste, a scale of 0 represented bitterness, 1 represented barely bitterness, 2 represented moderate bitterness, and 3 represented strong bitterness.

2.3.4. Determination of production yield:

To determine whether the method used had a good yield, samples were obtained and weighted as follows:

Production yield (%) = the total of mass recovered microparticles/the total mass of (drug + polymer) *100

2.3.5. Determination of encapsulation efficiency:

Dapoxetine HCL content in the formula was determined at maximum absorption wavelength (λ= 292nm) by using UV/Vis Spectrophotometer Instrument Ltd (T80+, UK). The solution of the formula which contains an amount equivalent to 30mg of Dapoxetine was prepared by dissolving solid dispersion in 25ml HCl (0.1N) and sonicated for 20 min until obtaining a clear solution then transferred 1mL of the previous solution into a 25 ml volumetric flask, and then HCl (0.1N) was added to make the volume up to 25ml then measured the absorption in the presence of the blank of Eudragit E100 in HCl. The calculation of encapsulation efficiency was determined using the formula: Encapsulation Efficiency (%) = weight of dapoxetine HCl in microparticles/weight of theoretical dapoxetine HCl amount *100

2.3.6. Fourier transform infrared FT-IR spectroscopy:

A Bruker ATR-FTIR spectrum analyzer (Massachusetts, USA) was used. Using Potassium Bromide as a baseline, a Dapoxetine HCl, Eudragit E100, Physical mixture, and microparticles were measured with an FT-IR spectrophotometer. These spectra are used to determine any interaction between polymer and drug.

2.4. Differential Scanning Calorimetry (DSC):

A DSC thermogram was recorded for Dapoxetine HCl, Eudragit E100, Physical mixture, and microparticles to confirm the formation of amorphous solid dispersions which indicated that taste-masked Dapoxetine was formulated. Samples (2-5mg) were prepared in closed aluminium pans and heated at a scanning rate of 5 cº/min in a temperature range between 30-400cº by using LINSEIS DSC calorimeter (LINSEIS DSC-PT10, Thailand).

2.5. Characterization of ODT formulations:

2.5.1. Determination of the powder mixture's physical characteristics:

2.5.1.1. Bulk/tapped volume and density:

The bulk and tapped volume, along with the density of the powder mixture, were measured using a tapped density tester (Model TDA-2, Mumbai). This was achieved by filling the graduated cylinder of the apparatus with 50grams of the powder mixture (TAD, DAP, DC-ODT). The bulk volume (Vb) was detected. We measured the volume of the cylinder after tapping it 10, 500, and 1250 times. V1250 is taken as the tapped volume if the difference between V500 and V1250 ≤2 Cm³. The volume was measured as V2500 when the discrepancy between V500 and V1250 was more than 2 cm³. The study was carried out on three occasions, and the findings were displayed as average values and standard deviations (SD). Equations (1) and (2) were utilized to determine the bulk and tapped densities.

Bulk density (DB) = m/Vb (1)

Tapped density (DT) = m/V1250 (or 2500) (2)

The volume (in mL) is measured after either 1250 or 2500 taps. The mass of the sample (g) is represented by m, while the volume of the sample (mL) is represented by Vb.

2.5.1.2. Angle of repose:

An angle of repose was measured to characterize the flow characteristics of the powder blend. A fixed funnel method was used to determine the angle of repose. Using this method, a cone is formed when a powder blend is poured through a funnel. The angle of repose can be calculated as the inverse tangent of the height of the cone (h) divided by half the width of the cone's base (r).

Angle of repose = tan^(-1)〖H/R〗

2.5.1.3. Compressibility index and Hausner Ratio:

Compressibility Index = (DT- DB)/DT×100

Housner ratio = DT/DB

Where DT is the Tapped density obtained for the ODT powder mixture, and DB is the Bulk density.

2.5.1.4. Moisture content:

The powder mixture's moisture content was also assessed through the loss on drying method utilizing a convection oven (HERAEUS D-6450 HANAU, India). The sample, weighing around 10 grams, was heated to 105°C until it reached a consistent weight.

2.5.2. Quality control tests of ODTs.

The ODTs underwent multiple quality control tests, such as hardness, weight uniformity, content uniformity, friability, wetting time, drug content, and water absorption ratio, as well as disintegration and dissolution tests.

2.5.2.1. Hardness determination:

Digital Tablet-Hardness Tester (Cyprus), tested ODTs for hardness. A 10-measurement average was used for hardness (Newton; N).

2.5.2.2. Weight uniformity:

Following European Pharmacopoeia 8^th ²⁹, a weight uniformity test was conducted. Using an analytical balance, 20 tablets were randomly selected and weighed individually. We calculated the mean weight and compared it to the individual tablet weights.

2.5.2.3. Drug content:

Five tablets were selected at random and crushed using a mortar and pestle. The ground powder, which is the same as 10mg of Tadalafil and 33.58mg of Dapoxetine HCl (equal to 30 mg of Dapoxetine base), was ingested and mixed in 10 ml of methanol. The specimen underwent ultrasonic exposure in a container for 30 minutes, then was stirred magnetically at 3000 rpm at ambient temperature. Twenty minutes later, the medium was filtered with 0.45 µm cellulose acetate membrane filters. Methanol was used to adjust the volume to 25 ml, then 1 mL of the initial solution was transferred to a 25 ml volumetric flask, and methanol was added to make the volume up to 25 ml. Subsequently, the levels of Tadalafil and Dapoxetine HCl were measured by calculating the absorbance at 284, 291nm using the established equations ³⁰. Repeated three times.

C_TADA= (189.11A₂ - 201.8A₁)/ (-7711.44)

C_DAPO= (335.59A₁- 352.7A₂)/ (-7711.44)

Where A₁, A₂ absorptivity of the mixture at wavelengths 284, 291nm respectively.

2.5.2.4. Wetting time and water absorption ratio:

A Petri dish with 6 ml of water and 1 ml of methylene blue was used to dye tissue paper that had been folded twice. The time required for the complete wetting of the paper was measured with a tablet placed on the paper. We conducted experiments to measure the wetting time of three tablets based on a specific formula. We weighed the wetted tablet to calculate water absorption ratio (R). Using the following equation: R=100(Wa-Wb)/Wb

Where Wb is the weight of the tablet before it absorbs water. Wa is the weight of the tablet after it has absorbed water. A standard deviation was calculated from three tablets of each formulation.

2.5.2.5. Friability test:

The friability of ODTs was measured using a device called the Erweka (TA20, Germany). Twenty tablets, all weighed accurately, were tested for friability. The test involved rotating the tablets for a total of 100 revolutions at a speed of 25 rotations per minute (rpm) for a duration of 4 minutes. Following 100 rotations, the tablets were weighed again and were subsequently contrasted with their initial weight. The percentage-based measurement of tablet friability, which is loss due to abrasion, was reported. Weight loss of under 1% is typically regarded as an appropriate amount. Using the following formula, we calculated the % of friability.

Percentage Friability = W – W0 × 100 / W

Where W0 is the initial weight of the tablet. W is the weight after friability. Tablets with a friability of less than 1% are considered acceptable.

2.5.2.6. Disintegration test:

A disintegration tester (Copley, USA) was used to test both formulations in vitro in the presence of six tablets in distilled water kept at 37 °C ±0.5 °C for at least 3 minutes before disintegration. The disintegration time is calculated by measuring the time it takes until no particles of tablets remain on the screen. The results presented are the average of six determinations (n=6).

2.5.2.7. Dissolution test:

Six tablets from each formulation were subjected to dissolution testing using a DRS Dissolution tester model in Prabhadevi, Mumbai, India. The phosphate buffer pH 6.8 was dissolved in 900 mL of dissolution media at 37 ± 0.5 °C and 50 ± 2 rpm with the paddle method. Samples of 5 mL were collected and replaced every 0, 1, 3, 5, 10, and 15 minutes at 37 ± 0.5 °C. The collected samples were filtered using a Millipore filter with a pore size of 0.45 mm. Next, pour into a 25 ml volumetric flask and top up to 25 mL with methanol. Following this, the levels of Tadalafil and Dapoxetine HCl were assessed by measuring the absorbance at 284, 291 nm. Three times repeated.

3. RESULTS AND DISCUSSION:

3.1. Selection of excipients:

3.1.1. Direct compression method:

The selection of excipients greatly impacts both the formulation and quality control testing of ODT formulations. An important factor to pay attention to in direct compression is the choice of appropriate excipients that have excellent flow properties and minimal segregation tendencies. Due to the presence of a wide range of particle sizes, flowability issues, and inadequate compressibility, direct compression excipients are constrained. Most ODT excipients usually consist of mannitol, serving as both a filler and sweetening agent. An artificial sweetener (like aspartame) was utilized. Despite its sweet taste, mannitol was disregarded in favor of aspartame to improve patient acceptance. The ODT formulations prepared compositions are listed in Table (2). Mannitol, a sugar alcohol produced by catalytic reduction of sugar, was the initial choice for diluting ODT during development. Mannitol in the mouth creates a cooling sensation because of its exothermic dissolution. Mannitol's smooth texture, lack of moisture absorption, and sweet flavor make it ideal for creating ODT formulations as an additional advantage. The capacity for tablets to break down is a crucial constraint in the creation of an ODT formula. Using superdisintegrants like cross povidone is suitable due to its effectiveness at low levels, ability to disperse, and rapid swelling. Cross povidone, in contrast to other superdisintegrants, breaks down through a combination of swelling and wicking. Because of its dense crosslinking, cross povidone rapidly expands in water without creating a gel. Evidence indicates that cross povidone particles are very porous and granular, resulting in the quick breakdown and absorption of liquid into the tablet. Smaller particles disintegrate slower than larger particles. The distinct particle shape of cross povidone disintegrants results in their excellent compressibility. Cross povidone can additionally be employed as a solubility booster.

3.1.2. Freeze-drying method:

In the manufacture of freeze-dried ODTs, polymers such as gelatine and xanthan gum are required for the glassy amorphous structure. The freeze-dried ODTs were therefore formulated with xanthan gum, which was used as both a matrix former and a viscosity modifier. The compositions of the prepared ODT formulations are presented in Table (2). The concentration of xanthan gum also affected the viscosity of the solutions before freeze-drying. It is important to use a viscosity enhancer if a drug is suspended in the formulation to avoid sedimentation. Xanthan gum concentration and tablet dimensions affect the strength of the tablets. When in contact with saliva, the xanthan gum swells, forming a jelly-like structure, which results in longer in vivo disintegration times. The filler was mannitol, which gives freeze-dried ODTs their crystallinity and hardness.

Table 2: Formulation composition of ODTs

Formulation	Ingredients	Amounts (mg)/Tablet
Tada, Dapo, DC-ODT	Tadalafil	10
	Dapoxetine HCl	33.58 mg Dapoxetine HCl equivalent to 30 mg Dapoxetine
	Mannitol	216.68
	Cross povidone	14
	Mg Stearate	2.8
	Aerosil 200	2.8
	Aspartame	0.14
Tada, Dapo, LYO-ODT	Tadalafil	10
	Dapoxetine HCl	203.44 mg Prepared microparticles equivalent to 30 mg Dapoxetine
	Mannitol	235.43
	Xanthan Gum	0.9
	Aspartame	0.225

3.2. Taste masking of Dapoxetine Hydrochloride:

The production yield was 77.36% and encapsulation efficiency was 99.03%. Analyses of the physicochemical properties of microparticles were conducted using an Attenuated Fourier transform infrared spectrophotometer FT-IR and differential scanning calorimetry DSC. By comparing the IR spectra of pure Dapoxetine HCl and Eudragit E100 to their physical mixture, it was determined that they were compatible. Figure (1) displays peaks associated with either the polymer or the drug substance, with no significant shifts observed. The peaks specific to Dapoxetine HCl were observed at 3053 cm^-1, 2931 cm^-1, 1268 cm^-1, and 1098 cm^-1, originating from the ether and C-N groups. Peaks were observed with the Eudragit E100 at 2960 cm^-1, and 1470 cm^-1 corresponding to ACHx groups, at 2711 cm^-1 for dimethylamino groups, 1730 cm^-1 for C=O ester vibration, and 1152 cm^-1 for the ester groups. The drug and polymer combination displayed identical peaks. Changes in the IR spectra were observed due to the inclusion of the drug in microparticles. The peaks of Eudragit E100 remained unchanged, while the 3053 cm^-1 peak of Dapoxetine HCl disappeared, and the peaks at 1268 cm^-1 and 1098 cm^-1 were less prominent. As a result, infrared analysis indicates that Dapoxetine HCl was effectively trapped or included in the polymer matrix and connected to the polymer chain through hydrogen or van der Waals bonds, showing no incompatibility with Eudragit E100. Because of their direct contact with polymer chains, the stretching and bending vibrations of the bonds were decreased. The Dapoxetine HCl thermal curve was determined using differential scanning calorimetry and is illustrated in Figure (2). The melting point of Dapoxetine HCl is represented by the sharp endothermic peak at 187.8 °C. The thermal examination of Eudragit E100 indicated a wide peak at 60°C. The thermogram of the blend of Eudragit E100 and Dapoxetine HCl demonstrated peaks matching those of the separate components, suggesting that the thermal characteristics of the mixture remain unchanged compared to the pure substances. This indicates that the thermal properties of Eudragit E100 and Dapoxetine HCl are preserved in the physical blend without any substantial changes in their thermal behavior due to interactions. Broad peaks that resemble each other can be seen in the thermograph of microparticles made with Eudragit E100 (peaking at 60°C). However, when the drug is mixed into the polymer, the remaining part of the thermogram undergoes significant alterations. In the differential scanning calorimetry (DSC) of the pure drug substance, the distinctive peak at 187.5°C indicating the melting point of Dapoxetine HCl was not observed in the thermal analysis of the microparticles. It is possible for the drug to become amorphous and be enclosed within the Eudragit matrix due to its encapsulation.

3.2.1. In-vivo taste evaluation:

Six healthy male volunteers participated in the taste test, with the results shown in Table (3). Eudragit E100 and Dapoxetine reduced or completely masked the bitter taste of the medicine after complexing. Therefore, throughout this inquiry, it was sought to provide excellent tablet delivery characteristics that would increase flavor masking.

Table 3: comparative taste evaluation.

Degree of Bitterness
Time	30 seconds	1 minute	2.5 minutes	5 minutes
Pure drug	3	3	3	3
Microparticles	1	0	0	0
TADA, DAPO, LYO-ODT	0	0	0	0

*Results are the mean of 3 observations

0= bitterness, 1= barely bitterness, 2=moderate bitterness, 3=strong bitterness.

Figure 1: FT-IR spectra of (a): Dapoxetine HCl, (b): Eudragit E100, (c): Physical mixture (drug + polymer) (d): Microparticles.

Figure 2: DSC thermogram of (a): Dapoxetine HCl, (b): Eudragit E100, (c): Physical mixture (drug + polymer) (d): Microparticles

3.3. Physical properties of the powder mixtures:

3.3.1. Bulk/tapped volume and density:

The bulk/tapped volumes and densities of powders are influenced by the ways they are prepared, treated, and stored, ultimately impacting their rheological properties. The estimated bulk/tapped densities values for (Tada, Dapo, DC-ODT). Powder densities were 0.704 and 0.746 as Table (4) respectively. Volumes and densities in bulk and tapped mixtures of ODT powder were very similar. These results suggest that the powder mixtures exhibit comparable flowability characteristics.

3.3.2. Angle of repose:

Angle of repose tests can offer insights into how friction and cohesion among powder particles influence their properties. The angle of repose value estimated for a powder blend (Tada, Dapo, DC-ODT) was (16.11 ± 1.11°; Table 4). As per USP 30 ³², a powder demonstrating an angle of repose value below 20° showcases outstanding flow characteristics. Based on this data, the flow characteristics of our ODT powder are deemed to be excellent. Based on these findings, ODT powders exhibit favorable compressibility index and Hausner ratio.

3.3.3. Compressibility index, Hausner ratio:

The Hausner ratio and compressibility index are common, rapid, and simple methods used to forecast the flow properties of powders. The compressibility index measures the strength and stability of powder bridges, while the Hausner ratio examines interparticulate friction. The compressibility index and Hausner ratios of the powder mixtures of Tada, Dapo, and DC-ODT were almost the same, with values of 5.63 ± 1.62 and 1.05 ± 0.03, respectively (Table 4). Per USP 30 guidelines, powders demonstrate excellent flow characteristics if their compressibility index is below 10% and Hausner ratios range from 1.00 to 1.11. Therefore, the (Tada, Dapo, DC-ODT) powder mixture demonstrates outstanding flow characteristics. These findings align with the angle of repose calculations conducted in this study.

3.3.4. Moisture content:

Powder flowability is influenced by the moisture content. Powder mixtures with a low moisture content act as lubricants between particles, thereby increasing their flowability. Conversely, when a powder mixture is high in moisture, the liquid bridges become stronger, causing the powder to stick together and leading to poor flow. In order to prepare high-quality tablets, moisture level measurements and controls must be made in powder mixtures. As a result, powder flows better at low moisture content. (Tada, Dapo, DC-ODT) the powder had a moisture content of less than 1% (0.80 ± 0.10%; Table 4), and this should not harm the powder's capacity to flow during compression. The physicochemical results of the powder combinations for (Tada, Dapo, DC-ODT) make it abundantly evident that the powder has good flow characteristics and is appropriate for use with direct compression technology.

Table 4: Results of Physical properties of the powder mixtures.

(Tada, Dapo, DC-ODT)
Bulk volume (mL)	71
Tapped volume (mL)	67
Bulk density (g/mL)	0.704
Tapped density (g/mL)	0.746
Compressibility index	5.63 ± 1.62
Housner ratio	1.05 ± 0.03
Angle of repose (°)	16.11 ± 1.11
Moisture content (%)	0.80 ± 0.1

3.4. Quality control tests of ODTs:

3.4.1. Determination of the hardness of ODTs:

The mechanical robustness of a tablet must be at its best to endure abrasions during packaging, handling, and transportation. Table (4) displays the hardness of both directly compressed (Tada, Dapo, DC-ODT) and freeze-dried (Tada, Dapo, LYO-ODT) orally disintegrating tablets. The ODTs' hardness is 107 ± 5.37N for (Tada, Dapo, DC-ODT) demonstrates strong mechanical strength to withstand physical and mechanical pressures. On the other hand, the high porosity of ODT tablets led to a hardness of 20.5 ± 2.15N for (Tada, Dapo, LYO-ODT). It was simple to detach them from the blisters without sticking. Because of the lack of strong attachment between the tablets and the blister cavity, the ODTs have little mobility in the packaging, indicating they will maintain stability when transported.

3.4.2. Friability test:

As per the 8th edition of the European Pharmacopoeia, the decrease in weight during a single measurement must not exceed 1%. The friability value of ODT formulations is less than 1% (0.86% for Tada, Dapo, DC-ODT), while the friability value (2.72% for Tada, Dapo, LYO-ODT). Tablet hardness is related to friability. When tablet hardness is increased, friability decreases. Due to the high porous and fragile structure of the lyophilizate, the hardness is low and the friability is greater than 1%, but this is not important because the lyophilizates are directly prepared within the blisters so they will not undergo the packaging process as the oral disintegrating tablet is prepared by direct compression.

3.4.3. Weight uniformity:

The average weight for tablet direct compression formulation (Tada, Dapo, DC-ODT) ranged from (280±2.0 mg), as presented in Table (5), and the average weight for tablet freeze-drying formulation (Tada, Dapo, LYO-ODT) ranged from (450±3.0 mg), which meet the European pharmacopeia's acceptable range of weight uniformities.

3.4.4. Wetting time, water absorption ratio and disintegration study:

Water absorption determines how quickly orally disintegrating tablets absorb water and thus disintegrate. When in contact with water, the water absorption ratio and wetting time of (Tada, Dapo, DC-ODT) were (3.07 ± 0.04%) and (50 ± 2 sec) respectively. Even though (Tada, Dapo, LYO-ODT) broke apart right away, they did not expand. Therefore, the calculation of the water absorption ratio was not possible due to (Tada, Dapo, LYO -ODT).

According to the 8th edition of the European Pharmacopoeia, oral disintegrating tablets must be broken up within 180 seconds. The disintegration time of (Tada, Dapo, DC-ODT) was 62 sec, while for (Tada, Dapo, LYO-ODT) it was 29 sec in Table (5), and both ODT formulations met the European Pharmacopeia 8th standard. Due to its increased porosity, freeze-dried ODT demonstrated a quicker disintegration time. As the porosity of the ODT increases, the time it takes for the tablet to disintegrate decreases due to enhanced water penetration capability.

The wetting time, water absorption ratio, and disintegration time of orally disintegrating tablets (ODTs) in their formulations are greatly impacted by the existence of superdisintegrants, like cross povidone. ODTs containing a disintegrant that swells easily demonstrate substantial water absorption. In our research, (Tada, Dapo, DC-ODT) had cross povidone. Cross povidone uses both swelling and wicking to facilitate disintegration, unlike other superdisintegrants that mainly depend on swelling alone. Due to its high crosslink density, cross povidone rapidly absorbs water without forming a gel. The highly porous texture of cross povidone particles allows for quick breakdown by absorbing fluids into the tablet. Larger particles break down faster than smaller ones. Due to their unique particle shape, cross povidone disintegrants are highly compressible substances.

Table 5: Results of Quality control tests of ODTs.

Tests	Tada, Dapo, DC-ODT		Tada, Dapo, LYO-ODT
Average Weight (mg)	280 ± 2		450 ± 3
Hardness (N)	107 ± 5.3		20.5 ± 2.15
Friability (%)	0.86		2.72
Disintegration time (Sec)	62		29
Wetting time (Sec)	50 ± 2		*
Water absorption ratio (%)	3.07 ± 0.04		*
Drug content (%) n=3	TADA	98.42 ± (1.82)	TADA	101.41 ± (1.03)
	DAPO	102.22± (1.07)	DAPO	100.28 ± (0.48)

3.4.5. Drug Content:

The mean percentage of Tadalafil and Dapoxetine HCl content in ODTs from both formulations is presented in Table (5). The drug content of Tadalafil and Dapoxetine HCl in the prepared (TADA, DAPO, DC-ODT) and (TADA, DAPO, LYO-ODT) falls within the acceptable range according to the European Pharmacopoeia 8^th. This indicates that the methods used in manufacturing and the materials used did not affect the stability of the Tadalafil and Dapoxetine HCl.

3.4.6. In vitro dissolution test:

Using a pH 6.8 buffer, we mimicked dissolution in the mouth, as well as evaluated the taste-masking effects of the microparticles. Figure (5) shows that in the phosphate buffer at pH 6.8, 43.42% of Tadalafil was released from the (TADA, DAPO, DC-ODT) after 3 minutes, and 78.38% from the (TADA, DAPO, LYO-ODT). Additionally, 51.27% of Dapoxetine was released from the (TADA, DAPO, DC-ODT), and 8.94% from the (TADA, DAPO, LYO-ODT).

Tadalafil showed quicker dissolution in (TADA, DAPO, LYO-ODT) compared to Tadalafil in (TADA, DAPO, DC-ODT). Due to the extremely porous nature of the (TADA, DAPO, LYO-ODT), the matrix dissolves quickly, leading to rapid disintegration of the tablets. However, Dapoxetine dissolved more quickly in the (TADA, DAPO, DC-ODT) compared to in the (TADA, DAPO, LYO-ODT). Due to the encapsulation of Dapoxetine with Eudragit E100. It dissolves in solutions with a pH lower than 5.0, but swells and allows for permeability in solutions with a pH higher than 5.0. To evaluate how well taste-masking works, the FIP/AAPS recommendations suggest taking several samples during the first few minutes of the dissolving test, specifically at 1, 3, 5, and 10 minutes 33. This approach establishes a physical obstacle between the drug component and the taste receptors through methods like microencapsulation, polymer coating of drug particles, pellet formation, or granulation of the drug substance. The taste-masking properties of the dosage form are intended to be managed by the minimal amount of active ingredient released during the initial minutes. Discuss the release of the drug at the taste-masking dissolving threshold, usually around 10%, and with no negative taste remaining. This amount needs to be evaluated through taste panel studies in vivo and varies based on the specific drug and dose used in the product.

In vitro dissolution test of (TADA, DAPO, DC-ODT)

In vitro dissolution test of (TADA, DAPO, LYO-ODT)

Figure 5: In vitro dissolution test of (TADA, DAPO, DC-ODT), and (TADA, DAPO, LYO-ODT)

4. CONCLUSION:

ODTs are being used more often to treat patients in psychiatric, geriatric, and pediatric care. This research successfully created ODT formulations with TADA and DAPO, showing good flowability (for DC-ODTs), fast disintegration times, and positive dissolution profiles. Spray-drying Dapoxetine solution with Eudragit E 100 produced microparticles that effectively masked the taste. The quantity of Dapoxetine discharged within 3 minutes during the dissolution examination was lower than the predicted limit stated in the literature. Moreover, the LYO-ODT showed quicker disintegration and dissolution compared to other forms. All created ODTs adhered to pharmacopeial standards. We suggest utilizing an ODT strategy for TADA and DAPO in order to improve patient adherence.

5. REFERENCES:

1. Hannan PA, Khan JA, Khan A, Safiullah S. Oral dispersible system: A new approach in drug delivery system. Indian J Pharm Sci [Internet]. 2016; 78(1): 2–7. Available from: http://dx.doi.org/10.4103/0250-474x.180244

2. Vishali T, Damodharan N. Orodispersible tablets: A review. Res J Pharm Technol [Internet]. 2020; 13(5): 2522. Available from: http://dx.doi.org/10.5958/0974-360x.2020.00449.7

3. Sunada H, Bi Y. Preparation, evaluation and optimization of rapidly disintegrating tablets. Powder Technol [Internet]. 2002; 122(2–3): 188–98.

4. Bafail RSM. Disintegration testing for orally disintegrating tablets (ODTs): An overview. Trop J Pharm Res [Internet]. 2024; 22(11): 2399–406. Available from: http://dx.doi.org/10.4314/tjpr.v22i11.21

5. Stange U, Führling C, Gieseler H. Freeze drying of orally disintegrating tablets containing taste masked naproxen sodium granules in blisters. Pharm Dev Technol [Internet]. 2015; 20(8): 1018–24. Available from: http://dx.doi.org/10.3109/10837450.2014.959179

6. Ölmez S, Sevtap I. Advantages and quality control of orally disintegrating tablets. Fabad J Pharm Sci. 2009; 34: 167–72.

7. Swamivelmanickam M, Venkatesan P, Sangeetha G. Preparation and evaluation of mouth dissolving tablets of loratadine by direct compression method. Res J Pharm Technol [Internet]. 2020; 13(6): 2629. Available from: http://dx.doi.org/10.5958/0974-360x.2020.00467.9

8. Anjan K, Mahapatra RP, Swain B, Revathi N, Nirisha PN. Orodispersible Tablets: A review on Formulation Development Technologies and Strategies. Research J Pharm and Tech. 2013; 6(9): 941–53.

9. Goel H, Rai P, Rana V, Tiwary AK. Orally disintegrating systems: innovations in formulation and technology. Recent Pat Drug Deliv Formul [Internet]. 2008; 2(3): 258–74. Available from: http://dx.doi.org/10.2174/187221108786241660

10. Ma D, Wang A, Wang H, Yang J, Luo D, Zhao Z, et al. A review of studies on the treatment of premature ejaculation with traditional Chinese medicine. Integr Med Nephrol Androl [Internet]. 2024; 11(3). Available from: http://dx.doi.org/10.1097/imna-d-24-00008

11. Sadishkumar S, Kumar S, Mohith SN, Prathiba R, Abilash S, Mahesh AR. In Silico Investigation of Chemical Components of Fragaria ananassa Species as Aphrodisiac Agents for Erectile Dysfunction. Research Journal of Pharmacy and Technology [Internet]. 2024; 17(7): 3315–9. Available from: http://dx.doi.org/10.52711/0974-360X.2024.00518

12. Shah M, Patel D. Development and characterization of tadalafil solid dispersion using skimmed milk for improved the solubility and dissolution release profile. Res J Pharm Technol [Internet]. 2020; 13(12): 6212–7. Available from: http://dx.doi.org/10.5958/0974-360x.2020.01083.5

13. Dorsey P, Keel C, Klavens M, Hellstrom WJG. Phosphodiesterase type 5 (PDE5) inhibitors for the treatment of erectile dysfunction. Expert Opin Pharmacother [Internet]. 2010; 11(7): 1109–22. Available from: http://dx.doi.org/10.1517/14656561003698131

14. Shin YE, Rojanasarot S, Hincapie AL, Guo JJ. Safety profile and signal detection of phosphodiesterase type 5 inhibitors for erectile dysfunction: a Food and Drug Administration Adverse Event Reporting System analysis. Sex Med [Internet]. 2023; 11(5): qfad059. Available from: http://dx.doi.org/10.1093/sexmed/qfad059

15. McMahon CG, McMahon CN, Leow LJ. New agents in the treatment of premature ejaculation. Neuropsychiatr Dis Treat [Internet]. 2006; 2(4): 489–503. Available from: http://dx.doi.org/10.2147/nedt.2006.2.4.489

16. Gao J, Peng D, Zhang X, Hao Z, Zhou J, Fan S, et al. Prevalence and associated factors of premature ejaculation in the Anhui male population in China: Evidence-based unified definition of lifelong and acquired premature ejaculation. Sex Med [Internet]. 2017; 5(1): e37–43. Available from: http://dx.doi.org/10.1016/j.esxm.2016.11.002

17. Krishnakumar P, Sundarrajan T, Kathiravan MK, Manikandan K. Spectroscopic estimation of dapoxetine HCl using multivariate analysis. Res J Pharm Technol [Internet]. 2020; 13(6): 2715. Available from: http://dx.doi.org/10.5958/0974-360x.2020.00483.7

18. Martin-Tuite P, Shindel AW. Management options for Premature Ejaculation and Delayed Ejaculation in men. Sex Med Rev [Internet]. 2020; 8(3): 473–85. Available from: http://dx.doi.org/10.1016/j.sxmr.2019.09.002

19. El-Said IA, Aboelwafa AA, ElGazayerly ON. Optimization of taste-masked dapoxetine oral thin films using factorial design: in vitro and in vivo evaluation. Pharm Dev Technol [Internet]. 2021; 26(5): 522–38. Available from: http://dx.doi.org/10.1080/10837450.2021.1894445

20. Corona G, Rastrelli G, Limoncin E, Sforza A, Jannini EA, Maggi M. Interplay between premature ejaculation and erectile dysfunction: A systematic review and meta-analysis. J Sex Med [Internet]. 2015; 12(12): 2291–300. Available from: http://dx.doi.org/10.1111/jsm.13041

21. Mohseni Rad H, Zahirian Moghadam T, Hosseinkhani A, Nima Soluki N, Amani F. Comparison of Dapoxetine /Tadalafil and Paroxetine/Tadalafil combination therapies for the treatment of the premature ejaculation: A randomized clinical trial. Urol J [Internet]. 2021; 19(2): 138–43. Available from: http://dx.doi.org/10.22037/uj.v18i.6644

22. Seftel AD. Re: Efficacy and safety of dapoxetine in men with premature ejaculation and concomitant erectile dysfunction treated with a phosphodiesterase type 5 inhibitor: randomized, placebo-controlled, phase III study. J Urol [Internet]. 2014; 191(4): 1077–8. Available from: http://dx.doi.org/10.1016/j.juro.2014.01.070

23. Development and Optimization of Liquisolid Tablets Containing Tadalafil and dapoxetine as a Combined Therapy for Male Sexual Dysfunction‏.

24. Pahwa R, Gupta N. Superdisintegrants in the development of orally disintegrating tablets: a review. International journal of pharmaceutical sciences and research. 2011; 2(11).

25. Gittings S, Turnbull N, Roberts CJ, Gershkovich P. Dissolution methodology for taste masked oral dosage forms. J Control Release [Internet]. 2014; 173: 32–42. Available from: http://dx.doi.org/10.1016/j.jconrel.2013.10.030

26. Andayani R, Hasbi H, Febriyenti F. Analysis of chlorpheniramine maleate in microcapsules formulation with eudragit E PO polymer using spray drying method. Res J Pharm Technol [Internet]. 2023; 5279–84. Available from: http://dx.doi.org/10.52711/0974-360x.2023.00855

27. Pagar HB, Shinde UP, Agrawal YS, Barhate SD, Luhade TS, Sonawane RO. Taste Masking: A Review. Research J Pharm and Tech. 2012; 5(2): 152–7.

28. Ghanchi SD, Dhawale SC. Taste Masking Technologies of Pharmaceuticals. Research J Pharm and Tech. 2011; 4(10): 1513–8.

29. Council of Europe. European Pharmacopoeia. 8th ed. Strasbourg: Council of Europe; 2014.

30. Affas S, Sakur AA. Spectrophotometric Method for Simultaneous Estimation of Dapoxetine and some Phosphodiesterase-5 inhibitors in new combinations. Res J Pharm Technol. [Internet]. 2019; 12(11): 5193. Available from: http://dx.doi.org/10.5958/0974-360x.2019.00899.0

31. Al-khattawi A, Mohammed AR. Compressed orally disintegrating tablets: excipients evolution and formulation strategies. Expert Opin Drug Deliv [Internet]. 2013; 10(5): 651–63. Available from: http://dx.doi.org/10.1517/17425247.2013.769955

32. United States Pharmacopeial Convention. United States pharmacopeia 30. Rockville, MD; 1991.

33. Siewert M, Dressman J, Brown CK, Shah VP, FIP, AAPS. FIP/AAPS guidelines to dissolution/in vitro release testing of novel/special dosage forms. AAPS PharmSciTech [Internet]. 2003; 4(1): E7. Available from: http://dx.doi.org/10.1208/pt040107

Received on 15.08.2024 Revised on 21.12.2024

Accepted on 14.02.2025 Published on 27.03.2025

Available online from March 27, 2025

Research J. Pharmacy and Technology. 2025;18(3):1336-1345.

DOI: 10.52711/0974-360X.2025.00194

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.