Physical Pharmacy- Part 3 PDF

PART III Flocculated and Non-Flocculated Suspensions:  In flocculated suspension the individual par cles are in contact with each other to form loose aggregates and create a network like structure.  Although the rate of sedimenta on is high but the sediment is loosely packed...

PART III Flocculated and Non-Flocculated Suspensions:  In flocculated suspension the individual par cles are in contact with each other to form loose aggregates and create a network like structure.  Although the rate of sedimenta on is high but the sediment is loosely packed which can re dispersed easily on shaking so as to reform the original suspension.  However; the flocculated suspensions meant for oral, Parenteral ophthalmic or external use may not be elegant because they are difficult to remove from bo les or vials and on transferring from the bo le the floccules remain s cking to the sides of the bo le.  These proper es can be improved by adding protec ve colloids.  In nonflocculated or deflocculated suspensions all individual par cles exist as sediment is formed slowly but the sediment is closely packed due to weight of upper layers of sediment is closely packed due to weight of upper layers of sediment materials.  A hard cake is formed which is difficult to re disperse to get original suspension.  The nonflocculated suspensions have pleasing appearance as compared to flocculated suspensions because the substances remain suspended for a sufficiently long me.  Flocculated Non-Flocculated Particles form loose aggregates and form Particles exist as separate entities. a network like structure. Rate of sedimentation is high Rate of sedimentation is low Sediment is rapidly formed Sediment is slowly formed Sediment is loosely packed and does not Sediment is very closely packed and a form a hard cake. hard cake is formed Sediment is easy to redisperse. Sediment is difficult to redisperse. Suspension is not pleasing in appearance. Suspension is pleasing in appearance. The floccules stick to the sides of the They do not stick to the sides of the bottle. bottle. SETTLING IN SUSPENSIONS Effect of Brownian Movement For particles having a diameter of about 2 to 5 μm (depending on the density of the particles and the density and viscosity of the suspending medium), Brownian movement counteracts sedimentation to a measurable extent at room temperature by keeping the dispersed material in random motion. The critical radius, r, below which particles will be kept in suspension by the kinetic bombardment of the particles by the molecules of the suspending medium (Brownian movement) was worked out by Burton. It can be seen in the microscope that Brownian movement of the smallest particles in a ield of particles of a pharmaceutical suspension is usually eliminated when the sample is dispersed in a 50% glycerin solution, having a viscosity of about 5 centipoise. Hence, it is unlikely that the particles in an ordinary pharmaceutical suspension containing suspending agents are in a state of vigorous Brownian motion. Sedimentation of Flocculated Particles When sedimentation is studied in locculated systems, it is observed that the locs tend to fall together, producing a distinct boundary between the sediment and the supernatant liquid. The liquid above the sediment is clear because even the small particles present in the system are associated with the locs. Such is not the case in de locculated suspensions having a range of particle sizes, in which, in accordance with Stokes’s law, the larger particles settle more rapidly than the smaller particles. No clear boundary is formed (unless only one size of particle is present), and the supernatant remains turbid for a considerably longer period of time. Whether the supernatant liquid is clear or turbid during the initial stages of settling is a good indication of whether the system is locculated or de locculated, respectively. According to Hiestand, the initial rate of settling of locculated particles is determined by the loc size and the porosity of the aggregated mass. Subsequently, the rate depends on compaction and rearrangement processes within the sediment. The term subsidence is sometimes used to describe settling in locculated systems. Sedimentation Parameters Two useful parameters that can be derived from sedimentation (or, more correctly, subsidence) studies are sedimentation volume, V, or height, H, and degree of locculation. The sedimentation volume, F, is de ined as the ratio of the inal, or ultimate, volume of the sediment, Vu, to the original volume of the suspension, Vo, before settling. Thus, F = Vu/Vo The sedimentation volume can have values ranging from less than 1 to greater than 1. F is normally less than 1, and in this case, the ultimate volume of sediment is smaller than the original volume of suspension, in which F = 0.5. If the volume of sediment in a locculated suspension equals the original volume of suspension, then F = 1. Such a product is said to be in “ locculation equilibrium” and shows no clear supernatant on standing. It is therefore pharmaceutically acceptable. It is possible for F to have values greater than 1, meaning that the inal volume of sediment is greater than the original suspension volume. This comes about when the network of locs formed in a particular suspension is so loose and luffy that the volume it is able to encompass is greater than the original volume of suspension. les have been added to contain the sediment. The sedimentation volume gives only a qualitative account of locculation because it lacks a meaningful reference point. A more useful parameter for locculation is β, the degree of locculation.  If we consider a suspension that is completely de locculated, the ultimate volume of the sediment will be relatively small. Writing this volume as V∞, based on the previous equation we have F∞ = V∞/V Where F∞ is the sedimentation volume of the de locculated, or peptized, suspension. The degree of locculation, β, is therefore de ined as the ratio of F to F∞, or β= F/F∞ By substitution, we have: 𝑉𝑢/𝑉𝑜 𝛽= = 𝑉𝑢/𝑉∞ 𝑉∞/𝑉𝑜 The degree of locculation is a more fundamental parameter than F because it relates the volume of locculated sediment to that in a de locculated system. We can therefore say Formula on of Suspensions Approaches to Stable Suspensions The preparation of physically stable suspensions generally involves two strategies:  1. Structured Vehicles: These are used to maintain deflocculated par cles in suspension. 2. Controlled Floccula on: This technique forms flocs that may se le quickly but can be easily resuspended with minimal agita on. Structured Vehicles  Typically pseudoplas c or plas c in nature, with rheological proper es discussed in the Rheology chapter.  These vehicles exhibit thixotropic behaviour, allowing them to "shear- thin" when agitated, facilita ng uniform redistribu on of par cles. While structured vehicles minimise sedimentation by entrapping particles, some settling is inevitable. Over time, compact caking may occur, necessitating the use of flocculated suspensions for optimal stability and appearance. Key Characteristics of Suspensions  Must flow readily from the container.  Ensure uniform par cle distribu on in every dose. We ng of Par cles Importance of Wetting Proper dispersion of an insoluble powder in the vehicle is a critical step in suspension formulation. Challenges in wetting include:  Adsorbed air layers and surface contaminants (e.g., grease).  Low we ability, leading to floa ng powders despite high density. Factors Influencing Wettability  Contact Angle: Determines we ng behaviour. Powders that float with a contact angle near 90° are less we able, such as sulfur or magnesium stearate (hydrophobic).  Hydrophilic Powders: Readily we ed by water when clean (e.g., zinc oxide, talc). Use of Surfactants  Reduce interfacial tension between par cles and vehicle.  Lower the advancing contact angle, promo ng we ng and dispersion.  Example: Octoxynol enhances prednisolone dissolu on by de-floccula ng tablet granules. Role of Hygroscopic Substances Substances like glycerin facilitate wetting by: 1. Displacing air in par cle voids. 2. Coa ng par cles for be er water penetra on. Techniques to Select Wetting Agents  Using trough experiments to observe penetra on of agents into powders directly. Controlled Floccula on Principles of Flocculation Achieving controlled flocculation prevents the formation of hard-to-redisperse sediments. Key agents include: 1. Electrolytes: Reduce zeta poten al to bridge par cles into a loose network. 2. Surfactants and Polymers: Promote floccula on at specific concentra ons. Zeta Potential Studies  Electrolytes like monobasic potassium phosphate lower zeta poten al, leading to floccula on at op mal levels.  Example: Bismuth subnitrate suspensions demonstrate maximum floccula on at a specific posi ve zeta poten al. pH Influence  Par cle charge is pH-dependent. Adjus ng pH (via HCl or NaOH) can produce posi ve, neutral, or nega ve surface charges, influencing suspension stability. Practical Observations  Flocculated systems maintain higher sedimenta on volumes and avoid caking.  Excessive floccula on or defloccula on reduces stability, emphasizing the importance of controlled floccula on. This systematic approach ensures that suspensions meet essential pharmaceutical standards for stability, uniformity, and ease of use. Rheologic Considera ons The principles of rheology play a crucial role in understanding various aspects of suspensions, including:   Viscosity and Se ling: The viscosity affects the se ling behavior of dispersed par cles.  Flow Proper es: Changes in flow proper es occur when the container is shaken or the product is poured.  Spreading Quali es: The lo on’s ability to spread on an affected area depends on its rheologic proper es. Rheology is also critical in the manufacturing of suspensions. During storage, the only shear force present is from particle settling, which is negligible. However, when the container is shaken or the product is poured, high shear rates are encountered. Mervine and Chase proposed that an ideal suspending agent should exhibit: 1. High Viscosity at Negligible Shear: Ensures stability during shelf storage. 2. Low Viscosity at High Shear: Allows easy flow during agita on, pouring, and spreading. Substances such as tragacanth, sodium alginate, and sodium carboxymethylcellulose demonstrate these desirable pseudoplastic properties. Conversely, Newtonian liquids like glycerin, while suitable for suspending particles, are too viscous for easy pouring and spreading. Additionally, glycerin’s tackiness and hygroscopic nature limit its utility in undiluted form. Thixotropic and Pseudoplastic Agents Thixotropic agents, which form a gel when at rest and become fluid upon disturbance, are particularly effective suspending media. For instance:  Bentonite displays a pronounced thixotropic hysteresis loop.  Veegum exhibits considerable thixotropy, confirmed through vessel inversion and rota onal viscometer tests.  Mixtures of bentonite and sodium carboxymethylcellulose exhibit both pseudoplas c and thixotropic characteris cs, making them excellent suspending agents. Prepara on of Suspensions The preparation and stabilization of suspensions involve several key principles of physical pharmacy: 1. Small-Scale Preparation: o Grinding and Leviga on: The insoluble material is ground into a smooth paste with a vehicle containing a dispersion stabilizer. o Gradual Addi on: The liquid phase is added incrementally, dissolving any soluble drugs. o Final Volume: The slurry is transferred to a graduate, and the mortar is rinsed with the vehicle to achieve the desired volume.  2. Large-Scale Preparation: o Equipment: Various machines like ball mills, pebble mills, and colloid mills are used. Among these, the colloid mill is widely u lized. o Colloid Mill Func on:  A high-velocity, cone-shaped rotor shears the suspension between the rotor and stator at a small adjustable clearance.  Shearing ac on disaggregates flocs, dispersing par cles evenly throughout the liquid. o Key Factors:  Clearance between disks.  Peripheral velocity of the rotor.  Non-Newtonian viscosity of the suspension. Operational Considerations:  The material should have a low yield value and an op mum viscosity to ensure proper flow.  High-viscosity materials or narrow plate adjustments can cause excessive heat, requiring cooling mechanisms.  Dilatant materials, such as suspensions with over 50% solids, pose challenges like overhea ng and motor stalling. To mi gate these issues, star ng with wider plate clearance or dilu ng the paste with a vehicle is recommended. Flocculation in Pharmaceutical Suspensions: Key Concepts and Advances 1. Role of Surfactants in Flocculation Ionic and nonionic surfactants are commonly utilized to induce flocculation of suspended particles. However, their concentration is critical, as surfactants may also act as wetting and deflocculating agents, leading to dispersion rather than flocculation. 2. Influence of Xanthan Gum on Flocculation Research by Felmeister and colleagues demonstrated that xanthan gum, an anionic heteropolysaccharide, enhances flocculation characteristics in suspensions of drugs like sulfaguanidine and bismuth subcarbonate. The addition of xanthan gum promotes a polymer-bridging phenomenon, increasing sedimentation volume. Similarly, hydrophilic polymers, such as gelatin, act as protective colloids, reducing caking tendencies by coating particles and stabilizing suspensions. Gelatin's flocculation efficiency varies with the pH and ionic strength of the medium. 3. Applications of Charged Polymers and Liposomes Positively charged gelatin-coated particles, prepared under acidic conditions, demonstrate enhanced flocculation stability due to their modified charge. Positively charged liposomes have also been employed as flocculating agents to stabilize negatively charged particles, preventing caking. These biocompatible vesicles, formed from phospholipids, are nontoxic and versatile in particle size. 4. Structured Vehicles and Compatibility Issues While controlled flocculation improves suspension stability, the visual appeal of the product depends on achieving a sedimentation volume (F) near unity. Suspending agents like carboxymethylcellulose, Carbopol 934, Veegum, tragacanth, and bentonite are commonly used to retard sedimentation. However, incompatibilities may arise due to charge differences between particles, flocculating agents, and suspending agents. For instance:  Positively charged particles flocculated with anionic electrolytes (e.g., potassium phosphate) are typically compatible with negatively charged hydrocolloids.  Conversely, negatively charged particles flocculated with cationic electrolytes (e.g., aluminum chloride) may become incompatible with hydrocolloids, forming undesirable masses. To address these challenges, protective colloids like gelatin, adjusted to the appropriate charge, can modify particle charge for compatibility with suspending agents. 5. Exploration of Natural Gums as Suspending Agents Entandrophragma angolense gum(ENTA) is a natural, biocompatible suspending agent for sulfamethoxazolesuspensions. At low concentrations (1–2 % w/v), ENTA outperformed traditional agents like Acacia gum and gelatin BP, maintaining a stable sedimentation volume (~1) for up to 7 hours at room temperature. 6. Rheological Considerations in Suspensions The viscosity and flow properties of suspensions are critical for stability and usability. Ideal suspending agents exhibit:  High viscosity under low shear (storage conditions) to prevent sedimentation.  Low viscosity under high shear (agitation and pouring) for ease of use. Substances like tragacanth, sodium alginate, and sodium  carboxymethylcellulose display desirable pseudoplastic behavior, making them effective suspending agents. Additionally, thixotropic materials like bentonite and Veegum form gels on standing and become fluid upon agitation, offering enhanced suspension stability. 7. Preparation and Stabilization of Suspensions Suspensions are prepared by dispersing solids into liquids, stabilized using dispersion stabilizers. On a small scale, this involves grinding insoluble materials into a smooth paste before gradually incorporating the liquid phase. On a large scale, equipment such as ball mills, colloid mills, and mixers achieve dispersion and stabilization. 8. Colloid Mill Functionality The colloid mill employs a high-velocity rotor to shear suspended particles, reducing aggregates and promoting even dispersion. Its efficiency depends on factors like rotor speed, disk clearance, and the suspension's viscosity. Dilatant materials with high solids content can pose challenges, necessitating careful adjustments or alternative milling techniques. Physical Stability of Suspensions The stability of pharmaceutical suspensions is influenced by a variety of physical and chemical factors. Below is a refined and detailed explanation of these concepts: Effects of Temperature on Suspension Stability 1. Flocculation in Sterically Stabilized Suspensions o Sterically stabilized suspensions, o en using nonionic surfactants, may undergo floccula on when exposed to elevated temperatures. o Mechanism: The repulsive forces between par cles, influenced by the surfactant-adsorbed layers, weaken due to dehydra on of the surfactant's polyoxyethylene groups. This reduc on in repulsion, combined with increased a rac ve forces, leads to floccula on. 2. Freeze–Thaw Instability o During freezing, par cles are forced closer by ice forma on, overcoming repulsive barriers (as explained by DLVO theory) and forming aggregates in the primary energy minimum. o Upon thawing, these aggregates persist unless sufficient energy is applied to overcome the primary energy peak.  o Observa on: Higher freezing rates produce smaller ice crystals, reducing par cle aggrega on compared to slower freezing rates, which form larger crystals. Par cle Growth and Ostwald Ripening 1. Temperature Fluctuations o Changes in temperature can alter par cle size, polymorphic forms, and drug solubility. These changes can nega vely affect drug absorp on and bioavailability. o Mechanism: Higher temperatures dissolve smaller par cles, crea ng a supersaturated solu on that favors the growth of larger crystals. This phenomenon, known as Ostwald ripening, destabilizes the suspension. 2. Inhibition of Crystal Growth o Polymers like polyvinylpyrrolidone (PVP) can inhibit crystal growth by forming a net-like film over the crystal surface. o Controlled Growth: The crystal can only grow through the openings of the polymer network, with smaller pore sizes requiring higher supersatura on for crystal growth. Role of Excipients in Stability 1. Surfactant Cloud Point and Flocculation o Sorbitol can induce floccula on in sulfamerazine suspensions stabilized with nonionic surfactants. o Key Factor: The cloud point of the surfactant determines the cri cal concentra on of sorbitol needed for floccula on. Preserva ves like methylparaben can lower the cloud point, altering floccula on behavior and suspension stability. 2. Preservative Adsorption and Charge Reversal o Adsorp on of ca onic preserva ves, such as cetylpyridinium chloride, onto nega vely charged par cles like zinc oxide can reverse the par cle’s charge. o Impact on Stability:  Posi ve charges on the adsorbed layer repel other similarly charged par cles, enhancing physical stability.  However, strong adsorp on reduces the free frac on of the preserva ve, poten ally diminishing its microbiological effec veness. Prac cal Implica ons and Strategies 1. Polymers and Surfactants  o Addi on of polymers or surfactants can minimize par cle growth by stabilizing the suspension. For example, PVP forms hydra on barriers that inhibit crystal growth. 2. Kelvin Equation and Supersaturation o Using the Kelvin equa on, the solubility of a small par cle can bepredicted in rela on to a larger crystal. Smaller par cles require highersupersatura on to grow, emphasizing the role of polymer networks incontrolling par cle growth. 3. Temperature Control o Maintaining a consistent storage temperature can prevent floccula on, freeze–thaw instability, and Ostwald ripening, ensuring long-term suspension stability. Advantages of Suspension: The drugs which are unstable in aqueous medium can be formulated in suspension forms in nonaqueous solvents. Drugs with unpleasant taste in solution form can easily be formulated as suspension to provide palatable medication. Suspension is an ideal dosage form to those patients who cannot swallow tablets or capsules. They prolong the action of drugs by using their derivatives in suspension form. Suspension for external use have fine particles size and so avoid the gritty feelings to the skin. Sterile suspensions are injected hypodermically to produce sustained action. Pharmaceutical Applications: (1) SUSPENSION FOR (ORAL ADMINISTRATION): These suspensions are administrated when there is a difficulty in the swallowing of other solid dosage forms (such as tablets or capsule) or the drug has unpleasant taste or odour. Examples of orally administered drugs are antacid (e.g. aluminium hydroxide, magnesium hydroxide) paracetamol suspension, Ponstan suspension etc. (2) SUSPENSION FOR (INJECTTION): Such suspensions have particle size such that they can easily pass through syringe needle and for this purpose their crystal should be of needle type. Such preparations are of particular importance in the field of depot therapy.  For example, kenokortA, Depo provera, solucortif etc. (3) SUSPENSION FOR (TOPICAL USE): In such type of suspensions, the particle size should be in the range that they cannot produce gritty feeling on the skin. Such suspensions are of prime importance in pharmacy. Their best examples are lotions (for example calamine) paste (zinc and salicylic acid paste and magnesium sulphate paste) etc. Microemulsions: Characteris cs, Forma on, and Applica ons The term microemulsion is somewhat misleading, as these systems are more akin to large or “swollen” micelles containing an internal phase, resembling solubilized solutions. Unlike conventional macroemulsions, microemulsions appear as clear, transparent solutions but may lack thermodynamic stability. They represent an intermediate state between stable solubilized solutions and relatively unstable emulsions. Key Features:  Composed of oil-in-water (o/w) or water-in-oil (w/o) droplets with diameters ranging from 10 to 200 nm.  Volume frac ons of the dispersed phase range from 0.2 to 0.8.  Unlike micellar systems, microemulsions require careful selec on of emulsifying agents and cosurfactants for their prepara on. Formation of Microemulsions: To create microemulsions, an emulsifying agent (e.g., anionic surfactants like sodium lauryl sulfate or potassium oleate) is dispersed in an organic liquid. The gradual addition of water, followed by a lipophilic cosurfactant like pentanol, reduces the surface tension, allowing for spontaneous emulsification. The surfactant and cosurfactant form a stabilizing film around the droplets to prevent coalescence. Optimization Strategies:  The use of surfactants and cosurfactants with similar Hydrophilic-Lipophilic Balance (HLB) values enhances solubiliza on and stabilizes the system, as demonstrated by Shinoda and Kunieda.  Ternary-phase diagrams help characterize the microemulsion region and iden fy the op mal ra os of oil, water, and surfactant-cosurfactant mixtures. Microemulsion Structures:  At low water content, the internal phase o en consists of spherical droplets. As the water content increases, these structures can transi on into cylindrical or lamellar forms, resul ng in gel-like microemulsions. Further water addi on reverts the system to a low-viscosity aqueous con nuous phase with spherical droplets. Applications in Drug Delivery:  1. Oral and Parenteral Drug Delivery: o Microemulsions improve the bioavailability of poorly water-soluble drugs by incorpora ng them into the internal phase. o For instance, Halbert et al. inves gated etoposide and methotrexate diester-loaded microemulsions for cancer chemotherapy. While etoposide demonstrated rapid release, methotrexate diester retained 60% incorpora on, showing poten al for controlled delivery. 2. Topical and Transdermal Applications: o Microemulsions enhance skin permea on and drug penetra on. Osborne et al. demonstrated the efficient delivery of water from w/o microemulsions, with diffusion rates increasing significantly as the water content rose from 15% to 58%. o Linn et al. compared cetyl alcohol and PABA delivery through mouse skin and found microemulsions outperformed macroemulsions in penetra on depth and speed. 3. Innovative Uses: o Patents have reported microemulsions for delivering fluorocarbons as blood subs tutes and for topically administering an hypertensive drugs. Challenges in Stability: Microemulsions are susceptible to phase separation upon dilution, and light-scattering techniques are used to determine droplet size. Extrapolation methods for measuring actual droplet diameters must consider these limitations. A ternary phase diagram is a graphical representation used in materials science, chemistry, and engineering to illustrate the phase relationships between three components in a system. These diagrams help in understanding how the compositions of mixtures evolve under certain conditions, such as temperature or pressure. Key Features of Ternary Phase Diagrams: 1. Three-Component System: o The diagram represents three components, usually labeled A, B, and C. o The sum of their propor ons always equals 100% (or 1.0 in frac onal terms). 2. Equilateral Triangle Representation: o The ternary diagram is an equilateral triangle, where:  Each vertex represents 100% of one component (pure A, pure B, or pure C).  The edges represent binary mixtures (e.g., A-B, B-C, or A-C).  Any point within the triangle corresponds to a specific composi on of the three components. 3. Composition Reading: o The composi on is determined by drawing parallel lines to the triangle edges. o For example, if a point lies closer to A, it indicates a higher propor on of A in the mixture. 4. Phase Regions: o The diagram is divided into regions corresponding to different phases (e.g., liquid, solid, two-phase coexistence). o Each region shows the dominant phase or phases at a par cular composi on. 5. Tie Lines and Phase Equilibria: o Tie lines connect two points in a two-phase region, indica ng composi ons of coexis ng phases.  o Phase equilibria are depicted based on temperature, pressure, or other condi ons. 6. Applications: o Alloys: Understanding the crystalliza on behavior of metals. o Petrochemical Industry: Studying the miscibility of oil, water, and surfactants. o Pharmaceu cals: Designing drug formula ons. o Geology: Analyzing the mineral stability in rocks. Example Use Case: For a ternary system of water (A), oil (B), and surfactant (C):  One vertex of the triangle represents pure water.  Another represents pure oil.  The third vertex represents pure surfactant.  Points within the triangle show the propor ons of these three in a mixture and which phases (oil-rich, water-rich, or micellar) are present under equilibrium condi ons. Ternary phase diagrams are indispensable tools for analyzing multicomponent systems and designing processes where phase composition and transitions are critical. Point A B C X1 50% 0% 50% X2 30% 20% 50% X3 60% 20% 20% X4 70% 30% 0% X5 20% 60% 20% X6 0% 90% 10% Point Acetic acid Chloroform Water X1 39.145 16.409 44.446 Y1 26.864 60.400 12.736 X2 32.946 10.163 56.892 Y2 20.079 70.802 9.119 X3 23.769 5.405 70.826 Y3 13.024 81.105 5.871 X4 11.346 2.037 86.617 Y4 5.969 91.408 2.623 Colloids as Drug Delivery Systems Colloidal systems are increasingly used as advanced drug delivery platforms. Seven primary colloidal drug delivery systems include: 1. Hydrogels 2. Micropar cles 3. Microemulsions 4. Liposomes 5. Micelles 6. Nanopar cles 7. Nanocrystals Key Colloidal Drug Delivery Systems 1. Hydrogels: o Colloidal gels where water acts as the dispersion medium. o Applica ons: Wound healing, ssue engineering scaffolds, and sustained drug release systems. o Features: Some are pH-, temperature-, or metabolite-sensi ve, enabling site-specific drug release. Future developments aim to enhance response me, biocompa bility, and biodegradability. 2. Microparticles: o Small polymer-based spheres (0.2–5 µm) used for vaccine and drug delivery. o Surface modifica ons enhance targeted delivery while minimizing nonspecific uptake. o Facilitate alterna ve administra on routes, such as mucosal delivery. 3. Microemulsions and Nanoemulsions: o Microemulsions: Thermodynamically stable systems with enhanced solubility and controlled drug release proper es. o Nanoemulsions: Metastable systems with droplet sizes