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Overview of emulsifying & stabilizing pharma excipients responsible for the preparation & stabilization of topical dosage forms such as emulsions.

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Overview of emulsifying & stabilizing pharma excipients responsible for the preparation & stabilization of topical dosage forms such as emulsions.

Q1. What are emulsifying agents and how are they classified?

An emulsifier or an emulsifying agent is a compound or substance that acts as a stabilizer for emulsions, preventing liquids that ordinarily don't mix from separating. Emulsions are heterogeneous and biphasic, thermodynamically unstable systems containing two immiscible fluids; for e.g. fat and water. While emulsion formulations are not popular for oral ingestion, they are increasingly used in the preparation of parenteral & topical dosage forms such as ointments, creams, and lotions. 

Emulsions are classified into the following types: 

  • Oil-in-water (O/W) emulsion
  • Water-in-oil (W/O) emulsion
  • Oil-in-water-in-oil (O/W/O) emulsion
  • Water-in-oil-in-water (W/OW) emulsion

 

Surface-active ingredients or surfactants, which adsorb at the oil–water interface during emulsion preparation and protect the newly formed droplets against immediate recoalescence, are used as emulsifying agents. An emulsifier keeps immiscible compounds from separating by increasing the kinetic stability of the mixture. Emulsifying agents can be classified according to: 1) chemical structure; or 2) mechanism of action

Emulsifiers classified on the basis of chemical structure:

1. Natural: Natural emulsifiers can be sourced from vegetables or animals. Most of these emulsifiers form hydrated lyophilic colloids (called hydrocolloids) which have little or no effect on interfacial tension, but exert a protective colloidal effect, reducing the potential for coalescence.

- Vegetable (e.g. agar, starch, pectin, etc.), animal (e.g. egg yolk, gelatin, etc.)

2. Synthetic: Emulsifying agents which are chemically synthesized or come from chemical sources are called synthetic emulsifiers, which are largely constituted of surfactants. They can be cationic, anionic, non-ionic or even semi-synthetic  in nature. 

- Cationic (e.g. benzalkonium chloride ), anionic  (e.g. alkali soaps, detergents, etc. ), non-ionic  (e.g. sorbitan esters, glycerine esters, etc).

3. Finely Dispersed Solids: These emulsifying agents form a particulate layer around dispersed particles. Most commonly these agents support the formation of o/w emulsions, but some may also form w/o emulsions

- Finely divided solid particle emulsifiers (e.g. bentonite hectorite, veegum, etc.)

4. Auxiliary Agents: Auxiliary emulsifying agents serve to stabilize emulsions through their ability to thicken the emulsion. Because these agents have only weak emulsifying properties, they are always used in combination with other emulsifiers.

- Fatty acids (e.g. stearic acid), fatty alcohols (e.g. stearyl or cetyl alcohol), and fatty esters (e.g. glyceryl monostearate)

 

Emulsifying Agents classified on the basis of mechanism of adsorption:

1. Monomolecular: Monomolecular adsorption is witnessed in synthetic surfactants that adsorb at the oil-water interface to form a mono-molecular film that rapidly picks up droplets as soon as they are formed. 

2. Multimolecular: In multilayer adsorption, usually observed in the presence of natural emulsifiers, the adsorption space accommodates more than one layer of molecules and not all adsorbed molecules are in contact with the surface layer of the adsorbent.

3. Solid Particle Film: Finely divided solid particles adsorbs at oil-water interface and form a rigid film of closely packed solids. This film acts as a mechanical barrier and prevents the coalescence of globules. 

Q2. How do surfactants facilitate emulsification?

There are various pharmaceutical excipients such as surfactants which offer bioavailability enhancement for active pharmaceutical ingredients (APIs) by increasing the solubility of solutions or by stabilizing emulsion formulations. Emulsion stability can be defined as a system’s ability to resist changes in its physicochemical properties over time. Emulsion stabilization is important in many industrial applications as several mechanisms such as creaming, flocculation and coalescence cause emulsion breakdown. Surfactants can act as stabilizing agents for emulsion formulations and lipid based drug delivery formulations.

Surfactants are amphiphilic molecules that have hydrophobic and hydrophilic parts. Based on the net charge surfactants can be classified into two major groups; Non ionic surfactants & ionic surfactants. The head of an ionic surfactant carries a net charge. If the charge is negative it functions as an anionic surfactant, if it is positive it is called a cationic surfactant, and if it has both cationic and anionic properties it is an amphoteric surfactant

Non ionic surfactants act as good emulsifying agents and stabilizers or stabilizing agents for oils and are better than anionic surfactants at removing organic soils. Non-ionic surfactants generally have much lower concentration of micelles (CMC values are directly proportional to solubility) and higher aggregation numbers than their ionic counterparts with similar hydrocarbon chains. Furthermore, non ionic surfactants can be used in formulating products that maintain skin health (topical products).

When a surfactant is added to an oil and water product, one end of the molecule dissolves in water and the other dissolves in oil to form emulsion formulations. By forcing these molecules to be near each other without separating surfactants act as emulsifiers or emulsifying agents . This push and pull of emulsifiers in oil and water keeps different substances suspended in a solution

Surfactants further increase the electrostatic repulsion or steric repulsion between the immiscible liquids. It acts on the interface and increases the kinetic stability of an emulsion so that the size of the droplets does not change significantly with time, thus stabilizing the emulsion.

Q3. What is the role of emulsifiers in pharmaceutical formulations?

Emulsifiers are used in pharmaceutical formulations to stabilize emulsions in order to achieve the physico-chemical characteristics required for optimal drug delivery of API (Active Pharmaceutical Ingredient). The selection of emulsifier pharmaceutical excipients depends on an emulsion's lipophilic/hydrophilic nature. 

From a thermodynamic perspective, an emulsion is an unstable system due to its natural tendency for a liquid/liquid mixture to minimize its interfacial interactions (and/or interfacial energies).  Due to its inherent instability, an emulsion will spontaneously separate out into two bulk phases via one of the following processes: creaming, sedimentation, flocculation, coalescence, phase inversion, etc. 

However, an emulsion can be stabilized by increasing the repulsion between the dispersed phases i.e., by increasing the electrostatic repulsion or steric repulsion between them. Emulsion stabilization can be achieved by using emulsifiers or stabilizers, sometimes even both. 

Emulsifying Agents: An emulsifying agent (emulsifier) is a surface-active ingredient which adsorbs at the newly formed oil–water interface during emulsion preparation, and it protects the newly formed droplets against immediate recoalescence. They are good for short term emulsion stabilization

Stabilizing Agents: Stabilizers are compounds that are not (or may be partly) surface active, but impart long-term stability to emulsions by stabilizing interfacial interactions via restricting them. 

 

Stabilizing emulsion formations by stabilization techniques (using emulsifiers & stabilizing agents) is imperative in the pharmaceutical industry as they offer the following advantages:

- Emulsifiers can facilitate the pharmaceutical drug delivery of drugs that are poorly water soluble in aqueous solutions. 

- They can facilitate taste and odor masking of unpleasant flavors and smells by emulsification, which in turn increases consumer utility. 

- Emulsions act as pharmaceutical drug delivery systems for therapeutic oil formulations

- Pharmaceutical emulsions are increasingly popular as pediatric formulations or for patients who suffer from swallowing difficulties. They can reduce irritant effects in the gastrointestinal tracts which may be associated with other drug delivery systems (DDS).

Q4. How are emulsifying agents used in the preparation and stabilization of emulsions?

Emulsions are heterogeneous and biphasic, thermodynamically unstable systems containing two immiscible fluids; for e.g. oil and water. They are prepared & stabilized by adding emulsifiers or emulsifying agents. Emulsifiers are amphiphiles that reduce the interfacial tension between the two liquid phases and contribute to the stabilization of dispersed droplets with electrostatic or steric effects. 

Emulsifiers have both a hydrophilic and a lipophilic part in their chemical structure. All emulsifying agents are adsorbed onto the oil and water interface to provide a protective barrier around the dispersed droplets. In addition to this protective barrier, emulsifiers stabilize the emulsion by reducing the interfacial tension of the system. The formation, stability, and performance of emulsions may be improved by using combinations of two or more emulsifiers, as compared to an individual type. 

There are various emulsification methods which are used in the preparation of emulsions including high pressure homogenization, rotor–stator homogenization, microchannel emulsification, membrane emulsification, microfluidics, and ultrasound emulsification. The preparation of W/O emulsions consists of dissolving a hydrophobic emulsifying agent in the continuous phase, followed by adding the aqueous dispersion in the continuous phase under moderate stirring. 

Emulsifying agents may enhance stability by imparting a charge on the droplet surface thus reducing the physical contact between the droplets and decreasing the potential for coalescence. Some commonly used emulsifying agents include tragacanth, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, and polymers known as the spans and tweens impart stability to the emulsion.

Q5. What are the different commercial emulsifying agents used in pharmaceutical formulations?

Emulsifying agents play a crucial role in pharmaceutical emulsion formulation and stabilization which is necessary for the development of topical dosage forms like gels, ointments, creams, etc. Some of the leading pharmaceutical companies offering commercial emulsifier excipients are listed below. 

- PMC Isochem
(E.g. Vitamin E TPGS)

PMC Isochem offers Tocophersolan based Vitamin E TPGS, a water soluble derivative of natural Vitamin E. Vitamin E TPGS a multirole pharmaceutical excipient which functions as an emulsifier, plasticizer, vehicle for lipid based pharmaceutical formulations, binder, and as a solubilizing agent. Tocophersolan (Vitamin E-TPGS) has been approved by the FDA as a safe adjuvant and subsequently has been widely used in drug delivery systems

- ABITEC
(E.g. Acconon Mixtures for Bioavailability and Emulsion, Capmul MCG and Propylyene Glycol Esters, etc.)

ABITEC offers a full portfolio of lipids that are useful as emulsifiers, co-emulsifiers, and surfactants. Emulsification of lipids and/or fatty acids allows them to be mixed with water-based substances, which has important implications for digestion. More specifically, in the area of drug delivery, emulsification plays a key role in the development of Self-Emulsifying Drug Delivery Systems (SEDDS) which enhance oral delivery and absorption of lipophilic drugs.  

- Croda
(E.g. Cithrol™ GMO HP, Super Refined™ CCMG 400, Super Refined™ Castor Oil, etc.)

Emulsion technology has always been a core area of Croda Industrial Chemicals’ business. Recognised as experts in its field, Croda has produced a number of successful emulsion systems in a broad range of applications. They offer anionic surfactants, cationic surfactants, non-ionic surfactants, polymeric surfactants, and dispersants. 

- Gattefossé
(E.g. Gelot™ 64, Plurol® Diisostearique, Tefose® 63, etc.)

To enable simple formulation of stable emulsion systems, Gattefossé offers a range of self-emulsifying bases consisting of all-in-one excipients. Due to their specific compositions combining lipophilic and hydrophilic surfactants with texture agents, they provide stable emulsions whatever the type and concentration of oil.

- Gangwal Chemicals
(E.g. Sepineo D.E.R.M.)

Gangwal Chemicals offers Hydroxyethyl Acrylate based Sepineo D.E.R.M, a ready to use liquid polymer for topical applications like gels, creams, lotions, foams, etc. It thickens over a wide range of pH (3-12) and acts as a thickener, emulsifier, stabilizer, texturizing agent, etc. 

- Corel Pharma Chem
(E.g. Acrysol EL-135)

Polyoxyl 35 Hydrogenated Castor Oil based Acrysol EL-135 by Corel Pharma Chem, acts as a stabilizer, solubilizer and film-former for solutions and emulsion formulations. It is a castor oil derivative, obtained through a chemical process which improves soft feeling and moisturizing effects. It solubilizes insoluble oily substances in aqueous systems, hence improving the transparency and shine of emulsion formulations


Applications:

Vitamin E TPGS (Tocophersolan) is used as a solubilizer, emulsifying agent, plasticizer, stabilizer, and vehicle for lipid-based formulations.

Ingredient(s): Tocophersolan

Dosage Form: Capsule, Cream / Lotion / Ointment, Injectable / Parenteral

Category: Emulsifying Agents

Route of Administration (Grade): Oral, Parenteral, Nasal, Ophthalmic, Topical
Pharmacopoeia Reference: USP 40 – NF 35

Technical Specifications: Specific Gravity: 1.06 at 50°C to 1.03 at 90°C; Solubility In Water: -20% at 20°C; Viscosity: 390cP at 50°C; Available in mol. wt. of 1500 g/mol, 200 g/mol, 2000 g/mol, 300 g/mol, 400 g/mol, 4000 g/mol.