Liquid Orals Introduction and Classification
- 1. Oral Liquids Dr. Amrendra Pratap Yadav
- 2. Introduction • Oral Liquids are homogeneous liquid preparations, usually consisting of a solution, an emulsion or a suspension of one or more medicaments in a suitable vehicle. Liquid dosage forms are either monophasic or biphasic. A monophasic liquid dosage form is one which contains only one phase. A biphasic liquid dosage form contains two phases. • Liquid preparations for oral use may contain suitable antimicrobial preservatives, antioxidants and other excipients such as dispersing, suspending, thickening, emulsifying, buffering, wetting, solubilizing, stabilizing, flavouring and sweetening agents and authorized colouring matter.
- 3. Classification of Liquid Orals Monophasic liquid dosage forms • Mixtures, elixirs, syrups, linctuses, draughts and drops etc. Biphasic liquid dosage forms • Suspensions and emulsions
- 4. Advantages of Liquid Dosage Forms • They are the most suitable dosage form for infants, children and geriatric patients. • The unpleasant taste of the drugs can be masked by adding sweetening and flavouring agents. • It is attractive in appearance and gives beneficial psychological effects. • The drug is rapidly available for absorption. Disadvantages of Liquid Dosage Forms • The liquid dosage forms have less stability when compared to solid dosage forms. • Liquids are bulky and therefore inconvenient to transport and store • Accidental breakage of the container results in loss of whole dosage form.
- 5. Formulation consideration • Vehicles • Solubilizers • Preservatives • Stabilizers • Organoleptic agents
- 6. Solvents Breaking of bond and reducing effective charge on ions thus increasing solute-solvent forces of attraction which are eventually greater than solute-solute and solvent-solvent forces of attraction. Examples: water, hydro-alcoholic liquid systems, polyhydric alcohols, acetic acid, ethyl acetate and buffers Oily vehicles include vegetable oils, mineral oils, organic oily bases Vehicles
- 7. Co-solvent • Water- miscible organic solvents that are used in liquid drug formulations to increase the solubility of poorly water soluble substances or to enhance the chemical stability of a drug. • An ideal co-solvent should possess values of dielectric constant between 25 and 80. Examples: water/ethanol (not cause toxicity or irritancy when administrated for oral or parental use) Other co-solvents are sorbitol, glycerol, propylene glycol and syrup Vehicles
- 8. Water • Tap Water: They contain large number of dissolved and suspended particles as impurities in either soluble or insoluble state. • Drinking water contains less than 0.1 % of total solid • Purified water IP Ethanol most commonly used solvent in liquid pharmaceutical formulation next to water It is generally used as hydro-alcoholic mixture to dissolve water and soluble drugs and excipients Diluted ethanol is prepared by mixing equal volumes of ethanol IP and purified water IP Vehicles
- 9. Glycerol • Clear, colorless liquid with thick, syrupy consistency, oily to the touch, odorless, very sweet and slightly warm to taste. • Soluble in all proportions, in water or alcohol • Also soluble in a mixture of 3 parts of alcohol and 1 part of ether • But insoluble in ether, chloroform, carbon di- sulphide, benzene, benzol, and fixed or volatile oils Vehicles
- 10. pH adjustment • By addition of buffer to the formulation • Buffers act by binding hydrogen ions in acids and donating hydrogen ions in bases • The selection of as suitable buffer should be based on suitability of acid-base form for use in oral liquids, stability of the drug and excipients in the buffer, and compatibility between the buffer and container. • For example, buffers containing carbonate, citrate, tartarate and phosphate salts may precipitate with calcium ions by forming sparingly soluble salts Solubilizers To increase the solubility of the drug
- 11. pH adjustment …. Cont • The other factors that may affect the solution pH include temperature, ionic, strength, dilution and the amount and the type of co-valents presents. • For example the pH of acetate buffers is known to increase with temperature, whereas the pH of boric acid buffers decreases with temperature. Drug in solution may itself act as a buffer. If the drug is a weak electrolyte such as salicyclic acid or ephedrine, the addition of base or acids, respectively will create system in which the drug can act as a buffer Eg: phosphate buffers, acetate buffers, citric acid phosphate buffers etc. Solubilizers
- 12. Co-solvency • By addition of water miscible solvent in which drug has good solubility. The solvent known as co-solvent. • Reduce the interfacial tenstion between aqupus solution and the hydrophobic solute. • For example Ethanol, sorbitol, glycerin, propylene glycol. • Solubility of phenobarbital In water 1.2 g/L In ethanol 13 g/L Solubilizers
- 13. Complexation • Drug-complexing agent complexation formed when complexing agent is added to solution. • For example disodium EDTA, dihydroxy ethyl glycine, citric acid. Micronization The processes involve size reduction of drug particle 1 to 10microns either by spray drying or fluid .energy mill Hydrotrophy Drug dissolve in the cluster of hydrotropic agent. Also there is drughydrotrophy agent complexation formation to increase drug solubility. Solubilizers
- 14. • Reduce the surface tension between the particles and the liquid vehicles • They air adsorbed at solid particles surfaces keep them away from vehicles which ultimately promotes penetration of the vehicle into pores and capillaries of the particles. • Sodium lauryl sulphate Wetting agents and surfactants
- 15. • Preservatives are of both acid and non-acid types and are bacteriostatic rather than bactericidal. • Preservatives must have following criteria: Effective against broad spectrum of microorganisms. Physically, chemically and microbiologically stable for lifetime of the product. Non toxic, non sensitizing, soluble, compatible and with acceptable taste and odour. Types of Preservatives Acidic: phenol, benzoic acid, sorbic acid Neutral : Chlorobutanol, benzyl alcohol Quarternary ammonium compounds: Benzalkonium chloride Preservatives
- 16. • Oxidation, photolysis, solvolysis and dehydration are common transformations taking place in liquid dosage forms. • Trace amounts of impurities, which are invariably present in the drug or excipient intitates the oxidation reaction • Drugs exists in reduced form show increased susceptibility when it is consistently exposed an open environment. • The pH of the solution may contribute in the oxidation of drugs because ionized forms of these drugs at particular pH are very prone oxidation Stabilizers
- 17. • Physical stability A stable formulation retains its viscosity, color, calarity, taste and odour throughout its shelf life Color can be measured spectrophotometrically. • Chemical stability of the formulation is affected by pH, temperature, Ionic Strength, Solvent effects, Light, Oxygen. Instability can be prevented by use of: Buffering agents, Antioxidants, Proper packaging (eg: use of amber bottle for light sensitive products) Stabilizers
- 18. Antioxidants act as chain terminators where it reacts with free radicals in solution to stop the free-radical propagation cycle. • A combination of chelating agents with antioxidants is often used to exert synergistic effect. • Oxidation of formulation component leads to products with an unpleasant odor, taste, appearance, precipitation, discoloration or even a slight loss of activity Eg acetone sodium bisulfite, acetylcysteine, ascorbic acid, thiourea Stabilizers
- 19. Emulsifying agents which prevent coalescence of the dispersed globules. Forms barriers at interface, and reduce interfacial tension Examples: sodium lauryl sulphat, cetrimide, macrogols Antifoaming agents: Antifoaming agents are effective at discouraging the formation of stable foams of stable foams by lowering surface tension and cohesive binding of the liquid phase. Examples: Simethicone, organic phosphates, alcohols, paraffin oils etc. Stabilizers
- 20. Suspending and Viscosity Enhancing Agents: Stabilizers