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Stability Problems of Emulsions and Methods to Overcome

Chemical instability, Microbial growth, Using biopolymers as emulsion stabilizers, Polysaccharide-protein conjugates in emulsions, Phase separation.

Stability problems of emulsions

Emulsions are colloid mixtures that are formed by mixing two immiscible liquids, usually oil and water, which dissolve into one of the liquids. Emulsions have two phases: a dispersed phase and a continuous phase. The first phase is comprised of particles, and the second is composed of the liquid surrounding the particles. The following table presents a summary of some types of emulsions based on the physical and chemical characteristics of the oil and water phases, the nature of the emulsifying agent, or the physical and chemical arrangements.

Examples of types of emulsions are;
  • Water in oil (W/O)
  • Oil in water (O/W)
  • Microemulsions
  • Macro emulsions
  • Multiple emulsions
  • Bilayer droplets
  • Pickering emulsions
  • Mixed emulsions
  • Glassy emulsions
Emulsions can be made from either water-in-oil or oil-in-water, with O/W emulsions being more common than W/O emulsions. Many food products consist partly or completely of emulsions such as margarine and butter (oil and water), mayonnaise, salad dressings, vinaigrettes, homogenized milk, beverages, and ice cream. The droplet size of the emulsions is further classified into three groups, namely, conventional emulsions (d > 200nm), microemulsions (d < 100nm) and nanoemulsions (d > 200nm).

Oil and water surfaces rapidly separate in emulsions due to their thermodynamic instability. Oil and water molecules are unable to effectively contact due to differences in density and the unfavorable contact between them. Emulsion stability means that the different phases can be maintained in their respective states; it is the ability of the phases to stay mixed and remain cohesive.

Emulsion stability is dependent on numerous factors, including particle size and particle size distributions, density between the continuous and dispersed phases, and chemical stability of the dispersed component.

The destabilization of emulsions can be attributed to a variety of processes, as illustrated in Figure 1. These include coalescence, sedimentation, Ostwald ripening, creaming, and phase inversion. The characteristic process of flocculation occurs when drops attract each other at the interface and form flocs without disturbing the stabilizing layer. Droplets flocculate due to gravitational forces, centrifugation, Brownian forces, and the difference between the repulsive forces and van der Waals forces. Due to the ensuing creaming and reduction of clouding caused by the larger particle size, as well as the closer contact between droplets, this phenomenon is undesirable.

Gravitational separation causes the separation (upward) as well as the sedimentation (downward). Emulsion droplets usually merge to form larger ones or rise to the surface of the emulsion when buoyancy is strong enough to cause them to rise. There is usually a relatively small difference in density for the dispersed phase and the continuous phase when impacted by gravitational force. Usually, this causes a separated emulsion with a layer of milk with generous droplet populations and a layer of watery emulsion with relatively few droplets. The creaming index can be used to quantify the degree to which emulsion creaming occurs before and after coalescence in O/W emulsions. The creaming index measures the extent of droplet aggregation; as such, the higher the value, the more agglomeration has taken place. Creaming can be observed visually or observed optically.

When droplets in a fluid come into contact with each other, they merge to form larger droplets. With time, this results in a reduction in droplet size and, ultimately, a decrease in emulsion stability. Larger droplets expand at the expense of smaller ones during Ostwald ripening, and the process is in some ways determined by the level of solubility of the dispersed phase in the continuous phase.

Destabilization mechanisms can be related to the type and concentration of stabilizers and emulsifiers, pH, ionic strength, temperature, homogenization parameters, and interactions between continuous and dispersed phases. The presence of emulsifiers, stabilizers, weighting agents, ripening inhibitors, and texture modifiers (thickeners and gelling agents) is vital for extending kinetic stability in emulsion systems over lengthy periods.

An intense mechanical force is applied to break down large droplets into smaller ones to create a fine emulsion. A high-speed mixer, colloid mill, or high-pressure valve homogenizer are commonly used to create food emulsions. In terms of thermodynamics, the emulsification process is very inefficient since the majority of the energy used is lost as heat. Generally, the size of the droplets formed by an emulsion depends on how long it takes for the interface to be covered with an emulsifier. During emulsification, slow emulsification rates result in a small number of droplets forming, coalescing, or flocculating.

Chemical instability
During the shelf life of the product, the API must be chemically stable in the dosage form concerning both potency and impurities under recommended storage and packaging conditions. For the drug product to be considered safe and effective, the API must meet predetermined requirements for potency and it must contain no impurities at all. APIs in emulsion dosage forms exhibit many of the same reaction kinetics characteristics as APIs in other solution-based dosage forms, such as functional group reactivity and reaction kinetics. The separation of the reacting species into their aqueous and oily phases enhances the stability of an emulsion and minimizes reactivity.

Microbial growth
Regulatory and compendial levels must be met in controlling a dose form's microbial load. Additionally to the health risks resulting from microbial growth, emulsions can also separate physically when microorganisms are present. The formulations must be treated with preservatives at appropriate concentrations to prevent microbial growth. Because bacterial growth will normally occur in the aqueous phase, the preservative should be concentrated there. When calculating the concentration of the surfactant in the aqueous phase, the oil and water partition coefficient of the preservative must be taken into account, which must be above the concentration of antimicrobials. Commonly used preservatives in emulsions are para-bens (methylparaben, propylparaben, and butylparaben).

Methods to overcome stability problems

Using biopolymers as emulsion stabilizers

To enhance the kinetic stability of emulsions, stabilizers, weighting agents, and ripening inhibitors are frequently used. Stabilizers stabilize emulsions by thickening the water phase of them, whereas emulsifiers adhere to newly formed droplets of an oil-water interface during homogenization, forming an Anti-aggregate membrane. Emulsifiers can modify the surface of each droplet as they sit at the interface between it and the continuous phase. In nature, they can exhibit both hydrophilic and hydrophobic properties. This also means that they can align with both phases of the aqueous and lipid phases. Molecular surface-modifiers, these molecules alter the droplet-continuous interface at the droplet interface. Oil or water-soluble emulsifiers form a thin layer with low interfacial tension and a fluid, closed-packed nature at the interface. An emulsion with the droplet size distribution being small is the result of Gibbs-Marangoni dynamics or weak electrostatic attraction.

Biopolymers are commonly used in emulsion systems as functional ingredients such as polysaccharides and proteins. While most biopolymers are capable of stabilizing emulsions, only a few are also capable of emulsifying. Biopolymers, for example, polysaccharides, lack significant surface activity at the oil-water interface, which is vital for emulsifying. Emulsifier polysaccharides are most commonly found in food to enhance texture and functionality, including gum Arabic, modified starch, modified cellulose, pectin, galactomannans, and modified cellulose. To function effectively as emulsifiers, biopolymers must combine adsorption and concentration. Biopolymer-coated droplets may coalesce in low concentrations, leading to their destabilization.

Among the polysaccharides studied are dietary fiber, starch, maltodextrin, pectin, carboxymethylcellulose (CMC), and several other gums. Emulsions are stabilized in the bulk phase or at the water-oil interface through modification of rheological properties or by adsorption. These mechanisms act as either steric barriers or electro steric barriers (or a combination of both). The molecules also reduce the interfacial tension, which creates less work for creating new surfaces, while also enhancing the formation of droplets and reducing their rate. However, proteins are said to reduce coalescence and flocculation by forming a viscoelastic, adsorbent film over oil droplets, which forms a physical barrier, impairing contact between droplets, preventing the formation of coalescence.

Polysaccharide-protein conjugates in emulsions

In recent years, there has been increased interest in using polysaccharide-protein conjugates as emulsifiers and stabilizers to harvest the combined benefits of protein and polysaccharides. The proteins and polysaccharides in emulsions combine to form a complex equation. By modifying the properties of their gelling networks, these biopolymers make excellent bio-emulsions owing to their ability to modify the rheological characteristics of the system. Thus, reduce the surface tension of the emulsion and slow down droplet movement in the thicker phase of the emulsion.

In addition to reducing interfacial tension, proteins also boost interfacial elasticity by adsorbing on droplet surfaces. As a result, polysaccharides interact electrostatically or hydrophobically to create hydrophobic-hydrophobic interactions, whereas electrostatic interactions primarily affect hydrophobic interaction. In general, the fact that some polysaccharides adhere to globule surfaces has less significance than the fact that they increase the viscosity of the continuous phase, preventing droplet motion, which is the most effective method of stabilizing emulsions.

The combined hydrophobic and hydrophilic properties of protein-polysaccharide complexes make them excellent emulsifiers. By adsorbing both proteins and polysaccharides inside the emulsion droplets, these biopolymers improve emulsion stability. As shown in Table 2, some protein-polyglycerol conjugates have been used as stabilizers in emulsions.

There are a variety of non-covalent interactions between proteins and polysaccharides, such as electrostatic interactions, hydrophobic interactions, hydrogen bonds, π-π stacking, and van der Waals forces. Polysaccharide-protein complexes act as a bridge between two surfaces, resulting in significant changes in the interactions between them and the emulsion stability. Under appropriate conditions, the properties of these biopolymers work together to enhance emulsion stability, Polysaccharides and proteins may interact in different ways. Figure 2 illustrates this interaction.

Neither polymer alone can match the properties of the complex polysaccharide protein. As a result of the biopolymer binding to the protein, the complex becomes more surface-active, allowing it to achieve surface layer saturation with a much lower concentration. Moreover, the covalently bound polysaccharide protects the protein embedded within the interfacial layer from destabilization due to unfavorable conditions.

Pseudoplastic flows are retarded at low concentrations by xanthan during inert or low shear conditions; shear conditions allow pumping and filling but not creaming of particles or sedimentation. A protein and xanthan combine to form a network of droplets that are held together by a xanthan layer. This relationship is the consequence of depletion flocculation acting indirectly on a protein and resulting in a mechanically stable protein droplet layer.

Phase separation mechanisms

A thermodynamically incompatible biopolymer mixture separates into distinct phases as a result of phase separation. A mixture of proteins and polysaccharides that is incompatible results in a precipitation of the proteins or the polysaccharides, or biphasic phase separation into protein-replete or polysaccharide-replete phases; A biopolymer system experiences an initial phase separation in which one phase rises to the top of the system while the other phase is dispersed through it as small liquid droplets. In the presence of thermal treatment, proteins and polysaccharides more concentrated than the minimum critical gelling concentration display microphase separation networks. When the heterotypic binding isn't the overriding drive, the continuous phase is composed of one polymer, whereas the discontinuous phase is composed of the other polymer.

In addition to medium conditions like pH and ionic strength, biopolymers have a large influence on phase separation. It segregates into a lower phase rich in proteins and an upper phase rich in polysaccharides at equilibrium. During the phase separation of a starch-gelatine system, a massive accumulation of colloidal particles was observed at the water-water interface. Phase separation and microstructure of the system changed as a result of particle accumulation.

An emulsion system can have either a single-phase or a phase-separated composition if two biopolymers do not interact with each other. Single-phase systems contain the two biopolymers separately, distributed throughout the medium, while phase-separated systems contain the two biopolymers separately. There are two ways to separate phases: associatively or segregatorily.

Protein-polysaccharide mixtures may undergo phase separation based on binary curves (Figure 3). Separating the region of co-solvability from the region of phase separation, the binodal curve was defined. In Figure 3, the binodal curve represents the concentration at which mixtures separate. The biopolymers exist as one phase below this line, and the polysaccharide-rich phase above it is evident.

Schematic of phase separation for a mixture of polysaccharides and proteins:
  1. Protein
  2. Polysaccharide
  3. Proteins and polysaccharides in the initial mixture;
  4. Phases with a high protein concentration;
  5. A phase rich in polysaccharides;
Phase separation involving distinct phases of different compositions; and coexistence among biopolymers but mutual exclusion between them.
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Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of Pharmaceutical Guidelines, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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