Taking medicine by mouth is the most common and preferred method. However, this approach can be challenging due to the digestive system, which can impact how much of the drug is absorbed and how effectively it works. One significant issue with oral medications is their poor dissolution rate. To address this, various techniques are used, such as employing drug carriers, forming drug salts, adding different surfactants, modifying the drug's structure, and using nanoparticles or liposomes [1]. Self-double emulsifying drug delivery systems (SDEDDS) are designed to enhance the solubility and dissolution rate of drugs that do not dissolve well in water. These systems exploit principles of self-emulsification to create a stable double emulsion, which help hydrophobic drugs disperse better, improving their absorption and bioavailability while also enabling tailored release profiles and reduced side effects. There are two types of double emulsions: water-in-oil-in-water (w/o/w) and oil-in-water-in-oil (o/w/o) [2]. Simvastatin is a statin drug that lowers LDL cholesterol levels by blocking the enzyme HMG CoA reductase. It belongs to BCS class II, meaning it has low solubility but high permeability. The effectiveness of oral simvastatin depends on how well it dissolves from its dosage form. This study focused on improving the poor water solubility of simvastatin [3].

MATERIALS AND METHODS

Preformulation Study

Preformulation studies focus on the physicochemical properties of a drug that could impact its performance and dosage form development. This is the first step in creating a stable, safe, and effective dosage form, aiming to establish the drug's kinetic rate profile and compatibility with other ingredients [4].

Analytical Methods

Calibration Curve of Simvastatin in pH 7 Phosphate Buffer

Calibration curve of Simvastatin is made by dissolving 100 mg of Simvastatin in methanol, then diluting it to 100 ml with phosphate buffer to achieve a concentration of 1000 ppm (Stock Solution A). From this solution, 10 ml is taken and further diluted with phosphate buffer to obtain Stock Solution B at 100 ppm. From this, pipette out aliquots of 0.2, 0.4, 0.6, 0.8, 1.0, 1.2, 1.4, 1.6, 1.8, and 2 ml and diluted with phosphate buffer to get concentrations of 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 ppm. Absorbance is measured at 238 nm, and a graph is plotted with concentration on the x-axis and absorbance on the y-axis [5].

Solubility Study

The solubility of Simvastatin in various oils, lipophilic surfactants, and hydrophilic surfactants is determined using the flask shake method. Excess drug is added to 250 ml conical flasks containing 100 ml of different oils and surfactants, and the flasks are shaken using a rotary shaker. The samples are filtered through Whatman filter paper, and absorbance is measured at 238 nm using a UV spectrophotometer. Solubility is calculated using the formula [6]:

Solubility= (Absorbance of sample/Absorbance of standard solution) × Concentration of standard solution × Dilution factor.

Construction of Pseudo-Ternary Phase Diagrams

Ternary phase diagrams are used to determine the concentration range of components. Pseudo-ternary phase diagrams are constructed using the water titration method. Plots are created with oil, surfactant, and co-surfactant in different ratios (1:1, 1:2, 1:3, 1:4, 4:1). The mixtures are diluted by adding water drop by drop under magnetic stirring. Data is used to construct ternary plots with a ternary plot maker [7].

Drug-Excipient Compatibility

FTIR spectroscopy is used to study drug-excipient compatibility. FTIR spectra of the pure drug, olive oil, Span 80, Tween 60, and their physical mixtures are recorded. The peaks of the pure drug, oil, surfactant, co-surfactant, and physical mixtures are compared to check for incompatibility [8].

Formulation of Self-Double-Emulsifying Drug Delivery System of Simvastatin

W/O/W double emulsion is prepared using a modified two-step emulsification method. The self-double-emulsifying drug delivery system (SDEDDS) changes the second emulsification step to self-emulsify into a w/o/w double emulsion due to gastrointestinal peristaltic movements in vivo, instead of artificial emulsification in vitro. The drug is dissolved in water, then oil and lipophilic surfactant are added to form the primary w/o emulsion. Hydrophilic surfactant is then added to form the w/o/w double emulsion [9].

Drug Content

Formulations F1-F9 of self-double emulsifying drug delivery systems, each containing an equivalent to one dose, were added to a 10 ml volumetric flask containing water and mixed. The solution was further diluted and analyzed using a UV spectrophotometer at 238 nm [10].

Determination of Self-Emulsification Time and Cloud Point

A USP type II apparatus was used to determine the self-emulsification time of the developed formulations. 500 ml of water was placed in a dissolution flask and equilibrated at 37°C. One ml of the double emulsion was added to the flask and stirred at 50 rpm. The time required to form a homogenous dispersion was recorded as the self-emulsification time [11]. The emulsion becomes cloudy when the temperature increases. The temperature at which cloudiness is observed is noted and considered the cloud point. One ml of each formulation was diluted with water and heated in a water bath. The temperature was gradually increased, and the point at which cloudiness was observed was recorded [12].

Rheological Properties Determination

Viscosity studies are important for w/o/w double emulsion to ensure physical stability during storage. The viscosity of the double emulsion was evaluated using a Brookfield viscometer with spindle 4 at 50 rpm [13].

Entrapment Efficiency

Percentage entrapment efficiency was determined by taking 1 ml of the double emulsion, diluting it with phosphate buffer (pH 7), and filtering the solution through Whatman filter paper. Drug content was analyzed using a UV spectrophotometer at 238 nm. The entrapment efficiency was calculated using the following equation [14]:

?= (Drug content obtained (mg)/Total amount of drug added (mg)×100

In-vitro Release Study

Dissolution studies were performed using a USP dissolution apparatus type II. The release studies were conducted at a paddle speed of 50 rpm in 900 ml of pH 7 phosphate buffer at 37±0.2°C. Two ml of the solution was withdrawn from the medium at intervals of 0, 5, 15, 30, 45, and 60 minutes. Absorbance was measured at 238 nm, and the percentage drug release was calculated [15].

Determination of Particle size

The particle size of developed formulation was determined by using Zeta Sizer [16].

Optimization of self-double emulsifying drug delivery system by response surface methodology (RSM)

The optimization of self-double emulsifying drug delivery system was done by using the design expert software (Design expert software stat ease version 13). The % of drug released in 60 minutes and % drug content were taken as the response variables [17].

Statistical analysis

One way analysis of variance (ANOVA) was applied for comparison of results. To demonstrate graphically the influence of each factor on response and to indicate the optimum level of factors, the contour and response surface plots were generated using Design expert software (Stat-ease, 13). All the data measured and reported were averages of a minimum of triplicate measurement and the values are expressed as ± standard deviation [18].

RESULT AND DISCUSSION

Analytical method

       
           
       
    Fig no. 1: Standard curve of Simvastatin in phosphate buffer pH 7 at 238nm

 Physico-chemical properties of drug- Organoleptic properties of simvastatin was studied and concluded that simvastatin is a White to off-white crystalline power, odourless & bitter and acrid in taste. The melting point was determined by capillary tube method and it was found to be 136 ± 1.05°C.

Solubility profile

Solubility studies were carried out in different oils, lipophilic surfactants and hydrophilic surfactants and the result are showed in table 2, 3& 4

Phase diagrams of the system containing olive oil as the oil phase, span 80 as the surfactant, and tween 60 as the co-surfactant were constructed at S:Cos ratios of 1:1, 1:2, 1:3, 1:4, and 4:1 to determine the existence of microemulsion regions, as shown in Figures 1-5, respectively. The phase study revealed that the microemulsion region obtained at S/CoS ratios of 1:1, 1:2, 1:3, and 1:4 was smaller compared to the S/CoS ratio of 4:1. As the concentration of the co-surfactant increases, the microemulsion region decreases, and as the concentration of the surfactant increases, the microemulsion region increases. This indicates that the concentration of the surfactant has a significant effect on the microemulsion region.

Drug identification was done using FT-IR studies. The peaks of simvastatin were obtained at 3544 cm??1; (OH-aromatic stretching), 2927 cm??1; (C-H stretching), and 1697 cm??1; (C=O stretching), among others. There was no appearance of new peaks and no absence of any interfering peaks in the FT-IR spectra of the pure drug compared to the physical mixtures of the drug and polymers, indicating no drug-excipient incompatibility.

Drug content

The drug content of the 9 formulations was found to be between 90.5% and 99.1%. The percentage of drug content for all SDEDDS formulations was within the acceptable limit of the drug content test.

The self-emulsification time of all formulations (F1-F9) was less than 200 seconds, indicating that they can form emulsions rapidly upon exposure to GI fluid. A speed of 50 rpm was used, providing the lowest level of agitation, indicating that normal GIT motility is sufficient for self-emulsification. Emulsions are unstable at higher temperatures, and the two phases tend to separate upon heating. The cloud point was above 50°C for all developed formulations, indicating their stability during processing and storage.

The formulation with the highest drug content F9 exhibited significantly higher viscosity ie 1531 cps compared to other formulations, which is a positive indicator of stability and formulation performance.

       
           
       
    Fig no.9: Viscosity of formulation F1-F9

The percentage entrapment efficiency of 9 formulations was found to be 82.12%- 97.75%

       
           
       
    Fig no.10: % entrapment efficiency of

The in-vitro drug release of all the 9 formulations were carried out by using USP type II apparatus with phosphate buffer pH 7 as dissolution medium. 98.83%±0.37 of drug was released fromF9 formulation within 60 minutes compared to other formulation

Optimization by Design Expert Software

Based on the fit summary, the quadratic model (Table No: 6) was selected as the best fit for % release and % drug content (Table No: 8). The results of ANOVA (Table No: 7 and Table No: 9) indicated that the selected models were significant, and all response variables indicated the reliability of the models.

Response 1: In-vitro drug release

Response 1: Drug content

Table no. 10: Desirability table showing solutions suggested and its desirability