Enhancing solubility and dissolution of felodipine using self-nanoemulsifying drug systems through in vitro evaluation

Abstract

The main objective of the present study was to improve the solubility and dissolution rate of felodipine (FLD), a drug that does not dissolve well in water, using a self-nanoemulsifying drug delivery system (SNEDDS). Many analyses have been performed in the laboratory using different oils, non-ionic surfactants, and water-soluble co-solvents to prepare FLD-loaded SNEDDS. It involves measurements of viscosity, refractive index, and droplet size. Solubility studies revealed the best way to load drugs, and pseudo-ternary phase diagrams showed the right amounts of surfactant and co-surfactant for preparing the nanoemulsion. An in vitro dissolution study showed that SNEDDS worked better than pure FLD, releasing over 95% of FLD within 20 min. SNEDDS loaded with felodipine are a good option for developing new oral medicines because they can hold more drugs, dissolve better, and dissolve more quickly. This new SNEDDS technology shows promise for improving the performance of drugs that do not dissolve well, which could lead to better therapeutic results.

Introduction

Drugs that are classified as Class II or IV of the Biopharmaceutics Classification System (BCS), which are poorly water-soluble, for them lipid-based formulations, are promising as an outstanding formulation method. Poor bioavailability and solubility of the drug have an impact on its oral administration. Poor intestinal permeability is a significant factor that influences the oral bioavailability of BCS II and IV medications. Lipid-based formulations have thus been successfully employed as oral delivery systems to increase their solubility¹. The drug is expected to dissolve in oral administration and be released into the gastrointestinal fluid before absorption. Poor bioavailability from the poor solubility of a drug reduces its capacity to dissolve in gastrointestinal fluid, which can decrease the therapeutic efficacy of the drug².

Felodipine (FLD), the dihydropyridine calcium antagonist, is a popular and effective antihypertensive medication. Compared to calcium antagonists that are not dihydropyridine derivatives, felodipine is more selective as a vasodilator and has less impact on the heart. Since FLD is a BCS II drug and is practically insoluble in water (water solubility, 19.7 mg/L; log P 3.8), the rate-limiting step in drug absorption is its dissolution. Consequently, FLD may experience low and erratic GIT absorption, which lowers its therapeutic value. Therefore, increasing FLD’s solubility may improve its dissolution and, hence, increase its oral bioavailability. In addition to patient compliance, the oral route is preferable owing to its prospective physiological benefits. Several formulation techniques, including microparticles, solid dispersions, and nanoparticles³.

Numerous conventional strategies have been used to address the FLD solubility issue, including the use of cosolvents, salts, surfactants, cyclodextrins, and various polymorphs. Each system has its advantages and disadvantages. Although FLD and nanocrystals have been developed using the supercritical antisolvent technique⁴ and self-microemulsifying systems⁵, nanonization method⁶. Self-nanoemulsifying drug delivery systems (SNEDDS) are promising delivery methods that have attracted considerable interest from researchers. They are based on lipids and surfactants. Oil, surfactant, co-surfactant, and co-solvent are all components of SNEDDS⁷. An oleogel was prepared in one of the study by structuring soybean oil with BW and stabilized with CNCs to prepare oleogel-in-water Pickering emulsions⁸.Also an PUE-loaded PEG-PE (PUE@PEG-PE) micelles was prepared, using PE as a core and PEG chains for the shell. Based on their excellent properties such as high stability, good biocompatibility, extended circulation time, and enhanced cellular uptake⁹.This study sugesst the use of polymers in the miscelss and nanocrystal formation.

Digestive motility of the stomach and intestine generates agitation required for self-emulsification, and SNEDDS spreads easily in the gastrointestinal system. Following delivery, the isotropic mixture comes into contact with the aqueous phase of the digestive system and produces an oil-in-water nanoemulsion with the help of gastrointestinal motility. The medicine is solubilized inside tiny oil droplets along the gastrointestinal tract (GIT) transit owing to spontaneous nanoemulsion production. The enormous interfacial surface area of nanosized droplets facilitates drug release and absorption¹⁰. The self-nanoemulsifying drug delivery systems are an effective, smart, and patient-friendly formulation strategy for poorly water-soluble medications. It may improve drug solubility, GIT dissolution behavior, and gut permeability, which could boost the absorption of the model drug FLD, which dissolves poorly in water¹¹. The current work aimed to improve the solubility and dissolution rate of FLD by formulating appropriate SNEDDS formulations. The design, development, and optimization of L-SNEDDS for FLD and the characterization of optimized FLD-loaded L-SNEDDS are included in the current work. To determine the drug release and dissolution rate of the developed formulation, in vitro dissolution studies were conducted.

Materials and methodology

Felodipine (FLD), a key drug used in our study, was procured from Balaji Drugs, Mumbai. A range of oils essential for formulation, namely castor oil, cinnamon oil, oleic acid, clove oil, and isopropyl myristate, were sourced from Cosmo Chem, Pune. Integral co-surfactants, including polyethylene glycol variants PEG 200 and PEG 400, were obtained from Cosmo Chem, Pune. Our surfactant comprised Tween 20, Tween 80, Span 80, and Span 20, all of which were acquired from Molychem Pvt. Ltd., Mumbai. All additional reagents and chemicals incorporated in our research were of analytical grade, ensuring their direct applicability without the need for further refinement. The procedures followed in our study were methodically designed to harness the optimal potential of these materials, ensuring both precision and replicability of our results.

Preformulation investigations and solubility profile of felodipine (FLD) for SNEDDS

The shake flask method was used for the saturation solubility test on various oils (cinnamon oil, clove oil, castor oil, oleic acid, and isopropyl myristate), and surfactants (Tween20, Tween80, Span 20, and Span 80), and cosurfactants (ethanol and propylene glycol, PEG 200, PEG 400) were screened to identify the SNEDDS components that would best dissolve FLD. In this experiment, a saturated solution (approximately 200 mg) was added to 2 mL of each vehicle in tubes with screw caps. To aid in the solubilization of the FLD, the liquids were thoroughly stirred for 10 min in a vortex mixer (MaxiMix II, Orlando, FL, USA). The resultant mixtures were agitated for 72 h in an isothermal mechanical shaker (Clifton Shaking Water Bath, London, UK) to achieve equilibrium. The samples were centrifuged at 3000 rpm for 15 min after reaching equilibrium to precipitate the FLD that had not yet dissolved. The supernatants were then divided into aliquots, which were removed and filtered through a membrane filter (0.45 μm, Whatman, Maidstone, UK). The drug concentrations in the filtered solutions were determined using a UV-Vis spectrophotometer (Jasco) set to a maximum wavelength of 362 nm¹². Solubility was calculated using three independent measurements and is presented as the mean value (mg/mL) ± SD.

Surfactant efficiency for emulsification

The ability of various surfactants (Tween 20, Tween 80, Span 20, and Span 80) to emulsify the oily phase was tested. The transparency and ease of emulsification were considered when selecting the surfactant. Briefly, 500 µL of the selected oil was combined with 500 µL of each surfactant. To achieve homogenization, the mixtures were slowly heated at 50⁰C for 2 min. In a glass-stoppered flask, 100 µL of each mixture was diluted with distilled water to a maximum volume of 50 mL. The stoppered flasks were repeatedly inverted to determine the number of inversions required to create a homogenous nanoemulsion (devoid of turbidity or phase separation). Additionally, after the formulated emulsions had stood for two hours, their % transmittance at 365 nm was measured using distilled water as a blank on a UV-Vis spectrophotometer. The transmittance percentage of each emulsion was calculated in triplicate, and the average values and standard deviations were calculated. We used a surfactant that produced a clear emulsion with fewer inversions and a higher percentage of transmission¹⁰.

Preliminary screening of co-surfactants for emulsification efficiency

The selected oily phase and surfactant were utilized to further test the effectiveness of the emulsification of various cosurfactants¹³ (e.g., ethanol and propylene glycol, PEG 200, and PEG 400). Preliminary screening of the surfactant was used to generate and assess mixtures of 200 µL of cosurfactant, 400 µL of the chosen surfactant, and 600 µL of the chosen oil. Only when the system contains PEG with a middle chain, an organic solvent that is somewhat miscible in water and for which there is a high enough PEG affinity, will emulsification take place. The viscosity modification of PEG (polyethylene glycol) helps to form and preserve the suspension of dispersed phase globules by increasing the medium viscosity.

Psedoternary phase diagram

To achieve a stable formulation of the self-nanoemulsifying drug delivery system (SNEDDS), a ternary phase diagram was constructed under ambient conditions using the precise technique of water titration [12]. A mixture of surfactant and co-surfactant (designated as Smix) was included in perceptive weight ratios of 1:1, 2:1, and 3:1. These ratios were strategically chosen to encapsulate both balanced proportions and elevated co-surfactant concentrations. The designated volumetric proportions of the selected oil phase were then merged with the predetermined Smix ratios in a series of specialized glass vials, spanning weight combinations from 1:9 to 9:1. This spectrum was formulated to meticulously describe and encapsulate the phase boundaries. To highlight the transitional boundaries of the emulsification process, the aqueous phase concentration was carefully increased at 5% intervals to ensure a comprehensive spectrum from 5 to 95% of the total formulation volume. Each titration was performed by vortex agitation for two minutes, postulated by a stabilization interval.

Visual transition metrics, predominantly the shift from clear to turbidity and its inverse, were rigorously cataloged. This rigorous observation facilitated the curation of the ternary phase diagram, with each axis representing the oil, Smix, or water components. The culminating phase diagrams were cleverly crafted using advanced CHEMIX ternary plot software (Specifically, CHEMIX School Ver. 3.60, created by Arne standards).

Preparation of Felodipine Self-Nanoemulsifying Drug Delivery systems (SNEDDS)

After locating the self-nanoemulsifying region, SNEDDS formulas were created with the necessary component ratios. Using pseudo-ternary phase diagrams, the ratio of surfactant to cosurfactant (Smix) was optimized¹⁴. As shown in Table 1, different amounts of Tween 80, propylene glycol 400, and cinnamon oil were used to prepare several SNEDDS formulations of FLD. the ternary phase diagram’s nano-emulsification zone served as the basis for determining the appropriate quantity of oil, surfactant, and co-surfactant. The amount of FLD was maintained constant throughout the experiment. To ensure thorough mixing, the oil, surfactant, and cosurfactant were weighed precisely and combined in stoppered glass vials using a vortex mixer. As the oil and Smix were continuously mixed, a quantity of FLD was added and mixed until it was completely dissolved. A clear solution was obtained after the systems were warmed to 45⁰C in a water bath for 20 min with gentle shaking. Following preparation, the formulations were stored at room temperature until further use.

Table 1.

Compositions of optimized FLD loaded SNEDDS.

Sl. no.	Formulation Batch	S-mix ratio	Drug (Felodipine) mg	Oil (Cinnamon oil) ml	Surfactant (Tween 80) ml	Co-surfactant (PEG 400) ml
1	F1	1:1	5	1	4.5	4.5
2	F2	1:1	5	2	4	4
3	F3	2:1	5	1	6	3
4	F4	2:1	5	2	5.50	2.50
5	F5	3:1	5	1	6.75	2.25
6	F6	3:1	5	2	6	2

Thermodynamic stability analysis of felodipine-loaded SNEDDS formulations

To ascertain the robustness and resilience of Felodipine Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) under diverse environmental conditions, a comprehensive thermodynamic stability assessment was conducted. This comprehensive analysis was compartmentalized into the following three fundamental evaluations:

• Heating-Cooling Cycles: The formulated SNEDDS underwent rigorous temperature fluctuations by alternating between the chilling vicinity at 4 °C and elevated thermal settings at 40 °C, which were maintained in a refrigerator. Each formulation was subjected to these conditions for a minimum of 24 h. This rigorous temperature fluctuation cycle was repeated for six iterations. Subsequently, the stable formulations were selected for centrifugation.

• Centrifugation Examination: To carefully estimate the stability of the formulations and their resistance to phase shifts, the selected candidates were centrifuged at 5000 rpm for 30 min. The primary objective was to distinguish between any signs of phase separation, creaming, or potential cracking. Formulations that showed excellent stability after this centrifugation assessment were earmarked for the subsequent freeze-thaw resilience test.

• Freeze-Thaw Resilience Evaluation: Safe Formulations and sound from the centrifugation assessment were subsequently exposed to extreme temperature variations, transitioning from an icy − 21 °C to a more moderate + 25 °C. During this assessment, each formulation was maintained at specified temperatures for an uninterrupted duration of 24 h. Formulations that steadily withstand these climatic rigors are cataloged as prime candidates for deeper evaluative research.

Initially, each Liquid SNEDDS (L-SNEDDS) was subjected to a sequence of 24-hour heating (at 40 °C) and cooling (at 4 °C) cycles. The integrity of the systems was strictly monitored, with those not manifesting any phase separation and subsequently undergoing the 30 min centrifugation challenge at 5000 rpm. The ultimate litmus test and freeze-thaw cycles were used to assess the durability of the formulations across a temperature range of -21 °C to + 25 °C.

Emulsification of SNEDDS formulations

To strictly measure the ability of the Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) to initiate spontaneous emulsification, a standardized testing protocol was implemented using the USP Type II dissolution apparatus (Electrolab, TDT-08 L model). This experimental setup was chosen for its relevance and precision in emulsification assessment under controlled conditions. For assessment, a predetermined quantity of each SNEDDS formulation (precisely 1 mL) was gently introduced into a calibrated dissolution vessel containing 500 mL of distilled water. This water was rigorously maintained at a temperature of 37 ± 0.5 °C, simulating physiological conditions. The emulsification process was further facilitated by an exactly designed stainless-steel dissolution paddle, which provided consistent stirring at a steady speed of 50 rpm, thereby ensuring uniform and gentle agitation [14].

After the introduction of the SNEDDS formulation, visual evaluations were performed to distinguish the emulsification rate and the resulting visual characteristics of the nano-emulsion. Based on these observations, the formulations were methodically graded according to the following criteria.

• Grade A: Exemplary emulsification resulting in a transparent or subtly bluish emulsion, achieved within 1 min.

• Grade B: Prompt emulsification yielding a slightly opaque emulsion, predominantly with bluish-white shade.

• Grade C: Emulsion manifesting a milky consistency, typically achieved within a time frame of 2 min.

• Grade D: Gradual emulsification culminating in a grayish-white, somewhat opaque emulsion with an oily texture, requiring a duration exceeding 2 min for formation.

• Grade E: Inadequate emulsification efficacy, characterized by either minimal emulsion formation or marked presence of large oil droplets surfacing the top of the mixture.

Such a structured and well-defined grading system ensures objective and comprehensive evaluation of the inherent capacity of SNEDDS formulations for spontaneous emulsification, which is crucial for their potential therapeutic applications.

In-Depth kinetic analysis of SNEDDS Emulsification dynamics

Deep-diving into the difficult procedure of SNEDDS during its transition through the emulsification stage is vital for ensuring optimal performance. To achieve this depth of understanding, a detailed and methodologically sound approach was designed based on replicable experimental parameters. Beginning with the core components of our study, we obtained a precisely measured aliquot of the SNEDDS formulation (exactly 1 mL). This was then synergized with 300 mL of distilled water, which was rigorously maintained at a steady temperature of 37 ± 0.5 °C, a parameter ensuring consistency in every evaluation. To mimic gentle physiological agitation and ensure thorough mixing, the assembly was subjected to magnetic stirring calibrated at an unwavering speed of 100 rpm. The ensuing transformation of the SNEDDS from its initial state to a seamlessly integrated nanoemulsion was monitored using keen observational techniques. It was not merely gauging the duration; it was about capturing qualitative shifts during the emulsification phase. The time span from the introduction of SNEDDS to its complete dissolution denoted as the emulsification duration,’ serves as a key metric¹⁵.

Viscosity measurement

Using an LV 63 spindle with a shear rate of 20 rpm and a Brookfield viscometer (Brookfield Engineering Labs, LVDV-I-PRIME, USA), the viscosity of the prepared SNEDDS was measured at 25 ± 0.5⁰C both before and after dilution¹⁶.

Spectroscopic characterization of optical clarity

Spectrophotometric measurements of the optical clarity of aqueous SNEDDS dispersions were performed. The composition was prepared in accordance with the plan and diluted 100 times with distilled water. At 362 nm, the % transmittance of the developed SNEDDS (a key indicator of optical clarity) was tested using pure water as a blank¹⁷.

Stability assessment of SNEDDS using refractive index

To determine whether the formulation was transparent, the Refractive Index was measured¹⁸. By dropping a sample of the formulation onto a slide and comparing it with water, which has an RI of 1.33, Abbes refractometry was used to determine the RI value. If the RI of the system is comparable to that of water, the formulation is transparent. The stability of the formulation was also assessed using the RI.

Droplet size analysis and polydispersibility index (PDI) determination

Droplet size has a significant impact on self-emulsification because it affects both medication release and absorption. Before the measurement, distilled water was used to dilute 1 mL of each SNEDDS formula 10 times. Dynamic light scattering (DLS) was used to measure the globule size and polydispersibility index of the synthesized nanoemulsion using a photon correlation spectrometer (Zetasizer, Malvern Instruments LTD, Malvern, UK), which examined fluctuations in light scattering caused by the Brownian motion of the particles. Light scattering was observed At a scattering angle of 90⁰, light scattering was seen at 25⁰C. All measurements were performed thrice, and data integrity was guaranteed by computing the mean and standard deviation¹⁹.

Zeta potential

The zeta potential of the diluted SNEDDS was calculated using a Zetasizer (Malvern Instruments). The results were recorded after the samples were placed in clear, disposable cuvettes. The charges on the emulsion droplets and their zeta potentials were measured²⁰.

pH

A pH meter, a sophisticated electronic device from Equiptronics (EQ-636), was used to determine the pH of the various formulations. The electrodes submerged in the SNEDDS formulations produced a reliable pH reading, which is vital for understanding formulation compatibility and stability. All measurements were performed in triplicate.

Drug loading efficacy

A volumetric flask was filled with 1 mL of SNEDDS (equal to 5 mg of FLD) and shaken or turned over two-three times to thoroughly mix the formulation. A UV-Vis Spectrophotometer (Jasco, Tokyo, Japan) was used to detect the absorbance at 362 nm after the samples were prepared in triplicate. Using a calibration plot, the amount of FLD was determined for each formula²¹.

FT-IR spectroscopic study

The interactions between the FLD and the polymer were investigated using the ATR techniques in FT-IR spectrophotometer (Jasco)²². The samples were examined in the range of 500 to 4000 cm^− 1.

DSC study

According to the method outlined by Kaur et al. (2015), the thermograms for raw FLD and FLD-SNEDDS were captured using a DSC Q200 TA with Universal V 24.4 software (Bangalore, India). Samples (2 mg) were crimped separately in an aluminum pan and heated at a rate of 10 °C/min from 0 °C to 400 °C. During the scanning, nitrogen gas flowed continuously at a rate of 50 mL/min. An empty aluminum pan was used as the reference²³. The melting point was calculated using the TA-Universal Analysis 2000 software (version 4.7 A).

In vitro dissolution study

USP apparatus II (Electrolab, TDT-08 L) was used to measure FLD release from the SNEDDS. 900 ml of 0.1 N HCl were used as the dissolution medium, which was agitated at 50 rpm for 16 min at 37 ± 0.5 °C. Aliquots (5 ml) were removed at prescribed intervals (2, 4, 6, 8, 10, 12, 14, and 16 min), filtered through a 0.45 μm membrane filter, and then measured spectrophotometrically (Jasco V-630) at 362 nm. Measurements were performed in three replicates²⁴.

Statistical analysis

All values are expressed as mean ± SD. The dissolution data were analyzed using the PCP Disso version 3.0 software (Pune, India). The uniformity of SNEDDS synthesis was determined using the polydispersity index (PDI) value. The PDI was found to be less than 1 for all formulations.

Results and analysis

Solubility

The oil, surfactant, and cosurfactant must be carefully chosen for the system to form a SNEDDS with appropriate physicochemical properties. To identify suitable SNEDDS components with a high solubilizing capacity for FLD, solubility tests were conducted. To obtain optimal drug loading, it is crucial to choose the right oil, surfactant, and cosurfactant with the highest solubilizing capacity for the drug under study. Oils are the principal excipients because they can increase the proportion of lipophilic drugs carried by the intestinal lymphatic system, thereby enhancing their absorption from the GIT. Oils can solubilize lipophilic drugs in precise amounts. Since cinnamon oil had the highest solubilization of any of the screening oils (32.34 ± 1.59 mg/mL), it was chosen as an oily phase for FLD (Fig. 1). Nonionic hydrophilic surfactants were investigated in this study. Because they are hydrophilic (HLB values > 10) and non-ionic, the investigated surfactants are superior in forming fine, uniform emulsion droplets that can empty quickly from the stomach and provide a large surface area that facilitates quick drug release and absorption. Surfactants also create a barrier against coalescence by forming a layer around emulsion droplets, which lowers the interfacial energy. This may prevent the drug from precipitating inside the GI lumen. Tween 80 demonstrated the strongest solubilizing capacity for FLD (37.5 ± 2.09 mg/mL) among the various surfactants evaluated. It is uncommon to create a transient negative interfacial tension and a fluid interfacial film with only one surfactant; instead, a cosurfactant is typically required. Cosurfactants reduce the bending stress of the interface, allowing an interfacial film with sufficient flexibility to adopt the many curvatures necessary to produce a nanoemulsion over a variety of compositions. As shown in Fig. 1, PEG 400, one of the many cosurfactants utilized in this investigation, has FLD’s highest solubility (52.68 ± 1.88 mg/mL).

Fig. 1.

Solubility studies of FLD in various oils, surfactants and co-surfactants.

Screening of surfactants for emulsification efficiency

Drug solubility is a significant factor in the SNEDDS component selection, although it is not the sole factor used to determine the surfactant used in the produced systems. The ability of a surfactant to emulsify is a critical factor. The ability of several surfactants to emulsify the chosen oil was evaluated. The number of flask inversions required to prepare an emulsion was used to gauge the emulsion-forming capacity of the surfactant, and the percentage UV transmittance of the emulsion two hours after preparation was used to determine its stability. The high transmittance results from optical clarity because opalescent dispersions scatter incident photons more than transparent dispersions. The scattering of light caused by the absence of optical homogeneities in the medium is responsible for the intensity of the light flowing through such dispersions. Therefore, the relative droplet size of the emulsion can be directly predicted using the % transmittance. This theory led to the notion that oil droplets are in a state of nanodispersion and that optically transparent aqueous dispersions have high transmittance (reduced absorbance). Table 2 lists the flask inversion rates and percentage transmittance values for various dispersions. For all the screened surfactants, Span 80 experienced the highest number of flask inversions (eight inversions), indicating the most challenging emulsion formation. Additionally, the least stable emulsions were those made with Span 80, as seen by the observed low percentage of UV transmission (78.15%±1.01). In contrast, using Tween 80 as an emulsifying agent only required a small number of flask inversions (five inversions) to generate an emulsion. Additionally, two hours after preparation, the UV transmission percentage exceeded 95.34%±0.56, indicating that the emulsions were stable. Thus, Tween 80 was selected as a surfactant for additional research because of its improved nanoemulsification efficiency. According to Lawrence’s study on microemulsions as drug delivery vehicles, these discrepancies in the emulsification performance of the examined surfactants were related to variations in their chain length and structure.

Table 2.

Emulsification study of surfactant and co-surfactant.

Sl. no.	Surfactant and co-surfactant	% transmittance*	No. of flask inversion
1	Tween 80	95.34%±0.56	5
2	Span 80	78.15%±1.01	8
3	Tween20	20.58%±0.99	6
4	Span 20	12.76%±0.89	6
5	PEG200	90.82%±1.21	7
6	PEG400	98.68%±0.18	4
7	Ethanol	72.96%±1.65	6

[*Values are expressed as mean ± S.D., n = 3]

Screening of cosurfactants for emulsification efficiency

The emulsifying ability of cinnamon oil and Tween 80 appeared to be improved by all the cosurfactants used in this investigation. The dispersibility and drug absorption of formulations containing surfactants were improved by the addition of a cosurfactant. In contrast to previously used cosurfactants, PEG 400 showed good emulsification efficiency with cinnamon oil and Tween 80 mixture, displaying maximum transmittance (98.68%±0.18%) and only four inversions.

Pseudo-ternary phase diagram

For those immersed in the domain of Self-Nano Emulsifying Drug Delivery systems (SNEDDS), understanding their post-dilution behavior is not just important; it is pivotal. Once inside the body, physiological fluids inevitably dilute the SNEDDS. This poses a latent challenge: the risk of drug precipitation, primarily due to diminishing solvent capacity. This challenge underscores the invaluable role of constructing pseudoternary phase diagrams in SNEDDS development. These carefully constructed diagrams are powerful tools for various applications. First, they offer visual demarcations of the regions where self-nanoemulsification occurs. Secondly, they guide researchers in determining the optimal proportions of oil, surfactant, and cosurfactant, which is essential for a successful SNEDDS formulation. Our aim was to explore the workings of these systems using different surfactant to cosurfactant ratios, specifically 1:1, 2:1, and 3:1. However, how do one assess these diagrams? The expansion of the nano emulsion regions becomes a benchmark. A larger region in these diagrams indicates the enhanced tendency of the system to self-nanoemulsify. An in-depth visual examination of these formulations revealed noteworthy findings. In the nano emulsion phase, the formulations were characterized by their distinctive clarity and transparency, especially upon dilution. This observation is illustrated in Figs. 2 and 3 illustrate the different samples. In Fig. 2, the pseudoternary phase diagrams highlighted performance of the Tween 80-PEG 400 combination (dubbed as ‘Smix’) at a 2:1 ratio. The evidence of an expansive nano emulsion zone is depicted in the eye-catching purple shade. This observation not only underscored the power of the 2:1 ratio, but also showed it as a favorite, especially when stability was dominant.

Fig. 2.

Pseudo-ternary phase diagram (Smix): (a) 1:1, (b) 2:1, (c) 3:1.

Fig. 3.

Graphical representation of particle size analysis.

Another interesting observation emerged when equal proportions of the cosurfactant and surfactant were introduced. This configuration reveals a more expansive nano emulsion domain. The underlying science behind this was the sharp reduction in interfacial tension coupled with a marked increase in interface fluidity. This composition, thereby, could be a key to sorting even more optimized SNEDDS formulations in future investigations.

Characterization and Assessment of FLD-Loaded SNEDDS: Thermodynamic Stability Investigations

In the dynamic realm of pharmaceuticals, the development of a stable and reliable drug delivery system often demands accurate and careful evaluation. FLD-loaded SNEDDS, a potential revolution in drug delivery, underwent a comprehensive array of tests to establish its thermodynamic stability, which is crucial for both its efficacy and long-term shelf life. Systematic Thermodynamic Stress Tests.

• Heat-Cool Cycles: To follow the varying storage conditions that the formulation might encounter during its lifecycle, it was subjected to regular heat-cool cycles. Such an exercise is very important for assessing the resilience of the formulation to temperature fluctuations that are common in real-world scenarios.

• Centrifugation: Centrifugation, a process that exposes formulations to high gravitational forces, is next in line. It is an established method for measuring the potential for phase separation or sedimentation, which are key indicators of formulation instability.

• Freeze-Thaw Cycles: Finally, the formulations were subjected to freeze-thaw cycles to examine their stability against potential crystallization or phase separation events that could occur due to temperature extremes.

After these thermodynamic stress tests, the FLD-loaded SNEDDS formulations F3, F4, F5, and F6 showed ideal buoyancy. No precipitation, cloudiness, or phase separation was observed, indicating their robustness and well-balanced composition. Detailed visual evaluation further substantiated these findings. There was a prominent absence of flocculation or phase separation across the board, confirming firm integrity. The physical attributes of each formulation are presented in Table 3, providing experimental evidence of their uninterrupted condition.

Table 3.

Results for thermodynamic stability study of SNEDDs formulations.

Formulation Batch	Observation based on thermodynamic stability studies			Inference
	Freeze thaw cycle	Heating/cooling cycle	Centrifugation
F1	✗	✗	✗	Fail
F2	✗	✗	✗	Fail
F3	✓	✓	✓	Pass
F4	✓	✓	✓	Pass
F5	✓	✓	✓	Pass
F6	✓	✓	✓	Pass

Correlation with existing Research paradigms: Ashok et al.‘s study on the albendazole self-emulsifying drug delivery system (SEDDS) offers a thoughtful description. Their findings emphasize that the entropy of such systems remains even when subjected to sudden temperature variations. The complete and detailed characterization of FLD-loaded SNEDDS underscores its potential as a reliable, stable, and effective drug delivery system. The results from thermodynamic stability investigations offer real evidence, cementing its place as a promising candidate for future pharmacological applications. The research background is ready with possibilities, and our findings provide a basis for further investigation and optimization.

Self-emulsification performance

In the complex field of drug delivery, Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) stand out for their potential to reshape conventional therapeutic delivery paradigms. To understand the self-emulsification ability of our thoroughly developed SNEDDS, we conducted a rigorous dispersibility test. The thorough visual assessment results, given in Table 4, shed light on the in vitro capabilities of the SNEDDS formulations evaluated against our proprietary grading criteria. Impressively, each SNEDDS formulation attained ‘Grade A’ designation, supporting their exemplary self-emulsification attributes. The drug absorption path is profoundly influenced by emulsification dynamics. For SNEDDS to meet their potential, their capacity for swift and flawless self-emulsification is imperative to ensure optimal drug release and subsequent absorption. To strengthen our findings, we combined them against established benchmarks. Notably, the research endeavors of Naseem et al. in developing a self-nanoemulsifying lipid carrier system for etoposide support our insights. Their investigative lens revealed that a subset of their formulations consistently retained their nanoemulsion integrity when exposed to conditions mirroring the gastrointestinal (GI) tract milieu. These formulations, analogous to our SNEDDS, were duly accorded a Grade A distinction. The outcomes of the dispersibility examination resonated with the expertise of our SNEDDS formulations. The common achievement of the ‘Grade A’ accolade accentuates their potential in facilitating enhanced drug absorption via efficient self-emulsification. These findings not only affirm the efficacy of the proposed SNEDDS but also provide a basis for further research trajectories and clinical appraisals.

Table 4.

Visual observations of the dispersibility test for various FLD SNEDDS formulae.

Formula	Observations	Grade
F1	Rapidly forming clear emulsion	A
F2	Rapidly forming clear emulsion	A
F3	Rapidly forming clear emulsion	A
F4	Rapidly forming clear emulsion	A
F5	Rapidly forming clear emulsion	A
F6	Rapidly forming clear emulsion	A

Dynamics of emulsification

The emulsification velocity serves as an insightful metric for measuring the ability of an SNEDDS system. In the realm of pharmaceuticals, the rapid transition of a system to a homogeneous mixture plays a crucial role in therapeutic efficacy. Hence, an investigation of the time dynamics of self-emulsification was performed. The metrics are listed in Table 5. Consistent observations highlighted that each formulation accurately completed the emulsification process within an impressive span of 25–60 s. This speedy self-emulsification underscored the formulation’s strong ability for rapid and flawless emulsification. Upon closer introspection, it was determined that the temporal dynamics of self-emulsification had a complicated relationship with the specific compositional establishment and proportions of the oil, surfactant, and cosurfactant. A salient observation indicated a direct correlation between surfactant concentration and emulsification spontaneity; as the concentration of the surfactant increased, the speed of the emulsification process surged, thereby curtailing the requisite self-emulsification span. This efficiency can be attributed to the ability of Tween 80, a surfactant known to moderate interfacial tension. Consequently, this induces sharp diffusion of the aqueous phase into the oil domain, resulting in pronounced interfacial perturbation and subsequent droplet release into the overarching aqueous environment.

Table 5.

Results for characterization of SNEDDs formulations.

Sl. no.	Formulation Batch	Density* (gm/ml)	pH*	Viscosity at 50 rpm* (cps)	Emulsification time (s)	Observation	%Transmittance*	Refractive index*	Drug Content* (mg/ml)	PDI
1	F1	1.090 ± 0.087	6.82 ± 0.52	30.23 ± 0.33	45	Clear Dispersion	95.25 ± 0.21	1.64 ± 0.02	4.20 ± 0.11	0.056
2	F2	1.097 ± 0.055	6.75 ± 0.36	23.5 ± 0.61	35	Clear Dispersion	92.62 ± 0.13	1.59 ± 0.10	4.34 ± 0.09	0.087
3	F3	1.004 ± 0.077	6.87 ± 0.41	18.6 ± 0.51	25	Clear Dispersion	97.85 ± 0.17	1.46 ± 0.06	4.78 ± 0.10	0.039
4	F4	1.058 ± 0.053	6.65 ± 0.58	23.8 ± 0.23	30	Clear Dispersion	92.18 ± 0.31	1.64 ± 0.30	4.08 ± 0.09	0.048
5	F5	1.007 ± 0.046	6.78 ± 0.66	16.2 ± 0.22	25	Clear dispersion	95.22 ± 0.22	1.52 ± 0.05	4.54 ± 0.08	0.076
6	F6	1.052 ± 0.021	6.62 ± 0.50	23.2 ± 0.15	60	Slightly turbid	91.72 ± 0.24	1.68 ± 0.11	4.25 ± 0.12	0.123

*Mean ± SD, n = 3.

To strengthen our findings, we drew parallels with the pioneering research led by Shailesh et al. Their innovative venture into developing an olmesartan-medoxomil-based SNEDDS showed a similar trend. Their SNEDDS formulations demonstrated flawless emulsification times ranging from 15 to 35 s, reinforcing the universality of our observations. The rapid self-emulsification dynamics of our FLD-loaded SNEDDS formulations indicated their potential to ensure optimal drug delivery. Such temporal efficiencies, underpinned by complex compositional interplays, have set the stage for further examination and possible clinical integration. The F3 formulation was chosen in preference to the others due to its excellent performance, which included a clear and almost immediate dispersion in an impressive 25 s. F4 and F6 both showed lower viscosity at 50 rpm in comparison to the other formulations. F3 formulation was boasting a drug content of 96.56 ± 2.75%. So it was selected for further analysis.

Probing viscosity dynamics in SNEDDS formulations: implications for stability and bioavailability

A fundamental region for the physical characterization and stability assessment of SNEDDS is the evaluation of viscosity. Beyond simple fluid dynamics, the viscosity of SNEDDS can significantly dictate its dispersion efficiency in aqueous environments. The governing principle is straightforward: escalated viscosities regularly slow down the emulsification tempo, potentially inducing ramifications on both drug bioavailability and orchestrated release patterns in vivo. Turning our attention to viscosity determination metrics, as detailed in Table 5, an interesting pattern emerges. As the concentrations of both the oil and Smix (Surfactant-cosurfactant mix) improved, there was a concomitant decrease in the viscosity levels of the SNEDDS formulations. Further, a careful assessment revealed that the FLD SNEDDS formulations spanned a viscosity ranging from 16.2 ± 0.22 cps to a slightly elevated 30.23 ± 0.33 cps. Upon delving deeper into the viscosity strata, it became clear that all formulated compositions exhibited comparatively passive viscosities. Such an observation, beyond the simple quantitative spectrum, indicates that the resultant nano emulsion predominantly adheres to an oil-in-water (O/W) modality. A necessary conclusion drawn from our experimental findings was the remarkably low viscosity values recorded for our SNEDDS formulations. Such reduced viscosities, which are far from simple statistical outliers, highlight the formulation’s inherent potential for expedited self-emulsification.

In the versatile domain of drug delivery, the viscosity dynamics of SNEDDS play a role in influencing therapeutic outcomes. Although higher viscosities might offer structural robustness, their potential dampening of emulsification rates cannot be sidestepped. The present analysis, by offering a nuanced understanding of viscosity behaviors, provides a solid foundation for further exploration and optimization of SNEDDS drug delivery paradigms.

Optical clarity through Spectroscopic characterization

The essence of % transmittance in SNEDDS

The percentage transmittance serves as a pivotal benchmark in the realm of Self-Nanoemulsifying Drug Delivery Systems (SNEDDS). Essentially, it gauges the isotropic nature of the formulation and provides insights into its homogeneity and dispersion properties. Evidently, all formulations in this study showed remarkable transparency, with their transmittance values converging close to the optimal 100% mark.

Translating high % transmittance to practical outcomes

When an SNEDDS formulation registers a transmittance value of 100%, it speaks volumes beyond simple clarity. This metric clearly implies that the globules within the formulation are primarily within the nanometric field. Nanoscale dispersion is manifold.

• Augmented Surface Area: A higher surface area invariably paves the way for an optimized drug release mechanism.

• Enhanced Absorption Potential: With nanoscale disposition, the formula is ready for sharp absorption within biological matrices.

• Boosted Oral Bioavailability: Owing to its aforementioned properties, the overall oral bioavailability of the drug has witnessed a significant surge.

Delving into the empirical landscape, as depicted in Table 5, the FLD SNEDDS formulations presented % transmittance values ranging between 91.72%±0.24 and 95.25%±0.21 upon a 100-fold dilution. These metrics, far from statistical points, are testimonials of the unmatched optical clarity inherent to the FLD-loaded SNEDDS formulations. The observations of the present study are consistent with those of previous research. For instance, the work of Maulik et al., which revolved around the creation of a stable lovastatin Self-Microemulsifying Drug Delivery System (SMEDDS), further reinforces our findings. Their formulated SNEDDS also exhibited near-perfect transmittance, floating close to the 100% mark. Spectroscopic characterization, by offering precise insights into the optical clarity of SNEDDS formulations, serves as an area for optimizing drug delivery outcomes. A high % transmittance not only underscores the formulation’s clarity, but also heralds its potential for superior drug release and absorption, setting the stage for transformative therapeutic interventions.

Assessment of refractive index

The refractive index (RI) is a fundamental parameter that measures the speed at which light propagates through a medium in comparison to its speed in a vacuum. In the context of Self-Nanoemulsifying Drug Delivery Systems (SNEDDS), the refractive index is a key metric, primarily because it offers insights into the formulation’s transparency and potential stability.

Refractive index

When refractive index of a formulation closely aligns with that of water, which is approximately 1.33, it augurs well for several reasons.

• Indication of Transparency: A refractive index close to that of water indicates that the formulation is transparent. This transparency is instrumental in ensuring effective delivery of the drug and optimal therapeutic benefits.

• Predictor of Stability: Such similarity in refractive indices is also suggestive of the stability of the formulation. A stable formulation ensures consistent drug delivery, thereby justifying the potential risks associated with phase separation or precipitation.

• Homogeneity of the System: A refractive index that aligns with the RI of water points towards the homogeneity of the SNEDDS system. Homogeneous systems typically ensure uniform drug dispersion, which is suitable for achieving consistent therapeutic outcomes.

As shown in Table 5, the refractive index values for all the investigated formulations confirm their transparency and anticipated stability. These indices, which match the established value of water, offer both qualitative and quantitative attestations of the formulations’ inherent qualities. A close alignment of the refractive index with the standard benchmark of water serves as a robust metric for a SNEDDS transparency, stability, and homogeneity of a SNEDDS formulation. Such parameters are paramount for ensuring that the drug delivery system is not only effective but also safe, paving the way for consistent and optimal therapeutic interventions.

Droplet dimensions and polydispersibility index (PDI) in SNEDDS

The magnitude of droplet dimensions is crucial in Self-Nanoemulsifying Drug Delivery Systems (SNEDDS). It essentially modulates the drug release mechanisms and absorption rates. A very small particle size augments the interfacial surface area, potentially supporting absorption and thus improving drug bioavailability.

Droplet dimensions: Optimal SNEDDS was characterized by a mean droplet dimension below 200 nm. The systems scrutinized adhered to this standard, underscoring their ability to be an effective SNEDDS. Such accomplishment stem from the strategic combination of appropriate surfactants and cosurfactants. This blend ensures minimal free energy within the system, preventing potential thermodynamic discrepancies during environmental oscillations, such as alterations in volume or pH.

Interactions of Surfactant/Cosurfactant: In agreement with the elucidations by Nepal et al., the surfactant-cosurfactant synergy establishes an alarming mechanical obstacle and uncomfortable potential globule aggregation. An interesting observation is the inverse correlation between the surfactant concentration and the mean droplet dimension. Elevated surfactant concentrations tend to manifest smaller droplet dimensions, attributable to an array of mechanisms, including augmented surfactant interface availability, a stabilized surfactant film at the oil-water boundary, and diminished interfacial tension.

Polydispersibility Index (PDI): Beyond the mean droplet dimension, the distribution spread of these droplets significantly controls the determination of SNEDDS efficacy. PDI offers a granular perspective for this dispersion. As dimensionless, PDI oscillates between 0.0 and 1.0, where proximity to zero indicates delicate particle uniformity.

The PDI metrics for the SNEDDS under evaluation, ranging between 0.039 and 0.123 ( Table 5), suggest a constricted globule dimension distribution. Such a restricted spread accentuates the system’s physical robustness and suggests a consistent emulsion profile. The magnitude and distribution of the droplets, epitomized by PDI, remain central to the operational efficacy of SNEDDS. Collectively, these parameters shape the release, absorption, and stability of this drug delivery system. The formulations under the lens exhibited noteworthy characteristics such as enhanced bioavailability and uniform therapeutic results. The selected formulation (F3) was subjected to particle size analysis, and the particle size was found less than 200 nm. The uniformity of SNEDDS was determined using the polydispersity index (PDI). PDI was less than 1 for all formulations (Table 5). The observed PDI values, ranging from 0.039 to 0.123, indicate a relatively narrow polydispersity, which correlates with a uniform droplet size distribution. These PDI values suggest a homogeneous dispersion, with minimal variation in droplet size, thereby reflecting a well-controlled formulation with consistent emulsion characteristics.

Determination of zeta potential

Zeta potential is a significant marker of the stability of a colloidal system. The essence of this potential is to ascertain the degree of repulsion between the adjacent charged particles in the dispersion. The magnitude of the zeta potential determines the propensity of the system to agglomerate or stabilize.

Criteria for Dispersion Stability: For colloidal dispersion to exhibit stability, individual particles should ideally possess a pronounced positive or negative zeta potential. This engenders a repulsive force between the particles, thereby fostering stability. Conversely, if the zeta potential dwindles, the particles lack the requisite repulsion to prevent aggregation, thus inciting instability. A benchmark zeta potential of + 30 mV or -30 mV usually indicates stability in unstable aqueous dispersions. It is generally posited that particles with zeta potentials beyond these thresholds tend to be stable.

Zeta Potential (F3): The optimized SNEDDS showed a high absolute zeta potential value of -16.8 mV. The stability of the emulsion was directly affected by the surface charge level. An increase in the electrostatic repulsive forces between the droplets often prevents the coalescence of the nanoemulsion droplets. Conversely, phase separation arises from a reduction in electrostatic repulsive forces, as shown in Table 6.

Table 6.

Zeta potential of F3.

Sl. no.	Measurement Results	Observation
1	Zeta potential	−16.8 mV
2	Mobility	1.35 μm/s/v/cm
3	Conductivity	142 us/cm
4	Zeta run time	30 s.

This assessment is in agreement with the study conducted by Kulkarni et al., in which a solid self-nanoemulsifying rosuvastatin calcium formulation was explored. The recorded zeta potentials spanned a range of -4.93 to -11.8 mV, further attesting to the premise that non-traditional zeta potential values, when orchestrated with the right system components, can still sustain a stable colloidal framework.

Density and pH evaluation

Formulations F3, F4, and F5 demonstrated notably low density, a characteristic that augments their excellent dispersibility in aqueous media. A lower density facilitates the dispersion of the formulation in the gastrointestinal tract, which can contribute to enhanced drug absorption and therapeutic outcomes.

The pH of the formulation is essential to ensure its compatibility with physiological pH and to predict its behavior upon oral administration. The pH of the formulations was determined using sophisticated electronic pH metering techniques. Notably, the formulations displayed a pH of approximately 6.8, classifying them as mildly acidic. This pH aligns well with the slightly acidic environment of the proximal small intestine, which could imply a favorable interaction profile upon administration. For a detailed quantitative understanding of the density and pH attributes of the SNEDDS formulations, refer to Figs. 3 and 4; Table 5, where these metrics are systematically cataloged for each formulation. These data provide a clear understanding of the physicochemical properties, which can be instrumental in predicting the in vivo performance of the formulations.

Fig. 4.

FT IR spectra of Felodipine.

Drug loading efficacy in SNEDDS formulations

The efficiency with which a drug is incorporated into a formulation, especially in advanced delivery systems such as SNEDDS, plays a pivotal role in the performance of the formulation. Uniform drug dispersion ensures consistent drug release and enhances the therapeutic efficacy. For all FLD-loaded SNEDDS formulations, the drug loading efficiency was determined to be in the range of 81.6% (4.08 ± 0.09) to 95.6% (4.78 ± 0.10), as tabulated in Table 5. Uniform dispersion of the drug in the formulations was evident from these metrics. Statistical analyses further confirmed that the variance in drug content between the different formulations was negligible. The F3 formulation had the highest drug concentration. This can be attributed to its augmented surfactant and cosurfactant concentrations, which have inherently high solubilizing potentials, enabling the optimal solubilization of the FLD dose of 5 mg. To substantiate this observation, it is worth noting a parallel in the literature: Ashish et al.‘s study on furosemide SNEDDS recorded drug loading ranging from 90.08% ±0.124–102.45% ±0.312% (Fig. 5).

Fig. 5.

FT IR spectra of Felodipine SNEDDS formulation (F3).

Fourier transform infrared spectroscopy (FT-IR) analysis

FT-IR spectroscopy is an essential tool for investigating molecular interactions in a formulation, particularly for sensitive potential interactions between the drug and excipients used. In the FT-IR spectrum of FLD, prominent peaks were detected at 3396.99 cm^− 1 (attributed to OH groups) and 1741.41 cm^− 1 (associated with C = O groups). Interestingly, in the S-SNEDDS precipitate spectrum, these peaks exhibited minor shift of 3489.56 cm^− 1 and 1738.51 cm^− 1, respectively. A detailed comparison of these peaks with the standard reference spectra implied the absence of any significant molecular interactions between the drug and its excipients. The spectral data strongly suggested that felodipine maintained compatibility with the excipients used. Notably, the peaks observed in the F3 formulation were closely aligned with the characteristic peaks, reinforcing the selection of this formulation for in-depth studies (Fig. 4a and 4b).

Differential scanning calorimetry (DSC)

Differential Scanning Calorimetry (DSC) is an analytical technique used to characterize the physical properties of substances, particularly their thermal transitions. In the context of drug formulations, DSC can be used to determine the physical state of the drug within the formulation and its possible interactions with excipients. The sharp melting point of FLD at 149.04 °C is indicative of its crystalline nature. While the optimized formulation F3 shows shift in melting point to 147.58⁰c showing the entrapment of the drug within the SNEDDS formulation. Notably, when evaluating the excipients, a distinct endothermic melting peak corresponding to the melting point of the pristine FLD was absent. This observation serves as an initial indication that no physical interactions occur between the drug and excipients. The absence of a well-defined endothermic peak in the SNEDDS formulation suggests that the FLD is in a solubilized state within the system. This is illustrated in both Fig. 6. The observed shift to a lower melting temperature, coupled with the absence of the crystalline peak at 149.04 °C, suggests that Felodipine has transitioned from its crystalline to an amorphous state within the SNEDDS system. This transition is typically associated with enhanced solubility, as amorphous forms generally exhibit superior dissolution characteristics compared to their crystalline counterparts. Furthermore, the lack of additional peaks in the DSC profile of the SNEDDS formulation supports the hypothesis that Felodipine is uniformly incorporated and entrapped within the formulation. This encapsulation in an amorphous form is likely to contribute to improved bioavailability due to enhanced solubility and the favorable interaction between Felodipine and the excipients. Thus, the DSC results corroborate the successful entrapment of Felodipine in an amorphous state within the SNEDDS formulation, indicating potential for improved solubility and compatibility with the excipient matrix.

Fig. 6.

Differential Scanning Calorimetry spectra of Felodipine and formulation F3.

Morphological study

Scanning electron microscopy (SEM) provides important details about the shape, size, and uniformity of nanoparticles, which are crucial for determining how effectively a drug is delivered and how well it works in the body. In this study, we focused on examining the F3-optimized formulation using SEM, as shown in Fig. 7. The SEM images of this formulation had an oval shape, and importantly, they showed complete drug adsorption on their surfaces. This strong and consistent drug attachment suggests that the formulation is well-designed, which could lead to better and more controlled drug release, ultimately improving the therapeutic effects.

Fig. 7.

SEM image of optimized formulation F3.

In vitro dissolution study

In vitro dissolution tests are crucial for understanding how a drug is released from its dosage form under simulated physiological conditions. The dissolution behavior of FLD from its SNEDDS formulations was compared with that of its pure form (API) encapsulated in hard gelatin capsules. It is important to emphasize that the dissolution media did not contain surfactants, such as sodium lauryl sulfate, or any dissolution-enhancing agents. The omission of these components ensures a genuine reflection of the dissolution properties of SNEDDS formulations, given that surfactants can often artificially augment dissolution rates.

As shown in Fig. 8, the dissolution profiles of various FLD SNEDDS formulations contrasted with those of pure FLD. Within 16 min, pure FLD showed a modest dissolution of just 14.78%±2.11. Conversely, SNEDDS formulations showed a significantly accelerated release profile. Specifically, the F3, F4, F5, and F6 formulations released more than 90% of the incorporated FLD within the same duration.

Fig. 8.

Graphical representation of % drug release of formulation.

• F3: 96.56%±2.75.

• F4: 90.45%±1.35.

• F5: 94.28%±1.89.

• F6: 92.84%±2.01.

The prominent enhancement in the dissolution rates of FLD from SNEDDS formulations can likely be attributed to the immediate formation of nano-emulsions upon contact with the dissolution medium. As the drug is encapsulated within nanosized droplets, it is present in a solubilized state, thus facilitating rapid dissolution. SNEDDS systems, with their inherent capability to deliver the drug in a solubilized nano-emulsion form, can potentially lead to improved oral bioavailability, ensuring efficient drug absorption when administered.

Discussion

Self-nano emulsifying Drug Delivery systems (SNEDDS) for drugs, such as FLD, have changed the way we think about bioavailability, especially for drugs with poor water solubility. This study not only showed how well the SNEDDS formulation works, what FLD looks like, and how it releases itself in SNEDDS but also showed what this means for using FLD to improve its dissolution profile. One of the best properties of SNEDDS is that it emulsifies quickly, which ensures that drugs undergo dissolution quickly and will help improve bioavailability. Reliable and effective drug transport is important for patients with chronic diseases. Because many people with long-term conditions may be taking more than one drug or have problems with their stomachs, a delivery method that reliably spreads the drug is very helpful. Another aspect worth emphasizing is the viscosity of the SNEDDS formulations. Low viscosities play a pivotal role in fostering swift emulsification²⁵. Spectroscopic characterization revealed the isotropic nature of SNEDDS, indicating a large surface area conducive to drug release²⁶. For a disease that requires high oral bioavailability, the ability of SNEDDS to ensure optimal drug absorption in the biological matrix is a major advantage of the developed formulation. This leads to a reduction in the dose of felodipine. The droplet size and distribution were evaluated for the Polydispersibility Index (PDI), especially when dealing with drugs that have traditionally suffered from suboptimal absorption profiles. Smaller droplets ensure a higher interfacial surface area, potentially paving the way for improved absorption, consistent therapeutic effect, and, in the long run, better patient compliance²⁷. The negative zeta potential demonstrated stability, which was largely attributed to the presence of non-ionic surfactants²⁸. Sustained stability ensures consistent drug delivery over extended periods, obviating concerns regarding degradation or altered release profiles.

In addition, the compatibility between the drug and excipients, as confirmed by FT-IR, and the crystalline form were analyzed through DSC analysis, providing further evidence for the reliability and consistency of SNEDDS formulations²⁹. The in vitro dissolution study showed that over 90% of the drug release was achieved in 16 min. Rapid release can result in a faster onset of action, which can be crucial in conditions requiring swift therapeutic responses. The results underscore the pivotal role of novel drug delivery systems, such as SNEDDS, in ensuring consistent, rapid, and efficient drug delivery, which is crucial for long-term and often intricate therapeutic effects. As healthcare continues to pursue personalized and efficient treatment, leveraging the advantages of SNEDDS could be a decisive step forward. Future investigations should ideally translate these in vitro achievements into in vivo success, thereby setting the stage for transformative care in disease management.

Conclusion and future prospects

A major leap in drug delivery methods has been made with the development of an L-SNEDDS formulation that uses PEG 400 as the cosurfactant, Tween 80 as the surfactant, and cinnamon oil as the oil basis. This formulation demonstrated efficient size dispersion with a particle size below 200 nm and achieved rapid self-emulsification in less than a minute. Furthermore, formulation F3 demonstrated an astounding drug content of 95.6%, confirming the system’s ability to administer medications with a high degree of accuracy. The stability of this formulation is crucial for its validation, and a number of thermodynamic stability studies have provided strong evidence. The L-SNEDDS continuously showed robustness in freeze-thaw experiments, centrifugation, and heating-cooling cycles. The integrity of the formulation was further reinforced by FTIR spectral analysis, which revealed no interaction between the medication and selected excipients. The in vitro dissolution studies showed a clear difference between our L-SNEDDS system and conventional drug delivery techniques: in the first 20 min, only 14.78%±2.11 of FLD was dissolved from the pure drug, but in the same amount of time, the SNEDDS formulations F3, F4, F5, and F6 released over 90% of FLD. These results highlight the potential of SNEDDS, particularly for medications falling under BCS classes II and IV, which have low water solubility. Because the pharmaceutical industry is constantly changing, FLD is not the only situation in which L-SNEDDS can improve drug delivery. This study established a standard for future therapeutic approaches, particularly in the context of chronic illnesses. With long-term, frequently complex treatments required for chronic illnesses, ‘s consistent and improved bioavailability of SNEDDS is priceless.

Author contributions

Conceptualization/supervision, and proofreading: AP, SD, RP, DEU. Investigation and literature review; PM, HMA, VS , Analysis and draft writing: VK, SM, FMMA, AK. All authors approved the final draft of the manuscript for submission.

Data availability

All data were available in the manuscript.

Declarations

Competing interests

The authors declare no competing interests.