LIQUID DOSAGE FORM T N Saifullah S Laboratorium Teknologi Farmasi Fakultas Farmasi UGM

Difinition 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. All liquid dosage forms are dispersed systems in which medical substance (the internal phase) is dispersed uniformly though-out the external phase. Medical substances in liquid dosage form can be in the different aggregate states: solid, liquid and gas

CLASSIFICATION OF LIQUID ORALS Two main types: 1.Monophasic liquids: Solutions Elixirs Syrup Liquid drops …etc 2. Biphasic liquids: Suspensions Emulsions 3

Solution is a homogeneous mixture composed of two or more substances Solution is a homogeneous mixture composed of two or more substances. In mixture, solute is dissolved in another substance, known as a solvent.

Liquid dosage forms for internal use name usually mixtures (from the Latin word of mіxturae - to mix up), the disperse phase - water only. They are measured out to the patients independently by spoons (table (soup)-spoon - 15 ml, dessert-spoon - 10 ml, tea-spoon – 5ml.).

By composition By nature of solvent. Simple- solutions Hydrogen's non-aqueous (alcoholic, glycerin, oily). which include only one substance. Multiple- solutions which include a few ingredients.

Formulation consideration: Solvents Preservatives Antioxidants Solubilizers Organoleptic agents etc. 9

SOLVENTS Water Alcohol Glycerol Polyethylene glycol Propylene glycol. 10

Water Compared to ordinary drinking water , purified water USP is more free of solid impurities. When evaporated to dryness, it must not yield greater than 0.001% of residue. Purified water is obtained by distillation, ion-exchange treatment, reverse osmosis and other relevant method 11

PRESERVATIVES Preservatives are added to prevent the microbial growth Preservative growth are necessary due to chances of microbial Raw material, processing containers & equipments, the manufacturing environment, operators, packing materials & the user. Phenol, chlorocresol, benzoic acid, etc. 12

Solubilizers: Wetting Agents and Surfactants Wetting agents– are used in liquid dosage forms to create a homogenous dispersion of solid particles in a liquid vehicle. Wetting agents are Surfactants (HLB Value 7 to 9) that when dissolved in water, lower the contact angle and aid in spreadability of water on the particles surface to displace the air layer at the surface and help in wetting and solubilization 15

pH Modifiers and Buffering Agents The pH– of an oral liquid formulation is a key point for API stability, solubilization and also to prevent microbial contamination. Buffers are used to control pH of liquid orals. Combination of buffers can also be used to gain a wider range of pH compared to the individual buffer alone. Buffer selection should be judicious to avoid incompatibility.

Suspending Agents and Viscosity-modifying Agents Suspending agents– impart viscosity, and thus retard particle sedimentation. Other factors considered in the selection of the appropriate agent include desired rheological property, suspending ability in the system, chemical compatibility with other excipients, pH stability, length of time to hydrate, batch-to-batch reproducibility, and cost.

Antioxidants Oxidation– may manifest as products with an unpleasant odor, taste, appearance, precipitation, discoloration or even loss of activity. The oxidation of an API in an oral liquid formulation needs to be prevented using anti-oxidents. Antioxidants act as free radicle scavengers and terminator of chain reaction in auto oxidation

Organoleptic agents etc: colour, flavor, sweetening agents Sugar (sucrose) or sugar substitutes (artificial sweeteners) One of the most popular is Sorbitol Solution USP, which contains 64% w/w sorbitol Flavor The flavours may be of natural origin (e.g. peppermint, lemon, herbs and spices) and are available as oils, extracts, spirits or aqueous solutions. Colours These are generally natural or synthetic watersoluble, photo-stable ingredients that are selected according to the flavour of the preparation. For example, mint-flavoured formulations are commonly a green colour, whereas in banana-flavoured solutions a yellow colour is commonly employed.

Stages of operations: 1.Tank selection Material of the to the product must not be additive • The shape and size of equipment must be selected according to the batch size The tanks are usually constructed of polished stainless steel of different grades Teflon and glass lined tank. Adequate clean-up procedures developed. 22

2.Mixing Simple mixing is essential to increase flow of liquids. If the liquid is of high viscosity, high electrical stirrer may be used. Addition of important. ingredients in proper order have vital At high viscosity the chance of air entrapment. 23

Air entrapment Minimize:- By reducing agitator speed By caring out the mixing procedure in enclosed tank under vacuum The alternative procedure to the all is versator 24

3. Dispersion Suspensions and emulsions require considerably greater shear forces Homogenizer Laboratory formulation is difficult to duplicate at large scale Dispersion produced by colloidal mill or an immersion homogenizer of equipment should evaluated for better Variety results. Colloidal mill 25

4. Filtration and clarification— Filtration procedure, requires careful evaluation to ensure that pilot scale-ups will exhibit the same degree of clarity as their laboratory counterparts. During the pilot run the clarity of the filtrate should be checked periodically, in order to establish schedule for changing pads, cake, or cartridges, depending on the type of filtration employed. In filtration, filter pads are used which is made up of asbestos and cellulose. Selection of filtration depends on The product viscosity Volumes Rate requirement 26

5. Transfer and filling Filling – important parameter in the from tank to tank and into containers. transfer of liquids New batches should not be started until the previous batches are completely filled and the tanks are emptied. 27

Methods for filling of liquids:- The selection of equipment depends on characteristic of liquid such as, viscosity, type of packaging, surface tension. Volumetric Gravimetric (specific weight) Gravimetric Volumetric (specific volume) Constant volume filling 28

Containers and closures: Glass Plastic It is more important to store the final product in container until its expiration. Most oral liquids are packed in either amber or flint glass containers with plastic or metal caps. 29

Pilot Plant Scale-Up Techniques for liquid orals Raw materials Weighing & Measuring Mixing Distilled water Filling Packing Finished Product storage Pilot Plant Scale-Up Techniques for liquid orals Quality Assurance 30

Manufacturing of Monophasic liquids: 31

Manufacturing of Biphasic liquids: WATER SURFACTANTS OTHER HELPING AGENTS PRESERVATIVES DISPERSE PHASE CONTINUOUS PHASE FOR SUSPENSION FOR EMULSION MIXING GRINDING OF DRUG & OTHER SOLIDS DISSOLVED DRUG IN OIL AQUEOUS SOLUTION DRUG SOLUTION IN OIL MILLED DRUG 32

OTHER ADDITIVES (FLAVOURS, COLOURING AGENT) Continuous phase Disperse phase PRE – MIX OR CRUDE DISPERSION OTHER ADDITIVES (FLAVOURS, COLOURING AGENT) pH ADJUSTMENT VOLUME ADJUSTMENT HOMOGENIZE FINE DISPERSE DELIVERY SYSTEM 33

Test parameters for solution, emulsion and suspension Appearance yes Specific gravity Viscosity PH Content uniformity Sedimentation No Resuspendability Particle size Release rate/disolution Microbial cont. 34

Storage area 36

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