Liquid dosage forms for oral administration -Suspensions and Emulsions

dispersions in which the drug is dispersed in the external phase (vehicle) solubility of drug in vehicle is low Diameter of disperse phase: 0.5 to 100m. when particle size < 0.5 m: colloidal.

Fundamentally unstable, leading to sedimentation particle-particle interactions and, ultimately, caking (compaction). understanding their physical stability : electrical properties of dispersed particles and effect of distance of separation between particles on their subsequent interaction.

Following dispersion within an aqueous medium, particles may acquire a charge due to either: ionisation of functional groups on the drug molecule and/or adsorption of ions to the surface of the particle. Following adsorption of ions on to the surface, a phenomenon referred to as the electrical double layer is established The boundary of this second layer will possess a potential, referred to as the zeta (ζ) potential. Zeta potential measures degree of electric charge on particles relative to bulk medium in which they are suspended compression of the electrical double layer by increased concentration of electrolyte. This approach may be used to stabilise pharmaceutical suspensions.

Three states of interaction are possible: 1. No interaction: particles sufficiently distant from one another. thermodynamically stable state (in absence of sedimentation). 2. Coagulation (agglomeration): particles form an intimate contact with each other; pharmaceutically unacceptable formulation- inability to redisperse the particles upon shaking. 3. Loose aggregation (termed floccules): loose reversible interaction between the particles; enabling the particles to be redispersed upon shaking.

when dispersed in a liquid medium, particles will experience (electrical) repulsive forces and attractive (London/van der Waals) forces. energies of attraction ( V a ) and repulsion ( V r ) V t= V a + V r Where: Overall energy of interaction between the particles ( V t )

particles in a suspension will sediment under the influence of gravity and settle at the bottom of the container larger particles reaching the bottom initially and the smaller particles occupying the space between the larger particles. particles at the bottom of the container are gradually compressed by the weight of those above and, in so doing, sufficient energy is available to overcome the primary maximum (repulsive forces) and the particles become sufficiently close to form an irreversible interaction at the primary minimum. This is referred to as caking . use stokes equation

For particles in which the zeta potential (and hence the primary maximum) is high, manipulation of the magnitude of the secondary minimum is required (controlled flocculation). Flocculation controlled by addition of electrolyte or charged surfactants that reduce zeta potential (and hence VR) to give satisfactory 2ndary minimum in which flocs can be formed

low rate of sedimentation disperse phase: easily redispersed with gentle shaking flow properties: formulation easily removed from the container aesthetically pleasing. many potential routes of administration

delivery system for low solubility drugs avoid large volume of solvent- solution of this drug avoid precipitation upon storage; when co-solvent is used taste masking of drugs difficulty in swallowing solid-dosage forms controlled drug delivery

Problems: correct dose of drug? unstable; formulation to ensure stability over the period of the shelf-life aesthetic suspension: difficult bulky, difficult for patient to carry.

Particle size: increase stability by modifying rate of particle sedimentation (Stokes law) Particle size should be minimised chemical methods (controlled precipitation) physical methods (i.e. milling). B. Wetting properties of drug Insoluble drug particles: hydrophobic, not easily wetted surface-active agents: decrease interfacial tension particles poorly wetted: aggregation

Small particles > solubility/ dissolution rate than larger particles when dispersed in an aqueous vehicle Change (increase) in storage temperature: smaller particles dissolve in the vehicle Crystallisation of dissolved drug may occur on surface of larger particles (increase diameter of suspended drug particles). Hydrophilic polymers decrease crystal growth: adsorption on to suspended drug particles (protection) Control crystal growth: temperature cycling (repeated freeze-thaw cycles), monitor particle diameter, physical stability.

Vehicle: Purified Water USP, buffers (citrate commonly used). Excipients: as for oral solutions. Major difference: excipients to physically stabilise suspensions; control of rate of particle/floccule sedimentation. Addition of electrolytes: (control flocculation)decreases zeta potential Surface-active agents: wetting, facilitating flocculation; C< 0.5% w/v non-ionic preferred: polyoxyethylene fatty acid sorbitan esters, sorbitan esters, lecithin ionic surfactants: greater toxicity • Hydrophilic polymers: physical stability, affect flow properties adsorb on to surface of suspended drug particles. Due to large MW: 1 section of polymer chain adsorb on to particles, remainder of chain into aqueous vehicle. 2 polymer-coated particles approach each other: prevent particles coming into close contact Ability to stabilise suspensions: C, Type of polymer increase viscosity ( decrease rate of sedimentation, increase physical stability - Stokes’ equation) flow properties (polymer C used in oral suspensions)

cream formulations; emulsions that offer greater consistency (viscosity); applied topically parenteral nutrition oral administration rectal administration of antiepileptic agents Emulsions: disperse systems in which an insoluble liquid is dispersed in a second liquid phase Disperse phase = phase that is sub-divided Continuous phase = phase in which disperse phase is distributed

Delivery of drugs with low aqueous solubility: drug dissolved in internal oil phase (o/w) oral administration: oil droplets absorbed (mechanism for oils). Taste masking: drug dissolved in internal phase (o/w); external phase may contain sweetening/ flavouring agents. Administration of oils with therapeutic effect (cathartic effect , i.e. liquid paraffin; droplets in an o/w emulsion reduction of irritation after topical administration: drug in internal phase (o/w) difficulty swallowing solid-dosage forms total parenteral nutrition

Thermodynamically unstable; appropriate formulation is needed to stabilise the emulsion from separation of the two phases. Pharmaceutical emulsions may be difficult to manufacture

oil is the disperse phase and water the external phase

water is the disperse phase and oil is the external phase.

emulsions whose disperse phase contains droplets of another phase

oil-in-water emulsion (o/w): oil is the disperse phase and water the external phase water-in-oil emulsion (w/o) water is the disperse phase and oil is the external phase. multiple emulsion (w/o/w ) emulsions whose disperse phase contains droplets of another phase oil, water, emulsifying agents Emulsion type: defined by stability of droplet phase: phase of lower stability coalesces to form external phase. Determinants of type of emulsion produced phase volume of internal phase (in practise phase volume ratio 50%- stability) Chemical properties of film surrounding internal phase viscosity of internal and external phases

Physical stability: no phase separation Flow properties: enable formulation to be easily removed from container. Formulation easily spread over affected area (external application) Aesthetically and texturally pleasing. Suitable flavour (emulsion for oral application) Correct texture: emulsions externally applied

Cracking: complete coalescence of the internal phase, resulting in separation of emulsion into two layers due to the destruction of the mono/multilayer film at the interface between the droplet and external phase. If an emulsion has cracked it cannot be recovered. may be due to: Incorrect selection of emulsifying agents. Presence of incompatible excipients Temperature Microbial spoilage.

In flocculated state: secondary interactions (van der Waals forces) maintain droplets at a defined distance of separation (within the secondary minimum). Application of i.e. shaking will redisperse these droplets to form a homogeneous formulation. Although flocculation may stabilise formulation, there is also the possibility that the close location of the droplets (at the secondary minimum) would enable droplet coalescence to occur if the mechanical properties of the interfacial film are compromised.

result of density difference between the oil and water phases; involves either sedimentation or elevation of droplets of internal phase, producing a layer of concentrated emulsion either at top or bottom of container. aesthetic problem (resulting emulsion is unsightly); upon shaking emulsion is rendered homogeneous. Rate of creaming: Stoke’s equation may be prevented if density difference between the two phases is zero (in practice, cannot be easily achieved). methods by which the rate of creaming may be reduced are: Reduce the average particle size of the disperse phase. Increase the viscosity of the emulsion.