MODULE 1.

June 4, 2024
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MODULE 1. TECHNOLOGY OF COSMETIC PRODUCTS

 

Content modules: 1. Technology of cosmetic creams, liquids and makeup tools

 

SOFT COSMETIC PRODUCTS, CREAMS. EMULSIONS.

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The following diagrams represent the formation of an emulsion. In diagrams A–C we see the interaction between two immiscible liquids without the addition of an emuliser. In diagram D we see how the addition of an emulisifer leads to the formation of an emulsion.

 

In diagram A two liquids not yet emulsified form two separate phases, a layer of oil on top of a layer of water.

 

Підпис: Phase II: Oil   Phase I: Water

 

In diagram B the liquids have been agitated (stirred vigorously), initally the water layer and oil layers have formed an emulsion.

 

 

In diagram C the unstable emulsion progressively separates back into two distinct layers (phases).

 

Eventually, after some minutes, the two liquids return to form two separate phases, a layer of oil on top of a layer of water.

 

Підпис: Phase II: Oil     Phase I: Water

 

It is worth highlighting at this point how important it is that we have a way of preventing this from happening, otherwise the majority of our consumer products, including shampoo, toothpaste, cosmetics, ice-cream, washing detergents and salad dressings, would all end up as seperated layers, with the active ingredients no longer able to work effectively.

 

In diagram B the oil and water have been agitated (stirred vigourously). If we were at this point to add an emulsifer, we would arrive at a stable emulsion, as shown in diagram D.

 

 

With the addition of an emulsifier (purple outline around particles) the interfaces between phase II (oil) and phase I (water) create a stabilised emulsion.

 

 

This addition of an emulsifier allows two otherwise immiscible layers to be mixed uniformly, dispersing an equal amount of each throughout the entire volume. The mixture is able to exist as a stable (non-separating) emulsion for a reasonable time (known as shelf-life).

 

 

 

How do emulsifiers work?

 

Emulsifiers are soap-like molecules. Soaps and emulsifiers are composed of a hydrophilic head and a hydrophobic tail.

 

Soaps are structured like this:

 

 

In the case of soap/surfactants, they use their hydrophilic head and hydrophobic tail properties to remove stains in the following process:

 

Screen shot 2011-02-06 at 11.55.44.png

 

The hydrophobic tails of the surfactant ‘burrow’ into the droplet of oil or grease stain on the fabric.

 

Screen shot 2011-02-06 at 11.55.53.png

 

This leaves the hydrophilic heads to face the surrounding water.

 

Screen shot 2011-02-06 at 11.56.00.png

 

The oil/grease stain is held inside the ball and suspended in water.

 

Emulsifiers work in a similar fashion: this is how they can suspend oil in water, for example. However, it is how they are made that makes them chemically different from surfactants/soaps.

 

 

Making an emulsifier

 

Emulsifiers are made from the chemical reaction between glycerol and a single unit of fatty acid, without the presence of a strong alkali.

 

 

The resulting polar hydrophilic head group is not charged (as it can be for surfactants). The resulting polarity comes from the hydrogen bond interactions of the hydroxyl (OH) groups and the surrounding water molecules.

 

 

The above ball (blue for hydrophilic head group) and stick (yellow for hydrophobic tail group) diagram represents the structure of an emulsifier. Note: The head group (blue) does not carry any charge.

 

How an emulsion is made

 

Emulsifiers use their hydrophilic head and hydrophobic tail properties to prevent oily liquids separating out from the aqueous liquids (water) in which they are suspended:

 

 

In the same way as a surfactant, the hydrophobic tails burrow into the oil droplet and the hydrophilic head groups are left on the surface to interact with the water molecules. Thus an oily substance can be suspended in a water layer for some time without separating out. The resulting liquid is called an emulsion.

 

oil-and-water1.jpg

 

DEFINITION:

 

An emulsion is a thermodynamically unstable system consisting of at least two immiscible liquid phases one of which is dispersed as globules in the other liquid phase stabilized by a third substance called emulsifying agent. The droplet phase is called the dispersed phase or internal phase and the liquid in which droplets are dispersed is called the external (continuous phase).

 

Appearance of emulsions:

The appearance of emulsion depends on the wavelength of visible light i.e. globules more than 120 nm reflect light and appear white to the eye.

 

TYPES OF EMULSIONS: 

 

1.     Macro emulsions (Simple Emulsions)

2.      Multiple emulsions

3.     Micro emulsions

 

1. Macro emulsions (Simple Emulsions):

 

i. Oil in water (o/w): Oil droplets are dispersed in a continuous aqueous phase. This emulsion is generally formed if the aqueous phase constitutes more than 45 % of the total weight and a hydrophilic emulsifier is used. These are referred for oral administration and cosmetics. These are useful as water washable drug bases.

ii. Water in oil (w/o):  Aqueous droplets are dispersed in continuous oily phase. . This emulsion is generally formed if the oily phase constitutes more than 45 % of the total weight and a lipophobic emulsifier is used. These are used for cosmetics. They are employed for treatment of dry skin and emollient applications.

 

 

2. Multiple emulsions:

They are developed with a view to delay the release of an active ingredient. They have three phases. They may be oil-in-water-in-oil (o/w/o) or of water-in-oil-in-water (w/o/w). An emulsifier is present to stabilize the emulsions and various ionic and nonionic surfactants are available for this purpose. Lipophilic (oil-soluble, low HLB) surfactants are used to stabilize w/o emulsions, whereas hydrophilic (water-soluble, high HLB) surfactants are used to stabilize o/w systemsIn these emulsions within emulsions any drug present in innermost phase must now  cross two phase boundaries to reach the external continuous phase.

Such emulsions also can invert. However, during inversion they form simple emulsions. So a w/o/w emulsion will get inverted to o/w emulsion.

Preparation of multiple emulsions:

i.                   Aqueous phase is added to oily phase, containing a lipophilic surfactant. Upon mixing a w/o emulsion is formed.

ii.                  This w/o emulsion is then poured into a second aqueous solution, containing hydrophilic surfactant. Upon mixing multiple emulsion w/o/w is formed.

Types of multiple emulsions:  w/o/w, o/w/o

.Applications :

 The important applications are in cosmetics ,pharmaceuticals and foods. For example, in cosmetics they have a fine texture and a smooth touch upon application, and they are aimed for slow and sustained release of active matter from an internal reservoir into the continuous phase (mostly water). They can serve as an internal reservoir to entrap matter from the outer diluted continuous phase into the inner confined space. They can also improve dissolutions or solubilization of insoluble materials. Due to these properties, multiple emulsions find applications related to protecting sensitive and active molecules such as vitamins C and E from the external phase—a process called antioxidation

3. Micro emulsions:

          They may be defined as dispersions of insoluble liquids in a second liquid that appears clear and homogenous to the naked eye. They are frequently called solubilised systems because on a macroscopic basis they seem to behave as true solutions.  Terms as transparent emulsions, micellar solutions, solubilised systems, and swollen micelle have all been applied to the same or similar systems.

        These emulsions appear to be transparent to the eye. They have globule radius below the range of 10-75 nm. The appearance of emulsion depends on the wavelength of visible light i.e. globules less than 120 nm do not reflect light and appear transparent to the eye. As in micro emulsions the globule size is less than 120 nm, they appear to be transparent.

       Blending of a small amount of oil and water results in a two phase system because “water and oil do not mix “If the same small amount of oil is added to an aqueous solution of a suitable surfactant in the micellar state, the oil may preferentially dissolve in the interior of the micelle because of its hydrophobic nature. This type of micellar micro emulsion is also called an o/w micellar solution. Similarly, w/o solubilization – especially that by a nonionic surfactant – has been attributed to swollen micelles. In these systems, sometimes called reverse micelle solutions, water molecules are found in the polar central portion of a surfactant micelle. the non portion of which is in contact with the continuous lipid phase. A third type of micro emulsion is formed by ionic surfactants (e.g. sodium stearate) in the presence of co-surfactant) e.g. pentanol or dioxyethylene dodecyl ether) with hydrocarbons (e.g. hexadecane) and water.

In general micro emulsions are believed to be thermodynamically stable. These micro emulsions are used for drug administration and toiletry products.

 

Determination of type of emulsion:

 

1. Dilution test:

An emulsion can only be diluted with its continuous phase.  O/w can be diluted with water and w/o can be diluted with oil. So when oil is added to o/w emulsion or water is added to o/w emulsion, separation of dispersed and continuous phase occurs. This test is useful for liquid emulsions.

2. Dye Solubility test:

Water soluble dye (methylene blue) will be taken up by the aqueous phase where as oil soluble dye will be taken by oily phase. When microscopically it is observed that water soluble dye is taken up by the continuous phase,   it is o/w emulsion. If the dye is not taken up by the continuous phase, test is repeated with oil soluble dye. Coloring of continuous phase confirms w/o emulsion. This test can fail if ionic emulsions are present.

3. Conductivity test:

An emulsion with continuous phase will possess more conductivity than an emulsion where oil is the continuous phase. So when a pair of electrodes, connected to a lamp and an electrical source are dipped into o/w emulsion, the lamp lights because of passage of current between two electrodes. If the lamp does not light, it is assumed to be w/o emulsion.

4. CoCl2 filter test:

Filter paper impregnated with CoCl2 and dried (blue) changes to pink when o/w emulsion is added. It may fail if emulsion is unstable or breaks in presence of electrolyte.

5. Fluorescence test:

Since some oils fluoresce under UV light, 0/w emulsions exhibit dot pattern, w/o emulsion fluoresce through out.  But this test is applicable if oil has the property of fluorescence.

 

Factors affecting the type of emulsion:

 

Type of emulsion produced (o/w or w/o) depends upon following factors:

i.       Type of emulsifying agent :  

Type of emulsion is a function of relative solubility of emulsifying agent. The phase in which it is soluble becomes the continuous phase

 

ii.     The phase volume ratio i.e. the relative amount of oil and water.

This determines the relative number of droplets formed and hence the probability of number of collision. The greater the number of droplets, greater is the chance for collision. Thus the phase present in greater amount becomes the external phase.

The polar portions of the emulsifying agents are better barriers to coalescence than hydrocarbon counterparts. So o/w emulsions can be formed with relatively high internal phase volume.    In  w/o emulsion (in which the barrier is of hydrocarboature) if the amount of internal phase is increased more than 40 %, it inverts to o/w emulsion because hydrocarbon part of surfactant caot form a strong barrier.

iii.  Viscosity of each phase :

An increase in viscosity of a phase helps in making that phase the external phase.

 

USES (APPLICATIONS) OF EMULSIONS:

Emulsions can be used for oral, parenteral or topical pharmaceutical dosage forms.

i. Oral Products

Emulsions are used for administering drugs orally due to following reasons: 

a. More palatable: Objectionable taste or texture of medicinal agents gets masked.

b. Better absorption: Due to small globule size, the medicinal agent gets absorbed faster.

ii. Topical products:

O/w emulsions are more acceptable as water washable drug bases for cosmetic purposes.

w/o emulsions are used for treatment of dry skin. Emulsions have following advantages when used for topical purpose:

a. Patient acceptance: Emulsions are accepted by patients due to their elegance, easily

 b. washable character,

c. acceptable viscosity,

d. less greasiness.

iii. Parenteral Emulsions:

a. i.v rout:

Lipid nutrients are emulsified and given to patients by i/v rout. Such emulsions have particle size less than 100 nm.

b. Depot injections:

W/o emulsions are used to disperse water soluble antigenic materials in mineral oil for i/m depot injection.

iv.  Diagnostic purposes :

Radio opaque emulsions have been used in X-ray examination.

 

THEORY OF EMULSIFICATION:

When oil and water are mixed and agitated, droplets of different sizes are produced. However, two immiscible phases tend to have different attractive forces for a molecule at the interface. A molecule of phase A is attracted to phase A but is repelled by Phase B. This produces interfacial tension between two immiscible liquids. (Interfacial tension at a liquid is defined as the work required to create 1 cm2 of new interface.

A fine dispersion of oil and water necessitates a large area of interfacial contact. Its production requires an amount of work equal to the product of interfacial tension and the area change. Thermodynamically speaking, this work is the interfacial free energy imparted to the system. A high interfacial energy favors a reduction of interfacial area, first by making the droplets to get spherical shape( minimum surface area for a given volume)  and then by causing them to coalesce (decrease iumber of droplets). This is the reason for including the words “Thermodynamically unstable” in definition of opaque emulsions. To make a stable emulsion droplets have to be stabilized so that they do not coalesce.

Droplet Stabilization: (Mechanism of action of emulsifying agents)

Droplets can be stabilized by making use of emulsifying agents. Emulsifying agents assist in the formation of emulsion by two mechanisms.

i.            By lowering the interfacial tension  And/or

Interfacial tension can be reduced by using surfactants.

ii.             By preventing the coalescence of droplets

i. By lowering the interfacial tension (Reduction in interfacial tension – thermodynamic stabilization):

The increased surface energy associated with formation of droplets, and hence surface area in an emulsion can be reduced by lowering of interfacial tension. Assuming the droplets to be spherical

                     ∆ F = 6 γV/d

∆ F = energy in put required

γ = interfacial tension

V = volume of dispersed phase in ml

d = mean dia of particles

If V= 100 ml of oil, d = 1 μm (10-4 cm), γ o/w = 50 dynes / cm,

∆ F = 6 x 50 x 100 / (1 x 10-4) = 30 x 107 ergs = 30 joules or 30 / 4.184 = 7.2 cal.

In the above example, addition of emulsifier which reduces γ from 50 to 5 dynes / cm will reduce the surface free energy from 7.2 to 0.7 cal. Such reduction in surface free energy can help to maintain the surface area generated during the dispersion system by ii. Preventing the coalescence of droplets Coalescence of droplets can be prevented by two methods – (a) By formation of rigid film, (b) By formation of electrical double layer.

A. By formation of rigid interfacial film – mechanical barrier to coalescence. Coalescence of droplets can be prevented by formation of films around each droplet of dispersed material. This film forms a barrier that prevents the coalescence of droplets. This film should possess some degree of surface elasticity, so that it does not break when compressed between two droplets. If broken it should form again rapidly. These films are of three types:

i. Monomolecular films:

The surface active agents form a monolayer at the oil water interface. This monolayer serves two purposes:

1.     Reduces the surface free energy.

2.     Forms a barrier between droplets so that they caot coalesce.

ii.           Multimolecular films :

Hydrated lyophilic colloids and finely divided solids form multimolecular films around droplets of dispersed oil. They do not reduce the interfacial tension but form a coating around droplets and prevent coalescing. The hydrocolloid which is not absorbed on the surface of droplet, increase the viscosity of continuous phase hence stabilizes the emulsion. 

iii.              solid particle films

Small solid particles which are wetted to some extent by both oily and aqueous phase, can act as emulsifying agent. If the particles are too hydrophilic, they get dispersed in aqueous phase. If the are too hydrophobic, they get dispersed in oily phase. Other requirement is that the particles should be smaller than the droplet size.

b.          By forming electrical double layer

Presence of a well developed charge on the droplet surface increases stability by causing repulsion between approaching drops. This charge is likely to be greater if ionized emulsifying agent is employed. i/v fat emulsions are stabilized with lecithin due to the electrical repulsion.

In an o/w emulsion stabilized by sodium soap, the hydrocarbon tail is dissolved in the oily phase and ionic heads are facing the continuous aqueous phase. As a result the surface of the droplet is studded with –vely charged carboxylic group. This produces a surface charge on the droplet… The cations of opposite charge are oriented near the surface, producing a double layer of charge. The potential produced by double layer creates a repulsive effect between the oil droplets and thus hinder coalescence.

 

 

FORMULATION AND PREPARATION TECHNIQUES  FOR EMULSIONS:  ADDITIVES FOR FORMULATION OF EMULSIONS

Following additives are needed to formulate a stable emulsion.

1. Emulsifying agents

2. Auxiliary emulsifiers.

3. Antimicrobial preservatives

4. Antioxidants

Kind of Emulsifiers

Only food emulsifiers defined as food additives are usable by law. Those emulsifiers are shown in the table.The following emulsifiers have been used ordinarily:

Kind of Food Emulsifiers      

Name

Common Name

Glycerin Fatty Acid Esters

Monoglyceride (MG)

Acetic Acid Esters of Monoglycerides

Acetylated Monoglyceride (AMG)

Lactic Acid Esters of Monoglycerides

Lactylated Monoglyceride (LMG)

Citric Acid Esters of Monoglycerides

CMG

Succinic Acid Esters of Monoglycerides

SMG

Diacetyl Tartaric Acid Esters of Monoglycerides

DATEM

Polyglycerol Esters of Fatty Acids

PolyGlycerol Ester (PGE)

Polyglycerol Polyricinoleate

PGPR

Sorbitan Esters of Fatty Acids

Sorbitan Ester (SOE)

Propylene Glycol Esters of Fatty Acids

PG Ester (PGME)

Sucrose Esters of Fatty Acids

Sugar Ester (SE)

Calcium Stearoyl Di Laciate

CSL

Lecithin

Lecithin (LC)

Enzyme Digested Lecithin / Enzyme Treated Lecithin

 

 

Glycerine Fatty Acid Esters (Monoglyceride, MG)

 

Glycerin fatty acid ester is made from glycerin and animal and plant oils/fats or their fatty acids. Those are generally produced by Inter-esterification method.

 Glycerin has three hydroxyl groups, one of which is esterified with a fatty acid and the ester is called monoglyceride.

 Di-and tri-glyceride have two and three fatty acid groups esterified at hydroxyl group, respectively.

1

Glycerin fatty acid ester produced by inter-esterification is a mixture of glycerin and these glycerides.

 Since monoglyceride with a strong surface activity is suitable as an emulsifier, mono & di-glyceride is produced by removing the glycerin from the mixture.

2

Furthermore, to enhance functionality, a highly-purified monoglyceride, called Distilled Monoglyceride, is produced by molecular distillation.

Monoglycerides have various characteristics depending on the kind and the content of the fatty acid used as the raw material. They are applied to much different fields; an emulsifier, foaming agent, anti-foaming agent, anti-tack agent, starch-modifying agent and anti-bacterial agent, so you need to select the most appropriate type for respective purposes.

Our representative products are Type P(V), PM, SF, OM, S-200, OL-200, M-150 etc.

 

Acetic Acid Esters of Monoglycerides  (Acetylated monoglyceride, AMG)

 

Acetic acid esters of monoglyceride called Acetylated Monoglyceride is an emulsifier in which acetic acid is bound with monoglyceride. It has little emulsifying activity but there are many characteristics and application fields as follows:

·        Soft acetylated monoglyceride is able to expand by more than 8 times with tension.

·        It is an extremely stable oil of which peroxide value does not increase even when heated at 97.7 °C for 1000 hours.

·        The combination of liquid acetylated monoglyceride and hydrogenated fats can improve the quality of fats, for example, margarine characterized with small temperature changes and wide plasticizing range, can be produced with them.

·        It is a liquid characterized by being less oily even at low temperatures and available as a solvent, lubricant, plasticizer for vinylacetate, etc.

·        Although it has no function as an emulsifier, it is usable for foaming fats and oils by itself or in combination with other emulsifiers because of its stable alpha-crystal structure.

Practically, it is used as powdered foaming agents, solvents, plasticizers for gums and coating agents for food.

Our representative products are G-002 and G-508.

 

Lactic Acid Esters of Monoglycerides (Lactyated monoglyceride, LMG)

 

4Lactic acid esters of monoglyceride is called lactylated monoglyceride in which lactic acid is bound with monoglyceride. Its foaming ability is stronger than its emulsifying ability. It is used in shortening for cakes, desserts and foaming for cream by itself or in combination with monoglyceride.

 

Citric Acid Esters of Monoglycerides (CMG)

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Citric acid esters of monoglyceride is called citrated monoglyceride, in which citric acid is bound with monoglyceride and the obtainable products are mixtures containing a few monoglycerides.

 It is a highly hydrophilic emulsifier and a stable alpha-crystal structure used for margarine, dairy products such as, coffee whitener and cream. Its also used as an emulsion stabilizer for mayonnaise and dressing by utilizing its strong acid-resistance.

Our representative products are K-30 and K-37.

 

Succinic Acid Esters of Monoglycerides (SMG)

 

6Succinic Acid ester of monoglyceride is called succinylated monoglyceride, in which succinic acid is bound with monoglyceride. It is insoluble in cold water, dispersible in hot water, and soluble in hot alcohol, fats and oils.

 Succinylated monoglyceride forms a complex with starch which is able to react with protein. It is used as a dough modifying agent and an emulsifier for shortening.

Our product is B-10.

Diacetyl Tartaric Acid Esters of Monoglycerides (DATEM)

 

7Diacetyl tartaric acid ester of monoglyceride is called DATEM, an emulsifier in which diacetyl tartaric acid is bound with monoglyceride. It is dispersible in cold and hot water, and soluble in fats and oils.

 As it is a hydrophilic emulsifier and acid resistant, it is used for emulsification and foaming of margarine, mayonnaise and dressing. Also, it can act on starch and protein, it is used as a dough modifier.

Our products are W-10 and W-90P

 

 Polyglycerol Esters of Fatty acids(PGE)

8

Polyglycerol esters of fatty acids is called polyglyceryl ester, an emulsifier in which fatty acid is bound by esterification with polyglycerine, and generally it is dispersible in water and soluble in oil.

 Its hydrophilicity and lipophilicity greatly change with the degree of its polymerization and the kind of fatty acid. Its HLB ranges from 3 to 13.

 It has a variety of functions depending on these conditions, and is usable for various purposes. It is used in many types of food as an O/W and W/O emulsifier for milk products containing acid and salt and a modifier to control the crystallization of fats.

Our products are J-2081, J-0081H, J-0381, and J-46B.

 

9Polyglycerol Polyricinoleate (PGPR)

 

Polyglycerol Polyricinoleate is called PGPR a strong lipophilic W/O emulsifier.

 It is a highly-viscous liquid, insoluble in water and ethanol, and soluble in fats and oils. It is used as a viscosity-reducing agent for chocolate.

Our products are PR-100 and PR-300.

 

Sorbitan Esters of Fatty Acids (Sorbitan ester)

 

Sorbitan esters of fatty acid is called sorbitan ester, which is produced by esterification of sorbitol and fatty acid. It is a mixture of sorbitol ester and sorbide ester, which are simultaneously produced as well as sorbitan ester.

 There are many types of sorbitan esters with different kinds of fatty acids and various degrees of esterification. Those are generally used as emulsifier for cream etc. It is applied in limited fields by itself because its special characteristics other than emulsifying capability are few; however, it is widely used as a major emulsifier in combination with other emulsifiers with different functions.

Our products are S-300(B), S-60, O-80, S-65F and B-150.

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Propylene Glycol Esters of Fatty Acids (PG ester)

 

Propylene glycol esters of fatty acids is called PG ester in which propylene glycol and fatty acid, are linked by ester bonding and the product obtained from inter-esterification is a mixture of monoester and diester.

11 To isolate the monoester with surface effects, high purity product of monoester is produced by molecular distillation as well as distilled monoglyceride.

 It has little emulsifying action, but has a tendency to keep its alpha-crystal structure.

Since it is usable as a foaming agent when combined with monoglyceride, it is used as a powder-foaming agent for cakes and desserts, liquid shortening, etc.

Our products are PS-100 and PB-100.

 

Sucrose Esters of Fatty Acids (Sucrose ester)

 

12Sucrose esters of fatty acid is called sucrose ester. It is a complex of sucrose and fatty acid, which has HLB ranging from 1 to 16.

Owing to the wide ranging HLB, it has many different functions. It is used as an emulsifying and dispersing agent for cream and bacteriocidal agents for canned coffee.

 

Calcium Stearoyl-2-Lactate (CSL)

 

13Calcium stearoyl 2 lactate is called CSL. It is a product obtained by bonding 2 lactic acids and stearic acid and partially neutralized with calcium. It is a mixture including unreacted stearic acid and salt.

 It is an anionic emulsifier having a strong ability to bind protein and is used as a dough modifier for flour foods like bread.

 

Lecithin (LC)

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Lecithin is a mixture containing phospholipid as the major component and widely found in animals and plants. It has long been used as a natural emulsifier.

 Lecithin is classified into

·        plant lecithin derived from soybeans, corn, rapeseed, etc.

·        fractionated lecithin isolated from special components of the raw materials

·        yolk lecithin made by excluding the phospholipid, which occupies about 30% of an egg yolk

The products in the market are paste lecithin and powdered lecithin of high purity.

 

Enzyme treated Lecithin  Enzyme digested Lecithin (LC)

 

15Enzyme-digested or enzyme-treated lecithin is improved through strengthening the hydrophilicity by a treatment with phospholipase.

 

Our products are Lecion LP-1 of high purity and Lecimal EL, an enzyme digested lecithin.

 

3. Natural emulsifying agents. :

i. Natural emulsifying agents from vegetable sources

These consist of agents which are carbohydrates and include gums and mucilaginous substances. Since these substances are of variable chemical composition, these exhibit considerable variation in emulsifying properties. They are anionic iature and produce o/w emulsions. They act as primary emulsifying agents as well as secondary emulsifying agents (emulsion stabilizers). Since carbohydrates acts a good medium for the growth of microorganism, therefore emulsions prepared using these emulsifying agents have to be suitable preserved in order to prevent microbial contamination. E.g. tragacanth, acacia, agar, chondrus (Irish Moss), pectin and starch.

Acacia: It is a carbohydrate gum which is soluble over a wide pH range. It can be used as emulsifying agent in the following ratio to prepare primary emulsions:

 

Type of oil

Ratio of oil : gum : water for primary emulsion

Fixed oil

4 : 1: 2

Mineral oil

3 : 1 : 2

Volatile oil

2 : 1 ; 2

Oleo gum resin

1 : 1 : 2

 

Tragacanth, pectin and starch are used as auxiliary emulsifying agents.

ii. Natural emulsifying agents from animal source

The examples include gelatin, egg yolk and wool fat (anhydrous lanolin).

Gelatin :

It is a protein .It has two isoelectric points, depending on the method of preparation. Type a gelatin derived from acid treated precursor, has an isoelectric point between pH 7 and 9. Type B gelatin obtained from an alkaline precursor has an isoelectric point around pH 5. . Type A gelatin acts best as an emulsifier around pH 3 where it is –vely charged: On the other hand type B gelatin suitable as emulsifier at pH 8 where it is –vely charged.

Type A gelatin (Cationic) is generally used for preparing o/w emulsion while type B gelatin is used for o/w emulsions of pH 8 and above.

Lecithin :

It is an emulsifier obtained from both plant (soyabean) and animal (e.g. egg yolk) sources and is composed of phosphatides. Although the   primary component of most lecithins is phosphatidyl choline. but it also contains phosphatidyl serine, phosphatidyl inositol, phosphatdylethanloamine and phosphatidic acid… It imparts a net –ve charge to dispersed particles. They show surface activity and are used for formulating o/w emulsions. Lecithins are good emulsifying agents for naturally occurring oils such as soy, corn, or safflower. Purified lecithin from soy or egg yolk is used for i/v emulsions.

cholesterol :

It is a major constituent of wool alcohols, obtained by the saponification and fractionation of wool fat. It forms w/o emulsion. It is because of cholesterol that wool fat absorbs water and form a w/o emulsion It is also present in egg yolk.

Wool fat

It is mainly used in w/o emulsions meant for external use. They absorb large quantities of water and form stable w/o emulsions with other oils and fats.

3.     Finely dispersed solids :

They form particulate films around the dispersed droplets, producing emulsions which are coarse grained but stable. Colloidal clays like bentonite, veegum are the examples of finely divided solids used as emulsifying agents.

Bentonite: It is a gray, odorless and tasteless powder which swells in the presence of water to form a suspension with a pH of about 9. Depend on the order of mixing, both o/w or w/o emulsion can be formed with bentonite. For o/w emulsion, bentonite is first dispersed in water and allowed to hydrate to form magma. Then oil phase is gradually added with constant agitation. To prepare w/o emulsion, bentonite is first dispersed in oil and then water is added gradually.

Veegum: Used as stabilizer in concentration of 1% for  cosmetic lotions and creams.  Prepared with anionic or non ionic emulsifying agents.

Properties of Emulsifiers

An emulsifier consists of water soluble hydrophilic parts and water-insoluble, oil-soluble lipophilic parts within its.

15b014

16b016When an emulsifier is added to a mixture of water and oil, the emulsifier is arranged on the interface, anchoring its hydrophilic part into water and its lipophilic part into oil.

On the interface surface of water and air and of oil and air, the hydrophilic part and the lipophilic part are adsorbed and arranged around the interface. The interfacial tension is reduced by the emulsifier.

 That is, the force to separate the oil and water is thus weakened, resulting in the easily mixing of oil and water.

HLB

The hydrophilicity and lipophilicity are different among emulsifiers, and the balance between the two is called HLB value. The value ranges from 0 to 20.

 An emulsifier with higher lipophilicity shows a lower HLB whereas higher hydrophilicity has high HLB, and the behaviors and functions to water depend on this HLB.

q1

 

 

wataer_oilAll compounds that have hydrophilic parts and lipophilic parts are not always useable as an emulsifier. when hydrophilicity is too great, such compounds disperse into water and the ones with great lipophilicity would disperse into oil.

 

When the hydrophilicity and lipophilicity are well-balanced, the emulsifier exhibits sufficient effects.

 

q2

 

Micelle

 

 Because an emulsifier has opposite properties; hydrophilic and lipophilic, its solution does not become a simple aqueous solution but a colloidal solution, of which properties greatly vary depending on its concentration.

 In an extremely-diluted solution, there is no special change, but the emulsifier gathers on the interface and the surface tension is reduced as an increase of its concentration.

 As further increase of the concentration, a uniform mono molecular layer is made on the surface and the surface tension drops to the minimum.

 

23cmc A further increase of the concentration causes micelle formation, micelles formation occurs when the excess molecules, in which the lipophilic groups are positioned face to face gather and there is no change in the surface tension.

 

24cmc2The concentration to start micelle formation is called critical micelle concentration (cmc) and the properties of the solution change greatly with a change of this concentration.

 

similar changes appears on the interface of oil and water , when the interfacial tension reaches the cmc point.

 

25type When the concentration exceeds cmc, spherical micelles appear at first and disperse into water.

 A further increase in the concentration causes rod-shape micelles.

 Finally, lamellar micelles with higher structures called liquid crystal are produced.

 

Solubilization

26solbilWhen a small amount of insoluble substance is incorporated in an emulsifier micelle, semi-transparent solution is produced. This phenomenon is called solubilization.

 

Solid monoglyceride has a large capacity of crystallization which affects its performance. It also makes a liquid crystal which has intermediate characteristics between solid crystal and liquid. The form varies with the kind of emulsifier, temperature and its concentration.

27crystal

In practical use, it is-necessary to select a suitable emulsifier with consideration to conditions, including temperature and food constituents.

 The point is how emulsifier binds with water and disperses in it, but it is difficult to predict the results based on an equation.

 In actual use, to predict the results based on the empirical rule is most desirable as well as information on the emulsifier.

 

2. Auxiliary emulsifying agents:

These are those compounds which normally caot form an emulsion on their own but can function as thickening agents and stabilize the emulsion. Sometimes they increase the viscosity of the external phase and help restricting the collisions of droplets… Some of them prevent coalescence by reducing van de waals forces between particles or by providing a physical barrier between droplets. Proteins, semi synthetic polysaccharides ( methyl cellulose, carboxy methyl cellulose), clays can be used as auxiliary agents.

 

3. Antimicrobial agents:

Emulsions often contain a number of ingredients such as carbohydrates, proteins, sterols and phosphatides, all of which readily support the growth of a variety of microorganisms. Even in the absence of any of the above mentioned ingredients, the mere presence of a mixture of lipid and water in intimate contact frequently allows microorganisms growth. So preservative is a must for emulsions.

Microbial contamination may occur due to:

i.                   contamination during development or production of emulsion or during its use.

ii.                 Usage of impure raw materials

iii.              Poor sanitation conditions

iv.              Invasion by an opportunistic microorganisms.

v.                 Contamination by the consumer during use of the product…

Precautions to prevent microbial growth;

i.                   Use of uncontaminated raw materials

ii.                 Careful cleaning of equipment with live stream.

Preservation:

Once a microbiologically uncontaminated product has been formed, a relatively mild antimicrobial agent is sufficient to protect the product against microbial contamination. The preservative system must be effective against invasion by a variety of pathogenic organisms and protect the product during use by consumer.

The preservative must be:

a.     Less toxic

b.     Stable to heat and storage

c.      Chemically compatible

d.     Reasonable cost

e.      Acceptable taste, odor and color.

f.       Effective against fungus, yeast, bacteria.

g.     Available in oil and aqueous phase at effective level concentration.

 

 

Examples of preservatives:

Type

Example

Characteristics and utility

Acids and acid derivatives

Benzoic acid

Antifungal agent

Alcohols

Chlorobutanol

Eye preparations

Aldehydes

Formaldehyde

Broad spectrum

Phenolics

Phenol

Broad spectrum

 

Cresol

 

 

Methyl p-hydroxy benzoate

 

 

Propyl p-hydroxy benzoate

 

Quaternaries

Chlorhexidine and salts

Broad spectrum

 

Benzalkonium chloride

 

 

Cetyl trimethyl ammonium bromide

 

Mercurials

Phenyl mercuric acetate

Broad spectrum

 

 

4. Antioxidants:

Many organic compounds are subject to autoxidation upon exposure to air. And emulsified lipids are particularly sensitive to attack. Many drugs commonly incorporated into emulsions are subject to autoxidation and resulting decomposition.

Upon autoxidation, unsaturated oils, such as vegetable oils, give rise to rancidity with resultant unpleasant odor , appearance, and taste. On the other hand mineral oil and related saturated hydrocarbons are subject to oxidative degradation only under rare circumstances.

Autoxidation is a free. radical chain oxidation . It can be inhibited, by the absence of oxygen, by a free radical chain breaker or by a reducing agent.

Examples of antioxidants

 

Antioxidant

use

 

Gallic acid

 

 

Propyl gallate

pharmaceuticals and cosmetics

Bitter taste

Ascorbic acid

 

 

Sulphites

 

 

L-tocopherol

pharmaceuticals and cosmetics

Suitable for oral preparations e.g. those containing vit A

Butylated hydroxyl toluene

pharmaceuticals and cosmetics

Pronounced odor, to be used at low conc.

Butylated hydroxylanisol

pharmaceuticals and cosmetics

 

 

 

 

 

 

 

 

.

CHEMICAL PARAMETERS FOR FORMATION OF EMULSION ( CHEMICAL FACTORS AFFECTING FORMULATION OF EMULSION) (SELECTION OF ADDITIVES FOR AN EMULSION):

The formulator must determine the physical and chemical characteristics of the drug, which includes the structural formula, melting point, solubility in different media, stability, dose and specific chemical incompatibilities. Then the required emulsifying agent(s) along with other additives and its (their) concentration(s) should be identified. The choice of materials to be used largely depends on the purpose for which the emulsion is to be used. While selecting the additives the chemical stability and safety must be kept in mind:

 

Chemical stability:

Chemical inertness of all the ingredients is very important. Soap caot be used as emulsifiers in a system having a pH of less than 5. Some lipids may undergo chemical changes due to oxidation (rancidity), Sometimes the hydrolytic changes may take place more easily due to micellar catalysis. This type of catalysis is observed when the reactive species is present on or near the micellar surface. E.g. hydrolysis of alkyl sulphates

 

Safety :

The formulator should be sure about the toxicological clearance of the components used in emulsion.

Lipid Phase:

Selection of lipid phase:

For pharmaceutical and cosmetic products, the oil phase, unless it is laxative ingredient, may include a wide variety of lipids of natural or synthetic origin. A drug in an emulsion type of dosage form distributes itself between the oil phase and the aqueous phase in accordance with its oil / water partition coefficient. In principle, the less soluble active ingredient is in the nonvolatile portion of the vehicle, the more readily it penetrates into and through a barrier. On the other hand some solubility of the active ingredient in the vehicle is necessary to ensure its presence in a fine state of subdivision. The release of medicinal agent from a dosage form is a function of the solubilities of the agent in the base and in the body membrane.  The Drug must not be so soluble in the base that it prevents penetration or transfer.

A final consideration in the selection of a lipid component for a topical preparation is its “feel”. Emulsions normally leave a residue of the oily phase on the skin after the water has evaporated. Also tactile characteristics of the combined oil phase are of great importance in determining consumer acceptance of an emulsion.

 

Phase ratio:

The ratio of the internal phase to the external phase is determined by

i.                   The solubility of the active ingredient which must be present at a pharmacologically effective level.

ii.                 Desired consistency: Low level of consistency results from less % of internal phase. It is generally difficult to formulate emulsions containing less than 25% of internal phase due to their susceptibility to creaming or sedimentation problems. However, a combination of proper emulsifying agents and suitable processing technology makes it possible to prepare emulsions with only 10 % dispersed phase. Similarly products containing more than 70% dispersed phase may exhibit phase inversion.

Selection of emulsifying agent :

Criteria For The Selection Of Emulsifying Agents

An ideal emulsifying agent should posses the following characteristics:

1.     It should be able to reduce the interfacial tension between the two immiscible liquids.

2.     It should be physically and chemically stable, inert and compatible with the other ingredients of the formulation.

3.     It should be completely non irritant and non toxic in the concentrations used.

4.     It should be organoleptically inert i.e. should not impart any colour, odour or taste to the preparation.

5.     It should be able to form a coherent film around the globules of the dispersed phase and should prevent the coalescence of the droplets of the dispersed phase.

6.     It should be able to produce and maintain the required viscosity of the preparation.

Choice of emulsifying agent

 Choice of emulsifying agent depends upon

i. Shelf life of the product

ii. Type of emulsion desired

iii.              Cost of emulsifier.

iv.              Compatibility

v.                 Non toxicity

vi.              Taste

vii.            Chemical stability.

An emulsifying agent suitable for a skin cream may not be acceptable for oral preparation or i/v preparation due to its toxicity

HLB method for section of emulsifying agent:

The selection of surfactant to be used as emulsifying agent can be done by Griffin’s method. It is based on balance between hydrophilic and lipophilic portion of the emulsifying agent.

Griffin developed the system of Hydrophilic lipophilic balance (HLB) of surfactants. The HLB value of the emulsifier can be found from the literature or determined experimentally or can be computed if the structural formula of the  surfactant is known. It is defined as the mol % of hydrophilic group divided by 5. A completely hydrophilic molecule (without any non polar group has an HLB value of 20. The molecules that are water soluble have high HLB value; those which are oil soluble have low HLB value. Each surfactant is given a value between 0-18. It is used in the rational selection of combination of nonionic emulsifiers. If an o/w emulsion is required, formulator should choose an emulsifier with an HLB value in the range of 8-18. Emulsifier in the range of 4-6 can be used for w/o emulsions. Griffin also evolved a series of “required HLB values” by a particular material if it is to be emulsified in the form of o/w or w/o emulsion. The required HLB values for a particular oil will differ depending upon whether o/w or w/o emulsion is required.

Fundamental to the utility of the HLB value concept is the fact that the HLB values are algebraically additive. Thus calculations can be done to find the correct ratio of combination of low HLB value and high HLB value surfactant for particular oil for a particular type of emulsion.

Example:

Liquid paraffin (Required HLB 10.5)   15 gms

Emulsifying agents :                                 5 gms

(A) Sorbitan monooleate (HLB 4.3)

(B) Polyoxyethylene 20 sorbitan mono oleate ( HLB 15.0)

Water

By allegation method, it can be found that (A) and (B) should be mixed in the ratio of 4.5 and 6.2 to get the required 10.5 HLB value. Because the formula calls for 5 gm of emulsifying agent, the required weights are 2.1 and 2.9 gms. Respectively. 

 

The formulator can chose a single emulsifying agent which can yield HLB value of 10.5. But more often in case of o/w emulsions, stable emulsion can be produced by utilsing a combination of a hydrophilic and hydrophobic surfactant. Such combination appears to produce mixed interfacial phases of high surface coverage as well as of sufficient viscosity to prevent creaming and promote stability. HLB values of combination may be determined by taking weighted average of the individual surfactant HLB values.  Many combinations can be tried to choose the best emulsifying agent.

If the HLB value of oil is not known, it becomes necessary to determine the parameter. Various blends are prepared to give a wide range of HLB mixture and emulsions are prepared in a standard manner. The HLB of the blend used to give the best product is taken to be the HLB of oil.

 

Selection of preservative:

The concentration of preservative to be used depends upon its ability to react with microorganisms. It is preferred to use combination of preservatives so the depending upon the preservative is available in both oil and water phase. Combination of methyl p-hydroxy benzoate (water soluble) and propyl –p-hydroxy benzoate (oil soluble)

If there is interaction between the emulsion ingredients and the preservative, extra preservative must be added to compensate for the loss due to interaction. pH also plays a role on the ability of acidic or phenolic preservatives. Other factors include the phase ratio, degree of aeration during preparation presence of flavors and perfumes, some of which have antimicrobial activity.

 

 

Selection of antioxidant:

The choice of antioxidant depends upon its safety, acceptability for a particular use and is efficacy. Antioxidants are normally used at conc. ranging from 0.001 to 0.1%. Almost all antioxidants are subject to discoloration in the presence of light, trace metals and alkaline solutions. Combination of two or more antioxidants have been shown to produce synergistic effects.

Selection of viscosity imparting agents:

Once the emulsifying agent is selected, a consistency that provided the desired stability and yet has the appropriate flow characteristics must be attained. Viscosity of emulsion can be altered by manipulating the composition of the liquid phase, by variations in the phase ratio and the surfactants and by addition of gums. Creaming of emulsions depends on their rheological character as well as on the surface characteristics of the interfacial film. The use of gums, clays and synthetic polymers in the continuous phase of emulsions is a powerful tool for enhancing an emulsion‘s stability. As per Stoke’s law, increase in viscosity minimizes creaming. Since emulsions should flow or spread and since higher viscosity favors stability, thixotropy in an emulsion is desirable.

A newly formed emulsion should be allowed to rest undisturbed for 24 -48 hrs to build up viscosity.

METHODS OF EMULSION PREPARATION (DESIGN OF EMULSIFICTION PROCESS) (EMULSIFICATION TECHNIQUES :

To prepare an emulsion, first the internal phase has to be broken up into droplets and they have to be stabilized. These two steps must be carried out before the internal phase can coalesce.  The break up of internal phase is rapid (by physical means) but the stabilization and the rate of coalescence are time and temperature dependent.

So in designing the emulsification process it is important to select physical and chemical parameters which favor emulsion formation

 

. Several methods are generally available to the pharmacist. Each method requires that energy be put into the system in some form. The energy is supplied in a variety of ways: triturating, homogenization, agitation, and heat.

Physical parameters affecting the stability of emulsion:

Location of the emulsifier, method of incorporation of the phases, the rates of addition , the temperature of each phase and the rate of cooling after mixing of the phases considerably affect the droplet size distribution , viscosity, and stability of emulsion.

Preparation Techniques:

The preparation techniques for emulsion can be divided into laboratory scale productions and large-scale productions.

LABORATORY SCALE TECHNIQUES (EXTEMPORANEOUS METHOD OF PREPARATION OF EMULSIONS} :

Emulsification process can be carried out by four methods: 

ü    Addition of internal phase to the external phase, while subjecting the system to shear or fracture.

ü    Phase inversion technique: The external phase is added to the internal phase. E.g. if o/w emulsion is to be prepared, the aqueous phase is added to the oily phase. . First w/o emulsion is formed. At the inversion point the addition of more water results in the inversion of the emulsion system and formation of an o/w emulsion. This phase inversion technique allows the formation of small droplets with minimal mechanical action and heat. A classical example is the dry gum method

ü    Mixing both phases after warming each: This method is used for creams and ointments.

ü    Alternate addition of two phases to the emulsifying agent: In this method, the water and oil are added alternatively, in small portions to the emulsifier. This technique is suitable for food emulsions.

Techniques used on laboratory scale

·                                Continental or dry gum method

·                                Wet gum method

·                                Bottle or Forbes bottle method

·                                Auxiliary method

·                                In situ soap method

Dry gum method (Continental method)

         The continental method is used to prepare the initial or primary emulsion from oil, water and a hydrocolloid or “gum” type emulsifier (usually acacia). The primary emulsion or emulsioucleus is formed from 4 parts of oil, 2 parts of water and one part of gum. The 4 parts of oil and 1 part of gum represent their total amount for the final emulsion.

         In a mortar the 1 part of gum (acacia) is levigate with 4 parts of oil until the powder is thoroughly wetted; then the 2 parts water is added all at once and the mixture is vigorously and continuously triturated until the primary emulsion formed is creamy white.

         Additional water or aqueous solutions may be incorporated after the primary emulsion is formed. Slid substances (e.g. active ingredients, preservatives, color, flavors) are generally dissolved and added as a solution to the primary emulsion, oil soluble substances in small amounts may be incorporated directly into the primary emulsion. Any substance which might reduce the physical stability of the emulsion, such as alcohol (which may precipitate the gum) should be added as near to the end of the process as possible to avoid breaking the emulsion. When all agents have been incorporated, the emulsion should be transferred to a calibrated vessel, brought to final volume with water, then homogenized or blended to ensure uniform distribution of ingredients.

Example

Cod liver oil 50 ml

Acacia         12.5 gm

Syrup       10 ml

Flavor oil       0.4 ml

Purified oil    up to 100 ml

         1. Accurately weigh or measure each ingredient

         Place cod liver oil in dry mortar

         Add acacia and give it a very quick mix.

         Add 25 ml of water and immediately triturate to form thick white, homogenous primary emulsion.

         Add flavor and mix.

         Add syrup and mix.

         Add sufficient water to total 100 ml.

Wet gum method:

In this method the proportion of oil and water and emulsifier (gum) are the same ( 4:2:1) , but the order and technique of mixing are different. The 1 part of gum is triturated with 2 parts of water to form a mucilage; then 4 parts of oil is slowly added in portions, while triturating. After all the oil is added, the mixture is triturated for several minutes to form the primary emulsion. Then other ingredients are added as in continental method. Generally speaking, the English method is more difficult to perform successfully, especially with more viscous oils, but may result in a more stable emulsion.

Bottle method:

This method may be used to prepare emulsions of volatile oils, or oligeneous substances of vary low viscosities. This method is a variation of dry gum method. One part of powdered acacia (or other gum) is placed in a dry bottle and 4 parts of oil are added, the bottle is capped and thoroughly shaken. To this the required volume of water is added all at once and the mixture is shaken thoroughly until the primary emulsion is formed. It is important to minimize the initial amount of time the gum and oil are mixed. The gum will tend to imbibe the oil and will become water proof.

 

Auxiliary method:

An emulsion prepared by other methods can also be improved by passing it through a hand homogenizer, which forces the emulsion through a very small orifice, reducing the dispersed droplet size toabout5 microns or less

In sito soap method:

Calcium Soaps: w/o emulsions contain oils such as oleic acid, in combination with lime water (calcium hydroxide solution, USP). Prepared by mixing equal volumes of oil and lime water

Example:

Nascent soap: Oil Phase: Olive oil / oleic acid; olive oil may be replaces by other oils but oleic acid must be added.

         Lime water: Ca (OH)2 should be freshly prepared.

         The emulsion formed is w/o

         Method of preparation : Bottle method

         Mortar method: When the formulation contains solid insoluble such as zinc oxide and calamine.

 

Large scale production: Commercially, emulsions are prepared in large volume mixing tanks and refined and stabilized by passage through a colloid mill or homogenizer.

The internal phase can be reduced to small droplets by application of energy in the form of heat, mechanical agitation, ultrasonic vibration or electricity.

Application of energy:

Energy may be supplied in the form of heat, homogenization or agitation

Heat:

Emulsification by Vaporization (Condensation method):

Vaporization is an effective way of breaking almost all bonds between molecules of a liquid, so emulsions may be prepared by passing vapor of a liquid into an external phase that contains suitable emulsifying agent. This process is called condensation method.

Disadvantages:

– Slow

– can be used for preparing dilute emulsions of materials having a relatively low vapor pressure.

Emulsification by Change in temperature (Phase inversion technique):

Change in temperature can be used as an effective way of making emulsion by phase inversion technique. In this method first the emulsion is prepared at a higher temperature. On cooling phase inversion takes place and a stable inversion with finely divided internal phase is produced.

Change in temperature due to cooling brings about phase inversion. The temperature at which phase inversion takes place is called phase inversion temperature (PIT). PIT is generally considered to be the temperature at which the hydrophilic and the lipophilic properties of the emulsifier are in balance and is therefore also called the HLB temp. PIT depends upon emulsifier concentration.

An o/w emulsion stabilized by a nonionic surfactant (e.g. polyoxyethlene – derived surfactant), contains micelles of the surfactant as well as emulsified oil. When temperature is raised, the water solubility of the surfactant decreases; as a result the micelle are broken and the size of emulsified oil droplets begins to increase. A continued rise in temperature causes separation into oil phase, a surfactant and water. It is near this temperature that now water insoluble surfactant begins to form a w/o emulsion containing both water –swollen micelle and emulsified water droplets in a continuous oil phase.

Low energy emulsification :

The emulsification by change in temp. requires considerable expenditure of energy during both heating and cooling cycles of emulsion formation. In low energy emulsification, all of the internal phase, but only a portion of the external phase is heated. After emulsification of the heated portions, the remainder of the external phase is added to the emulsion concentrate, or the preformed concentrate is blended into the continuous phase. In those emulsions in which a phase inversion temp. exists, the emulsion concentrate is preferably prepared above PIT which results in emulsion having extremely small droplets size. Good emulsions can be prepared by this method careful control of variables like emulsification temp. Mixing time, mixing intensity, amount of external phase employed during emulsification and the method of blending 

Mechanical equipment for emulsification (Agitation) 

Some sort of Agitation is needed to break internal phase into droplets. To break up the internal phase into droplets the liquid jet at high speed through a small diameter nozzle may be introduced into a second liquid or liquid may flow into a second liquid which is being agitated vigorously.

Once the initial break up into droplets gas occurred, the droplets continue to be subjected to additional forces due to turbulence, which causes further breakdown into smaller droplets.

The amount work depends on the length of time during which energy is supplied; thus timing becomes another physical parameter.

Timing:

During the initial period of agitation required for emulsification, droplets are formed. However as agitation continues, the chance for collision between droplets becomes more frequent and coalescence occurs. It is advisable, therefore to avoid excessive period of agitation during and after the formation of emulsion. The optimum time of agitation has to be determined empirically.

The best way of forming emulsion by shaking is to use intermittent shaking. The reason for time dependent droplet stabilization may be distribution of the emulsifier between the phases, slow formation of the film on the surface of the droplets or interruption of droplet formation by continuous shaking.

Timing also affects the speed with which the two immiscible liquids are blended. In the case of o/w emulsions, the rate at which the oil phase is added to the aqueous phase can affect the particle size and hence the stability of emulsion.

There is also a relationship between temp. and timing i.e. the cooling / heating cycle. It is common to prepare emulsions at high temp. . The cooling rate of the initially formed emulsion also has a profound influence on the ultimate characteristics of the emulsion.

Various types of equipment are available to bring about droplet break up and emulsification either in laboratory or in production. Such equipment can be divided into four categories:

1.     Mechanical stirrers, 2. Homogenizes 3. Ultrasonifiers 4. Colloid mills

The most important factor involved in the preparation of emulsion is the degree of shear and turbulence required to produce a given dispersion of liquid droplets. The amount of agitation required depends on total volume the liquid to be mixed, the viscosity of the system, and the interfacial tension at the oil water interface.

 

 

 

Mechanical stirrers:

An emulsion may be stirred by means of various impellers mounted on shafts, which are placed directly into the system to be emulsified. Impellers may be of following types:

      Propeller type mixers: Simple top entering propeller mixers are adequate for routine development work in the laboratory and production if the viscosity of the 

The degree of agitation is controlled by propeller rotation but the pattern of liquid flow and resultant efficiency of mixing are controlled by the type of impeller, its position in the container, the presence of baffles, and the general shape of the container. These stirrers caot be used when:

a.                       vigorous agitation is needed,

b.                       Extremely small droplets are needed.

b.    Foaming at high shear rates must be avoided.

These mixers may have paddle blades, counter rotating blades or planetary blades.

       Turbine type mixers: If more vigorous agitation is required or viscosity is more, turbine type mixers can be used.

      .

Homogenizers:

In homogenizers the dispersion of two liquids is achieved by forcing their mixture through a small inlet orifice at big pressures.

A homogenizer consists of a pump that raises the pressure of the dispersion to a range of 500 to 5000 psi and an orifice through which the fluid impinges upon the cognizing valve held in place on the valve seat by a strong spring. As the pressure builds up, the spring is compressed and some of the dispersion escapes between the valve and valve seat. At this point, the energy that has been stored in the liquid as pressure is released instantaneously, and subjects the product to intense turbulence and hydraulic shear.

Homogenizers can be made with more than one emulsifying stage, and it is possible to recycle the emulsion through the homogenizer more than one time.

Homogenizers raise the temp. of the emulsion, hence cooling may be  required.

It can be used when a reasonably monodisperse emulsion of small droplet size ( 1 nm) is required.

Colloid mills :

They operate on principle of high shear which is normally generated between rotar and stator of the mill. Colloid mill consists of a fixed stator plate and a high speed rotating rotator plate. Material drawn or pumped through an adjustable gap set between the rotor and stator is homgenised by the physical action and his centrifugal force is created by high rotation of the rotor which operates within 0.005 to0.010 inch of the stator.

Ultrasonifiers:

Ultrasonic energy s used to produce pharmaceutical emulsions.

These transduced piezoelectric devices have limited output and are expensive.

They are useful for laboratory preparation of emulsions of  moderate viscosity and extremely low particle size.

Commercial equipment is based on principle of Pohlmn liquid whistle. The dispersion is forced through an orifice at modest pressure and is allowed to impinge on a blade. The pressure range is from 150-350 psi. This pressure causes blade to vibrate rapidly to produce an ultrasonic note. When the system reaches a steady state, a cavitational field is generated at the leading edge of the blade and the pressure fluctuations of approx 60 tonnes psi can be achieved in commercial equipment.

 

 

Chemical parameters : ( Selection of ingredients for emulsions, Formualtion of emulsions) ( Discussed earlier)

EXAMPLE : ORAL EMULSION

 A. Cotton seed oil ( 460 gms)

     Sulfadiazine 200 gms

     Sorbitan monostearate     84 gms.

 

B. Poly oxyethylene (20) sorbitan   monostearate   36 gms

    Sodium benzoate                                                  2.0 gms

    Sweetener                                                              q.s

    Water                                                               1000gms

C. Flavor oil                                                         q.s.

 

Procedure : 

1.     heat (A) to 50 o C and pass through colloidal mill

2.     Add (A) at 50 o c to (B) at 65 o (C) and stir while colloning to 45o (C)

3.     Add ( C ) and continue to stir until room temp. is reached.

Discussion :

i.       Viscosity of the final product must be high in order to keep sulphadiazine in suspension. (Sulfadiazine is water insoluble compound.)  This could be achieved by increasing the internal phase.

ii.           Internal phase: As the product is meant for oral use, Cotton seed oil is used as internal phase to prepare o/w emulsion.

iii.        Type of emulsion: O/w emulsion is preferred as it has better taste.

iv.        Emulsifying agent :

HLB of 10 is needed to prepare o/w cotton seed oil emulsion. A combination of two emulsifying agent ( sorbitan monostearate and polyoxythylene (20) sorbitan mono stearate is used to get a net value of HLB 10. Combination is preferred as it gives a better interfacial film around globules.

Ratio required to get required HLB of 10 = a x 4.7 +b x 14.9 ,

a and b are the weight fractions of each of the two emulsifiers.

a + b = 1.

iv. Procedure:

The blend of oil, drug and lipophilic emulsifier is warmed and passed through a colloidal mill to reduce the particle size of sulphadiazine.

 The emulsion is formed by adding the drug suspension to the aqueous phase Mixing of two phases is done at low temperature in order to avoid settling of sulphadiazine. Heating the drug suspension to 65 o C reduces the viscosity and causes excessive settling of drug particles.

Addition of flavoring oil at low temp. prevents its loss by volatility

EMULSION STABILITY ( INSTABILITY)

Physical stability:

The term emulsion stability refers to the ability of an emulsion to resist changes in the properties over time. , the more stable the emulsion, the more slowly its properties change.

Stability (Instability) of the emulsion is related to four major phenomenons:

i.      Flocculation 

ii.       Creaming or sedimentation

iii.      Aggregation or coalescence

iv.       Phase inversion

h.    Flocculation :

Flocculation is defined as the association of particle within an emulsion to form large aggregates. However these aggregates can easily be redispersed upon shaking. It is considered as a precursor to the irreversible coalescence. It differs from coalescence mainly in that interfacial film and individual droplets remain intact.  Flocculation is influenced by the charges on the surface of the emulsified globules. The reversibility of flocculation depends upon strength of interaction between particles as determined by

a the chemical nature of emulsifier,

b the phase volume ratio,

c. the concentration of dissolved substances, especially electrolytes and ionic emulsifiers.

i. Creaming and sedimentation :

The upward or down ward movement of dispersed droplets is termed creaming or sedimentation respectively. In any emulsion, creaming or sedimentation takes place depending on the densities of disperse and continuous phases. Creaming or sedimentation is undesirable as it may lead to coalescence.

 

Factors affecting rate of creaming:

Rate of creaming is governed by Stoke’s law. As per Stoke’s law 

 

=2r 21ρ2 ) g  / 9η

 

υ = rate of creaming or sedimentation

r = radius of droplets of dispersed phase

ρ1 , ρ2 = density of dispersed and continuous phase respectively

g  = gravitational rate constant

η = viscosity of continuous phase.

 

 

Droplet size:

As per Stoke’s law, rate of creaming is directly proportional to the square of radius or diameter of the droplet size. Smaller is the diameter of the droplet, lesser  will be the rate of creaming. So reduction in droplet size helps in reducing creaming or sedimentation.

Difference in densities of dispersed and continuous phase:

As per Stoke’s law no creaming is possible if densities of the two phases are equal. So Creaming can be avoided by adjusting the density of dispersed phase.

Viscosity of the continuous phase:

As per Stoke’s law, rate of creaming is inversely proportional to viscosity of the continuous phase. So increase in viscosity of the continuous phase by adding thickening agents can reduce the rate of creaming.

Factor affecting viscosity of Viscosity:

1.           Viscosity of continuous phase: Is directly proportional to the viscosity of continuous phase. .Clays and gums increase the viscosity of continuous phase. For w/o emulsions addition of polyvalent metal soaps or use of high melting waxes and resins in the oil phase can be used to increase the viscosity.

2.           Volume of internal phase: Depends upon the volume of internal phase. More the volume of internal phase greater is the viscosity.

3.           Particle size of dispersed phase: On the particle size of dispersed phase Smaller the globule size, more will be the viscosity. That is why emulsion stability can be improved by reduction in globule size.

 

iii.Coalescence (Cracking):

 It is the process in which the emulsified particles join to form larger particles. The major factor which prevents coalescence is the mechanical strength of electrical barrier. That is why natural gums and proteins are so useful as auxiliary emulsifiers when used at low level , but can even be used a primary emulsifiers at high concentration.

Reasons for (Coalescence) cracking:

i.                   Globule size: If globule size is big, (more than 1-3 µm), emulsion may first cream and then crack. A homogenizer can reduce the size of globules.

ii.                 Storage Temperature: Extremes of temperature can lead to cracking. When water freezes, it expands, so undue pressure is expected on dispersed globules and the emulsifying film. which may lead to cracking. On the other hand, increase in temperature decreases the viscosity of the continuous phase and disrupts the integrity of interfacial film. An increasing number of collisions between droplets will also occur, leading to increased creaming and cracking.

iii.              Changes which affect the interfacial film: These may be physical, chemical or biological effects.

a.     Addition of a common solvent.

b.     Microbial contamination may destroy the emulsifying agent.

c.      Addition of an emulsifying agent of opposite nature for example cationic to anionic.

iv.              Incorporation of excess disperse phase : Increasing the quantity of continuous phase will increase the concentration of globules and lead to their

Chemical instability (Stability)

This may be due to

Oxidation

Hydrolysis

Microbial growth.

 

EVALUATION OF EMULSION STABILITY

The primary objective of studying stability emulsion is to predict its shelf life under normal storage conditions. The final evaluation of the product for its shelf life must be done in the container in which it is packed because:

i.            The ingredients may interact with the container,

ii.            Some material may leach out from the container

iii.            Loss of water and volatile ingredients may occur through the container or closures.

The problem of stability assessment under normal conditions is that they last long periods of time. To shorten the time many types of stress tests conditions are used to provide a basis for prediction of the stability of an emulsion. These can provide valuable information but one must be aware of the risk that changes occurring under stress conditions may not necessarily take place under normal storage conditions. Stress conditions normally employed for stability studies are (a) Time stress, (b) thermal stress, and (c) Centrifugation:

 

Thermal stress:

The instability of emulsion at higher temperature may include phenomenon such as 

a.           temperature dependent solubility,

b.            degradation reactions occurring only at higher temperature

c.             temperature induced phase changes and altered rheological behavior

d.           structural deformation and reformation

It is considered reasonable to use the time for destabilization at 40o C multiplied by 4 to give an estimate of shelf life at room temperature.

1. Aging and temperature:

In this method the sample of emulsion is stored at various temperatures and parameters like viscosity, %ge of phase separation, particle size, zeta potential, rheolgical parameters, electrical conductivity are monitored. The normal effect of aging an emulsion at elevated temp. is acceleration of the rate of coalescence or creaming. and this is usually coupled with changes in viscosity.

There are many ways of running such aging tests: The two most common procedures are:

i.       To age one sample of the emulsion at different temperatures; for instance 4oC, room temp. 35o C, 43oC, for 2, 4, and 6 weeks.

ii.                 Freeze – thaw cycle test:  To age the same sample and cycle the temperature many times between two extreme values: Such a test is completed after 4-5 days.

A correlation can be established between the two tests. Then the cycling test allows the prediction of stability of the tested emulsion and saves a lot of time.

2.                       Phase inversion temperature : 

It is the temperature at which the emulsion inverts. This method is useful for assessing stability of o/w emulsions.

Basic principle: The HLB of nonionic emulsifier changes with temperature. The higher the temperature, the lower the HLB. In case of ethoxylated nonionics, this decrease of HLB is explained by dehydration of ethoxylate with increase in temperature.

Experimental:

i. Weigh 200 g of emulsion in a beaker. Adjust heating rate 1o C / min

ii. Adjust stirring speed to get a vortex 1 cm deep.

iii. Record the temp. When vortex disappears.

Conclusion:

It has been found that PIT is inversely proportional to the rate of droplet coalescence

So if PIT is more, rate of coalescence will be less. So the emulsions must have a PIT as high as possible as – always higher than the storage temp.

 

ii. Gravitational stress (Centrifugation):

The shelf life can be predicted rapidly by observing the separation of dispersed phase due to creaming or coalescence when emulsion is exposed to centrifugation. Stoke’s law shows that creaming is a function of gravity, so increase in gravity accelerates separation. It has been found that centrifugation at 3750 rpm in a 10 cm radius centrifuge for a period of 5 hrs is equivalent to the effect of gravity for about one year. Gravitational stress such as centrifugation may allow phase separation to occur quickly.

Ultracentrifugation at high speed (25000 r.p.m.) or more can be expected to cause effects that are not observed during normal aging of an emulsion. It creates three layers – a top layer of coagulated oil, an intermediate layer of uncoagulated emulsion and pure aqueous layer. Rapid formation of a clear oily layer is the first clue to abnormal phenomenon taking place during ultracentrifugation.

 

iii. Agitation;

Simple mechanical agitation can contribute to the energy with which two droplets impinge upon each other. Agitation can bring about coalescing of globules and then breaking of emulsion. (Preparation of butter from milk). Conventional emulsions may deteriorate from gentle rocking on a reciprocating shaker. This is related to impingement of droplets and in part to reduction of viscosity of a normal thixotropic system.

 

PARAMETERS FOR ASSESSING THE EMULSION STABILITY:

Physical parameters:

The most useful parameters commonly measured to assess the effect of stress conditions on emulsions include:

1.     phase separation

2.     Viscosity

3.     Electrophoretic properties

4.     Particle size number analysis

 

1.     Phase Separation : 

The rate and extent of phase separation after aging of an emulsion may be observed visually or by measuring the volume of separated phase. The separated phase may be due to coalescence or due to creaming.

It is important to differentiate between coalescence and creaming, since the means of correcting these defects are different. A simple means of determining separation due to creaming or coalescence is to withdraw small samples of the emulsion from top and the bottom of the preparation after some period of storage and comparing the composition of the two samples by appropriate analysis of water content, oil content or any other suitable constituent.

2.     viscosity : 

Changes in viscosity during aging can give an idea about shelf life of an emulsion. Viscometers of cone plate type or instruments having co-axial cylinders can be used to measure the viscosity.

The viscosity changes in first few days are different for w/o and o/w emulsions as rule globules in freshly prepared w/o emulsion flocculate quite rapidly. So the viscosity drops quickly and continues to drop for sometime. (5-15 days at room temp.) And then remains relatively constant. In o/w emulsions flocculation causes increase in viscosity for some time.

After this initial change almost all emulsions show changes in consistency with time, which follow a linear relationship on a log scale. The complete absence of slope (no change in viscosity with age) is ideal. However, slight increase of viscosity between 0.04 and 400 days. Is acceptable. Other emulsions exhibit much more drastic and suddeonlinear increases in viscosity after two to three months aging. Such behavior is frequently followed by a drop in viscosity probably associated with phase inversion

.

 

 

 

 

 

 

 

 

 


A

 

 

 

 

 

 

 

 

 


Підпис: Storage time in days

 

 

A = Ideal shelf life

B = Typical shelf life.

C = Questionable shelf life

 

3.     Electrophoretic properties :

i.      Zeta potential :

The zeta potential enables the formulator to evaluate the effect of the repulsive forces between globules. It is observed that zeta potential of ± 50 mV minimum is needed to get satisfactory stability of dispersion. Stability of emulsions can be evaluated through zeta potential measurements. Zeta potential of emulsion is useful for assessing flocculation since electrical charges on particles influence the rate of flocculation if zeta potential comes down with aging; the emulsion is less stable… Maximum zeta potential is associated with maximum emulsion stability.

 

ii. Electrical conductivity 

It can also be used to evaluate emulsion stability. The electrical conductivity of o/w or w/o emulsions is determined with the aid of Pt electrodes. Measurements are made on emulsions stored for short time at room temp. Or 37o C. Conductivity depends on degree of dispersion. O/w emulsions with fine particles exhibit low resistance. If resistance increases, it is a sign of aggregation and instability. A fine emulsion of water in w/o product doe not conduct current until droplet coagulation i.e. instability occurs.

iii. Dielectric constant measurements:

An inverse relationship existed between log of rate of increase in dielectric constant and the absolute temperature. This can be used as a prediction test.

 

 

4.     Particle size,  number analysis : 

Particle size is inversely proportional to the stability. Changes of the average particle size or of the size distribution of droplets are important parameters for evaluating emulsions. Particle analysis can be carried out by
microscopic methods. Electronic counting devices e.g. coulter counter.

Chemical parameters:

Autoxidation of polyethylene glycols may occur in emulsions. This can cause formation of undesirable odors, of acidic components and of all types of oxidative by products. The instability of nonionic esters leading to hydrolytic degradation may result in changes in dielectric constant of emulsion.

 

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