1. INTRODUCTION

Oral medication administration is considered more convenient and non-invasive method for delivering therapeutic drugs. It is the preferred route due to its simplicity of use, patient comfort, and the ability to provide consistent, controlled doses over time. Patients generally find oral dosage forms, such as tablets, capsules, and liquids, to be simpler to manage than other forms of drug administration, such as injections or infusions (Bhalani et al., 2022; Qader et al., 2024).

A significant number of unique drug candidates exhibit low solubility in water, hence reduced and variable oral bioavailability. Lipid-formulation systems such as self-nanoemulsifying drug delivery systems (SNEDDS) have proven to be useful solutions to counteract the problem (Buya et al., 2020). SNEDDS consist of isotropic mixtures comprising an oil phase and a surfactant, often supplemented with a co-surfactant or co-solvent. In response to mild agitation in aqueous gastrointestinal fluids, SNEDDS spontaneously form fine oil-in-water nano-emulsions with typically nanometer-sized droplets (usually <200 nm) (Buya et al., 2020; Alqahtani et al., 2021).

Apart from increasing solubilization, SNEDDs can confer numerous biopharmaceuticals. Nanoscale droplets offer an extensive interfacial surface area, hence enhancing medication release and absorption rates. Surfactants and lipids in SNEDDS can interact with biological membranes to enhance drug transport; studies indicate that SNEDDS formulations can fluidize enterocyte membranes and block P-glycoprotein efflux pumps, thus enhancing the transcellular permeability of encapsulated pharmaceuticals (Baloch et al., 2019)

Domperidone (DOM) (C22H24CIN5O2), a dopamine D₂-receptor antagonist and lipophilic agent classified as a Class II BCS (its chemical structure shown in Figure 1), is extensively utilized to treat gastrointestinal conditions such as nausea and vomiting. Notwithstanding its therapeutic advantages, DOM's inadequate water solubility and significant metabolism in the first pass leads to low oral bioavailability (Nagpal et al., 2016). It exhibits partial insolubility in water (0.0925 mg/mL) and has low oral bioavailability (13-17%), and its log P 3.9 (Bhatia et al., 2024)

DOM's lipophilicity and high permeability make it ideal for inclusion into SNEDDS preconcentrates, whereby it can be dissolved in an oil/surfactant mixture and shielded against early precipitation in the stomach environment. Presenting DOM in a solubilized, easily absorbed form should help SNEDDS increase its effective concentration in the intestine. Furthermore, if the SNEDDS facilitates lymphatic absorption of DOM, first-pass hepatic extraction may be significantly reduced, thereby enhancing systemic exposure. Generally, the SNEDDS method fits the necessity of improving the solubility and absorption of DOM without changing its therapeutic aim or mechanism (Alqahtani et al., 2021; Okur et al., 2024).

Liquid SNEDDS (L-SNEDDS) are often prepared as pourable liquids or semi-solids suitable for encapsulation in soft or hard gelatin capsules for delivery. The liquid state of SNEDDS can be converted into a solid intermediate (S-SNEDDS) by adsorption onto solid carriers or spray-drying for enhanced handling; nevertheless, the emphasis in this context is on the liquid preconcentrate. The objective of formulation development is to achieve a DOM-loaded SNEDDS that is optimized for minimal droplet size, low polydispersity, high drug solubilization, and effective self-emulsification upon dilution (Govindan et al., 2024).

This study aims to develop, optimize, and characterize an SNEDDS loaded with DOM to improve stability, solubility, and bioavailability by conducting in-vitro drug release and Self- emulsification characterization.

Domperidone in India - Chemicalbook.in

Figure 1: Chemical structure of DOM.

2. MATERIALS AND METHOD

Materials:

Domperidon(DOM) was provided by Pioneer Pharmaceutical Manufacturer, Sulaymaniyah. Iraq. Capryol 90, Labrafac MC60, Labrafil M 1944CS, and Transcutol HP were received from GATTEFOSSE SAS, France. Cremophor EL, Polyethylene glycol (PEG) 200 supplied by Simson PL. India. Labrasole got from AV-Souwv, Biotech. China. Tween 20, PEG 400, PEG 600, and propylene glycol (PG) were received from the Reagent of the Library. India. Tween 60, Tween 80, and HCL, 37% (Scharlau Chemie, Spain), Span 20 (Sino Pharma- China), Cedar oil (BDH- England), and all other oils used in the study supplied by AVONCHEM. U. K. Absolute ethanol (Merc, Germany). Dena Kanii, Erbil supplied deionized water. Iraq.

Methods:

Characterization of Domperidone:

Preparation of Calibration Curve:

To make a 40µg/ml stock solution of DOM, 25 mg of DOM was dissolved in 100 mL of absolute ethanol, with 4 mL transferred to a 25 mL volumetric flask, and absolute ethanol added to form 1000µg/25 ml. Serial dilution was then performed. The absorbance of each solution against the blank was measured at l max (286 nm) as shown in (Figure 2), by UV spectroscopy (Shimadzu 1900- Japon) absorbances against concentrations were plotted to create a calibration curve (Qasim et al ., 2024).

Fourier Transform Infrared Spectroscopy (FTIR)

FTIR is a commonly used analytical method for characterizing medications and excipients in pharmaceutical sciences. Detecting vibrations in chemical bonds when exposed to infrared (IR) radiation, gives vital information on molecular structures. The resulting FTIR spectrum is a crucial tool for structural identification, purity evaluation, polymorphism analysis, and drug-excipient compatibility investigations since it acts as a distinct fingerprint of a chemical. (JASCO FT/IR- 4600, Japon) used and the spectra was recorded in the wavelength range of 4000 cm⁻¹ to 400 cm⁻¹ with the KBr pellet technique. The procedure entails distributing the sample in potassium bromide (KBr) and compressing it into a disc by applying a pressure of 50 kg/cm² using a hydraulic press (Nagpal et al., 2016)

Differential Scanning Calorimetry (DSC)

Shimadzu DSC-60A plus Series (Japan) was used for DSC thermogram analysis. Software “LabSolution TA, version 1.01 SP1” assessed the figure (peak area and integration). Samples with weights ranging from 3 to 5 mg were positioned in flat-bottomed aluminum pans and subsequently sealed hermetically with aluminum lids utilizing a pan press (Thermal Scientific Inc, Amarillo, TX). The pan was gradually heated from 20 to 300°C at 10°C/min. The reference standard was an empty sealed aluminum crucible.

Solubility Study of DOM in Different Oils, Surfactants, and Co-Surfactants:

The solubility of DOM was systematically analyzed in a range of oils, surfactants, and cosurfactants. A glass tube was filled in each case with 3 mL of each vehicle and subjected to an excess amount of DOM. Glass tubes were then placed in a thermostatically controlled vibrating shaker bath (Stuart Scientific, SBS30, U.K.) at 25 ± 0.5 ◦C for 72 hours for proper mixing after their preparation with vortex mixer (ISOLAB, Germany). The contents of each vial were centrifuged and then filtered by 0.45 μm syringe filter. Absolute ethanol was then added for dilution and subsequent determination of drug content by using UV-spectrophotometry (Shimadzu 1900, Japan) at DOM's maximum wavelength of 286 nm. The experiments were performed thrice (A. Ahmed et al., 2022; Qader et al., 2022).

Construction of Pseudo-Ternary Phase Diagram:

Pseudo-ternary phase diagrams were utilized to optimize the oil ratios in terms of the S._mix (surfactant to co-surfactant ratio). The diagram was prepared at room temperature using the aqueous titration process to evaluate the concentration of the components for the present range of SNEDDS. The selection of oil, surfactants, and cosurfactants was done after conducting miscibility studies and then arranged in various combinations for the evaluation of phases. Various combinations of the surfactant/cosurfactant mixtures (S._mix) in varying proportions of 1:1, 1:2, 2:1, and 3:1 were used for emulsification of the chosen oil. Phase diagrams were established through vortexing of mixed volume ratios of oil and S._mix (9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8, and 1:9) in a glass tube to get an emulsion mixture in the clear and homogeneous form in the solution state, then titrated with the aqueous solution. Phase clarity evaluation of the mixture of lipid and S._mix was performed through visual observation (Qader & Hussein, 2021; B. Nair et al., 2022). The volume of water required to induce a phase transition from clarity to turbidity was documented, and pseudo-ternary charts were generated utilizing the ProSim drawing tool (Taher et al., 2015). All the ratios in this study are reported as Volume-to-volume ratios (v/v%).

Preparation of DOM loaded Liquid- SNEDDS:

After identifying the self-nano emulsifying region, SNEDDS formulations were made with the appropriate component ratios. Several effective SNEDDS formulae were created, and DOM concentration was maintained at the same level in each mix. Five milligrams of DOM dissolved in 1 ml of each SNEDDS formulation.

In short, a vortex mixer was used to thoroughly mix oil, surfactant, and co-surfactant after they had been accurately weighed and placed in a stoppered glass tube (Nasr et al., 2016; Dalal et al., 2021). The oil and S._mixmixture was mixed with a certain amount of DOM until the medicine was fully dissolved v/v% (Mittal et al., 2025). Formulas were then prepared and kept at room temperature until used again.

Characterization and Evaluation of DOM-Loaded Liquid SNEDDS:

The subsequent characteristics were employed to assess the formulations.

Thermodynamic Stability Study:

The SNEDDS formulations were centrifuged, heat-cooled, and freeze-thawed. The formulations' physical properties were visually examined after each procedure for six cycles. For the heating-cooling cycle test, the formula was held at 45 ± 1°C and 25 ± 1°C for 24 hours. The formulas that passed heating- cooling test and underwent freeze-thaw and stress testing. Six freeze-thaw cycles were performed between -20 ±2°C and 25 ±1°C with at least 24 hours of storage time at each temperature. After 20 minutes of centrifugation at 4000 rpm, formulas showing no cracking, creaming, and phase separation indicated stability (Qader & Hussein., 2021).

Robustness to Dilution:

Studying how dilution affects emulsion properties allowed for the simulation of in-vivo dilution behaviours. The test involved the combination of 1 mL of formulation with media at dilutions of 10, 100, and 1000 times, employing pure water, 0.1 N HCl, and phosphate buffer at pH 6.8 within a beaker, while employing a magnetic stirrer to maintain continuous stirring at 100 rpm (Qader et al., 2022) At 37 ± 0.5 °C, the media's temperature was maintained and then placed to be kept in volumetric flasks. This test was conducted to confirm that the formulation was homogeneous. After being kept for a full day at room temperature, the visual examination was performed on the systems that were received to look for indications of phase separation, turbidity, or precipitation (Nasr et al., 2016; B. Nair et al., 2022).

Determination of the Efficiency of Self-Emulsification:

A USP dissolving apparatus type II assessed the produced formulation's self-emulsification effectiveness. To conduct the test, 500 mL of distilled water was mixed with 1 mL of the formulation in a beaker. The paddle was rotated at 50 rpm to provide mild agitation. The last view of the nano-emulsion and the rate of emulsification were used to visually evaluate the created formulations (Mohite et al., 2024).

A grading system was utilized to visually assess the formulation's in-vitro performance:

Grade A: These systems effectively form a clear and transparent nanoemulsion in one minute.

Grade B: Production of a lower clear nanoemulsion.

Grade C: Development of milky emulsion in 2 minutes.

Grade D: Suboptimal white emulsion formed, with more than 2 minutes of emulsification required.

Grade E: Development of substantial oil globules demonstrating inadequate emulsification

Self-Emulsification Time:

Emulsification time for all SNEDDS recipes (1 mL) was evaluated in 300 mL of water at 37±0.5°C. The components were gently mixed with a magnetic stirrer at a steady speed of 100 rpm. The amount of time needed to emulsify SNEDDS formulations and create nano-emulsion was recorded in seconds (Nasr et al., 2016; Buya et al., 2020).

Turbidity Measurement (% of Transmittance)

A UV-visible double-beam spectrophotometer (Shimadzu-1900, Japan) was utilized to measure the transmittance of diluted samples (100-fold with water) at 650 nm in triplicate using spectrophotometry. Distilled water was used as a blank (Nasr et al., 2016).

Surface Morphology:

TEM was utilized to assess the surface morphology of optimized SNEDDS. Samples underwent a one hundredfold dilution with distilled water prior to analysis. A droplet of the resulting nanoemulsion on a Carbon-Cu grid was treated with two percent phosphotungstic acid. At 70-90kV, the (PHILIPS, CM120, The Netherland) was used for the analysis (Ke et al., 2016).

Globule size and Poly Dispersity Indes (PDI)

The size of the globule regulates the degree and speed of drug release and absorption and is hence an essential factor in the self-emulsification efficacy. Each of the SNEDDs was diluted one hundred times using distilled water before it was measured using one- millilitre of the formulation. The PDI value shows the homogeneity of the size of particles in the formulation. Improved stability of the nanoemulsion is ensured by globules of uniform size (Verma & Kaushik., 2020; Eleftheriadis et al., 2019).A Zeta Sizer (Anton Paar Instrument, Austria) was employed to evaluate the globule size and PDI of SNEDDS.

Zeta potential:

The Zeta potential of SNEDDS was evaluated through the measurement of electrophoretic mobility. using one ml of each SNEDDS diluted hundred time with distil water. Assessments were conducted using an Anton Paar Zeta sizer, through using (Litesizer DLS/ Anton Paar) cuvette (Verma & Kaushik., 2020; Eleftheriadis et al., 2019).

Drug Loading Efficacy:

For the estimation of DOM concentration, 1 mL of the SNEDDS solution with 5 mg of DOM was diluted in volumetric flasks using absolute ethanol and well-mixed by inverting and shaking the flasks two to three times (Qader et al., 2022). Three triplicates were prepared and drug concentration was found after appropriate dilution at 286 nm by using the UV-visible spectrophotometric method (Shimadzu 1900- Japan) (Nasr et al., 2016). Drug loading efficiency was calculated using formula (1): - Drug loading efficiency (%) = (1)

In-vitro DOM- SNEDDS Release Study:

Utilizing USP type II (Paddle type) dissolution equipment (Pharma Test, PT-DT7, Germany), in- vitro drug release study

was conducted. Free gelatine capsules (size "00") containing 10mg of DOM were used to fill SNEDDS, the samples were then placed in 900 mL of 0.1 N HCl dissolution media and set in at 37 ± 0.5 °C. The paddle speed was held at 50 rpm all the time. A 5 ml aliquot was removed at 5, 10, 15, 30, 45, 60, 90, and 120-minute intervals and then filtered through 0.45μm membrane filters. The concentration of DOM was quantified via spectrophotometry (Shimadzu-1900) at a wavelength of 284 nm. The created optimized batch's dissolving profile was contrasted with that of the marketed product and the pure drug (Laddha et al, 2014; Nasr et al., 2016). A statistical analysis of the in- vitro release data was conducted utilizing the similarity factor (f2). The f2 test results vary from 0 to 100, Two dissolution profiles were deemed similar when the f2 value is equal to or greater than 50. the release patterns of the optimized SNEDDS formulations were compared to a reference (Marketed DOM) (El-Sayyad et al., 2017). The equation of similarity factor proposed by Moore and Flanner is represented in equation (2).

(2)

Where n= the number of time intervals at which the % of dissolution was assessed.

Rt = the % dissolved of one formulation at a specific time point

Tt = denotes the % dissolved of the formulation to be compared at the identical time point.

3. RESULTS

Characterization of Domperidone:

Preparation of A Calibration Curve:

Based on l max at a wavelength of 286 nm (Figure 2), by UV spectroscopy (Shimadzu 1900- Japan). Using absolute ethanol as blank. The calibration curve of DOM in absolute ethanol was constructed (Figure 3). The plots showed good linearity between concentration and absorbance, the correlation coefficient obtained was 0.9987, and the linear regression equation of (y = 0.0293x - 0.0087) (Singh and Rai, 2013).

Figure 2: Lambda max of drug in absolute Ethanol

Figure 3: Calibration Curve of a drug in absolute Ethanol.

Fourier Transform Infrared Spectroscopy (FTIR)

The DOM IR Spectrum confirms functional groups with unique peaks. Peaks at 3016.12 cm⁻¹, 2935.13 cm⁻¹, and 2819.42 cm⁻¹ indicate aromatic and aliphatic C-H stretching vibrations. The peak at 1685.48 cm⁻¹ is due to the amide functional group stretching with (C=O), a crucial part of DOM's structure. C-N stretching causes the 1265.07 cm⁻¹ and 1212 cm⁻¹ peaks, confirming the presence of the benzimidazole ring. The bands confirm the drug's aromatic character at 833.87 cm⁻¹ and 728.84 cm⁻¹ of aromatic C-H out-of-plane bending vibrations (Bhatia et al., 2024). FTIR spectra of pure DOM appear in Figure 4.

Figure 4: FTIR spectra of pure DOM

Differential Scanning Calorimetry (DSC)

The thermal behaviour of DOM displayed a clear sharp endothermic peak at 248.28 °C, which was corresponding to its melting point, indicated high crystallinity of pure drug (Bhatia et al., 2024) as appear in (Figure 5).

Figure 5: Differential scanning calorimetry of pure DOM

Table 1: Optimized content of excipients of DOM liquid SNEDDS

Formulas	Oil	Surfactant	Co-surfactant	S._mix	Oil: S._mixratio	Oil (v/v%)	Surf. *(v/v%)*	Co-surf. *(v/v%)*
F1	Orange	Cremophor EL	Transcutol HP	2:1	2:8	20	53.33	26.67
F2	Orange	Labrasole	Transcutol HP	1:2	2:8	20	26.67	53.33
F3	Orange	Tween80:Span20	Transcutol HP	1:2	2:8	20	26.67	53.33
F4	Orange	Tween 80	Transcutol HP	1:2	2:8	20	26.67	53.33
F5	Coconut	Cremophor EL	Transcutol HP	2:1	2:8	20	53.33	26.67
F6	Coconut	Tween80:Span20	Transcutol HP	1:1	2:8	20	40	40
F7	Coconut	Cremophor EL	(PG)	1:1	2:8	20	40	40
F8	Capryol-90	Labrasole	Transcutol HP	2:1	2:8	20	53.33	26.67
F9	Capryol-90	Tween80:Span20	Transcutol HP	1:2	2:8	20	26.67	53.33
F10	Capryol-90	Tween 80	Transcutol HP	1:1	2:8	20	40	40
F11	Cedar	Cremophor EL	Transcutol HP	1:1	2:8	20	40	40
F12	Cedar	Labrasole	Transcutol HP	2:1	2:8	20	53.33	26.67

Figure 8: DOM loaded liquid -SNEDDS formulas

(a) (b)

Figure 10: Globule size in nm for (a) F1, (b) F4, (c) F5, and (d) F7

(a) (b)

(c) (d)

Figure 11: Zeta potential for (a) F1, (b) F4, (c) F5, and (d) F7

Table 2: Thermodynamic studies, the efficiency of self-emulsification, and robustness to dilution of DOM- loaded liquid SNEDDS

Form.

Heat- Cool Cycles

Freeze-Thaw Cycles

Centrifugation Test

Grade

Deionized water

0.1 N HCL

Phosphate buffer

pH 6.8

100

1000

100

1000

100

1000

F10

F11

F12

The ( Ö ) indicates that the formulations passed the test, with no precipitation, phase separation cloudiness, or turbidity& and

the (c) mean phase separation or turbid

Table 3: Self-emulsification time, % transmittance, Drug Loading Efficacy of drug-loaded formulas, globule size, PDI, zeta potential for DOM-L-SNEDDS

Formulation	Self- Emulsification time	%Transmittance	Drug Loading Efficacy (%)	Globule size (nm)	PDI	Zeta Potential (mV)
F1	21.44 ± 0.05	97.83 ± 0.31	103.32 % ± 0.11	37.52 ± 2.26	0.28 ± 0.03	-0.23 ± 0.23
F2	39.02 ± 0.71	67.63 ± 0.15	89.53% ± 0.18	240.73 ± 4.1	0.35 ± 0.01	-8.4 ± 0.87
F3	24.13± 0.16	81.17 ± 0.51	88.01% ± 0.19	159.9 ± 3.41	0.29 ± 0.001	-0.37 ± 0.21
F4	18.71± 0.57	99.86 ± 0.05	93.71% ± 0.004	42.55 ± 3.09	0.68 ± 0.2	-0.13 ± 0.06
F5	23.95± 0.15	97.47 ± 0.35	97.44% ± 0.28	5.45 ± 0.39	0.67 ± 0.37	-0.03 ± 0.06
F6	18.17 ± 0.33	96.63 ± 0.15	94.01% ± 0.099	31.59 ± 0.82	0.29 ± 0.013	-0.1 ± 0.1
F7	32.17± 1.19	97.43 ± 0.30	100.7% ± 0.102	16.68 ± 0.64	0.55 ± 0.48	-0.07 ± 0.1
F8	24.28 ± 0.46	54.45± 0.97	87.94% ±0.29	171.5 ± 2.5	0.44 ± 0.14	-10.17 ± 0.65
F9	13.75 ± 0.53	55.28 ± 0.27	88.91% ± 0.003	421.6 ± 3.83	0.31 ± 0.02	-1.9 ± 0.81
F10	15.2 ± 0.52	98.13 ± 0.29	91.57% ± 0.09	139.97 ± 4.43	0.34 ± 0.04	-0.27 ± 0.03
F11	19.07 ± 0.16	95.2 ± 0.89	94.88% ± 0.13	342.2 ± 2.05	0.31 ± 0.03	-12.7 ± 0.078
F12	21.78 ± 0.44	24.37 ± 0.21	95.3% ± 0.043	241.03 ± 1.96	0.33 ± 0.08	-11.1 ± 0.17

· Value expressed as mean ± SD, n=3

4. DISCUSSION

DOM powder purity was measured by recording melting point (242-244 C⁰), and DSC thermogram show a distinct endothermic peak at 248.28 °C, corresponding to the melting point, indicates the great crystallinity of the pure substance (Bhatia et al., 2024). Solubility study of drug applied in a wide a range of vehicles to select proper oils, surfactants, and cosurfactants with maximum solubility.

The oil phase is crucial for keeping the medication solubilized in the formulation and preventing its precipitation (Modi et al., 2023). Solubility studies highlighted the superior solubilizing potential for DOM in orange oil; drug solubility was (47.94 ± 0.085 mg/ml). orange oil, exhibits a strong affinity for lipophilic compounds, rendering it an effective solvent for poorly water-soluble drugs, this may be attributed to the medium chain length (ten carbons) (Mayta & Rodríguez, 2018). then, followed by coconut oil at 30.3 ± 0.148mg/ml, capryol-90 29 ± 0.046 mg/ml, and cedar oil 20.65 ± 0.31mg/ml among other various oils tried. Surfactants play an essential role in SNEDDS by reducing interfacial tension, which aids in the dispersion mechanism and creates a flexible film around the globules. Non-ionic hydrophilic surfactants are regarded as more appropriate than ionic surfactants for the formulation of nanoemulsions. Mainly because they exhibit lower toxicity compared to ionic surfactants (Nagi et al., 2017). The study revealed that Cremophor EL exhibits a DOM solubility of (25.55 mg/mL ± 0.102), marking it as the highest among the tested substances (Laddha, et al, 2014). Cosurfactants reduce the bending stress present at the oil/water interface (Nasr et al., 2016). Transcutol HP as cosurfactant shows the greatest DOM solubility (Abd-Elhakeem et al., 2019).; followed by Propylene glycol (PG). These vehicles were selected to prepare several effective SNEDDS formulas, at different S._mix ratios, based on a miscibility study that was conducted to evaluate the clarity, turbidity, and phase separation of a variety of oils in the presence of a variety of surfactants and co-surfactants at varying ratios.

Pseudo- ternary phase diagrams were developed to delineate self-nanoemulsifying regions and to determine appropriate concentrations of oil, surfactant, and cosurfactant for the formulation of SNEDDS (Nasr et al., 2016; Qader et al., 2022). The nanoemulsion phase was recognized as the area in which clear and transparent formulations were achieved upon dilution, as determined through visual inspection of the samples. Pseudo-ternary phase diagrams indicated that the region designated for nanoemulsion (the yellow area) was most extensive in the formulae have 1:1, and 2:1 ratio rather than 1:2 ratio duo to use high amount of surfactants, Tween 80, and Cremophor EL with high HLB value, could emulsify oil better in oil- water interphase (Rathore et al., 2022).

Based on formulation optimization and Pseudo- ternary phase diagrams, through utilizing 378 formulation possibilities. Twelve most successful formulas were created and labelled as F1to F12, the medication quantity in each formulation remained stable at 5 mg of DOM per ml of SNEDDS (Table 1) details the content of each formula.

Freeze-thaw cycles, centrifugation, and heat-cool cycles among the thermodynamic stability tests validate that the SNEDDS formulations loaded with DOM are stable under stress and different conditions. Ensuring that the SNEDDS does not phase separate or drug precipitate upon storage and transportation depends on the stability of formulations at various temperatures and mechanical conditions (Nasr et al., 2016). The robustness to dilution indicates the formulations' capacity to maintain stability without precipitating or forming distinct phases separation after dilution, as it is crucial for their performance in the gastrointestinal tract (Buya et al., 2020). Our findings show these formulations contain labrasole, and span 20 as surfactant, formed less clearly nanoemulsion compared to others. The self-emulsification time (ranging from 13.75 to 32.17 seconds) and visual observations of the formulations show that most formulations rapidly formed clear nanoemulsions, indicating the efficient self-emulsifying properties of the SNEDDS. Their result is shown in Table 3. This rapid formation is key to ensuring the drug is quickly available for absorption after oral administration, improving its bioavailability (Abd-Elhakeem et al., 2019). Percentage (%) of transmittance, ranged from 99.983% ± 0.055 to 24.367 ± 0.208, their result matches with robustness to dilution, formulation makes less clear nano emulsion have lower transmittance (Nasr et al., 2016; Qader et al., 2022).

TEM photographs show clear particles that there was no globule aggregation and that the globules of all formulae were evenly distributed. TEM investigation demonstrated that all selected successful four formulae produced uniform, spherical droplets <50 nm, meeting the nanometric size range requirements for nanoemulsifying formulae (Nasr et al., 2016). Droplet size is one of the most important SNEDDS performance component since it affects both the absorption drug and the rate and amount of drug release. Also, it has been noted that the interfacial surface area increases with decreasing particle size, potentially improving bioavailability and accelerating absorption. Systems meeting the SNEDDS criterion have a mean droplet size of less than 200 nm (Nasr et al., 2016 ).From twelve formulations, eight formulation sizes at the SNEDDS region below 200 nm, globule size for all formulations shown in Table 3, and particle size (nm) showed in (Figure 10).

The poly-dispersibility index (PDI), a dimensionless metric that ranges from 0.0 to 1.0 and represents particle homogeneity, is utilized to represent the distribution of droplet sizes. A greater homogeneity of particles results in a PDI score approaching zero. The PDI for all formulas between (0.28 ± 0.03 to 0.68 ± 0.2) below one, all within the accepted range (Taher et al., 2015). PDI for all formulas detected in Table 3. The stability of colloidal dispersions is contingent upon the zeta potential, which underscores its significance. For smaller globules, a high zeta potential will indicate electrical stability, as an increase in surface charge counteracts particle aggregation (Verma & Kaushik., 2020). Zeta potential values were found to be in the range of (-0.03 ± 0.06 to -12.7 ± 0.078 mV), indicating that the formulations exhibit low negative charge, this low negative charge for formulas due to the use of non-ionic surfactants that create a -vely charged interface at neutral pH (Abd-Elhakeem et al., 2019; Verma and Kaushik, 2020). Non-ionic surfactants stabilize the particle by stearic hindrance rather than electrostatic repulsion (Nasr et al., 2016). Drug loading efficiency varied between 87.94% and 103.32%, demonstrating that the formulations effectively incorporated substantial quantities of DOM, essential for optimizing therapeutic efficacy and reducing the necessary formulation volume. High drug loading efficiency indicates the formulation's ability to deliver an adequate dose within a reduced volume, which is crucial for patient compliance and administration convenience (Qader & Hussein, 2021). Based on previous characterization studies four successful formulations (F1, F3, F5, and F7) chosen for in-vitro drug release profile.

The in-vitro drug release profile (Figure 12) of four effective DOM SNEDDS formulations (F1, F4, F5, and F7) was analysed in comparison to the pure drug and commercial tablets. The SNEDDS formulations demonstrated significantly enhanced drug release relative to pure DOM and marketed tablets, with formulations such as F1 and F4 allowing for up to 95% drug release within 120 minutes. The nanoemulsion's capacity to expand the drug's surface area, facilitating speedier absorption and dissolution, is responsible for this improved release (Mohite et al., 2024; Laddha et al., 2014) The results are consistent with prior research showing the superiority of SNEDDS in improving the bioavailability of poorly soluble medications (Laddha et al., 2014). The similarity factor (f2) was computed to see if the dissolution profile of SNEDDS formulations would resemble that of the commercial tablets. The (f2) calculation indicated that the releasing profile of L-SNEDDS is dissimilar to that of the commercial tablet (f2 < 50) (El-Sayyad et al., 2017; Sabri & Hussien, 2020). The results demonstrate that F1-releasing profile at 30 minutes. 3.9-fold and 8.3-fold increases above the marketed product and pure DOM.

CONCLUSION

This study effectively created formulations of liquid SNEDDS aimed improving the availability and solubility of DOM, a medication that has limited oral absorption and poor water solubility. Among various oils and surfactants tested, orange oil and Cremophor EL displayed the greatest solubility for DOM. F1 and F4 were the most notable of the 12 evaluated formulations due to their quick emulsification times, small droplet sizes (less than 50 nm), and significant drug loading (up to 103%). Over 95% of the DOM was released in 120 minutes by these formulations, which is up to 3.1 times more effective than commercial tablets. The increased surface area of nano-sized droplets enhances release and absorption efficiency. This concept highlights SNEDDS as an effective solution for oral formulations and holds tremendous promise for enhancing the administration of additional poorly soluble medicines.

Acknowledgments:

The authors gratefully acknowledge the Department of Pharmaceutics and Research lab of College of Pharmacy, Hawler Medical University, for providing the research facilities. Special thanks to Awa Medica Drug Company (Erbil, Iraq), and Tishk International University (Faculty of Pharmacy) for their invaluable assistance during experimental work. We also extend our appreciation to Pioneer Pharmaceutical Manufacturer (Sulaymaniyah, Iraq) for supplying Domperidone.

Ethical Statement:

The Ethical Committee of Hawler Medical University- College of pharmacy- Erbil, Kurdistan region, approved this research (HMUE1ph 01/06/2025-633).

Author Contributions:

All authors have reviewed the final version to be published and agreed to be accountable for all aspects of the work.

Concept and design: Adnan B. Qader

Acquisition, analysis, or interpretation of data: Sara T. Rasool and Adnan B. Qader

Drafting of the manuscript: Sara T. Rasooland Adnan B. Qader

Declaration:

Conflict of Interest: The authors declare that there is no conflict of interest regarding the publication of this paper.

Funding: This research received no specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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