Emulsion Formulation
Emulsion Formulation
Over the past several decades, emulsion formulations have been explored for
resolving a variety of
drug delivery challenges. Unlike solutions for oral or parenteral administrations, which are
usually
homogeneous one-phase systems or molecular dispersions, emulsions are colloidal
dispersions of
at least two immiscible phases stabilized with the aid of a third component generally
referred to as
the emulsifying agent.
Definition
These are dispersed systems, a first liquid divided in the form of fine droplets in a
second liquid immiscible with the first.
An emulsion can be defined as a mixture of two immiscible phases (namely, water and
oil) with an emulsifier added to stabilize the dispersed droplets (Davis et al., 1987). As
conventionally defined, emulsions will have droplet diameters of more than 100 nm (up to 50
µm), and thus are opaque or milky in appearance.
Table 10.1 summarizes the lipids most commonly used in parenteral emulsions. Long- and
medium-chain triglycerides (LCT and MCT, respectively), either alone or in combination, are
used in commercial parenteral emulsions owing to their long history of safety. LCT are
derived from vegetable sources such as soybean oil, safflower oil, sesame oil, and
cottonseed oil, whereas MCT are obtained by re-esterification of fractionated coconut oil
(mainly caprylic and capric fatty acid).
Surfactants
The allowed concentration (after dilution) for administration for each of the
surfactants is listed in Table 10.2.
Other surfactants that have been used in parenteral products are synthetic nonionic
surfactants including Cremophor® EL (Polyoxyl-35 castor oil), Solutol HS-15
(polyoxyethylene- 660-hydroxystearate), Tween® 20, 40, and 80, Span® 20, and Poloxamer
188. Poloxamer 188 has been shown to be superior in stabilizing emulsion during autoclaving
compared to other surfactants (Jumaa and Muller, 1998).
Emulsion classification
Macroemulsion
Microemulsion
Nanoemulsion
Emulsion Instability
Emulsion Stability: Strong and Stable or Weak and Feeble
Stokes’ Law states that the terminal velocity, V, in m/s, is given by:
3-reduced the density difference between the two phases by increasing zeta potential.
Zeta potential
Zeta potential. Zeta or electrokinetic potential is related to the surface charge of the emulsion
droplets and it is generally measured by electrophoretic techniques. The zeta potential is
highly dependent on the surfactants used.
A charged drug molecule at the interface will also affect the zeta potential.
Zeta potential is measured using a Zetasizer Nano ZS (Malvern Panalytical) system which
calculates zeta potential using the principle of electrophoresis.
During a zeta potential analysis, charged colloidal dispersions are placed into a zeta cell and
upon application of an external electric field, the particles travel toward the electrode that has
a charge opposite to that of the particle. Their velocity, or electrophoretic mobility, under the
influence of an electric field, is measured using LASER Doppler velocimetry. It is then used
to calculate the zeta potential by applying the Henry equation:
By increasing zeta potential the particles repel each other تتنافر, To overcome this
difficulty, we use an emulsifier (Surfactant).
What is a Surfactant?
A surfactant is a substance, that when added to water, reduces the surface tension of the
solution thus increasing its substrate wetting properties. At low concentrations, a surfactant
has the property of migrating and being adsorbed on the interfaces present in the system. It
alters the interfacial free energies of these interfaces. Thus, a surfactant is a surface-active
agent.
Surfactants can be referred to by a variety of terms: soap, wetting agent, dispersing agents,
substrate wetting additives, emulsifiers, surface-active agents, stabilizers, or solubilizers.
They are necessary for the wet stage of polymers and coatings. Chemists use surfactants to
change the composition of a liquid which enables specific properties that meet the needs for
market applications. Since surfactants can also cause detrimental effects in the film, such as
blisters, surfactant leaching, and less water resistance, chemists need to use the lowest levels
possible while maintaining the coating’s performance.
There are four basic classes of surfactants: nonionic, anionic, cationic, and amphoteric. All
four types of surfactants can be utilized in pigment dispersions.
1. Nonionic Surfactants
Chemists use nonionic surfactants after polymerization to achieve stability, and then in
the grind for wetting and dispersing pigments and again in the letdown to achieve optimal
substrate wetting. Nonionic surfactants also help with stability of the formulation, heat age
stability, freeze/thaw resistance, and in-can stability.
With nonionic surfactants, chemists should consider the HLB values as well as a cloud
point. The HLB value plays a critical part in its functions and properties like emulsification,
solubility, wetting, and dispersion. The cloud point affects storage conditions and if the cloud
point is too low the coating may have phase separation and instability. For low-foam
applications, the cloud point of the product should be just below the application temperature.
HLB value is an empirical expression for the relationship of the hydrophilic ("water-
loving") and hydrophobic ("water-hating") groups of a surfactant. The higher the HLB
value, the more water-soluble (hydrophilic) the surfactant. The HLB value of nonionic
surfactants is a measurement – on a scale of 1 to 20 – of the degree of water/oil solubility of a
given surfactant. The HLB of a particular surfactant is directly related to the structure of both
its hydrophilic and hydrophobic parts and plays a critical role in its function and properties.
To calculate HLB, take the molecular weight of the surfactant hydrophilic chain, divided by
the total molecular weight, and then multiply by 20.
HLB= [0-20] ;
2. Anionic Surfactants
3. Cationic Surfactants
Chemists use cationic surfactants for their positive charge and anti-static properties.
Typically, we see cationic surfactants used in textiles for their fabric softening ability and
coatings for their anti-corrosive and anti-static properties.
4. Amphoteric Surfactants
Amphoteric surfactants are naturally cationic at low pH and anionic at high pH. They
are very mild and non-irritating when used in cleaners and detergents.
Applications for Surfactants
Emultion direction
To formulate W/O emulsion we use emulsifier with weak HLB 3 to 6 enough.
These surfactants have lipophilic trait, i.e very soluble in the lipo phase.
To formulate O/W emulsion we use emulsifier with strong HLB > 8.
These surfactants have hydrophilic trait, i.e very soluble in the hydro phase.
Final HLB= ([HLB emulsifier A * molar masse A] + [HLB emulsifier B * molar masse B])
Molar masse A+ Molar masse B
The HLB value of surfactants that provides the lowest interfacial tension between the
oil and water phases for a given lipid mixture is called the required HLB. Each of the
lipophilic ingredients used in an o/w emulsion has a required HLB value (e.g., 6–7 for
cottonseed oil and 14 for castor oil).
Oil………………………………….20%
Emulsifier 1
…………………5%
Emulsifier 2
Water…………………………QSP 100%.
We heat the oil and water at 70 °C, mixed with mechanical stirring.
2) Formulation of the second layer: Gradually add water to the simple emulsion plus
hydrophilic emulsifier, using gentle agitation.
N.B
The addition of two or more emulsifiers does not necessarily mean the formulation of a
multiple emulsion, but the goal is to have an additive HLB.
CHARACTERISTICS OF EMULSIONS
There are a number of physicochemical properties of emulsions that are important to consider
when developing an emulsion formulation for a drug. These include, but are not limited to,
particle (droplet) size, viscosity, osmolarity, and zeta potential, which are used to monitor the
physical stability of emulsions. Assays of potency and degradant levels are used to monitor
the chemical stability of emulsions.
Many of these lipophilic drugs will also exhibit a strong food effect
where the bioavailability increases due to the solubilizing effects of
ingested food and concomitant excretion of bile (Charman et al., 1997;
Fleisher et al., 1999). By introducing the drug in solubilized form,
lipid-based formulations have the potential to increase
bioavailability and eliminate the food effect.
Emulsifiers
Often lipid-based oral formulations contain emulsifiers (surfactants) to facilitate dispersion of
the drug and formulation components after ingestion. Surfactants can be classified according
to their hydrophilic–lipophilic balance (HLB) number (Griffin, 1949);
use for the stabilization of oil-in-water emulsions Houria Bouziane1 | Soumia Seddari2 | Fatiha Boudjema3 |
Nadji Moulai-Mostefa.
The main objective of the present study was to examine the possibility of
formulating stable acid O/W emulsions using NaCn/XG complexes
prepared at pH 4. The stability of emulsions can be enhanced by using the
electrostatic interactions between PR and PS. For this, two approaches
were proposed; one of them is called the “layer by layer” training method.
N.B
XG, Xanthan gum = polysaccharides (PS)…
Proteins (PR) and polysaccharides (PS) are among the most used biopolymers for the
replacement of synthetic surfactants (Silva et al., 2015). The stabilization of emulsions by PR
alone or in combination with PS has been the objective of several previous works (Perugini et
al., 2018; Seddari et al., 2022). The complexation between PR and PS has also been studied
because of the benefits that can bring in the stabilization of dispersed systems when carried
out under appropriate conditions (HadjSadok et al., 2010; Jones et al., 2011; Warnakulasuriya
& Nickerson, 2018). It has been observed that most often, the complexation between PR and
PS macromolecules results from a non-covalent association, mainly due to attractive
electrostatic interactions (Albano et al., 2019; Dai et al., 2022).
Sodium caseinate (NaCn) which is the major protein in milk, can be used as a natural
emulsifier for the formulation of oil-in-water (O/W) emulsions owing to its amphiphilic
properties (Tavasoli et al., 2022).
However, emulsions stabilized by NaCn are unstable at pH near to its isoelectric point (pI 4.6)
due to the reduction of electrostatic repulsion between oil droplets (Perugini et al., 2018).
There are many pharmaceutical forms especially topical ones that are
prepared at acidic pH (Angelova-Fischer et al., 2018; Blaak et al., 2017; Kilic et al., 2019).
Acid food emulsions based on the whey protein isolate/xanthan gum complex have also been
successfully formulated (Matsuyama et al., 2021). They are manufactured and distributed at a
pH close to 4. Therefore, it would be interesting to study the possibility of formulating stable
emulsions with NaCn under acidic conditions.
Self-emulsifying drug delivery systems (SEDDSs) are oral dosage forms consisting of drug,
oils, surfactants, and sometimes cosolvents (Constantinides, 1995; Pouton, 1997; Pouton,
2000). On addition to water (or on introduction to the gastrointestinal [GI] tract) and with
gentle agitation, the system will easily form an emulsion or microemulsion (defined in the
following).
Selfemulsification may be driven by several mechanisms (López-Montilla et al., 2002). The
mechanisms most likely involved in dispersion of pharmaceutical formulations are diffusion
and stranding, those driven by osmotic pressure imbalances (Greiner and Evans, 1990), phase
transformations, and changes owing to alteration of environmental conditions (e.g., pH). If the
droplet size after dispersion is substantially less than 1 micron, the SEDDS is often designated
as a selfnanoemulsifying drug delivery system (SNEDDS).
Published study example Ref. Self-double-emulsifying drug delivery system (SDEDDS): A new way for oral delivery of drugs with
high solubility and low permeability Xiaole Qi, Lishuang Wang, Jiabi Zhu ∗, Zhenyi Hu, Jie Zhang.
The present studies have clearly demonstrated the potential utility of SDEDDS for
formulating pidotimod (Pidotimod is an immunostimulant) with sustained release in vitro
and improved oral bioavailability in vivo. The optimal formulation of the pidotimod-
SDEDDS (F4) was successfully developed. The SDEDDS readily released the lipid phase to
form fine water-in-oil-in-water double emulsions, with a sustained release of pidotimod.
Pharmacokinetic studies in rats revealed that the absorption of pidotimod from SDEDDS
showed 2.56-fold increase in bioavailability as compared to the same oral dose (80 mg/kg) of
the pidotimod aqueous solution. Moreover, the SDEDDS were found to be stable over a
period of 6 months under 25 ◦C. Our studies illustrated the potential use of novel self-double-
emulsifying drug delivery systems for oral delivery drug with high solubility and low
permeability.
low permeability Xiaole Qi, Lishuang Wang, Jiabi Zhu ∗, Zhenyi Hu, Jie Zhang.
Ref. Self-double-emulsifying drug delivery system (SDEDDS): A new way for oral delivery of drugs with high solubility and
The various structures formed are the result of the amphiphilicity of the
surfactant whose hydrophilic domain and lipophilic domain drive it to the
interface of oil/water systems. These phases include the well-organized
structure of lamellar, hexagonal and cubic liquid crystals, the water
continuous L1 phase, which includes micelles and o/w microemulsions,
and the oil continuous L2 phase, which includes inverse micelles and w/o
microemulsions (Figure 11.6).
Drug candidates for lipid-based drug delivery are poorly aqueous- soluble and
lipophilic (typically log P > 3). Being a poorly soluble drug alone is not sufficient, as
solubility in the lipid components for LBDDSs is required. Initiating development of an
LBDDS will begin with a solubility screening study in select lipid excipients, emulsifiers, and
cosolvents (e.g., ethanol, propylene glycol, PEG 400). The primary solvent will typically be
an alkylglyceride, and cosolvents are used to increase the solubility in the blend.
Formulation material
magnetic stirrer
homogenizer (Ultra-turrax T-25, IKA, Germany)
Rheology Material
Tensiometer
Anton Paar Modular Compact Rheometer MCR 302.
Microprocessor pH/ion Meter pMX 2000 (WTW, Germany).