Microemulsion: A Comprehensive Review on Formulation, Characterization and Evaluation

Mohammad Altamash*, Shaikh Azeem Hasddiin, Mohammad Zubair

JIIUI’s Ali-Allana  College of Pharmacy, Akkalkuwa Dist Nandubar – 425415, Maharashtra India

*Correspondence: iamaltamash122@gmail.com

DOI: https://doi.org/10.71431/IJRPAS.2026.5619

INTRODUCTION

The pharmaceutical industry continually faces the challenge of delivering therapeutics with adequate bioavailability, particularly for Biopharmaceutics Classification System (BCS) Class II (low solubility, high permeability) and Class IV (low solubility, low permeability) drugs, which collectively account for nearly 40% of approved drugs and over 70% of molecules in the drug development pipeline [1,3]. Conventional dosage forms often fail to achieve therapeutic plasma concentrations for such compounds, necessitating innovative formulation strategies

Microemulsions (MEs) represent one of the most extensively researched colloidal drug delivery platforms over the past five decades. Initially observed by Hoar and Schulman in 1943 as transparent, stable dispersions formed upon addition of a medium-chain alcohol to an emulsion, the term 'microemulsion' was formally coined by Schulman et al. in 1959 [1,28]. The comprehensive physicochemical definition provided by Danielsson and Lindman in 1981 — 'a system of water, oil and amphiphile(s) which is a single optically isotropic and thermodynamically stable liquid solution' — remains the gold standard [2]. 

MEs are distinguished from conventional emulsions and nanoemulsions by three defining characteristics: (i) thermodynamic stability arising from the ultralow interfacial tension at the oil–water interface, (ii) spontaneous formation requiring minimal energy input, and (iii) nanometric droplet size (10–200 nm) conferring optical clarity [3,4,13]. These attributes translate into practical advantages including enhanced drug solubilisation, prolonged shelf life, ease of manufacture, and improved bioavailability via multiple routes of administration [5,10]. 

This review systematically addresses the theoretical framework of ME formation, excipient selection criteria, methods of preparation, pseudoternary phase diagram construction, comprehensive evaluation strategies, and diverse therapeutic applications across oral, transdermal, ocular, nasal, parenteral, and topical routes. Regulatory aspects and future perspectives are also discussed to provide an integrated view of the current state of ME science. 

Physicochemical Principles of Microemulsion Formation 

Thermodynamic Stability 

The Gibbs free energy of formation (DGf ) for a dispersed system is governed by DGf = gDA TDSmix , where g is the interfacial tension, DA the change in interfacial area, T the absolute temperature, and DSmix the entropy of mixing [13,29]. For conventional emulsions, g is sufficiently high (10–50 mN/m) that DGf is positive and the system is thermodynamically unstable, tending to separate over time. In MEs, the combination of surfactant and co-surfactant reduces g to transient or sustained negative values (10-3 mN/m range), rendering DGf negative and formation spontaneous [3,25,26]. 

The entropy gain from droplet dispersion (TDSmix > 0) further drives the system toward a single-phase microemulsion. This is fundamentally different from kinetic stability offered by nanoemulsions, which are formed under high energy but lack thermodynamic driving force [13,31]. The ultralow interfacial tension in MEs is achieved primarily through the formation of a mixed interfacial film where the surfactant and co-surfactant molecules pack synergistically, as described by the packing parameter (P) concept of Israelachvili [29]. 

Packing Parameter and Geometry 

The geometry of self-assembled amphiphilic systems is described by the critical packing parameter P = v/(a0 ·l c ), where v is the hydrophobic tail volume, a0 the optimal head-group area, and l c the critical chain length [29]. For P < 1/3, spherical micelles form; 1/3 < P < 1/2 produces cylindrical structures; P » 1 gives planar bilayers; P > 1 leads to reverse (water-in-oil, w/o) structures. MEs span the P range 1/3 to > 1 depending on formulation composition [3,13]. 

Winsor Classification

Winsor (1948) classified microemulsion equilibria into four types based on phase behaviour [26]: Winsor Type I (o/w ME in equilibrium with excess oil phase), Winsor Type II (w/o ME in equilibrium with excess water), Winsor Type III (bicontinuous ME co-existing with both excess oil and water phases), and Winsor Type IV (single-phase isotropic ME, the pharmaceutical optimum). Transition from Type I through IV can be achieved by varying salinity, temperature, surfactant HLB, or oil chain length [13,26]. 

Hydrophile–Lipophile Balance (HLB) 

The HLB system developed by Griffin assigns numeric values (0–20) to surfactants reflecting their hydrophilic–lipophilic character. HLB values of 3–6 favour w/o MEs, while values of 8– 18 promote o/w systems [3,29]. Required HLB for a given oil phase is matched by blending surfactants: HLBblend = S(f i × HLB i ), where f i is the weight fraction of each surfactant. Cosurfactants (short-chain alcohols or polyols) disrupt liquid crystalline phases, increase interfacial fluidity, and fine-tune the effective HLB [3,4,22]. 

Comparative Overview: ME vs. Emulsion vs. Nanoemulsion 

Table 1 summarises the key physicochemical distinctions between conventional emulsions, nanoemulsions, and microemulsions. These differences have important implications for formulation design, stability, and therapeutic performance [3,13,31,32].

Table 1. Comparative physicochemical properties of emulsion, nanoemulsion and microemulsion

Components of Microemulsion

 The physicochemical performance of a ME is critically dependent on the judicious selection of its constitutive excipients: oil phase, surfactant, co-surfactant, and aqueous phase. Each component contributes uniquely to the thermodynamic and kinetic properties of the final system [3,4,34].

Oil Phase

 The oil phase constitutes the lipophilic core of o/w MEs or the dispersing medium of w/o systems. Oils are classified as long-chain (LCFA, e.g., soybean oil, olive oil), medium-chain triglycerides (MCT, e.g., Captex 355, Miglyol 812), or synthetic fatty acid esters (e.g., isopropyl myristate, ethyl oleate). MCTs are preferred for ME formulation owing to their lower viscosity, superior chemical stability, and established GRAS status [7,14,41]. The solubilisation capacity of the oil for the drug is a primary screening criterion, typically determined by saturation solubility assay. 

Surfactants 

Surfactants adsorb at the oil–water interface, reducing interfacial tension and providing a steric or electrostatic barrier against droplet coalescence [29]. Pharmaceutical-grade non-ionic surfactants (Tween 20, Tween 80, Cremophor EL, Span 80, Labrasol) are most widely employed due to their low toxicity and broad compatibility [3,22,35]. Ionic surfactants (sodium dodecyl sulphate, dioctyl sodium sulphosuccinate, lecithin) confer electrostatic stabilisation and are used in parenteral and ocular MEs [11,21]. Gemini and biosurfactants represent emerging alternatives with improved environmental profiles [4]. 

Co-surfactants 

Short-chain alcohols (butanol, hexanol), polyols (propylene glycol, PEG 400, glycerol), and ether derivatives (Transcutol P, diethylene glycol monoethyl ether) serve as co-surfactants. Their primary roles include: (i) reducing the critical micelle concentration (CMC) of the main surfactant, (ii) increasing the fluidity and flexibility of the interfacial film, (iii) reducing the bending modulus, and (iv) widening the ME existence region in the pseudoternary phase diagram [3,4,13]. The surfactant-to-co-surfactant mass ratio (Km) is a critical formulation variable, typically ranging from 1:1 to 4:1 [22,34]. 

Aqueous Phase 

Purified water or water for injection (WFI) constitutes the aqueous phase. Buffer systems (phosphate, citrate) may be incorporated to maintain pH stability. Electrolytes alter the ionic strength, affecting droplet charge and ME type transitions [3,26]. The water content is a major determinant of the structural transition from w/o to bicontinuous to o/w ME as water is progressively added during dilution studies.

Table 2. Commonly used excipients in microemulsion formulation

Pseudoternary Phase Diagram Construction 

The pseudoternary phase diagram is the cornerstone tool for identifying the composition space within which a stable ME exists. It is constructed by treating the surfactant and co-surfactant as a single pseudo-component (Smix ) at a fixed Km ratio [22,34,36]. 

Construction Methodology 

The three vertices of the ternary diagram represent: (i) oil phase, (ii) aqueous phase, and (iii) Smix (surfactant + co-surfactant). Stock mixtures of oil and Smix are prepared at fixed ratios (e.g., 1:9, 2:8, 3:7 … 9:1 w/w). To each mixture, water is added dropwise with gentle agitation at 25 ± 0.5 °C until a clear single-phase system forms, or until phase separation occurs [22,36]. The volume of water at each transition point is recorded and mapped onto the triangular coordinate system. 

The experiment is repeated at multiple Km ratios (typically 1:1, 1:2, 2:1, 1:3, 3:1) and at different temperatures if thermotropic behaviour is of interest. The area enclosed within the ME existence boundary represents the microemulsion region (MER). A larger MER indicates greater formulation flexibility and higher water solubilisation capacity [22,34]. 

Interpretation and Optimisation 

Within the MER, sub-regions may be distinguished using conductivity measurements: low conductivity corresponds to w/o MEs, rising conductivity marks the bicontinuous region, and high conductivity is characteristic of o/w MEs [3,13]. D-optimal or Box-Behnken response surface designs are frequently superimposed on the pseudoternary diagram to optimise the composition for desired droplet size, drug loading, and zeta potential [36,48]. Regression models correlate excipient concentrations with critical quality attributes (CQAs), enabling Quality by Design (QbD)-compliant development [15,48]. 

METHODS OF PREPARATION 

Spontaneous Emulsification / Self-Emulsification 

The hallmark of MEs is spontaneous formation upon gentle mixing of oil, surfactant, cosurfactant, and water in the appropriate proportions identified by the pseudoternary phase diagram. No external energy (homogenisation, sonication) is required [3,13]. Selfmicroemulsifying drug delivery systems (SMEDDS) exploit this principle: the drug is dissolved in the oil–surfactant–co-surfactant pre-concentrate, which forms an ME in situ upon contact with gastrointestinal fluids [14,15]. 

Phase Titration Method

Phase titration is the most common preparative method for small-scale research batches. The oil phase and Smix are mixed at the selected Km ratio, and the aqueous phase is added stepwise until a clear, single-phase system is obtained and confirmed by visual inspection, light transmission, and conductivity measurement [22,36]. 

High-Pressure Homogenisation (for nanoemulsions reference) 

Although true MEs form spontaneously, high-pressure homogenisation (500–1500 bar) is sometimes applied during scale-up to ensure uniformity when drug loading reduces the thermodynamic driving force. This approach is more relevant to nanoemulsion manufacturing and is used as a secondary processing step for MEs in special cases [32,33]. 

Titration by Heating/Phase Inversion 

Phase inversion temperature (PIT) methods exploit the temperature dependence of the spontaneous curvature of non-ionic surfactants. At the PIT, the effective HLB transitions from w/o to o/w, creating very small droplets. Rapid cooling locks in the ME structure [32,37]. This is suitable for heat-stable drugs and excipients. 

Solid-State Microemulsion Preconcentrates 

Liquid MEs can be converted to solid dosage forms by adsorption onto porous carriers (aerosil, Neusilin US2), spray drying, or freeze drying. The resulting powders reconstruct the ME upon hydration and offer improved patient compliance, stability, and manufacturability for commercial-scale production [8,49]. 

Physicochemical Evaluation 

Thorough characterisation of MEs is essential to establish identity, quality, purity, and biopharmaceutical performance. Evaluation encompasses physical, chemical, and biopharmaceutical assessments as detailed below [3,10,22,35]. 

Droplet Size and Size Distribution 

Dynamic light scattering (DLS), also referred to as photon correlation spectroscopy (PCS), is the gold-standard technique for droplet size determination in ME systems. DLS measures the temporal fluctuations in scattered light intensity caused by Brownian motion of nanoscale droplets, from which the hydrodynamic diameter (dh ) and polydispersity index (PDI) are derived via the Stokes–Einstein equation: D = kBT / (3phd), where D is the diffusion coefficient, kB Boltzmann's constant, T temperature, and h viscosity [3,22]. A PDI < 0.2 indicates a monodisperse system desirable for MEs. Nanoparticle tracking analysis (NTA) provides number-weighted size distributions and concentration data, complementing DLS. 

Zeta Potential 

Zeta potential (z) reflects the electrokinetic potential at the slipping plane of the electrical double layer surrounding each droplet. Values beyond ±30 mV indicate sufficient electrostatic repulsion to prevent aggregation. For non-ionic ME systems, steric stabilisation dominates, and z may be near zero yet the system remains stable [3,22]. Zeta potential is measured by electrophoretic light scattering (ELS) using instruments such as the Malvern Zetasizer or Brookhaven ZetaPALS. 

Conductivity and ME Type Identification 

Electrical conductivity differentiates ME type. w/o MEs exhibit conductivity values < 10 µS/cm (isolated water pools); bicontinuous MEs show intermediate conductivity (10–1000 µS/cm); and o/w MEs have conductivity > 1000 µS/cm (continuous aqueous phase) [3,13]. Conductance percolation threshold measurement also provides insight into the droplet–droplet interactions and dynamic exchange of contents between water pools [13,27]. 

Viscosity and Rheology 

ME viscosity is measured using cone-and-plate or concentric cylinder rheometers. Most MEs exhibit near-Newtonian behaviour at low surfactant concentrations, while bicontinuous MEs may be weakly viscoelastic [13,16]. Oscillatory rheology (G', G'' frequency sweeps) elucidates microstructure. For topical and transdermal MEs, viscosity is a critical quality attribute influencing spreadability, skin contact time, and permeation [17,20]. 

Optical Properties — Transmittance and Refractive Index 

Optical clarity is a hallmark of true MEs. Transmittance is measured spectrophotometrically at 650 nm against water as blank; MEs should exhibit > 99% transmittance. Refractive index (RI) is determined with an Abbe refractometer; a single RI value (no layering) confirms singlephase character [3,35]. 

Dye Solubility Test 

This simple qualitative method uses water-soluble (methylene blue) and oil-soluble (Sudan III/IV) dyes to confirm ME type. In o/w MEs, methylene blue diffuses freely throughout; in w/o MEs, Sudan IV dissolves in the continuous oil phase. Bicontinuous MEs dissolve both dyes to some extent [3,22]. 

Morphological Analysis

Transmission electron microscopy (TEM) and cryo-TEM provide direct visual evidence of ME structure, droplet shape (typically spherical), size, and organisation. Sample preparation involves negative staining (phosphotungstic acid, uranyl acetate) for conventional TEM or vitrification for cryo-TEM [3,35]. Atomic force microscopy (AFM) complements TEM by providing surface topography and droplet height mapping in near-native conditions. 

Small-angle X-ray scattering (SAXS) and small-angle neutron scattering (SANS) are powerful non-destructive techniques revealing ME microstructure, droplet geometry, interparticle interactions, and internal oil–water–surfactant organisation in solution [3,13]. These techniques are particularly valuable for bicontinuous and lamellar liquid-crystalline mesophases. 

Thermodynamic Stability Studies

Thermodynamic stability is assessed through a battery of stress tests: (i) centrifugation at 3,000–15,000 rpm for 30 min, (ii) freeze-thaw cycling (-20 °C to +25 °C, 3–6 cycles), (iii) heating-cooling cycling (4–45 °C, 3–6 cycles), and (iv) long-term storage at 4 °C, 25 °C/60% RH, and 40 °C/75% RH (ICH Q1A conditions) [3,10,22]. Absence of phase separation, creaming, or significant change in droplet size confirms stability. 

Drug Content and Chemical Assay

Drug encapsulation efficiency (EE%) = [(Total drug – Free drug)/Total drug] × 100. Free drug is separated by ultracentrifugation or membrane ultrafiltration. Total and free drug concentrations are quantified by validated HPLC, UV-Vis, or LC-MS methods appropriate for the analyte [10,22]. Drug content uniformity is assessed across multiple samples per ICH Q2(R1) requirements. 

In Vitro Drug Release

 Drug release from MEs is studied using modified Franz diffusion cells (membrane-based) or dialysis bag (reverse dialysis) methods [10,20,24]. Commonly used membranes include cellulose acetate (MWCO 12–14 kDa), Strat-M synthetic membranes (transdermal), and reconstituted human epidermis for skin permeation. Release data are fitted to mathematical models (zero-order, first-order, Higuchi, Korsmeyer-Peppas, Hixson-Crowell) to elucidate release mechanisms [10,35].

Table 3. Evaluation parameters, methods and acceptance criteria for microemulsions

Biopharmaceutical and In Vivo Evaluation

Ex Vivo Permeation Studies

Ex vivo permeation utilises excised biological membranes (rat/rabbit skin, bovine cornea, porcine buccal or intestinal mucosa) mounted in Franz diffusion cells. Drug flux (µg/cm²/h), permeability coefficient (P), lag time (T lag ), and enhancement ratio (ER) relative to control are determined. Skin Review Article | Microemulsion: Formulation and Evaluation Journal of Pharmaceutical Sciences and Research integrity is confirmed pre- and post-experiment by transepidermal water loss (TEWL) and electrical impedance [20,24,43]. 

In Vivo Pharmacokinetic Studies 

Pharmacokinetic (PK) parameters including Cmax , Tmax , AUC0-¥ , t 1/2 , and absolute/relative bioavailability are determined in rodent (Wistar rat, Sprague-Dawley) or beagle dog models following appropriate dosing. Blood samples are collected at defined intervals and drug/metabolite concentrations analysed by validated LC-MS/MS methods [12,51]. Non-compartmental analysis (NCA) via software such as Phoenix WinNonlin is used for PK parameter estimation. 

MEs have consistently demonstrated 1.5–5-fold improvements in oral bioavailability for BCS Class II drugs compared to plain drug suspensions or conventional formulations, attributed to increased solubilisation, lymphatic transport bypass of hepatic first-pass metabolism, and enhanced membrane permeability [7,12,14,51]. 

In Vitro–In Vivo Correlation (IVIVC) 

Level A IVIVC, established when in vitro release data point-to-point correlate with in vivo absorption, is the highest regulatory expectation. For MEs, the rapid drug release combined with enhanced permeability can produce Type A correlations, facilitating biowaivers for scaleup changes. Convolution/deconvolution approaches are used to establish and validate IVIVC [14,15,49]. 

Cytotoxicity and Safety Assessment 

In vitro cytotoxicity is evaluated in relevant cell lines (Caco-2 for oral, HaCaT/3T3 for dermal, ARPE-19 for ocular) using MTT assay, LDH release assay, and flow cytometric apoptosis/necrosis analysis. The IC50 of ME components and the formulated ME are compared to establish the therapeutic safety window [47]. In vivo acute and sub-acute toxicity studies in rodents per OECD guidelines complete the safety profile. 

Therapeutic Applications of Microemulsions 

The versatility of MEs has been exploited across virtually every route of administration. Table 4 provides a structured overview by route, drug example, and key advantage [7,11,14, 43,45,48].

Table 4. Therapeutic applications of microemulsions by route of administration.

Oral Drug Delivery 

Oral MEs and SMEDDS are the most commercially advanced ME platforms. The landmark product Neoral (cyclosporine A, Novartis) replaced the earlier Sandimmune formulation with a SMEDDS that eliminated food-effect variability and improved dose proportionality through enhanced lymphatic uptake [7,14]. Similarly, Fortovase (saquinavir), Norvir (ritonavir), and Aptivus (tipranavir) are marketed SMEDDS-based products. Oral MEs exploit the lipid digestion cascade: lipolysis of the oil phase by gastric and pancreatic lipases generates fatty acids and monoglycerides that form mixed micelles with bile salts, further solubilising hydrophobic drugs [7,14,49]. 

Transdermal Drug Delivery 

The stratum corneum (SC) constitutes the primary barrier to transdermal permeation. MEs enhance percutaneous absorption through multiple mechanisms: (i) acting as a reservoir for drug saturation at the skin surface, (ii) facilitating partitioning into the SC via increased thermodynamic activity, (iii) hydrating the SC with the aqueous phase, and (iv) permeating the SC lipid bilayers via the surfactant/co-surfactant components [6,20,24]. Diclofenac, ketoprofen, and lidocaine transdermal MEs have demonstrated 3–8-fold enhancement in permeation flux compared to aqueous gels [18,24,27]. 

Ocular Drug Delivery 

Conventional ophthalmic solutions have pre-corneal drainage, lacrimation-induced dilution, and poor transcorneal penetration, resulting in < 5% drug reaching intraocular tissues. Ophthalmic MEs address these limitations by forming a thin, stable film over the corneal epithelium, prolonging contact time, and enhancing corneal permeability [21,29,38]. Restasis (cyclosporine 0.05% ophthalmic emulsion) illustrates the commercial viability of this approach. ME formulations of pilocarpine, timolol, and voriconazole have shown 2–4-fold improvements in AUCaqueous humour in animal models [21,38]. 

Nasal and Brain-Targeted Delivery

The nasal olfactory pathway offers a non-invasive route for brain-targeting via the olfactory mucosa and trigeminal nerve, bypassing the blood-brain barrier (BBB). ME nasal sprays of sumatriptan, zolmitriptan, and clonazepam have demonstrated rapid onset and nose-to-brain drug transport in rodent models, with brain-to-blood concentration ratios (DTP%) of 60–80% [31,41].  

Parenteral Applications 

Parenteral MEs must meet stringent sterility, isotonicity, and biocompatibility requirements. Diprivan (propofol 1% in soybean oil/lecithin/glycerol ME) is the most widely used parenteral ME globally [11]. Paclitaxel MEs using Cremophor EL-free formulations have been developed to eliminate the severe hypersensitivity reactions associated with the original Taxol® formulation [11,45]. Intravenous MEs must have droplet size < 500 nm (preferably < 200 nm) and meet USP/Ph. Eur. requirements for injectable preparations [11]. 

Stability and Scale-Up Considerations 

Long-term stability of MEs is investigated per ICH Q1A(R2) guidelines at accelerated (40 °C/75% RH), intermediate (30 °C/65% RH), and long-term (25 °C/60% RH) conditions over 6–24 months. Critical stability-indicating parameters include droplet size, PDI, zeta potential, pH, drug content, and visual appearance [10,35]. 

Common degradation pathways for MEs include: Ostwald ripening (driven by Laplace pressure differences between droplets of different size), coalescence (merging of droplets after surfactant film rupture), flocculation (reversible aggregation), and creaming/sedimentation (density-driven separation). Thermodynamically stable MEs are inherently resistant to Ostwald ripening, a significant advantage over nanoemulsions [3,13]. 

Scale-up from laboratory to pilot and commercial scale presents challenges including maintaining precise Smix ratios, ensuring raw material batch-to-batch consistency, achieving GMP compliance, and transferring mixing/filling operations to closed stainless-steel systems. Continuous manufacturing approaches using microreactors and in-line process analytical technology (PAT) are emerging as solutions [15,48]. 

Quality by Design (QbD) and Regulatory Perspectives 

The ICH Q8(R2) Quality by Design framework has been applied to ME development to systematically identify the quality target product profile (QTPP), critical quality attributes (CQAs), critical material attributes (CMAs), and critical process parameters (CPPs) [15,36]. Risk assessment tools (Ishikawa diagrams, Failure Mode and Effect Analysis) guide the selection of factors for design of experiment (DoE) studies (Box-Behnken, Central Composite, D-optimal designs) [15,36,48]. 

MEs for oral administration are regulated as lipid-based drug delivery systems (LBDDS) under existing NDA/ANDA or MAA frameworks; no specific ME guidance exists. The FDA Guidance for Industry on Dissolution Testing of Lipid-Based Formulations (draft 2020) and EMA Guideline on Pharmaceutical Development (CPMP/QWP/054/98) provide partial guidance. Biorelevant dissolution media (FaSSIF, FeSSIF, FaSSGF) are recommended for in vitro release testing of oral MEs to predict in vivo behaviour [7,14,15]. 

For topical and transdermal MEs, the FDA Q2 guideline on biopharmaceutics for topical drug products and the EMA guideline on equivalence testing for topical formulations apply. SUPACSS guidance accommodates post-approval scale-up changes for semisolid topical products including MEs [20,24].

Recent Advances and Novel ME Systems 

Solid Self-Microemulsifying Drug Delivery Systems (S-SMEDDS) 

Liquid SMEDDS are converted to free-flowing powders by adsorption on Aerosil 200, Neusilin US2, or Fujicalin, then compressed into tablets or filled into hard gelatin capsules. S-SMEDDS preserve the bioavailability advantage of liquid MEs while providing improved patient acceptability, dose accuracy, and packaging compatibility [8,49]. 

Vesicular Microemulsions (Transfersomes, Ethosomes) 

Transfersomes incorporate edge activators (Span 80, Tween 20) that confer deformability to vesicular bilayers, allowing them to squeeze through SC pores under transepidermal osmotic gradients. Ethosomes contain 20–45% ethanol, disrupting SC lipid order and enhancing drug partitioning into deeper layers [6,42].  

Nanoemulgels and ME-Based Hydrogels 

MEs gelled with Carbopol 940, HPMC, or xanthan gum produce nanoemulgels that combine the permeation-enhancing properties of ME with the sustained-release and patient-friendly application of a semisolid dosage form. This approach is widely applied for transdermal antiinflammatory drugs and antifungals [17,20,43]. 

Stimuli-Responsive Microemulsions 

pH-sensitive, thermoresponsive, and photo-responsive MEs have been engineered using smart surfactants (azobenzene, spiropyran derivatives) or pH-responsive co-surfactants for sitespecific or triggered release in tumour microenvironments (pH 5.5–6.8) or inflammatory sites (elevated temperature). These systems represent an active area of translational nanomedicine research [4,34]. 

Microemulsions for Bioactive Food Ingredients 

MEs are used in the food and nutraceutical industries to improve the solubility and oral bioavailability of polyphenols (curcumin, resveratrol), omega-3 fatty acids, coenzyme Q10, and fat-soluble vitamins. Food-grade GRAS surfactants (lecithin, sucrose monoesters, quillaja saponins) ensure safety for this application [23,34,50]. 

Challenges and Future Perspectives

Despite significant advances, ME development faces several unresolved challenges: 

•      High surfactant load (20–40%) raises GI tolerability and systemic toxicity concerns, particularly for ionic surfactants [3,4,47]. 

•      Limited drug loading capacity for high-dose APIs due to finite solubilisation capacity of the ME [3,10]. 

•      Sensitivity to composition variations — even minor deviations from the ME existence region can lead to phase separation [22,36]. 

•      Lack of standardised in vitro models and biorelevant media for ME evaluation, complicating IVIVC [14,15]. 

•      Regulatory ambiguity: no dedicated ME guidelines exist, creating uncertainty in NDA/ANDA submissions [15]

•      Scale-up and aseptic manufacturing challenges for parenteral ME products [11,48].

Future research directions include: artificial intelligence-guided formulation screening and phase diagram prediction using machine learning; CRISPR-guided excipient toxicity profiling; 3D-printed personalised ME oral dosage forms; ME-mediated mRNA and nucleic acid delivery for gene therapy; and biodegradable, green chemistry-based surfactant systems. The integration of continuous manufacturing platforms with real-time PAT monitoring will accelerate the commercialisation of novel ME products [4,15,48].

CONCLUSION 

Microemulsions represent a thermodynamically grounded, versatile, and clinically validated platform for the delivery of poorly water-soluble and membrane-impermeable drugs. Their unique combination of spontaneous formation, nanometric droplet size, ultralow interfacial tension, and long-term stability distinguishes them from all other colloidal drug carriers. The systematic application of pseudoternary phase diagram construction, combined with QbDbased DoE optimisation, enables rational and scientifically defensible formulation development. 

Comprehensive evaluation encompassing DLS, zeta potential, TEM, SAXS, rheology, thermodynamic stability testing, and biopharmaceutical assessment provides the evidentiary basis for regulatory submissions. Across oral, transdermal, ocular, nasal, parenteral, and topical routes, ME formulations have demonstrated consistent bioavailability enhancement and therapeutic improvement in both preclinical and clinical settings. Continued advances in smart ME design, solid-state conversion, and continuous manufacturing will further expand the translational impact of this remarkable colloidal technology.

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