Excipients for Liquid Dosage Forms

I'm going to give you a minute to think about it. I'm going to give you a minute to think about it. Hello students, I am Urooj Ahmed Khan working as a teaching assistant in Delhi Institute of Pharmaceutical Sciences and Research that is DIPSER. In this module, we will deal with excipients for liquid dosage forms under paper Product Development I. The learning objectives of this module are different excipients used in monophasic liquid dosage forms and in biphasic liquid dosage forms particularly in emulsions and suspensions and their mechanism of actions, different types of surfactants used in liquid dosage forms and finally, the determination of HLB value of surfactants. Coming to introduction part, liquid dosage forms are basically of two types that is monophasic liquid dosage form. and biphasic liquid dosage form. We will start with excipients for monophasic liquid dosage forms. Liquid dosage forms are intended to be used by geriatric or pediatric population and include solutions, suspensions and emulsions. They may be prepared by dissolving a substance in aqueous vehicle or a non-aqueous vehicle by suspending it in a suitable medium or by incorporating the drug in an oil or water phase. In pharmaceutical terms, solutions are the liquid preparations containing one or more soluble chemical substances, which are dissolved in a suitable solvent that is usually water or in a mixture of mutually miscible solvents and do not by reason of their ingredients or the method of preparation. or use, drop into other group of products. With rare exceptions, the ingredient must be in solution form in order to be absorbed and which makes the drug immediately available for absorption and hence making it more rapidly and efficiently absorbed than the same amount of the drug when administered in a tablet or capsule. The formulation of solution is a cumbersome process and presents an array of technical problems to the industrial pharmacist. Certain drugs are inherently unstable, some are poorly soluble. To unravel the formulation problems with the pharmaceutical liquids, an interesting dichotomy of investigative skills is required. The solubility and stability factors can be approached with the precision long associated with exact sciences while flavouring and other organoleptic characteristics are the subjective factors. Thus, the successful formulation of a dosage form requires a blend of scientific acuity and pharmaceutical art. The various excipients involved in the manufacturing of liquid dosage forms are Vehicles, solubilizers, complexing agents, buffering agents and antifoaming agents. Now, we will start with vehicles. Vehicles are the liquid bases which carry the active pharmaceutical ingredient and other excipients in the formulation in the dissolved or dispersed state. Vehicles may be aqueous or oily. Aqueous vehicles include water, polyhydric alcohols, Hydroalcoholic solutions and buffers. Oily vehicles include vegetables or mineral oils, organic oily bases or emulsified bases. Portable water is the one which contains 0.1% of the total solid purified water USP. Is used as vehicle in all the liquid formulations except for the parenterals for which water for injection is used. The quality of water is defined by the USP in terms of conductivity. Alcohol also known as ethyl alcohol is used as hydroalcoholic mixture that is capable of dissolving both alcohol soluble and water soluble drugs and excipients glycerol serves as an excellent solvent for range of substances such as alkyl neutral salts tannins etc glycerin is added to the oral formulations in the form of co-solvent to solubilize hydrophobic drugs to improve the viscosity and also as taste masking agent Propylene glycol with purity of more than 99.8% has multiple uses such as solvent for automatics in flavor concentrate industry, wetting agents for natural gums, solvent in elixirs and pharmaceutical preparations, emulsifiers in creams, and as humectants, preservatives, and stabilizers. Lipid-based vehicles are used to solubilize the hydrophobic drugs by forming self-emulsifying system using a surfactant. The lipid in the formulation keeps the hydrophobic drug in solution state and facilitates its dissolution and absorption as the lipid vehicle is metabolized in gastrointestinal tract. Now, moving to solubilizers. These are used in the aqueous base formulations to modify the polarity of water so as to dissolve a non-polar drug. They alter the polarity, viscosity, sulphur extension, density, boiling point and specific heat of solution in various ways. The mechanism of solubility enhancement using co-solvents is not well understood. Co-solvents reduce the interfacial tension between the aqueous solutions and the hydrophobic solute. Some of the examples of solubilizers include sugars, sorbitols, alcohols, ethanol, propylene glycol and polyethylene glycols such as PEG-400. Recent reports suggest a number of solvents that can be used in oral liquids. These include glycophrudol, glycerol, dimethyl cetyl, glycerol formal, dimethyl acetamide, ethyl lactate, ethyl carbonate and 1,3-butylene glycol. However, With the exception of dimethylacetamide, all the other solvents mentioned above are not acceptable for systemic use. Dimethylacetamide can be used as a co-solvent in parenteral products but it's not suitable for use in oral liquids owing to its objectionable odour and taste. Thus, a very narrow spectrum of solvents is available for use in oral liquid formulations. Coming to Complexing Agent. Complexing agents serve to enhance the solvability of a compound. This can be achieved if both the drug molecule and complexing agent have proper size, charge and lipophilicity that allow for favourable solubility enhances non-covalent interactions. The most commonly used complexing agent is cyclodextrin. Cyclodextrin constitute a group of structurally related natural products which are formed during the bacterial digestion of cellulose. They are the cyclic oligosaccharides made up of alpha-1-folding. alpha-D glucopyranose units with a lipophilic central core and a hydrophilic outer corona. The limited free rotation around the bonds linking the glucopyranose units make cyclodextrin toroidal or cone-shaped. The parent or natural cyclodextrin may contain 6, 7 or 8 glucopyranose units referred to as alpha, beta and gamma cyclodextrins respectively. Cyclodextrin act as a molecule container that entraps the gas molecules in their internal cavity forming inclusion complexes in aqueous solution. The lipophilic moiety is taken up into the hydrophobic central cavity of the cyclodextrin. and they are in rapid equilibrium with the free drug molecules in the solution. No covalent bonds are formed or broken down during drug-cyclodextrin complex formation. The driving forces for the formation of inclusion complex include release of enthalpy-rich water molecules from the cavity, Vandervol force, electrostatic and or hydrophobic interactions, hydrogen bonding, release of a conformational strain and charge transfer interactions. The drug-cyclodextrin complex Offers several advantages which include solubility and hence bioavailability enhancement, improvement in drug stability, reduction of gastrointestinal or skin or eye irritation associated with drugs, prevention of drug-drug or drug excipient incompatibility and odor and taste masking of bitter drugs. Moving towards buffering agents, they are used to maintain pH of the formulation to ensure the physiological compatibility of the formulation. with the biological fluids and also to maintain the formulation stability. The required amount of buffer capacity is usually between 0.01 and 0.1 molar while the concentration of 0.05 and 0.5 molar is sufficient. The choice of buffer to be used in the formulation is based on whether the acid-base forms are listed for use in oral liquid dosage form Drug and Excipient Stability in Buffer Compatibility between the buffer and the container Several factors such as amount and the type of co-solvents present, dilution, ionic strength and temperature may contribute to affect the pH of the solution. For instance, with the increase in temperature, the pH of the acetate buffers increases while the pH of boric acid buffers The buffer may negatively influence the solubility of drug and excipients. The effect depends on the polarity of solute and salt when combined in the formulation. Non-polar solutes are solubilized by weakly polar organic salts while they are desolubilized by polar salts. Conversely, polar solutes are solubilized by polar salts and desolubilized by organic salts. Comparison of the two that have multiple charged species in solution can also be determined the potential reaction between the drug and excipients. For example, buffer that use citrates, phosphates, Carbonates and tartrates may precipitate with calcium ions forming sparingly soluble salts, the precipitation being dependent on the pH of the solution. Antifoaming agents The foams may be formed in a liquid dosage form either during the manufacturing process or when it is reconstituted. Defoaming and antifoaming are like two faces of a same coin, utilizing the same type of material for their prevention, differing slightly in their mechanism of foam prevention. De-foaming indicates breaking, rapid knockdown and controlling the pre-existing foam. Foam inhibition or anti-foaming implies preventing the foam from forming during its first occurrence. Anti-foaming agents lower the surface tension and with the cohesive binding of the liquid phase, avoid the formation of foams. Example of an anti-foaming agent is Cymethicone. Cymethicone has found its use as anti-foaming agent since a long time ago. To control or eliminate foam, Cymethicone has low intermolecular forces, lack of ionized moieties and least surface viscosities. Thus, is a vitally acceptable anti-foaming agent. When applied to non-aqueous foams, silicon fluids produce the effect by entering into the foams, spreading out over the surface of the foam and thin out. disrupting the foam surface resulting in the destabilization and breakage of the foam bubbles. The anti-foaming effect of silicones is primarily attributed to two mechanisms. First, the fine droplets of anti-foams enter into the liquid film that is present between the bubbles and rapidly wet out or cover the bubbles, reducing the surface tension and hence rupture of the film. The anti-foaming agent droplets enters into the liquid film between the bubbles and forms a mixed monolayer on the bubble surface. The less coherent monolayer destabilizes the film. PDMS show a considerable effectiveness in non-aqueous systems but have little foam-inhibiting activity in the aqueous surfactant solutions. For this purpose, hydrophobic silica can be included in the formulation to significantly increase the effectiveness of the antifoam agent. The hydrophobic silica is de-wetted by the bubble film which helps in thinning the film and promote instability by causing the foam to collapse due to direct mechanical shock. Other excipients which are commonly used in liquid formulations are preservatives, antioxidants and sweetening agents. Now, moving to second part of this module that is excipients for biphasic liquid dosage forms. Biphasic liquid includes suspensions, emulsions are a special type of dosage forms with their properties depending on the presence of a boundary region between the two phases. The suspensions are marked by the interface consisting of a liquid and an insoluble solid while emulsions constituting the two immiscible liquids usually oil and water to form an interface. An interface between the liquid and air is also present. Interface is marked by the fundamental property of possessing a positive free energy with the molecules at the interface in a higher energy state compared to those located in the bulk phase. The primary objective in a biphasic formulation is to reduce the positive interfacial free energy value to zero. through various means. The suspensions utilize the approach of reducing the amount of interface that is via flocculating or aggregating of particles while the emergence rests on the coalescence of the globules to form one macro phase in order to reduce the interfacial energy. Another method is to vary the composition of the interface to make it rich in surface active agents. Surfectants may be contained within a system in different forms as single molecules in solution or may be adsorbed at the air liquid surface. They may form a layer at the oil-water interface or may form oriented clusters in the aqueous phase referred to as missiles. Suspensions are heterogeneous systems comprising of two phases, the external or continuous phase which is generally a liquid or a semi-solid and the dispersed or internal phase consisting of a particulate matter essentially insoluble in but dispersed throughout the continuous phase. The insoluble matter may be intended either for physiologic absorption or for coating functions. On the other hand, emulsion is an intimate mixture of the two immiscible liquids which exhibit an acceptable shelf life near room temperature. On mechanical agitation, the two immiscible liquid phases tend to form droplets whose lifetime is increased with the addition of an emulsifier. The phase that persist in droplets form an extended period of time is called the internal or dispersed or discontinuous phase while it is surrounded by the external that is also known as continuous phase. On the basis of their structure, the emulsifiers can be described as molecules which comprise of both hydrophobic and hydrophilic portions, thus are frequently called as amphiphilic that is water and oil loving. Different excipients used in biphasic liquid dosage forms are wetting agents, deflocculant and dispersing agents, flocculating agents, suspending agents, emulsifying agents, viscosity modifiers. Now, the very first type of biphasic excipients are wetting agents. They are used to homogeneously disperse solid particles into liquid vehicle with the removal of adsorbed air and hence facilitate the easy penetration of the solvent into the pores of the particle within a short period of time. They consist of a bright hydrophobic chain with a central hydrophilic group or may also comprise of short hydrophobic chain with hydrophilic groups at the end. Wetting agents used for aqueous vehicles are alcohol, glycerin and polyglycols. Wetting agents used for non-aqueous vehicles are mineral oil. The extent of wetting by the wetting agent is defined by contact angle. The contact angle is referred to the angle by the intersection of the liquid solid and the liquid vapor interface. Small contact angles that is less than 90 degree is observed with the spreading of liquid on the surface corresponding to a high wettability while a larger contact angle that is greater than 90 degree is observed. when the liquid appears as a bead on the surface corresponding to reduced wettability. Smaller contact angles indicate the spreading of fluid over a larger surface area while greater contact angles indicate the reduced contact with the surface and formation of a compact liquid droplet. Thomas Young in 1805 gave an equation called as Young's equation which describes that the contact angle of a liquid drop on the solid surface is related to the mechanical equilibrium of the drop under the action of three interfacial tensions. The equation on the screen is Young's equation. Now, moving towards deflocculants and dispersing agents. These agents do not appreciably lower surface and interfacial tension. Thus, they have little tendency to create foam or wet particles. Most deflocculants, however, are not generally considered safe for internal use. And as a result, the only acceptable dispersant for oral product is lecithin or a lecithin derivative. Because lecithins vary in water solubility and dispersibility characteristics, proper control of product specifications must be maintained to obtain reproducibility. In a deflocculated suspension, the dispersed particles remain as discrete separate units of the body. that results in low settling of the dispersed particles. The supernatant of such suspension remain cloudy after shaking for an appreciable interval of time. This is attributed to the very slow settling rate of the smallest particles in the suspension, which prevents the liquid entrapment within the sediment, giving a compacted structure which is difficult to redisperse. This phenomena is referred as caking and it is the most severe physical stability problems that can be encountered in a suspension. Moving to flocculating agents. Flocculating agents are neutral electrolytes capable of reducing the zeta potential of suspending charged particles to zero. The optimal concentration of flocculating agent necessary to produce the flocculated state can be quantified using the Scurzel's-Hardy rule which states that The valence of ions having a charge opposite to that of the hydrophobic particle appears to determine the effectiveness of the electrolyte in aggregating the particles. The aggregating value or the efficiency increases with the valence of the ions. Divalent ions are 10 times as effective as monovalent. The trivalent are 1000 times as effective as monovalent. Furthermore, this rule is valid only for systems where the aggregating electrolyte does not undergo any chemical interaction with the ions of the double layer of the particle surface. In case of weakly charged, water insoluble, organic non-electrolytes, monovalent ions including sodium or potassium chlorides in small concentrations that is 0.0121 percent are often adequate to induce flocculation while in case of insoluble, highly charged Polyelectrolyte species, water-soluble divalent or trivalent ions such as aluminum chloride, calcium salts, citrates, sulfates, and potassium biphosphate at concentration 0.01 to 1% may be required for flocculation formation. The floccules exhibit a porous loose structure in which the dispersion medium can easily flow through during sedimentation. allowing a greater entrapment of the liquid phase. The floccules so formed are easily redispersible on moderate agitation. Flocculated particles form a type of lattice which resists complete settling of particles and are thus less prone to compaction and cake formation. The supernatant in case of flocculated suspensions quickly becomes clear due to a rapid settling of large floccules so formed. Suspending agents. They minimize the inter-particle attraction and aggregation by functioning as an energy barrier thus retard settling and agglomeration of the particles. The suspending agents can be cellulose derivatives, natural or synthetic gums and clays. The broad categories of suspending agents include protective collides, surfactants and viscosity inducing agents. Coming to protective collides. Suspension systems form clusters of particles thus exhibit poor drainage in bottles or vials making the formulation inelegant in appearance. These properties may be improved by the addition of protective collides. Protective collides, unlike surfactants, do not reduce the interfacial tension. However, They increase the zeta potential and form a mechanical barrier or sheath around the particles. They are used in higher concentrations than the surfactants. Modified cellulose polymers such as methylcellulose, sodium carboxymethylcellulose and hydroxypropyl methylcellulose are the widely used protective collides in oral, topical and parenteral dosage forms. Sodium carboxymethylcellulose is an anionic polymer. whereas methyl cellulose and hydroxypropyl methyl cellulose are non-ionic. Sodium carboxymethyl cellulose is used at a concentration of up to 0.5% in injectable preparations. Sodium carboxymethyl cellulose also has some limitations such as incompatibility with number of electrolytes and quaternary ammonium compounds and also forms complexes with certain surfactants. On the other hand, HPMC and methyl cellulose gel on heating are affected in the presence of electrolytes. Polyacrylic acid carbopole is another synthetic polymer widely used in external lotion and gel preparations. Although carbopole is extremely sensitive to electrolytes but it is suited for use of both in aqueous and non-aqueous systems. They function primarily as protective collides and modify the viscosity of the medium. Claes. Claes are another group of excipient. Quite useful in suspension formulation. Clays are hydrated aluminium or magnesium silicates. They form colloidal dispersions of high viscosities on further hydration with water. They possess acid neutralizing capacity as the aqueous clay dispersion has an alkaline pH 8.5 to 9.5. Clay form firm opaque gels at a concentration of 5 to 10%. Alkaline buffers are usually added to the clay dispersion to maintain the pH. Clay suspensions and gels should be preserved with non-ionic antimicrobial preservatives such as paraben esters and benzoates to prevent mould and bacterial growth. Its viscosity increase with heat and ageing but become less prominent in more concentrated systems. Thank you for watching. Emulsifying agents adsorb at the interface or on the surface of the suspending droplets, reducing the interfacial tension and preventing droplet coalescence. The emulsifying agents include surface active agents, hydrophilic collides and finely divided solids. They assist in the emulsion formation by three mechanisms, reduction of interfacial tension, thermodynamic stabilization, interfacial film formation. Mechanical barrier to coalescence, electrical repulsion, electrical barrier to approach of particles. Now, the first mechanism, reduction of interfacial tension. Emulsifying agents act as an interfacial barrier, lowering the interfacial tension between the two liquids. The attractive forces of the dispersed liquid gets reduced for its own molecules which decreases the interfacial free energy of the system preventing the coalescence or phase separation. Interfacial film formation, the emulsifier which is absorbed at the interface surrounds the dispersed droplets and forms a coherent monomolecular or multi-molecular film. preventing the coalescence of droplets as they approach each other. The type of emulsifier and the characteristic of the film it forms determines the stability of the emulsions. Monomolecular film formation, surface activations Surfectants form monomolecular film by absorbing at the oil-water interface. Due to the amphiphilicity of the surfactants, it aligns itself in the most energetically favorable position. with the hydrophobic portion in the oil phase and hydrophilic part in the aqueous phase, thus stabilizing the emulsions. The formation of monomolecular films depends upon the nature, characteristics and the concentration and combination of surfactant. Now gaseous films, gaseous films are characterized by the separation of adsorbed surfactant molecules as they approach each other. They do not adhere to each other laterally and undergoes free movement around the interface. Gaseous film formation is exhibited by anionic surfactant sodium dudesyl sulfate. When the film is to the dispersed phase droplet, the immersion is stable. The monolayer film should be strongly anchored to the droplets of the dispersed phase for the immersion to be stable. As The loosely fixed films tend to move away from the interface and leading to the coalescence. Condensed films The emulsifier at high concentration forms a rigid film between the two immiscible phases which provides mechanical resistance to both adhesion and coalescence of the droplets. Examples include long straight chain fatty acids, palmitic and stearic acids. They form tightly packed films which steeply rise from the compression. Expanded films Non-ionic surfactants and oleic acid forms expanded films. The hydrocarbon chains in the oleic acids are less orderly packed in liquid and less cohesive. It also has a polar unsaturated double bond with greater affinity for water. The presence of branched and bent shaped hydrocarbon chains bulky head groups and multiple polar groups causes lateral cohesion to be reduced and expanded films to form. Interfacial complex condensed films A single surfactant usually forms tough interfacial film. Thus, a combination of water-soluble surfactant which produces a gaseous film and an oil-soluble surfactant is preferred to produce a stable interfacial complex condensed film which improves the stability of the emulsion. Thus, the molecules are efficiently packed between each other with the film so formed being flexible, elastic, coherent, highly viscous and resistant to rupture. Lamellar Liquid Crystalline Films Stable emulsions are now believed to comprise liquid crystalline layers on the interface of emulsified droplets with the continuous phase. A three-dimensional association structure is formed on interaction of emulsifier with water. The three-component system comprised of oil, water, and laminar liquid crystals, the latter consisting of consecutive layers of water-emulsifier oil-water. The final mechanism, electrical repulsion. The interfacial film formed at the surface of the droplets produce repulsive electrical forces between the approaching droplets. The electrically charged groups oriented on the surface of the emulsified globules form electrical double layer which generates repulsion between the droplets. The electrical repulsion theory can be simply explained considering the case of oil in water emulsion stabilized by sodium soap. The ionic heads of the surfactants are oriented towards the continuous aqueous phase while the hydrocarbon tail faces the oil droplets. Thus, the droplet surface is stirred with the charged groups, negatively charged carboxylate groups in this case, which produces surface charge on the droplet. The cations of opposite signs orient near the surface resulting in diffuse double layer of charge. The double layer produces a potential which creates a repulsive effect between the oil droplets and thus causing hindrance in the coalescence of the droplets. The zeta potential is hence determined. The zeta potential for emulsion stabilized by a surfactant compares satisfactorily with calculated double layer potential. Furthermore, the change in zeta potential parallels rather agreeably the change in double layer potential on the addition of electrolyte. These and related data on the magnitude of the potential at the interface can be used to calculate total repulsion between oil droplets as a function of the distance between them. This representation of the electrical double layer at an oil-water interface is depicted on the screen. Moving towards hydrophilic polymers that are water sensitive that is, swallable or soluble, can be used as auxiliary emulsifiers and thickening agents. The clay of smectite or amphibole groups are used in makeup preparations. Bentonite, a typical smectite clay, swells in the presence of water at pH greater than 6. Etapolgite clay derived from the amphibole group thickens due to the particle anisotropy, which impairs the formation of compact sediment. Most natural hydrocolloids are polysaccharides. The next part is finely divided solids, solid particle film formation. Finely divided solids when combined with surfactants and or macromolecules which increase the viscosity work as good emulsifier. The category of finely divided solids includes polar inorganic solids, example heavy metal hydroxides, certain non-swelling clays and pigments, non-polar solids, such as carbon or glyceryl triesterate, nonpolar solids tend to be wetted by oil to a greater extent than by the aqueous phase, whereas the reverse is true for polar solids. The nonpolar solids favor the formation of water in oil emulsions in the absence of surfactants because the wetting by oil promotes the coalescence of oil droplets during the initial steps of emulsification. Finely divided solid particles form a stable film by adhering at the interface. They perform the action by wetting one of the faces. When wetted by water, the contact angle is less than 90 degree and oil in water type emulsions are formed. While when wetted by oil, water in oil type emulsions are formed. Now coming to surface active agents or surfactants. Agents that are well known class of emulsifying agents. Are the substances having both hydrophobic and hydrophilic regions in their molecular structures? They are amphiphilic in nature and thus are soluble in both oil and water. The surfactants when added into the dispersed system orient themselves in a monomolecular layer with its hydrophilic polar group facing the polar that is water solvent and hydrophobic non-polar groups facing the non-polar solvents. They lower the interfacial tension and readily emulsify the dispersed system. Increase in the surfactant concentration in an aqueous solution results in the reduction of interfacial tension. Upon further addition, the surfactant molecules are closely packed in results in the saturation at the surface beyond which excess surfactants goes into the bulk and form missiles within the aqueous solution. These are grouped into four major categories. depending on the nature of the charge carried by the hydrophilic region of the surfactants that are anionic, cationic, non-ionic and ampholytic surfactants. The different surfactants used in emulsion preparations are tabulated on this screen. Now, moving to the next part of this module that is determination of HLB values. HLB is also known as hydrophilic-lipophilic balance. The emulsifiers can be selected based on the knowledge of their lipophilic and hydrophilic behavior and on the type of emulsion produced with a given aqueous or lipid. The method is practical but tedious and empiric in nature. Griffin in 1947 systematized the approach of emulsifier. selection by developing somewhat empirical system for determining the HLB of surfactants. The HLB value of the emulsifier can be determined experimentally or computed through the structural formula of the surfactant. Different ways to determine HLB values of a surfactant can be enumerated as number 1, based on polyhydric alcohol fatty acid esters, the HLB value may be estimated by the following formula HLB is equals to 20 bracket 1 minus S by A where S is the saponification number of the ester and A is the acid number of the fatty acid. Secondly, for those whose saponification number cannot be determined, their HLB values may be calculated by the formula HLB is equals to E plus P divided by 5 where E is the weight percent of oxyethylene chains in the surfactant and P is the weight percent of the polyhydric alcohol groups, examples sorbitol or garcerol in the substance. Thirdly, if the hydrophilic region is polyoxyethylene, the HLB value is calculated by HLB is equals to E by 5. Davies method permits the calculation of HLB value by algebraically adding the values assigned to a particular atomic grouping. within the molecule of the emulsifier which can be calculated by the formula depicting on the screen. A single emulsifier however, can yield the required time of emulsion of the desired viscosity but in case of oil in water emulsions, combination of surfactants is utilized to obtain a stable emulsion. The combinatorial approach of utilizing a hydrophilic and lipophilic surfactant produces mixed interfacial phases. with a sufficient surface coverage and viscosity preventing creaming and promoting stability. The HLB value of surfactant mixtures of surfactant A, that is HLB A and B, HLB B can be calculated by the formula depicted on the screen. Application of surfactants based on HLB value is depicted on the screen. HLB value 1, 2, 3 having application as anti-foaming agents. HLB value having 3 to 6 is can be used as water in oil emulsifying agents and those having HLB value of 7 to 9 can be used as wetting agents. On the other hand, HLB values having 8 to 16 can be used as oil in water emulsifying agents. On the other hand, the HLB values of 13 to 15 can be used as detergents while 15 to 18 can be used as solubilizing agents. The next type of excipients are viscosity modifiers. A consistency that provides the desired stability is the chief characteristic of an emulsion. The appropriate flow characteristic can be attained by manipulating the composition of lipid phase. and surfactant by the addition of gums. Rheologic character along with the surfact characteristic of interfacial film influences creaming of the fillet emulsion. An increase in viscosity generally minimizes creaming, rising or sedimentation. The use of gums, clays and synthetic polymers in the continuous phase of emulsion is a powerful tool For enhancing an emulsion's stability, it is recommended to keep the newly formulated emulsion undisturbed for 24 to 48 hours before determining whether its rheological properties, as it requires some time to build up the viscosity. The viscosity of emulsion responds to changes in composition in accordance with the following generalizations. Number 1. A linear relationship is observed between the emulsion viscosity and viscosity of the continuous phase. For example, the addition of polyvalent metal soaps or high melting waxes in a water in oil emulsion increases the viscosity. Emulsion viscosity is not very sensitive to viscosity changes of the internal phase. Secondly, the higher the volume of the internal phase, the higher is the upper end viscosity. Third, three interacting effects. must be balanced to control emulsion viscosity, that are, a reduced particle size of the dispersed phase increases emulsion viscosity. Second, emulsion stability is enhanced by a reduction in particle size. Third, increase in viscosity is observed with the flocculation or clumping which tends to structure the internal phase. On the other hand, the viscosity of emulsions can be increases upon ageing. Third phase. The choice of oil phase of an emulsion is primarily dependent on the ultimate use of the product. The oil portion of pharmaceutical and cosmetic products include variety of lipids of the natural or the synthetic origin with their consistency ranging from mobile liquids to fairly hard solids. Most commonly used lipids for pharmaceutical or cosmetic emulsions have been depicted in the table. The first factor influencing the selection of lipid component is the drug solubility in the oil portion of the emulsion. Drug distribution in the oil phase and aqueous phase in an emulsion depend on its oil or water partition coefficient. The solubility of drug in the oil phase determine its absorption by the gastrointestinal tract or the skin. Principally, the lesser the drug solubility in the non-volatile part of the vehicle, the greater is its penetration into the barrier. Furthermore, A finite solubility of the drug in the vehicle is crucial to ensure its presence in a fine state of subdivision. Thus, altogether it can be stated that the active ingredient must not be so soluble in the base that it prevents penetration or transfer. Another consideration in the selection of oil phase for a topical preparation is its feel. The extractions normally leave a residue of the oily components on the skin. after the water has evaporated. Therefore, the tactile characteristics of the combined oil phase are of great importance in determining consumer acceptance of an emulsion. The emulsion internal and external phase ratio is determined by the solubility of the drug molecule or by the desired consistency. The low levels of the internal phase results in a formation of fluid emulsions whereas higher percentages of the internal phase results in a heavier emulsion. A high internal phase ratio normally requires a high level of emulsifying agent. This point affects the decision concerning the phase ratio. So finally, we have concluded that the inherently unstable drug in a solution form and a poor soluble drug presents many technical problems to the formulator. A precise understanding of the components of a dosage form is necessary so as to solubilize the lipophilic molecule. and stabilize the unstable therapeutic moiety. The primary objective in a biphasic dosage form is to reduce the positive interfacial free energy value to zero which is achieved by various means such as using wetting agents, suspending agents, emulsifying agents. The basic mechanism of action of each excipient along with their physicochemical properties have been put forth. So, as to develop the optimal monophasic or biphasic liquid formulation for optimal drug delivery.

and biphasic liquid dosage form. We will start with excipients for monophasic liquid dosage forms. Liquid dosage forms are intended to be used by geriatric or pediatric population and include solutions, suspensions and emulsions.

They may be prepared by dissolving a substance in aqueous vehicle or a non-aqueous vehicle by suspending it in a suitable medium or by incorporating the drug in an oil or water phase. In pharmaceutical terms, solutions are the liquid preparations containing one or more soluble chemical substances, which are dissolved in a suitable solvent that is usually water or in a mixture of mutually miscible solvents and do not by reason of their ingredients or the method of preparation. or use, drop into other group of products.

With rare exceptions, the ingredient must be in solution form in order to be absorbed and which makes the drug immediately available for absorption and hence making it more rapidly and efficiently absorbed than the same amount of the drug when administered in a tablet or capsule. The formulation of solution is a cumbersome process and presents an array of technical problems to the industrial pharmacist. Certain drugs are inherently unstable, some are poorly soluble. To unravel the formulation problems with the pharmaceutical liquids, an interesting dichotomy of investigative skills is required. The solubility and stability factors can be approached with the precision long associated with exact sciences while flavouring and other organoleptic characteristics are the subjective factors.

Thus, the successful formulation of a dosage form requires a blend of scientific acuity and pharmaceutical art. The various excipients involved in the manufacturing of liquid dosage forms are Vehicles, solubilizers, complexing agents, buffering agents and antifoaming agents. Now, we will start with vehicles.

Vehicles are the liquid bases which carry the active pharmaceutical ingredient and other excipients in the formulation in the dissolved or dispersed state. Vehicles may be aqueous or oily. Aqueous vehicles include water, polyhydric alcohols, Hydroalcoholic solutions and buffers.

Oily vehicles include vegetables or mineral oils, organic oily bases or emulsified bases. Portable water is the one which contains 0.1% of the total solid purified water USP. Is used as vehicle in all the liquid formulations except for the parenterals for which water for injection is used. The quality of water is defined by the USP in terms of conductivity. Alcohol also known as ethyl alcohol is used as hydroalcoholic mixture that is capable of dissolving both alcohol soluble and water soluble drugs and excipients glycerol serves as an excellent solvent for range of substances such as alkyl neutral salts tannins etc glycerin is added to the oral formulations in the form of co-solvent to solubilize hydrophobic drugs to improve the viscosity and also as taste masking agent Propylene glycol with purity of more than 99.8% has multiple uses such as solvent for automatics in flavor concentrate industry, wetting agents for natural gums, solvent in elixirs and pharmaceutical preparations, emulsifiers in creams, and as humectants, preservatives, and stabilizers.

Lipid-based vehicles are used to solubilize the hydrophobic drugs by forming self-emulsifying system using a surfactant. The lipid in the formulation keeps the hydrophobic drug in solution state and facilitates its dissolution and absorption as the lipid vehicle is metabolized in gastrointestinal tract. Now, moving to solubilizers.

These are used in the aqueous base formulations to modify the polarity of water so as to dissolve a non-polar drug. They alter the polarity, viscosity, sulphur extension, density, boiling point and specific heat of solution in various ways. The mechanism of solubility enhancement using co-solvents is not well understood. Co-solvents reduce the interfacial tension between the aqueous solutions and the hydrophobic solute. Some of the examples of solubilizers include sugars, sorbitols, alcohols, ethanol, propylene glycol and polyethylene glycols such as PEG-400.

Recent reports suggest a number of solvents that can be used in oral liquids. These include glycophrudol, glycerol, dimethyl cetyl, glycerol formal, dimethyl acetamide, ethyl lactate, ethyl carbonate and 1,3-butylene glycol. However, With the exception of dimethylacetamide, all the other solvents mentioned above are not acceptable for systemic use.

Dimethylacetamide can be used as a co-solvent in parenteral products but it's not suitable for use in oral liquids owing to its objectionable odour and taste. Thus, a very narrow spectrum of solvents is available for use in oral liquid formulations. Coming to Complexing Agent.

Complexing agents serve to enhance the solvability of a compound. This can be achieved if both the drug molecule and complexing agent have proper size, charge and lipophilicity that allow for favourable solubility enhances non-covalent interactions. The most commonly used complexing agent is cyclodextrin.

Cyclodextrin constitute a group of structurally related natural products which are formed during the bacterial digestion of cellulose. They are the cyclic oligosaccharides made up of alpha-1-folding. alpha-D glucopyranose units with a lipophilic central core and a hydrophilic outer corona. The limited free rotation around the bonds linking the glucopyranose units make cyclodextrin toroidal or cone-shaped.

The parent or natural cyclodextrin may contain 6, 7 or 8 glucopyranose units referred to as alpha, beta and gamma cyclodextrins respectively. Cyclodextrin act as a molecule container that entraps the gas molecules in their internal cavity forming inclusion complexes in aqueous solution. The lipophilic moiety is taken up into the hydrophobic central cavity of the cyclodextrin. and they are in rapid equilibrium with the free drug molecules in the solution.

No covalent bonds are formed or broken down during drug-cyclodextrin complex formation. The driving forces for the formation of inclusion complex include release of enthalpy-rich water molecules from the cavity, Vandervol force, electrostatic and or hydrophobic interactions, hydrogen bonding, release of a conformational strain and charge transfer interactions. The drug-cyclodextrin complex Offers several advantages which include solubility and hence bioavailability enhancement, improvement in drug stability, reduction of gastrointestinal or skin or eye irritation associated with drugs, prevention of drug-drug or drug excipient incompatibility and odor and taste masking of bitter drugs.

Moving towards buffering agents, they are used to maintain pH of the formulation to ensure the physiological compatibility of the formulation. with the biological fluids and also to maintain the formulation stability. The required amount of buffer capacity is usually between 0.01 and 0.1 molar while the concentration of 0.05 and 0.5 molar is sufficient.

The choice of buffer to be used in the formulation is based on whether the acid-base forms are listed for use in oral liquid dosage form Drug and Excipient Stability in Buffer Compatibility between the buffer and the container Several factors such as amount and the type of co-solvents present, dilution, ionic strength and temperature may contribute to affect the pH of the solution. For instance, with the increase in temperature, the pH of the acetate buffers increases while the pH of boric acid buffers The buffer may negatively influence the solubility of drug and excipients. The effect depends on the polarity of solute and salt when combined in the formulation.

Non-polar solutes are solubilized by weakly polar organic salts while they are desolubilized by polar salts. Conversely, polar solutes are solubilized by polar salts and desolubilized by organic salts. Comparison of the two that have multiple charged species in solution can also be determined the potential reaction between the drug and excipients. For example, buffer that use citrates, phosphates, Carbonates and tartrates may precipitate with calcium ions forming sparingly soluble salts, the precipitation being dependent on the pH of the solution. Antifoaming agents The foams may be formed in a liquid dosage form either during the manufacturing process or when it is reconstituted.

Defoaming and antifoaming are like two faces of a same coin, utilizing the same type of material for their prevention, differing slightly in their mechanism of foam prevention. De-foaming indicates breaking, rapid knockdown and controlling the pre-existing foam. Foam inhibition or anti-foaming implies preventing the foam from forming during its first occurrence.

Anti-foaming agents lower the surface tension and with the cohesive binding of the liquid phase, avoid the formation of foams. Example of an anti-foaming agent is Cymethicone. Cymethicone has found its use as anti-foaming agent since a long time ago. To control or eliminate foam, Cymethicone has low intermolecular forces, lack of ionized moieties and least surface viscosities.

Thus, is a vitally acceptable anti-foaming agent. When applied to non-aqueous foams, silicon fluids produce the effect by entering into the foams, spreading out over the surface of the foam and thin out. disrupting the foam surface resulting in the destabilization and breakage of the foam bubbles.

The anti-foaming effect of silicones is primarily attributed to two mechanisms. First, the fine droplets of anti-foams enter into the liquid film that is present between the bubbles and rapidly wet out or cover the bubbles, reducing the surface tension and hence rupture of the film. The anti-foaming agent droplets enters into the liquid film between the bubbles and forms a mixed monolayer on the bubble surface. The less coherent monolayer destabilizes the film. PDMS show a considerable effectiveness in non-aqueous systems but have little foam-inhibiting activity in the aqueous surfactant solutions.

For this purpose, hydrophobic silica can be included in the formulation to significantly increase the effectiveness of the antifoam agent. The hydrophobic silica is de-wetted by the bubble film which helps in thinning the film and promote instability by causing the foam to collapse due to direct mechanical shock. Other excipients which are commonly used in liquid formulations are preservatives, antioxidants and sweetening agents. Now, moving to second part of this module that is excipients for biphasic liquid dosage forms.

Biphasic liquid includes suspensions, emulsions are a special type of dosage forms with their properties depending on the presence of a boundary region between the two phases. The suspensions are marked by the interface consisting of a liquid and an insoluble solid while emulsions constituting the two immiscible liquids usually oil and water to form an interface. An interface between the liquid and air is also present.

Interface is marked by the fundamental property of possessing a positive free energy with the molecules at the interface in a higher energy state compared to those located in the bulk phase. The primary objective in a biphasic formulation is to reduce the positive interfacial free energy value to zero. through various means.

The suspensions utilize the approach of reducing the amount of interface that is via flocculating or aggregating of particles while the emergence rests on the coalescence of the globules to form one macro phase in order to reduce the interfacial energy. Another method is to vary the composition of the interface to make it rich in surface active agents. Surfectants may be contained within a system in different forms as single molecules in solution or may be adsorbed at the air liquid surface.

They may form a layer at the oil-water interface or may form oriented clusters in the aqueous phase referred to as missiles. Suspensions are heterogeneous systems comprising of two phases, the external or continuous phase which is generally a liquid or a semi-solid and the dispersed or internal phase consisting of a particulate matter essentially insoluble in but dispersed throughout the continuous phase. The insoluble matter may be intended either for physiologic absorption or for coating functions.

On the other hand, emulsion is an intimate mixture of the two immiscible liquids which exhibit an acceptable shelf life near room temperature. On mechanical agitation, the two immiscible liquid phases tend to form droplets whose lifetime is increased with the addition of an emulsifier. The phase that persist in droplets form an extended period of time is called the internal or dispersed or discontinuous phase while it is surrounded by the external that is also known as continuous phase. On the basis of their structure, the emulsifiers can be described as molecules which comprise of both hydrophobic and hydrophilic portions, thus are frequently called as amphiphilic that is water and oil loving. Different excipients used in biphasic liquid dosage forms are wetting agents, deflocculant and dispersing agents, flocculating agents, suspending agents, emulsifying agents, viscosity modifiers.

Now, the very first type of biphasic excipients are wetting agents. They are used to homogeneously disperse solid particles into liquid vehicle with the removal of adsorbed air and hence facilitate the easy penetration of the solvent into the pores of the particle within a short period of time. They consist of a bright hydrophobic chain with a central hydrophilic group or may also comprise of short hydrophobic chain with hydrophilic groups at the end.

Wetting agents used for aqueous vehicles are alcohol, glycerin and polyglycols. Wetting agents used for non-aqueous vehicles are mineral oil. The extent of wetting by the wetting agent is defined by contact angle. The contact angle is referred to the angle by the intersection of the liquid solid and the liquid vapor interface. Small contact angles that is less than 90 degree is observed with the spreading of liquid on the surface corresponding to a high wettability while a larger contact angle that is greater than 90 degree is observed.

when the liquid appears as a bead on the surface corresponding to reduced wettability. Smaller contact angles indicate the spreading of fluid over a larger surface area while greater contact angles indicate the reduced contact with the surface and formation of a compact liquid droplet. Thomas Young in 1805 gave an equation called as Young's equation which describes that the contact angle of a liquid drop on the solid surface is related to the mechanical equilibrium of the drop under the action of three interfacial tensions.

The equation on the screen is Young's equation. Now, moving towards deflocculants and dispersing agents. These agents do not appreciably lower surface and interfacial tension.

Thus, they have little tendency to create foam or wet particles. Most deflocculants, however, are not generally considered safe for internal use. And as a result, the only acceptable dispersant for oral product is lecithin or a lecithin derivative. Because lecithins vary in water solubility and dispersibility characteristics, proper control of product specifications must be maintained to obtain reproducibility. In a deflocculated suspension, the dispersed particles remain as discrete separate units of the body.

that results in low settling of the dispersed particles. The supernatant of such suspension remain cloudy after shaking for an appreciable interval of time. This is attributed to the very slow settling rate of the smallest particles in the suspension, which prevents the liquid entrapment within the sediment, giving a compacted structure which is difficult to redisperse.

This phenomena is referred as caking and it is the most severe physical stability problems that can be encountered in a suspension. Moving to flocculating agents. Flocculating agents are neutral electrolytes capable of reducing the zeta potential of suspending charged particles to zero.

The optimal concentration of flocculating agent necessary to produce the flocculated state can be quantified using the Scurzel's-Hardy rule which states that The valence of ions having a charge opposite to that of the hydrophobic particle appears to determine the effectiveness of the electrolyte in aggregating the particles. The aggregating value or the efficiency increases with the valence of the ions. Divalent ions are 10 times as effective as monovalent.

The trivalent are 1000 times as effective as monovalent. Furthermore, this rule is valid only for systems where the aggregating electrolyte does not undergo any chemical interaction with the ions of the double layer of the particle surface. In case of weakly charged, water insoluble, organic non-electrolytes, monovalent ions including sodium or potassium chlorides in small concentrations that is 0.0121 percent are often adequate to induce flocculation while in case of insoluble, highly charged Polyelectrolyte species, water-soluble divalent or trivalent ions such as aluminum chloride, calcium salts, citrates, sulfates, and potassium biphosphate at concentration 0.01 to 1% may be required for flocculation formation.

The floccules exhibit a porous loose structure in which the dispersion medium can easily flow through during sedimentation. allowing a greater entrapment of the liquid phase. The floccules so formed are easily redispersible on moderate agitation. Flocculated particles form a type of lattice which resists complete settling of particles and are thus less prone to compaction and cake formation.

The supernatant in case of flocculated suspensions quickly becomes clear due to a rapid settling of large floccules so formed. Suspending agents. They minimize the inter-particle attraction and aggregation by functioning as an energy barrier thus retard settling and agglomeration of the particles. The suspending agents can be cellulose derivatives, natural or synthetic gums and clays. The broad categories of suspending agents include protective collides, surfactants and viscosity inducing agents.

Coming to protective collides. Suspension systems form clusters of particles thus exhibit poor drainage in bottles or vials making the formulation inelegant in appearance. These properties may be improved by the addition of protective collides.

Protective collides, unlike surfactants, do not reduce the interfacial tension. However, They increase the zeta potential and form a mechanical barrier or sheath around the particles. They are used in higher concentrations than the surfactants.

Modified cellulose polymers such as methylcellulose, sodium carboxymethylcellulose and hydroxypropyl methylcellulose are the widely used protective collides in oral, topical and parenteral dosage forms. Sodium carboxymethylcellulose is an anionic polymer. whereas methyl cellulose and hydroxypropyl methyl cellulose are non-ionic. Sodium carboxymethyl cellulose is used at a concentration of up to 0.5% in injectable preparations.

Sodium carboxymethyl cellulose also has some limitations such as incompatibility with number of electrolytes and quaternary ammonium compounds and also forms complexes with certain surfactants. On the other hand, HPMC and methyl cellulose gel on heating are affected in the presence of electrolytes. Polyacrylic acid carbopole is another synthetic polymer widely used in external lotion and gel preparations.

Although carbopole is extremely sensitive to electrolytes but it is suited for use of both in aqueous and non-aqueous systems. They function primarily as protective collides and modify the viscosity of the medium. Claes.

Claes are another group of excipient. Quite useful in suspension formulation. Clays are hydrated aluminium or magnesium silicates. They form colloidal dispersions of high viscosities on further hydration with water. They possess acid neutralizing capacity as the aqueous clay dispersion has an alkaline pH 8.5 to 9.5.

Clay form firm opaque gels at a concentration of 5 to 10%. Alkaline buffers are usually added to the clay dispersion to maintain the pH. Clay suspensions and gels should be preserved with non-ionic antimicrobial preservatives such as paraben esters and benzoates to prevent mould and bacterial growth. Its viscosity increase with heat and ageing but become less prominent in more concentrated systems. Thank you for watching. Emulsifying agents adsorb at the interface or on the surface of the suspending droplets, reducing the interfacial tension and preventing droplet coalescence.

The emulsifying agents include surface active agents, hydrophilic collides and finely divided solids. They assist in the emulsion formation by three mechanisms, reduction of interfacial tension, thermodynamic stabilization, interfacial film formation. Mechanical barrier to coalescence, electrical repulsion, electrical barrier to approach of particles. Now, the first mechanism, reduction of interfacial tension. Emulsifying agents act as an interfacial barrier, lowering the interfacial tension between the two liquids.

The attractive forces of the dispersed liquid gets reduced for its own molecules which decreases the interfacial free energy of the system preventing the coalescence or phase separation. Interfacial film formation, the emulsifier which is absorbed at the interface surrounds the dispersed droplets and forms a coherent monomolecular or multi-molecular film. preventing the coalescence of droplets as they approach each other.

The type of emulsifier and the characteristic of the film it forms determines the stability of the emulsions. Monomolecular film formation, surface activations Surfectants form monomolecular film by absorbing at the oil-water interface. Due to the amphiphilicity of the surfactants, it aligns itself in the most energetically favorable position. with the hydrophobic portion in the oil phase and hydrophilic part in the aqueous phase, thus stabilizing the emulsions. The formation of monomolecular films depends upon the nature, characteristics and the concentration and combination of surfactant.

Now gaseous films, gaseous films are characterized by the separation of adsorbed surfactant molecules as they approach each other. They do not adhere to each other laterally and undergoes free movement around the interface. Gaseous film formation is exhibited by anionic surfactant sodium dudesyl sulfate. When the film is to the dispersed phase droplet, the immersion is stable.

The monolayer film should be strongly anchored to the droplets of the dispersed phase for the immersion to be stable. As The loosely fixed films tend to move away from the interface and leading to the coalescence. Condensed films The emulsifier at high concentration forms a rigid film between the two immiscible phases which provides mechanical resistance to both adhesion and coalescence of the droplets. Examples include long straight chain fatty acids, palmitic and stearic acids. They form tightly packed films which steeply rise from the compression.

Expanded films Non-ionic surfactants and oleic acid forms expanded films. The hydrocarbon chains in the oleic acids are less orderly packed in liquid and less cohesive. It also has a polar unsaturated double bond with greater affinity for water. The presence of branched and bent shaped hydrocarbon chains bulky head groups and multiple polar groups causes lateral cohesion to be reduced and expanded films to form.

Interfacial complex condensed films A single surfactant usually forms tough interfacial film. Thus, a combination of water-soluble surfactant which produces a gaseous film and an oil-soluble surfactant is preferred to produce a stable interfacial complex condensed film which improves the stability of the emulsion. Thus, the molecules are efficiently packed between each other with the film so formed being flexible, elastic, coherent, highly viscous and resistant to rupture.

Lamellar Liquid Crystalline Films Stable emulsions are now believed to comprise liquid crystalline layers on the interface of emulsified droplets with the continuous phase. A three-dimensional association structure is formed on interaction of emulsifier with water. The three-component system comprised of oil, water, and laminar liquid crystals, the latter consisting of consecutive layers of water-emulsifier oil-water.

The final mechanism, electrical repulsion. The interfacial film formed at the surface of the droplets produce repulsive electrical forces between the approaching droplets. The electrically charged groups oriented on the surface of the emulsified globules form electrical double layer which generates repulsion between the droplets.

The electrical repulsion theory can be simply explained considering the case of oil in water emulsion stabilized by sodium soap. The ionic heads of the surfactants are oriented towards the continuous aqueous phase while the hydrocarbon tail faces the oil droplets. Thus, the droplet surface is stirred with the charged groups, negatively charged carboxylate groups in this case, which produces surface charge on the droplet.

The cations of opposite signs orient near the surface resulting in diffuse double layer of charge. The double layer produces a potential which creates a repulsive effect between the oil droplets and thus causing hindrance in the coalescence of the droplets. The zeta potential is hence determined.

The zeta potential for emulsion stabilized by a surfactant compares satisfactorily with calculated double layer potential. Furthermore, the change in zeta potential parallels rather agreeably the change in double layer potential on the addition of electrolyte. These and related data on the magnitude of the potential at the interface can be used to calculate total repulsion between oil droplets as a function of the distance between them.

This representation of the electrical double layer at an oil-water interface is depicted on the screen. Moving towards hydrophilic polymers that are water sensitive that is, swallable or soluble, can be used as auxiliary emulsifiers and thickening agents. The clay of smectite or amphibole groups are used in makeup preparations. Bentonite, a typical smectite clay, swells in the presence of water at pH greater than 6. Etapolgite clay derived from the amphibole group thickens due to the particle anisotropy, which impairs the formation of compact sediment. Most natural hydrocolloids are polysaccharides.

The next part is finely divided solids, solid particle film formation. Finely divided solids when combined with surfactants and or macromolecules which increase the viscosity work as good emulsifier. The category of finely divided solids includes polar inorganic solids, example heavy metal hydroxides, certain non-swelling clays and pigments, non-polar solids, such as carbon or glyceryl triesterate, nonpolar solids tend to be wetted by oil to a greater extent than by the aqueous phase, whereas the reverse is true for polar solids. The nonpolar solids favor the formation of water in oil emulsions in the absence of surfactants because the wetting by oil promotes the coalescence of oil droplets during the initial steps of emulsification.

Finely divided solid particles form a stable film by adhering at the interface. They perform the action by wetting one of the faces. When wetted by water, the contact angle is less than 90 degree and oil in water type emulsions are formed. While when wetted by oil, water in oil type emulsions are formed.

Now coming to surface active agents or surfactants. Agents that are well known class of emulsifying agents. Are the substances having both hydrophobic and hydrophilic regions in their molecular structures? They are amphiphilic in nature and thus are soluble in both oil and water. The surfactants when added into the dispersed system orient themselves in a monomolecular layer with its hydrophilic polar group facing the polar that is water solvent and hydrophobic non-polar groups facing the non-polar solvents.

They lower the interfacial tension and readily emulsify the dispersed system. Increase in the surfactant concentration in an aqueous solution results in the reduction of interfacial tension. Upon further addition, the surfactant molecules are closely packed in results in the saturation at the surface beyond which excess surfactants goes into the bulk and form missiles within the aqueous solution.

These are grouped into four major categories. depending on the nature of the charge carried by the hydrophilic region of the surfactants that are anionic, cationic, non-ionic and ampholytic surfactants. The different surfactants used in emulsion preparations are tabulated on this screen.

Now, moving to the next part of this module that is determination of HLB values. HLB is also known as hydrophilic-lipophilic balance. The emulsifiers can be selected based on the knowledge of their lipophilic and hydrophilic behavior and on the type of emulsion produced with a given aqueous or lipid.

The method is practical but tedious and empiric in nature. Griffin in 1947 systematized the approach of emulsifier. selection by developing somewhat empirical system for determining the HLB of surfactants.

The HLB value of the emulsifier can be determined experimentally or computed through the structural formula of the surfactant. Different ways to determine HLB values of a surfactant can be enumerated as number 1, based on polyhydric alcohol fatty acid esters, the HLB value may be estimated by the following formula HLB is equals to 20 bracket 1 minus S by A where S is the saponification number of the ester and A is the acid number of the fatty acid. Secondly, for those whose saponification number cannot be determined, their HLB values may be calculated by the formula HLB is equals to E plus P divided by 5 where E is the weight percent of oxyethylene chains in the surfactant and P is the weight percent of the polyhydric alcohol groups, examples sorbitol or garcerol in the substance. Thirdly, if the hydrophilic region is polyoxyethylene, the HLB value is calculated by HLB is equals to E by 5. Davies method permits the calculation of HLB value by algebraically adding the values assigned to a particular atomic grouping.

within the molecule of the emulsifier which can be calculated by the formula depicting on the screen. A single emulsifier however, can yield the required time of emulsion of the desired viscosity but in case of oil in water emulsions, combination of surfactants is utilized to obtain a stable emulsion. The combinatorial approach of utilizing a hydrophilic and lipophilic surfactant produces mixed interfacial phases. with a sufficient surface coverage and viscosity preventing creaming and promoting stability.

The HLB value of surfactant mixtures of surfactant A, that is HLB A and B, HLB B can be calculated by the formula depicted on the screen. Application of surfactants based on HLB value is depicted on the screen. HLB value 1, 2, 3 having application as anti-foaming agents.

HLB value having 3 to 6 is can be used as water in oil emulsifying agents and those having HLB value of 7 to 9 can be used as wetting agents. On the other hand, HLB values having 8 to 16 can be used as oil in water emulsifying agents. On the other hand, the HLB values of 13 to 15 can be used as detergents while 15 to 18 can be used as solubilizing agents.

The next type of excipients are viscosity modifiers. A consistency that provides the desired stability is the chief characteristic of an emulsion. The appropriate flow characteristic can be attained by manipulating the composition of lipid phase. and surfactant by the addition of gums. Rheologic character along with the surfact characteristic of interfacial film influences creaming of the fillet emulsion.

An increase in viscosity generally minimizes creaming, rising or sedimentation. The use of gums, clays and synthetic polymers in the continuous phase of emulsion is a powerful tool For enhancing an emulsion's stability, it is recommended to keep the newly formulated emulsion undisturbed for 24 to 48 hours before determining whether its rheological properties, as it requires some time to build up the viscosity. The viscosity of emulsion responds to changes in composition in accordance with the following generalizations. Number 1. A linear relationship is observed between the emulsion viscosity and viscosity of the continuous phase. For example, the addition of polyvalent metal soaps or high melting waxes in a water in oil emulsion increases the viscosity.

Emulsion viscosity is not very sensitive to viscosity changes of the internal phase. Secondly, the higher the volume of the internal phase, the higher is the upper end viscosity. Third, three interacting effects. must be balanced to control emulsion viscosity, that are, a reduced particle size of the dispersed phase increases emulsion viscosity. Second, emulsion stability is enhanced by a reduction in particle size.

Third, increase in viscosity is observed with the flocculation or clumping which tends to structure the internal phase. On the other hand, the viscosity of emulsions can be increases upon ageing. Third phase. The choice of oil phase of an emulsion is primarily dependent on the ultimate use of the product. The oil portion of pharmaceutical and cosmetic products include variety of lipids of the natural or the synthetic origin with their consistency ranging from mobile liquids to fairly hard solids.

Most commonly used lipids for pharmaceutical or cosmetic emulsions have been depicted in the table. The first factor influencing the selection of lipid component is the drug solubility in the oil portion of the emulsion. Drug distribution in the oil phase and aqueous phase in an emulsion depend on its oil or water partition coefficient.

The solubility of drug in the oil phase determine its absorption by the gastrointestinal tract or the skin. Principally, the lesser the drug solubility in the non-volatile part of the vehicle, the greater is its penetration into the barrier. Furthermore, A finite solubility of the drug in the vehicle is crucial to ensure its presence in a fine state of subdivision. Thus, altogether it can be stated that the active ingredient must not be so soluble in the base that it prevents penetration or transfer.

Another consideration in the selection of oil phase for a topical preparation is its feel. The extractions normally leave a residue of the oily components on the skin. after the water has evaporated. Therefore, the tactile characteristics of the combined oil phase are of great importance in determining consumer acceptance of an emulsion.

The emulsion internal and external phase ratio is determined by the solubility of the drug molecule or by the desired consistency. The low levels of the internal phase results in a formation of fluid emulsions whereas higher percentages of the internal phase results in a heavier emulsion. A high internal phase ratio normally requires a high level of emulsifying agent. This point affects the decision concerning the phase ratio. So finally, we have concluded that the inherently unstable drug in a solution form and a poor soluble drug presents many technical problems to the formulator.

A precise understanding of the components of a dosage form is necessary so as to solubilize the lipophilic molecule. and stabilize the unstable therapeutic moiety. The primary objective in a biphasic dosage form is to reduce the positive interfacial free energy value to zero which is achieved by various means such as using wetting agents, suspending agents, emulsifying agents.

The basic mechanism of action of each excipient along with their physicochemical properties have been put forth. So, as to develop the optimal monophasic or biphasic liquid formulation for optimal drug delivery.

Transcript for:Excipients for Liquid Dosage Forms

Transcript for:
Excipients for Liquid Dosage Forms