Oral Liquid Dosage Form (Emulsion) PDF

University of Tripoli, Faculty of Pharmacy, Dept. of Industrial Pharmacy. Pharmaceutical Technology II (P451P) Oral Liquid Dosage Form (Emulsion)  Definition of emulsion:  An emulsion may be defined as a bipha...

University of Tripoli, Faculty of Pharmacy, Dept. of Industrial Pharmacy. Pharmaceutical Technology II (P451P) Oral Liquid Dosage Form (Emulsion)  Definition of emulsion:  An emulsion may be defined as a biphasic system consisting of two immiscible liquids, one of which (the dispersed phase) is finely and uniformly dispersed as globules throughout the second phase (the continuous phase).  Since emulsions are a thermodynamically unstable system, a third agent, the emulsifier is added to stabilize the system. The process of formation of an emulsion is termed emulsification.  Emulsifier stabilizes the system by forming a thin film around the globules of dispersed phase.  Either the dispersed phase or the continuous phase may vary in consistency from that of a mobile liquid to semisolid. Thus, pharmaceutical emulsions range from lotions (low viscosity) to creams (high viscosity).  The particle size of the dispersed phase commonly ranges from 0.1 to 100 μm. In emulsion terminology:  The dispersed phase: is the discontinuous or internal phase  The dispersion medium: is the continuous or external phase  Purpose of emulsion:  Increased drug solubility; many drugs have limited aqueous solubility but have maximum solubility in oil phase of emulsion.  Increased drug stability; many drugs are more stable when incorporated into an emulsion rather than in aqueous solution.  Prolonged drug action; incorporation of a drug into an emulsion drugs with can prolong bioavailability, as with certain intramuscular injections preparation  Improved taste; drugs with unpleasant taste are more palatable and thus more conveniently administered in emulsion form.  Improved appearance; oily materials intended for topical applications are more appealing in emulsion form.  Types of emulsion: Emulsions typically consist of a polar (e.g., aqueous) and a relatively nonpolar (e.g., an oil) liquid phase. The types of emulsions are: By: Dr. Nagib Elmarzugi & Dr. Malak Shmela  University of Tripoli, Faculty of Pharmacy, Dept. of Industrial Pharmacy. Pharmaceutical Technology II (P451P) 1. Oil-in-water (O/W) emulsion 2. Water-in-oil (W/O) emulsion 3. “Multiple emulsions”: a). Water-in-oil-in-water (W1/O/W2) emulsion b). Oil-in-water-in-oil (O1/W/O2) emulsion.  classification of emulsion according to size of liquid droplets:  Macro-emulsions → 0.2 – 50 Micro meter  Micro-emulsions → 0.01 – 0.2 Micro meter  classification of emulsion according to the route of administration 1. Oral emulsions e.g., castor oil, liquid paraffin 2. External emulsions e.g., creams 3. Parenteral emulsions e.g., vitamins 4. Rectal emulsions e.g., enema.  Composition of emulsion: An emulsion usually consists of following three components: 1. Aqueous phase. 2. Oily phase. 3. Emulsifying agents.  Raw material of emulsion: 1. Aqueous phase: The aqueous phase of an emulsion consists of purified or deionized water which contains water soluble drug, preservatives, coloring and flavoring agents. 2. Oily phase: The oily phase of an emulsion consists of fixed, volatile or mineral oil which contains oil soluble vitamins and antiseptics. The oil used in formulation of emulsion should be prevented from auto oxidation. For example: fixed oils are castor oil, cod liver oil, almond oil, liquid paraffin, shark liver oil, and volatile oil containing turpentine oil, sandal wood oil, cinnamon oil etc. 3. Emulsifying agents: “The chemical agents that are used to maintain emulsion stability and to reduce the coalescence between the 2 immiscible liquids are called emulsifying agents”. It is the component of emulsion which binds the two immiscible liquids, and stabilize the emulsion. By: Dr. Nagib Elmarzugi & Dr. Malak Shmela  University of Tripoli, Faculty of Pharmacy, Dept. of Industrial Pharmacy. Pharmaceutical Technology II (P451P)  Properties of emulsifying agent:  It must be compatible with formulation ingredients.  Must not interfere with stability and efficacy of the product.  Should be nontoxic, Should be odourless, colourless and tasteless  Should be stable and not deteriorate in the preparation.  Should increase the viscosity of the product.  The amount of emulsifying agent used should be the minimum amount sufficient enough to produce a satisfactory emulsion. This is because not enough amounts lead to coalescence and very high amounts reduce emulsion stability.  Some emulsifiers, known as auxiliary emulsifiers, also have viscosity imparting properties. 5. Viscosity enhancing agent Viscosity enhancing agent is added to enhance the stability of emulsion, especially the viscosity of the external phase. It reduce phase separation which results from creaming and coalescence 6. Preservatives: 1. Preservatives is important in emulsion because it is highly susceptible to microbial growth. Preservative efficacy can be reduced by:  Interaction with one of the emulsion ingredients  partitioning between both phases  Interaction with the container  The storage temperature in the final container. Loss of preservative efficacy due to interaction with ingredients can be rectified by adding an equal amount to the complexed material. In the case of partitioning, a combination of more than one preservative can be used 7. Antioxidants: Antioxidants is added to protect the emulsion from auto-oxidation. A combination of more than one antioxidant can be used to produce synergistic effects. Manufacturing of Pharmaceutical emulsions By: Dr. Nagib Elmarzugi & Dr. Malak Shmela  University of Tripoli, Faculty of Pharmacy, Dept. of Industrial Pharmacy. Pharmaceutical Technology II (P451P) Emulsions may be prepared by using different methods, depending on the nature of the emulsion components and instrumentation available for use. On a small scale, as in the laboratory or pharmacy, emulsions may be prepared using equipment such as a porcelain mortar and pestle, mechanical blenders, and homogenizers. Manufacturing of Pharmaceutical emulsions  In small-scale extemporaneous preparation of emulsions, four methods may be used: 1. continental, or dry gum, method 2. English, or wet gum, method 3. in situ soap method 4. mechanical method  On a large scale, injectable and ophthalmic emulsions are manufactured using the mechanical method in aseptic conditions. The manufacture of an emulsion must be undertaken in a predictable and controlled manner, in order to obtain: 1. Uniformity of surface coverage. 2. Monodispersed droplet sizes in the population produced. 3. The smallest droplet size possible.  Preparation of Emulsions and Techniques of Emulsification The preparation techniques of emulsion formulations can be divided into laboratory-scale productions and large-scale productions. Each method requires the introduction of energy into the system by trituration, homogenization, agitation, or heat. For stable emulsions, appropriate preparation and formulation techniques are required. Following physical and chemical properties before the preparation of an emulsion are considered: i. Structure formula. ii. Melting point. iii. Solubility in different media. iv. Stability. v. Dose. vi. Specific chemical incompatibilities. vii. Selection of an appropriate emulsifying agent and its concentration. The main four emulsification methods are: By: Dr. Nagib Elmarzugi & Dr. Malak Shmela  University of Tripoli, Faculty of Pharmacy, Dept. of Industrial Pharmacy. Pharmaceutical Technology II (P451P) 1. The emulsion system is subjected to shear or fracture at the time of addition of the internal phase (Addition of internal phase to external phase). 2. The addition of external phase into the internal phase, this is known as phase inversion technique. In an oil-in-water emulsion system the aqueous phase is added into the oil phase, at first a water-in-oil emulsion is formed which on further addition of water results in the inversion of the phase and hence forms an oil-in-water emulsion. 3. Separate heating of both phases and then mixing them together. This method is frequently used for the preparation of creams. 4. In small portions, alternate addition of the two phases to the emulsifying agent, which is suitable for food emulsion preparation. Method 1: Addition of internal phase to external phase: This is the most satisfactory method for producing emulsions. It involves the following steps: A. The internal phase and external phase are prepared  The oily and aqueous phases are heated separately  If the ingredients of the oily phase are solid or semisolid in nature, they must be melted first  Both phases should be heated to a temperature above the highest melting point of any ingredient present (especially when waxes are present)  Other ingredients are dissolved in the phase in which they are soluble in B. The internal phase is dispersed in the dispersion medium 1. The internal phase is pumped slowly into the tank containing the external phase 2. Constant agitation should be maintained throughout the addition procedure 3. It is important to heat the aqueous phase to the same temperature as the oil phase during the dispersion step (this has the advantage of reducing the system's viscosity which enables shear forces to be transmitted through the product more easily) C. The resultant product is stabilized 1. Ingredients that may affect the physical stability of the emulsion such as electrolytes are added (they should be diluted as much as possible and added carefully with constant mixing) 2. Volatile ingredients such as flavours and perfumes are added last 3. They should be added after slight cooling of the emulsion 4. They should be sufficiently dissolved (to allow sufficient blending of the ingredients) 5. The final product is processed to produce a smooth, elegant, and uniform product (performed after complete cooling of the emulsion) By: Dr. Nagib Elmarzugi & Dr. Malak Shmela  University of Tripoli, Faculty of Pharmacy, Dept. of Industrial Pharmacy. Pharmaceutical Technology II (P451P) Method 2: Addition of the external phase to the internal phase (phase inversion method): Let us take a model of o/w emulsion: In this method water (external phase) is first added slowly to the oil (internal phase) to promote the formation of a more w/o emulsion due to the presence of more oil than water. After further addition of water phase inversion to an o/w emulsion should take place (called inversion point). This method allows the formation of small droplets with minimal mechanical action and heat. Ex; dry gum method Method 3. Mixing both phases after warming each phase: This method is use when waxes or other substances which require melting are used. The oil-soluble emulsifying agents, oils and waxes are melted and mixed thoroughly. The water-soluble ingredients dissolved in the water and warmed to a temperature slightly higher than the oil phase. The oil phases are then mixed and stirred until cold. For convenience, but not necessity, the aqueous solution is added to the oil mixture. This method frequently is used in the preparation of ointments and creams. Method 4. Alternate addition of the two phases to the emulsifying agent Model: Let us prepare an o/w type of emulsion. (i) A portion of the oil is added to all of the oil-soluble emulsifying agents with mixing. (ii) Equal quantity of water is added to all of the water-soluble emulsifying agents with mixing. (iii) Aqueous solution is mixed with oil phase stirred until the emulsion is formed. (iv) Further portions of water and oil are added alternately until the final product is formed. N.B. The high concentration of the emulsifying agent in the original emulsions makes the initial emulsification more likely and the high viscosity provides effective shearing actin leading to small droplets in the emulsion. This method is often used successfully with soaps. This method is most suitable for preparing food emulsions.  Emulsification equipment Various types of equipment are available for emulsification both for laboratory scale and large scale. Usually equipment for emulsification is selected on the basis of resulting emulsion. Equipment for emulsification works on the mechanism to break up or distribute the dispersed phase into the continuous phase so that the size of the droplets of the dispersed phase is sufficiently small to avoid coalescence and instability  Equipment for emulsion preparation: For small scale preparation: Different techniques are used to prepare emulsion on small scale, some of which are described below: By: Dr. Nagib Elmarzugi & Dr. Malak Shmela  University of Tripoli, Faculty of Pharmacy, Dept. of Industrial Pharmacy. Pharmaceutical Technology II (P451P) 1. Mortar and pestle 2. Agitator 3. Mechanical mixers  Equipment for emulsion preparation: For large scale preparation: The production of emulsions on a large scale requires considerable amounts of energy for heating and mixing. Careful considerations of these processes has led to the development of low energy emulsification equipment that uses an appropriate emulsification temperature and selective heating of ingredients. The choice of suitable emulsification equipment depends on the intensity of shearing required to produce optimum droplet size as well as optimum volume and viscosity of the emulsion. The equipment required in the manufacturing of emulsions include: 1. Measuring equipment: Equipment for measuring liquids and solids in small and large amounts 2. Equipment for bulk material handling: This includes TOTE® bins and their discharging equipment 3. Tanks and tank accessories: The tanks used in the manufacturing process include preparation or mixing tanks used during production and storage tanks used for holding the finished product until released by the QC department. 3. Tanks and tank accessories: The tanks should have the following features:  They are obtainable in a number of different sizes  They are usually constructed of polishes stainless steel with a round bottom  They are completely covered and equipped with see-through charging points and illumination for easy observation of contents.  They should be jacketed to carefully control heating and cooling cycles.  They may be equipped with means of agitation.  The mixing tanks may be fitted with baffles in order to modify circulation of the emulsion  Tanks can be operated under a controlled vacuum to avoid the problem of unwanted aeration  Accessories that are used with tanks include piping, valves, pumps, flow meters, and controls 4. Filtration equipment: Unwanted particulates are more effectively removed by filtering each phase (oily and aqueous) separately before emulsification 5. Droplet break-up and emulsification equipment: Several equipment are used: By: Dr. Nagib Elmarzugi & Dr. Malak Shmela  University of Tripoli, Faculty of Pharmacy, Dept. of Industrial Pharmacy. Pharmaceutical Technology II (P451P) A. Mechanical stirrers: High power propeller and impeller type mixers that have a propeller attached to a shaft driven by an electric motor are convenient and portable and can be used for stirring and emulsification and are usually constructed so that the contents of the tank may be either heated or cooled during the production process. Disadvantages:  Propellant mixers are generally used for low viscosity emulsion preparation.  It is not suitable when extremely fine droplets are required.  It is not suitable when foaming at high shear rates must be avoided. B. Colloid Mills: Advantage:  Very high shearing force can be generated  Very fine particles can be prepared  Useful for preparation of relatively viscous emulsions Disadvantages:  Subsequent cooling may be required as the shear forces applied usually lead to a raise in the temperature. Cooling can be achieved by using jacketed equipment. C. Homogenizers: During emulsification, the dispersion of two liquids is carried out by forcing them through a small orifice at a high pressure. Modern emulsions can be prepared by a variety of various emulsification equipment, all are working nearly on similar mechanism that is agitated. Among all the equipment for emulsification, rotor/stator high pressure homogenizer is the most continuously operated device. High pressure homogenizers are provided with a high pressure pump and homogenizing nozzle. The high pressure pump raises the pressure up to 50 to 500 bar. The size of the dispersed phase is reduced: 1. Due to the mechanical collision against the walls of homogenizer because of high liquid acceleration. 2. Due to the shear force occurring within the gap between rotor and stator. Advantages:  Homogenizers are used when a reasonably monodisperse emulsion of small droplet size is required.  Their throughput is little affected by viscosity and varying designs are available which are useful for handling liquids or pastes. (Not affected by viscosity). By: Dr. Nagib Elmarzugi & Dr. Malak Shmela  University of Tripoli, Faculty of Pharmacy, Dept. of Industrial Pharmacy. Pharmaceutical Technology II (P451P) Disadvantages:  subsequent cooling may be required as they may raise the temperature of the emulsion E. Microfluidizer: Microfluidizers have been used to produce very fine particles. The process subjects the emulsion to an extremely high velocity through micro channels into an interaction chamber as a result particles are subjected to shear, turbulence, impact and cavitation. Advantages:  Lack of contamination in the final product  Ease of production scale up. 6. Equipment facilitating the removal of entrapped air: Air entrapment is difficult and time-consuming to remove, it can affect the physical and chemical stability of the product, and it can affect the reproducibility of the filling process. The versator is an example of an equipment that can be used to remove entrapped air when entrapped air cannot be rectified with process or equipment modifications. The versator can be used with heat and shear sensitive materials which makes it ideal for suspensions also. 7. Filling equipment: The filling of emulsions can be performed using in-line piping and pumps for automated filling. Portable transport tanks can be used for manual transport of the final product to the filling line.  Physical instability of emulsion: Physical stability of an emulsion is characterized by the maintenance of elegance with respect to appearance, odor, color, taste, opacity, and viscosity. Four major phenomena are associated with the physical instability of emulsions: 1. flocculation 2. creaming 3. coalescence 4. breaking 5. foaming 6. inversion 1.Flocculation: By: Dr. Nagib Elmarzugi & Dr. Malak Shmela  University of Tripoli, Faculty of Pharmacy, Dept. of Industrial Pharmacy. Pharmaceutical Technology II (P451P) It is the association of small emulsion particles to form large aggregate which is re- dispersible upon shaking. It is a reversible process in which the droplets remain intact. Flocculation is considered as the precursor of coalescence. This is because the presence of excess surfactant in the continuous phase of an emulsion can lead to flocculation of emulsion droplets. Loose clusters formed due to the aggregation of dispersed phase globules are called floccules and the phenomenon is termed as flocculation. It causes an increase in the rate of creaming and is said to be a precursor of coalescence. However, in flocculation the interfacial film and individual droplets remains linked together. Prevention of flocculation: On shaking, the emulsion is easily re-dispersed. High charge density of the dispersed droplets will cause the presence of high energy barrier and reduce the incidence of flocculation. Effects of any ions in the formulation must be considered early in the formulation process, particularly in emulsions for parenteral nutrition containing high levels of electrolytes. 2.Creaming: Creaming is the phenomenon in which the dispersed phase separates out, forming a layer on the top of the continuous phase. It is notable that in creaming, the dispersed phase remains in globules state so that it can be re-dispersed on shaking. Creaming can be minimized if the viscosity of the continuous phase is increased  O/W emulsions generally face upward creaming when the globules of the dispersed phase are less dense than the continuous phase.  In contrast, W/O emulsions face downward creaming when the globules of the dispersed phase are denser than the continuous phase Creaming and sedimentation: As the dispersed droplets are subjected to gravity force, they tend to move upward (creaming) or downward (sedimentation) but not both. Creaming usually happens in o / w emulsions. Sedimentation usually happens in w / o emulsion. The process is reversible and gentle shaking redistributes the droplets throughout the continuous phase. However, creaming is undesirable because, it is inelegant and inaccurate dosing is possible if shaking is not thorough. Additionally, creaming increases the likelihood of coalescence of globules and therefore break down of the emulsion due to cracking. Prevention of creaming By: Dr. Nagib Elmarzugi & Dr. Malak Shmela  University of Tripoli, Faculty of Pharmacy, Dept. of Industrial Pharmacy. Pharmaceutical Technology II (P451P)  Reducing the droplet or globule size through efficient emulsification may result in the stabilization of the emulsion by avoiding creaming.  An increase in the viscosity of the system may also help in the stabilization of the emulsion. 3.Coalescence: Coalescence takes place when the mechanical and/or electrical barrier is not efficient to prevent the large droplets to aggregate and finally leads to complete phase separation (breaking) of the emulsion formulation (serious) Coalescence can be caused by:  Inadequate concentration of emulsifier(s) which leads to an insufficient protective mechanical or electrical barrier  Excessive agitation periods during and after emulsion formation Coalescence can be prevented by:  Optimizing the concentration of the emulsifier used  Intermittent agitation should be adapted as continuous agitation after emulsion formation can increase the chance of droplet collision leading to coalescence 4.Phase Separation (Breaking) Phase separation or breaking (irreversible) may or may not be observed visually. Generally creaming, coalescence and flocculation occur before the phase separation and thus makes its visibility and quantitative analysis difficult to evaluate. Centrifugation of the samples or determination of creaming index helps in the quantitative determination of this process. Prevention of breaking Breaking of an emulsion can be avoided by controlling the factors responsible for other forms of instability such as flocculation, creaming and coalescence. Instability in emulsions can also be controlled by: 1. A number of other factors such as proper selection of formulations ingredients, their appropriate quantity, 2. optimum hydrophilic-lipophilic balance (HLB), 3. Appropriate storage conditions, etc. Types of Instability in Emulsions By: Dr. Nagib Elmarzugi & Dr. Malak Shmela  University of Tripoli, Faculty of Pharmacy, Dept. of Industrial Pharmacy. Pharmaceutical Technology II (P451P) 5.Foaming: Foaming in emulsion can be caused by:  Agitation or during transfer of the emulsion  When using water-soluble surfactants as emulsifiers The problem of foaming can be prevented by:  Using a closed system (with minimum free air space) and/or under vacuum when performing emulsification  Regulating the mechanical stirring process (particularly during cooling) to cause air to rise to the top  Incorporating foam depressants (as a last resort because they provide a source of chemical incompatibility) 6.Inversion: Emulsion inversion occurs when an emulsion changes from an o/w to a w/o emulsion or vice versa. Inversion can be caused by:  The addition of an electrolyte  Changing the phase-volume ratio. Inversion can be prevented by:  Using a proper emulsifier and in an optimized concentration  Ensuring that the volume of the dispersed phase does not exceed 50% of the total emulsion volume By: Dr. Nagib Elmarzugi & Dr. Malak Shmela University of Tripoli, Faculty of Pharmacy, Dept. of Industrial Pharmacy. Pharmaceutical Technology II (P451P) By: Dr. Nagib Elmarzugi & Dr. Malak Shmela