The History Of Drug Delivery System

Published Date: 02 Nov 2017

In formulating the emulsion, there are several techniques or methods available that can be used which are:

Continental or Dry Gum Method

This method is also known as "4:2:1" Method which means 4 parts (volume) of oil, 2 parts of water and 1 part of gum. Emulsion is prepared using this method in the way that the acacia gum or other oil in water (o/w) emulsifier is triturated with oil in a dry Wedgwood or porcelain mortar until they mixed well. Then the two parts of water are added at once and the mixture is triturated immediately.

English or Wet Gum Method

In this method the proportion of oil, water and gum used are equal with that of the Dry Gum Method; only the order of mixing is differ. Mucilage of the gum is prepared by triturating acacia or other emulsifier with water. Mucilage is a thick aqueous solution of gum used for suspending insoluble substances and for increasing viscosity (Mosby’s Medical Dictionary, 8th edition). After that the oil is added slowly in portions and the mixture is triturated to emulsify the oil. If the mixture becomes too thick during the process, additional portion of water is added into the mixture before another portion of oil added.

Bottle or Forbes Bottle Method

This method is useful for extemporaneous preparation of emulsion from volatile oils or oleaginous substance of low viscosity and not suitable for high viscosity oil. Acacia powder is put in a dry bottle before two parts of oil is added. Then the bottle containing the mixture is shaken. Volume of water which is approximately equal to the oil is then added and the mixture is shaken thoroughly after every addition.

Preparation of bulk emulsion requires a large, high technology equipment to ensure the emulsion prepared is within the good manufacturing practice’s criteria and comply with the quality control and quality assurance. Common equipment used in pharmaceutical industry in formulating emulsion includes:

Silverson-mixer homogenizer

The homogenizer is capable of producing a fine droplet of particles size in the range of 2-5 microns. It generates high shear rates that rapidly homogenize the product to the required uniformity.

Colloid mill

The mill uses the power of mechanical shear to reduce phase droplet sizes and create very stable emulsion. There are 3 shear points that subject material to a higher degree of grinding than conventional mills. Undispersed material is forced into a cavity formed by a spinning Rotor and fixed Stator, centrifugal force propels the material to the outside of the Rotor, causing intense hydraulic shear that breaks agglomerates and homogenizes the solids and liquids.

Choice of emulsion type

Emulsions preparations consist of two types which is oil in water (o/w) emulsions or water in oil (w/o) emulsions. To decide whether to formulate w/o or o/w emulsions is depends on the indication to which area of the body the emulsion is going to be administered.

For oral administration, o/w emulsions is preferred over the w/o emulsions. This is because the inclusion of suitable flavoring agent in the aqueous phase will mask any unpleasant taste and thus it is more pleasant to take by the patient as compared to w/o emulsions.

For intravenous administration, both w/o and o/w emulsions can be chosen. W/o emulsions is suitable for intramuscular injection as the water-soluble drugs can provide depot therapy which can slow the drug release from the site of administration and therefore prolong the availability of the drug in the body.

Semi-solid emulsions are most widely used for external application. For instance creams, lotions and liniments. All these preparation available in w/o and o/w emulsion. O/w emulsions are used for the topical application of water soluble drugs mainly for local effect. They do not have greasy texture and thus, they are easily washed from the skin surfaces. Whereby for w/o emulsions, they have occlusive effects in which they can inhibit evaporation of eccrine secretions. This in turn will hydrate the upper layers of the stratum corneum and useful for dry skin conditions. This type of emulsions usually prepares as moisturizing creams to prevent water loss form the skin.

Choice of oil phase

In choosing oil phase of an emulsion, it is necessary to determine the route of administration first before selecting suitable oils to be used in the formulation. For external use of emulsion, it must contain oils that are present as carriers for the active agent. The oil phase must also have effect on viscosity of the product and be able to transport the drug into the skin. Example of oils that is widely used in this type of preparation is liquid paraffin, hard paraffin, soft paraffin and light liquid paraffin. They can be used alone or in combination with each other in order to control the consistency of an emulsion. The product can be spread easily but will be sufficiently viscose at the same time to form a coherent film over the skin.

For intravenous route, the oils used must have high calorific value in emulsion. Example of oils with high calorific value is cottonseed oil, soya bean oil and safflower oil.

The aqueous phase

Water or aqueous phase is a continuous phase and the system is called w/o emulsion. This o/w emulsion system generally formed if the aqueous phase constitutes more than 45% of the total weight and a hydrophilic emulsifier is used.

Volume concentration of dispersed phase

One of the behaviors of emulsion shows that the viscosity of the final product as a whole would be higher than the viscosity of the continuous phase on its own. So when the disperse phase concentration increases, the viscosity of the product also increases. It is crucial to ensure that the disperse phase concentration does not increase above 60% of the total product, otherwise phase inversion may occur.

Particle size of dispersed phase

Viscosity of emulsion can be increased by reducing the mean globule diameter (particle size) of dispersed phase. This can be achieved by homogenization. Generally there two mechanisms available that can be applied which are by:

Promote flocculation by reduction of mean globule size. Flocculation is a condition in which part of the continuous phase is trapped within aggregates of droplets and result in the increase of the disperse phase concentration. Emulsion with polydispersed droplets system will tend to exhibit a lower viscosity than a monodispersed droplets system. This is because due to the difference in the electrical double-layer size and also in the energy of interaction curves. These interaction differences can be seen in their flow behavior.

Using hydrophilic colloid to stabilize the emulsion. Hydrophilic colloid will form a multimolecular film around the dispersed globules. Decreasing in mean globule size will increase the total surface area and therefore more colloid will be adsorbed onto the droplet surface. This will increase the volume concentration of the dispersed phase.

Viscosity of continuous phase

The viscosity of an emulsion is directly proportional to the viscosity of its continuous phase. The viscosity can be increased by addition of material that is soluble with the material of its continuous phase.

If water is the continuous phase, the viscosity can be increased by using the sweetening agents like syrup and glycerol. This is achieved because both syrup and glycerol are water soluble material and addition of these two materials into water is shown can increase its viscosity. Besides that, hydrocolloids are also known to have the capability in increasing the viscosity of continuous phase. They are used as emulsifying agents to stabilize the o/w emulsions by forming multimolecular layers around the dispersed globules.

If oil is the continuous phase, inclusion of soft paraffin or hard paraffin or certain waxes can increase its viscosity.

Viscosity of dispersed phase

In emulsification process, viscosity of dispersed phase has shown to act as a damping factor for particle anchoring at o/w interface.

Choice of emulsifying agent

The choice of emulsifying agent is depends on its emulsifying ability, routes of administration and also its toxicity. The emulgents that is suitable for internally used pharmaceutical emulsions are mainly naturally occurring materials and their semi-synthetic derivatives such as polysaccharides, glycerol esters, cellulose esters, sorbitan esters and polysorbates. All of these emulgents are non-ionic in which they have tendency to be less irritant and less toxic compared to their anionic and cationic counterparts. Ionic emulsifying agent is not used for oral emulsion particularly because it has irritant effect to the gastrointestinal tract as well as laxative effect.

For parenteral emulsion, only certain types of non-ionic emulsifying agents are suitable and that include lecithin, polysorbate 80, methylcellulose, gelatin and serum albumin.

Nature and concentration of emulsifying agent

Emulsifying agent available in formulating emulsions are natural emulsifying agent and surface-active agents (surfactants).

Most of the natural emulsifiers are derived from either plant or animal that will form hydrated lyophilic colloid (hydrocolloid). Hydrocolloid has a nature to form multimolecular films at the o/w interface and also can increase the viscosity of the continuous phase of an o/w emulsion. The higher the concentration of hydrocolloid the higher the viscosity of the product will be. Besides that, it is also have little or no effect on interfacial tension but exert a protective colloid effect, reducing the potential for coalescence by providing a protective sheath around the droplets, imparting a charge to the dispersed droplets so that they repel each other and causing swelling to increase the viscosity of the system.

Surfactants have a characteristic of forming condensed monomolecular films that will influence the degree of flocculation. Flocculation happens by the way that the surfactant forming linkages between adjacent globules and creating a gel-like structure. Flocculation system gives a greater viscosity and it depends on surfactant concentration.

Ideal emulsifying agent

Ideal emulsifying agent should possess the following characteristics:

Should not be toxic especially for oral emulsion

Should has no sensitizing or allergic reactions for emulsion intended for topical application

Should be capable of forming coherent film around the dispersed globules

Should be capable of reducing the interfacial tension between the dispersed phase and continuous phase

Should be able to increase the viscosity of the continuous phase and thus increase the stability

Should be chemically stable

Should be able to resist decomposition and degradation by microorganisms

Should be cheap and have pleasant taste and odor

Should be suitable over a wide range of different pairs of liquids

Formulation by the HLB method

Hydrophile-lipophile balance (HLB) method is designed to produce the most physically stable emulsion for oil/water combination of emulgents. This method can be applied to ionic and non-ionic surfactants. To prepare emulsion by this method, there are few calculations involved. Example of an o/w emulsion calculations is shown as below:

Liquid paraffin 35%

Wool fat 1%

Cetyl alcohol 1%

Emulsifier system 7%

Water to 100%

First, total percentage of oil phase and the proportion of each are calculated:

Total percentage of oil phase = 35% + 1% + 1%

= 37%

The proportion of each is:

Liquid paraffin 35/37 x 100 = 94.6%

Wool fat 1/37 x 100 = 2.7%

Cetyl alcohol 1/37 x 100 = 2.7%

Second, the total HLB number required is calculated:

Liquid paraffin (HLB 12) 94.6/100 x 12 = 11.4

Wool fat (HLB 10) 2.7/100 x 10 = 0.3

Cetyl alcohol (HLB 15) 2.7/100 x 15 = 0.4

Total HLB required = 12.1

From the above calculation, this type of formulation requires an emulsifying agent blend of HLB 12.1. Assuming a blend of sorbitan monooleate (HLB 4.3) and polyoxyethylene sorbitan monooleate (HLB 15) is to be used as emulsifying system.

Lastly, the proportions of each agent to be added to give an HLB value of 12.1 are calculated as follows:

Always calculate the higher HLB emulsifier first

%H = (X-L) X 100 %L = 100 - %H

(H-L) = 100 – 72.9

= (12.1- 4.3) X 100 = 27.1%

(15 – 4.3)

= 72.9%

X = required HLB = 12.1

L = low HLB emulsifier = 4.3

H = high HLB emulsifier = 15

Other formulation additives

Additives that are usually added in the formulation of emulsion are:

Buffers

The inclusion of buffers is to maintain chemical stability, control tonicity and endure physiological compatibility.

Density modifier

It is added to prevent sedimentation and creaming. When the disperse phase and continuous phase having the same densities, then the sedimentation and creaming will not occur. Examples are sucrose, dextrose, glycerol and propylene glycol.

Humectants

It is incorporated into formulation to reduce the evaporation of water from the packaged product when the closure is removed or from the surface of the skin after application. However if it is used in high concentration for topically used, it can cause dehydration. Examples of humectants are glycerol, polyethylene glycol and propylene glycol.

Antioxidants

It is added to prevent deterioration and therefore prolong the stability of the final product. For instances butylated hydroxyanisole, butylated hydroxytoluene and dodecyl esters of gallic acid.

Flavors, colors, and perfumes

All of them are usually added in the formulation of emulsion because to enhance the physical appearance of the final product and also to increase patient acceptance towards the product.

Sweetening agents

Inclusion of the sweetening agents is to mask any unpleasant taste that might be come from the other ingredients. Commonly used sweetening agents are sucrose, sorbitol and glycerol.

Evaluation of emulsion and stability testing of emulsion

There are several methods of evaluation and assessing stability of emulsion and there are include:

Macroscopic examination

This examination is done to assess the physical stability of an emulsion by examining the degree of creaming or coalescence occurs over a period of time. The test is carried out by calculating the ratio of the volume of the creamed or separated part of the emulsion and the total volume of the emulsion. Then the value is compared for different products.

Globule size analysis

We can predict that the coalescence happened in emulsion when the mean globule size increase with time, but at the same time the mean globule size decrease in numbers. Therefore we can measure changes in globule size and numbers to compare the rates of coalescence for different products. This can be done by undergoing microscopic examination, using electronic particle counting devices or laser diffraction sizing.

Viscosity changes

Viscosity of an emulsion might change if there is any variation in globule size, globule number or in orientation or migration of emulsifier over a period of time. Suitable equipment to measure viscosity is capillary viscometer, falling-sphere viscometer and rotational viscometer.

Accelerated stability test

There are several ways to conduct accelerated stability test which is storage at adverse temperatures, centrifugation and rheological assessment. For storage at adverse temperatures, the emulsion is first storage at 40°C for few hours followed by refrigeration or freezing until the emulsion becomes instable. Meanwhile for centrifugation, it is done to increase the sedimentation rate. This process may destroy the structure of a flocculated system that would remain intact under normal strorage condition. In rheological assessment, the high shear rates is applied to destroy the structure of the emulsion. This is to assess at which rate the emulsion is going to destcruct by the force applied.