CHAPTER 10: LIQUID PREPARATIONS

Angco, Shann ReexchelCaindoc, Ruby Ann

Alvor, CarminaLapinid, Ella Ann Patricia

Sangkula, Nafiesa

Preformulation- The process of optimizing a drug through the determination and/or definition of those physical and chemical properties considered important in the formulation of a stable effective and safe dosage form.

•Safe handling of ingredients and equipment•Proper sequence of addition of ingredients•Optimum environmental conditions•Precautions to be observed•Expected interactions•Need for overages

Solutions - when a solid, liquid or gas is dissolved in another liquid, a homogeneous mixture is formed which is called a solution

Homogeneous liquid – has the same uniform appearance and composition throughout

Heterogeneous liquid - consists of visibly different substances or phases

Mixtures (or suspensions) – liquid preparations containing suspended, insoluble, solid substances

Purified water – major ingredient or vehicle in most liquid preparations

Solutions (Single phase systems)

1.Simple solution – dissolving the solute in a suitable solvent which may contain other ingredients which stabilize or solubilize the active ingredient

2.Solution by chemical reaction – reacting two or more solutes with each other in a suitable solvent

3.Solution by distillation – distilling the volatile principles from a drug inside a copper wire cage which allows the free passage of vapors and boiling water

4.Solution by extraction – extraction from vegetable or animal origin with water or with water containing other substances

Principal methods of extraction

a.Maceration – the solid ingredients are placed in a stoppered container with the whole of the solvent and allowed to stand for a period of at least 3 days (until the soluble matter is dissolved) with frequent agitation -The mixture is strained, the mark, pressed and combined liquids are classified by filtration or decantation after standing.

b.Percolation – the active ingredient is extracted from a macerated drug mass in a narrow cone-shaped vessel open at both ends (percolator) through the passage of an extracting liquidated menstruum.

c.Digestion – form of maceration in which gentle heat is used during the process of extraction

d.Infusion – dilute solution of the readily soluble constituents of crude drugs. Fresh infusions are prepared by macerating the drugs for a short period of time with either cold or boiling water

e.Decoction – this process extracts water soluble and heat stable constituents from crude drugs by boiling in water for 15 minutes, cooling, straining, and passing sufficient cold water through the drug to produce the required volume

f.Complex solution – combination of at least two of the above procedures with or without controlled application of heat

Solutions-may be classified into aqueous solution and non-aqueous solutions.

AQUEOUS SOLUTIONS

1. Aromatic Waters

Medicated Waters are clear, saturated aqueous solutions of volatile oils or other aromatic or volatile substances. They do not contain preservatives. Aromatic Water is prepared by distillation (e.g. Stronger Rose Water) or by solution (e.g. Camphor Water)

2. Aqueous Acids

Derived into two groups:

a. Hydracids – do not contain oxygen (e.g., hydroiodic , hydrobromic, hydrochloric, and hydrofluoric acids.

b. Oxygen-containing acids , e.g. hypophosphorus, nitric, phosphoric and sulfuric acids.

3. Douches

- Are aqueous solutions used as a cleansing or antiseptic agent directed against part or into cavity of the body such as the eye, pharynx, nasal passage and vagina. Douches are most frequently dispensed in the form of a powder with directions for dissolving in a specified quantity of water, usually warm

4. Enemas

- are rectal injections employed to evacuate the bowel, to influence the general system by absorption, or to affect locally the seat of disease. Official enemas are those of aminophylline, hydrocortisone and methyl prednisolone acetate. Other enemas are starch, barium sulfate and soap.

5. Gargles

-used to treat the pharynx and nasopharynx by forcing the air from the lungs through the gargle which is held in the throat. E.g. Phenol Gargle and Potassium Chlorate and Phenol Gargle

6. Washes

-most often used for its deodorant, refreshing or antiseptic effect. It may contain alcohol, local anti-infective agents such as hexetidine and cetylpyrindinum chlorine, glycerin, synthetic sweeteners and surface active, flavoring and coloring agents. Well known commercial mouth washes are Listerine, Astringosol.

7. Juices-prepared from fresh ripe fruits. Used in making syrup which are employed as vehicles. The freshly expressed juice is preserved with benzoic acid and is allowed to stand at room temperature for several days, until the pectins which as naturally present are destroyed by enzymatic action of pectinase as indicated by the filtered juice yielding a clear solution with alcohol. Sulfurous acids as sodium metabisulfite is added as preservatives

8. Sprays-are solutions of various drugs in aqueous vehicles are applied to other mucous membranes of the nose and the throat by means of nebulizer. It’s an isotonic with nasal secretions and approximately same pH. Such sprays may contain antibiotics. Antihistamine, vasoconstrictors alcohol, suitable solubilizing and wetting agents.

SWEET OR OTHER VISCID AQUEOUS SOLUTIONS

Viscous liquids or semi-solids

Basic sweet/ viscid substances:sugars,polyols, or polysaccharides (gums)

Viscid sweetened sugar-free solutions- vehicle for drugs used by diabetics

TYPES OF PREPARATIONS

1. Syrups2. Honeys3. Mucilages4. Jellies

SYRUPSConcentrated solution of sugar• Syrup or simple syrup - 65% or more retard growth of microorganisms•Medicated syrup•Flavored syrup- aromatic oils, vehicle, flavor

Preparation of Syrupsa. Solution with heatb. Agitation without heatc. Percolationd. Addition of medicating liquid such as fluid extracts, tinctures

Addition of preservatives- glycerin, methylparaben, prophylparaben, benzoic acid, sodium benzolfate

Combination of alkylesters of p-hydroxybenzoic acid- effective inhibitors of yeast

Storage: tight, light resistance containers in a cool place

Cannot be sterilized in an autoclave withoutCaramelization- caramer: yellowish or brownish color by the action of heat upon sucrose

Polyols ( such as glycerin or sorbitol)- retard crystallization; increase solubility

Inversion- invert sugars (dextrose plus levulose)

Invert Sugars:More readily fermentableTends to darken in color due to levuloseIts two reducing sugars retard exidationSucrose: Invert sugar - 1:23Levulose:Sucrose: Dextrose- 173:100:74

In British Pharmaceutical Codex (BPC)- prepared by hydrolyzing sucrose with HCl and neutralizing with Ca or NaCO3.

The sucrose in 66% w/w solution must be atleast 95% inverted

HONEYSUse of honey instead of syrup as a baseOxymell and Squill Oxymel given in BPC

MUCILAGESThick, viscid, adhesive liquids

JELLIES

Nonaqueous solutions

1.Alcoholic or Hydroalcoholic solutions:

a.Elixirs – are clear pleasantly flavoured, sweetened hydro-alcoho-liquids intended for oral use. Main ingredient are ethanol and water but glycerine sorbitol,mpropylene glycol, flavouring agents, preservatives and syrup are often used in preparation of the final product. - Prepared by simple solution or admixture of several ingredients.

b. Spirits – popularly known as essences; are alcoholic solutions of volatile substances prepared usually by simple Solutions or by admixture of the ingredients. Other ways of preparing spirits:

By solution with maceration (e.g. Peppermint Spirit)Chemical reaction (e.g. Ethyl Nitrate) Distillation (e.g. brandy and whisky)

- Serve as flavouring agents while others are used for the therapeutic effect of the medicinal substance they contain.

- Reduction of high alcoholic content of spirits by admixture with aqueous preparations often cause turbidity.

- spirits require storage in tight, light-resistance containers to prevent evaporation and to limit oxidative changes.

2.Ethereal solutions

a.Collodions – are liquid preparations containing pyroxylin (a. nitrocellulose) in a mixture of ethyl ether and ethanol.- they are applied to the skin by means of a soft brush and when the ether and ethanol have evaporated leaves a film of pyroxilin on the surface.Ex. Salicylic Acid Collodion USP – keratolytic agentCollodion USP, and flexible collodion – water-repellant protectives, minor cuts and scratches

3.Glycerin solutions – are solutions or mixtures of medicinal substances in not less than 50% glycerine.Glycerin – it is used to dilute a glycerite, Phenol Glycerin BPC to form the pharmaceutical preparation.Glycerites – are hydroscopic and should be stored in highly closed containers.

4.Oleaginous solutions:a.Liniments – are solutions of various substances in oil, they are usually applied with friction and rubbing of the skin. - alcoholic elements are used generally for their rubefacient, counter-irritant, mildly astringent and penetrating effect.

b.Oleovitamins – are fish liver oils diluted with edible vegetable oil of solutions of the indicated vitamins or vitamin concentrates (usually vit. A and D) in fish liver oil. - A popular commercial dosage form is the soft geletin capsule.

c.Toothache drops – are preparations used for temporary relief of toothache by application of a small cotton saturated with product into the tooth cavity.

- Clove oil and mixture of phenols with camphor are probably the most frequently used toothache remedies.

MIXTURES (TWO-PHASE SYSTEMS)Emulsions - is a dispersion in which the dispersed phase is composed of small globules of a liquid distributed throughout the vehicle in which it is immiscible.

In emulsion terminology, the dispersed phase is the internal phase and dispersion medium is the external or continuous phase.

MIXTURES (TWO-PHASE SYSTEMS)2 types of Emulsion:

1. Oil-in-water (o/w) - these are emulsions with an oleaginous internal phase and an aqueous external phase. It may be diluted or extended with water or an aqueous preparation

2. Water-in-oil (w/o) - these are emulsions having an aqueous internal phase and an oleaginous external phase. It may be diluted with an oleaginous or oil-miscible liquid.

MIXTURES (TWO-PHASE SYSTEMS)

MIXTURES (TWO-PHASE SYSTEMS)Emulsifying agent - prevents the separation of the two phases.

Classified of Emulsifying Agents:

NATURAL EMULSIFYING AGENTS

PURELY DIVIDED SOLIDS

SYNTHETIC EMULSIFYING AGENTa. Anionicb. Cationicc. Nonionic

MIXTURES (TWO-PHASE SYSTEMS)PURPOSE OF EMULSIONS AND EMULSIFICATION:

Emulsification enables the pharmacist to prepare relatively stable and homogenous mixtures of two immiscible liquids.

It permits the administration of a liquid drug in the form of minute globules rather than in bulk.

For orally administered emulsions, the o/w type permits palatable administration of an otherwise distasteful oil by dispersing it in a sweetend, flavored aqueous vehicle.

MIXTURES (TWO-PHASE SYSTEMS)Four methods of preparation based on the mode of addition of the ingredients are described as follows:

EMULSIFIER - IN WATER METHOD: the emulsiying agent is dissolved in the water and the oil is added, with agitation, to the aqueous solution.

EMULSIFIER - IN OIL METHOD or CONTINENTAL/DRY GUM METHOD: also referred to as 4:2:1 method because for every 4 parts by volume of oil, 2 parts of water and 1 part of gum are added in preparing the initial or primary emulsion.

MIXTURES (TWO-PHASE SYSTEMS) SOAP METHOD: the two types of soaps developed by this method are calcium soaps and soft soaps.

Calcium soaps are w/o in emulsions that contain certain vegetable oils, such as oleic acid, in combination with limewater. They are prepared simply by mixing equal volumes of oil and limewater.

MIXTURES (TWO-PHASE SYSTEMS) ALTERNATE ADDITION METHOD: the emulsion is prepared by adding water and oil alternately to the emulsifying agent. Also called the "English or Wet Gum Method" for the preparation of emulsions.

By this method, the same proportions of oil, water, and gum are used as in the continental or dry gum method, but the order of mixing is different, and the proportion of ingredients may be varied during the preparation of the primary emulsion as is deemed necessary by the operator.

MIXTURES (TWO-PHASE SYSTEMS)Equipments for breaking up the internal phase into droplets can be divided into four broad categories:

1. Agitator or mechanical stirrers e.g propeller shaft stirrers - immersed in a tank of self-contained units with propeller and paddle systems.

2. Homogenizers - the dispersion of two liquids is achieved by forcing their mixture through a small inlet orifice at high pressures.

MIXTURES (TWO-PHASE SYSTEMS)3. Ultrasonifiers - the dispersion is forced through an orifice at modest pressures and is allowed to impinge upon a blade which vibrates rapidly to produce an ultra sonic note.

4. Colloid Mills - Consist of a rotor and stator with conical milling surfaces. Dispersion is affected as it passes between the milling surfaces.

A suspension is a two-phase system which consists of a finely divided solid and dispersed in a solid, liquid or gas. It should possess certain basic desirable properties:

PROPERTIES OF AN EFFECTIVE SUSPENSION

1. Slow sedimentation rate the dispersed phase should settle slowly without forming a hard cake.

2. Resuspendable or redispersable after standing for sometime, the dispersed phade should be uniformly redispensible on shaking.

3. Purable: the viscosity should be such that the preparation pours easily and freely.

4. Chemically stable.

5. Acceptable to the consumer on the basic of its taste, color, and cosmetic qualities.

CLASSIFICATIONS OF SUSPENSION

1. Gels are semisolid systems of either suspensions made up of small inorganic particles or large organic molecules interpenetrated by a liquid. They may be a thixotropic forming semisolids on standing and becoming liquid on agitation. To ensure homogeneity, they should be shaken before use. An example of this type of preparation is the aluminum Hydroxide Gel.

2. Magma and Milks are aqueous suspensions of insoluble, inorganic drugs and differ mainly from gels mainly in that the suspended particles are larger. Since they are thick and viscous, there is no need to add a suspending agent to the preparation. Like the gels, all magmas require a label directing that they be shaken well before use. Freezing must be avoided. Some official preparations are prepared by simple hydration like Bentonite Magma USP or by chemical reaction like Milk of Magnesia USP and Milk of Bismuth.

3. Lotions are usually liquid suspension intended for external application to the body. They may be prepared by triturating the ingredients to a smooth paste and then cautiosly adding the remaining liquid phase. Some important points to be to be considered during manufacture of lotions are:

a. Lotions are usually applied without friction. Therefore, the insoluble matter should be very finely divided approaching colloidal dimensions,for more soothing and satisfactoy effect. b. A wide variety of ingredients may be added to the preparation to produce better dispensions or to accentuate the cooling, soothing, drying, moisturizing or protective properties of the lotion.

c. Cosmetic aspect is of great importance.d. Lotions tend to separate or stratify on long standing. They require a shake well label.e. Lotions should be labeled "For External Use Only".f. Care should be taken to avoid contamination during manufacturing, even if presevatives are present.

4. Mixtures are aqueous liquid preparations which contain suspended, insoluble, solid substances and are intended for internal use. The insoluble substance does not make the mixture very viscous and the particles may be suspended by the use of suitable suspending or thickening agents. They should have a "Shake Well" label affixed to the container in which they are dispensed. Since they are subject tomic-robial contamination, a preservative should be added to the formulation. An example of this type of preparation is Kaolin Mixture and Pectin and Brown Mixture NFXII.

GALENCIALS(EXTRACTIVES)

Extraction involves the separation of medicinally active portions of plant or animal tissues from the inactive or inert components by use of selective solvents in standard extraction procedures. Such extratives are relatively impure liquids, semisolids or powders which may be used perse or maybe processed further ford oral or external use. Such preparations have been popularly called galencials, after Galen, the 2nd century Greek physician. They include classes of preparation such as:

Decoctions

These are preparations containing water soluble and heat-stable constituents extracted form crude drugs by boiling the latter in water infusions.These are dilute solutions of readily soluble constituents of crude drugs prepared by short maceration of the drugs with either cold or boiling water.

Tinctures

Tinctures are alcoholic or hydroalcoholic solutions prepared from vegetable materials or from chemical substances (e.g. iodine tincture). Traditionally, the tinctures of potent vegetable drugs essentially represent the activity of 10 grams of the drug in each 100 mL of tincture, the potency being adjusted following assay. Most other tincture of vegetable drugs represents the extractive from 20 grams of the drug in 100 mL of tincture.

Tinctures prepared from vegetable drugs are made by two processes:

1. Process P: percolation whih included a modification so that tinctures that require assay for adjustment to specified potency may be thus tested before dillution to final volume. An example of this is Belladonna Tincture.

2. Process M: maceration e.g. Compound Benzoin Tincture and Sweet Orange Peel Tincture.

COMPOUNDING PROCEDURES:The rationale foremost of the steps in compounding liquid preparations lies in the knowledge of equilibrium solubility. The rate at which solution is achieved is influenced by the compounding procedures.

Descriptive Term Parts of Solvent Required for of part of Solute

Very soluble Freely soluble

Sparingly soluble Slightly soluble

Very slightly soluble Practically insoluble or insoluble

Less than 1From 10

From 10 to 30 From 100 to 1000

From 1000 to 10,00010,000 and over

Guidelines :As the proportion of solvents required increases or more concentrated solutions are being made, it may be advantageous to employ heat.

Solutes present in small concentrations should be pre-dissolved prior to mixing to main portion of the batch to ensure complete solution of the substance before the batch is further processed.

To produce a clear liquid preparation, the final bulk product is clarified by cycling through a filtration system with or without prior addition of a filter aid. The polished solutions then stored in a holding tank until released by Quality Control.