LIQUID PREPARATIONS

Marilyn A. Ngo, M.S. Pharmacy

Liquid Preparations may be dispensed in one of 3 ways

In its original container Repacking a bulk product at the time a prescription is presented by the patient Compounding the solution, suspension or emulsion in the dispensary

Classification of Liquid Preparation

Solutions (single phase system) Mixtures (two phase system) Galenicals (extractives) Sterile Products

Oral Solutions

Homogenous mixtures of one or more solutes dissolved in suitable solvent or mixture of mutually miscible solvents Solutions are classified on the basis of physical properties, method of preparation, use and type of ingredients Syrup, Elixir, Spirit, Aromatic water, tincture, fluidextract

ADVANTAGES OF SOLUTIONS AS AN ORAL DOSAGE FORM

Liquids are easier to swallow than solids and are therefore particularly acceptable for pediatric and geriatric use A drug must usually be in solution before it can be absorbed Solution is a homogenous system and therefore the drug will e uniformly distributed throughout the preparation

DISADVANTAGES OF SOLUTIONS AS AN ORAL DOSAGE FORM

Liquids are bulky and therefore inconvenient to transport and store Stability of ingredients in aqueous solution is often poorer than if formulated as a tablet or capsule Solutions often provide suitable media for the growth of microorganisms and may therefore require the incorporation of a preservative Many liquid preparations are designed so that the normal dosage of the drug is present in 5mL, or a multiple of 5 mL, of the product The taste of a drug, which is usually unpleasant, is always more pronounced when in solution than in solid form

Design & Formulation

Involves the combination of ingredients with medicinal agents to enhance the acceptability of effectiveness of the product Several considerations- concentration of the drug, solubility of the drug, selection of the liquid vehicle, physical and chemical stability, preservation of the preparation, appropriate excipients such as buffers, solubilizers, sweetening agents, viscosity controlling agents, color and flavors Successful design and formulation of liquids, as well as other dosage forms, requires both scientific and pharmaceutical acuity

Solubility

Solubility of a substance at given temperature is defined as quantitatively as the concentration of the dissolved solute in a saturated solution (I.e. the dissolved-solute phase) Generally, the drugs are present in solution at unsaturated concentrations, otherwise, the drug may crystallize as a result of changes in temperature or by seeding from other ingredients or particulate matter present Effects of pH, effect of molecular structure, effect of temperature

Solubilization Techniques

Solubilization process by which the apparent solubility of a poorly water soluble substances is increased Any material can be solubilized in any solvent by proper choice of solubilzing agent Techniques include addition of cosolvent, salt formation, prodrug method, micellization

Stability

Drug substances in general are less stable in liquid media than in the solid dosage form. It is necessary to consider the effects upon stability caused by excipients such as colorants, flavors, preservatives, solubilizers, thickening agents, sweetening agents Chemical Stability consider both the pH solubility profile and stability profile in order to select the optimum pH for formulating the liquid oral dosage form Physical Stability involves the formation of precipitate, less soluble polymorph, adsorption of the drug substances onto container surfaces, microbial and product appearance The acceptability of the product is a subjective evaluation and includes properties such as color, odor, taste and clarity

CHOICE OF SOLVENT

Aqueous solutions Non-aqueous solutions Miscellaneous solutions

Aqueous Solutions

Purified Water Water for Injections Although water is very widely used for inclusion in pharmaceutical preparations, it may not be possible to ensure complete solution of all ingredients at all normal storage temperatures. Cosolvency, pH, solubilization, complexation, chemical modification, particle size control

Water

Purified water is obtained by deionization, distillation, ion exchange, reverse osmosis, filtration or other suitable procedures Water for Injections, Bacteriostatic Water for Injections, or Sterile Water for Injections for parenteral administration Major impurities in water are calcium, iron, magnesium, silica and sodium

Non-Aqueous solutions

Fixed oils of vegetable origin Alcohols Polyhydric alcohols Dimethylsulphoxide Ethyl ether Liquid paraffin

Alcohols

Second most commonly used solvent in pharmaceutical industry for many organic compounds When mixed with water, a hydroalcoholic mixture is formed capable of dissolving both alcohol-soluble and water-soluble substances, a feature especially useful for extraction and purification of active constituents from crude drugs and synthetic procedures Alcohol, diluted alcohol, rubbing alcohol, isopropyl rubbing alcohol

Recommended Alcohol content OTC oral drugs

Children under 6 years of age 0.5% Children 6 to 12 years of age 5% Children over 12 years of age and adults 10%

Glycerin

Clear, syrupy liquid with a sweet taste and is miscible with water and alcohol Used in wide variety of pharmaceutical formulations include oral, otic, ophthalmic, topical and parenteral preparations In topical preparations, glycerin is used for its humectant and emollient properties In oral preparations, glycerin is used as solvent, sweetening agents, antimicrobial preservatives and viscosity increasing agent

Propylene Glycol

Widely used as solvent, extractant, preservative in a variety of liquid pharmaceutical formulations including parenteral Viscous liquid and miscible with water and alcohol Often used in place of glycerin As an antiseptic it is similar to ethanol, and against molds it is similar to glycerin and only slightly less effective than ethanol Used as carrier for emulsifiers and as vehicle for flavors, as opposed to ethanol, due to its lack of volatility

Miscellaneous Solvents

Isopropyl myristate and isopropyl palmitate Dimethylformamide and dimethylacetamide Kerosene Xylene Glycofurol

Other Formulation Additives

Buffers Density modifiers Isotonicity modifiers Viscosity enhancement Preservatives Reducing agents and antioxidant Sweetening agents Flavors and perfumes Colors

Buffers

These are materials which, when dissolved in a solvent, will enable the solution to resist any change in pH should an acid or alkali be added Carbonates, citrates, gluconates, lactates, phosphates, tartrates Most body fluids has a pH of 7.4 Although buffers ensure pH stability, the buffer system can effect other properties such as solubility and kinetics Can act as general-acid or general-base catalysts and cause degradation of the drug substance. Ionic strength contribution of the buffer systems can also effect stability. Therefore, the effect of buffer species should be studies before selecting any buffer system

Buffers Commonly Used in Liquid Pharmaceutical Products

Buffer Acetic acid and a salt Citric acid and a salt Glutamic acid 3.5-5.7 2.5-6 8.2-10.2 pH Usual conc (%) 1-2 1-3 1-2

Phosphoric acid salts

6-8.2

0.8-2

Density Modifiers

It is rarely necessary to control the density of solutions EXCEPT when formulating spinal anesthetics Solutions of lower density than cerebrospinal fluid will tend to rise after injection and those of higher density will fall Most widely used material for density modification is DEXTROSE

Isotonicity Modifiers

Compounds contributing to the isotonicity of a product reduce the pain of injection in areas with nerve ending Buffers may serve as tonicity contributors as well as stabilizers for pH Dextrose and NaCl

Viscosity Enhancement

It may be difficult for aqueous based topical solutions to remain in place on the skin or in the eyes for any significant time because of their low viscosities To counteract this effect, low concentrations of gelling agents can be used to increase the apparent viscosity of the product Povidone, hydroxyethylcellulose, carbomer

Preservatives

When choosing a suitable preservative it must be ensured that: adsorption of the preservative onto the container from the product does not occur; and its efficiency is not impaired by the pH of the solution or by the interactions with other ingredients Must fulfill certain criteria for acceptability safety and lack of toxicity after oral intake; must be soluble, stable and microbiologically active; compatible with the active ingredients as well as other components of the formulation In general, alcohol content of 15% by weight in acid solutions and 18% by weight, in alkaline solutions is sufficient to prevent microbial growth Most alcohol containing preparations such as elixirs, spirits, tinctures are self preserving and will not require preservation

Alcohols

Ethanol is useful as preservatives when it is used as solvent, however, it does need a relatively high concentration, somewhat greater than 15% to be effective Too high concentration may result in incompatibilities in suspension and emulsion system Propylene glycol is used as solvent in oral solution and topical preparations, and it can function as a preservatives in the range of 15 to 30% Chlorobutanol and phenylethyl alcohol, used in lower concentrations (about 1%) as preservatives

Acids

Benzoic acids, sorbic acid Benzoic acid has low solubility in water, inhibitory action varies from 0.1-0.5%, activity depends on the pH of the medium because only the undissociated acid has antimicrobial properties. Optimum activity occurs at pH values below 4.5 and pH values above pH 5, benzoic acid is almost inactive

Esters

Parabens are esters of p-hydroxybenzoic acid and include methyl, ethyl, propyl, butyl derivatives Water solubility of the parabens decreases as the molecular weight increases, from 0.25% for the methyl ester to 0.02% for the butyl ester Stable over a pH range 4-8 Broad spectrum of antimicrobial activity,and most effective against molds and yeasts Antimicrobial activity increases as the chain length of the alkyl moiety is increased but aqueous solubility decreases, therefore a mixture of parabens is frequently used to provide effective preservations

Quarternary Ammonium Compounds

Benzalkonium Chloride mixture consisting principally of homologs C12H25 and C14H29. This preservative is used at relatively low concentrations (0.002-0.02%) Optimal activity over the pH 4-10. Stable at room temperature Because of its cationic nature it is incompatible with many anionic compounds such as surfactants and can bind to nonionic surfactants Used as external preservatives

Antimicrobial Preservatives

Benzalkonium chloride, benzathonium chloride, benzyl alcohol, bronopol Centrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorcresol, cresol Ethanol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylmercuric nitrate Propylene glycol, thimerosal

Antifungal Preservatives

Butyl parabens, methyl paraben, ethyl paraben, propyl paraben Benzoic acid, potassium sorbate Sodium benzoate, sodium propionate Sorbic acid

Common Preservatives Used in Pharmaceutical System

Acidic Phenol (0.1-0.5%), alkyl esters of phydroxybenzoic acid (0.001-0.2%), benzoic acid and its salt (0.1-0.3%), boric acid and its salt (0.5-1%) Neutral chlorobutanol (0.5%), benzyl alcohol (3%) Mercurial thiomersal (0.001-0.1%), nitromersol (0.001-0.1%) Quarternary ammonium compounds benzalkonium chloride (0.002-0.02%), cetylpyridinium chloride (0.0005-0.0007%) Esters butyl paraben (0.1-0.4%), methyl paraben (0.1-0.25%), propyl paraben (0.1-0.25%)

Reducing Agents and Antioxidants

The decomposition of pharmaceutical products by the oxidation can be controlled by the addition of reducing agents such as sodium metabisulfite, or antioxidants such as butylated hydroxyanisole or butylated hydroxytoluene For unit dose parenteral products, such as injections of nicotinamide and ascorbic acid, it is possible to use Water for Injections free from dissolved air and to replace the air in the headspace by nitrogen or another inert gases

Sweetening Agents

Low molecular weight carbohydrates, such as sucrose, are traditionally the most widely used sweetening agents Sucrose has the advantage of being colorless, very soluble in water, stable over a pH range of about 4 8, and by increasing the viscosity of fluid preparations, will impart to them a pleasant texture in the mouth. It will mask the bitter and salty drugs and has soothing effect on the membranes of the throat

Sweetening Agents

Polyhydric alcohols such as sorbitol, mannitol and to a lesser extent glycerol, also possess sweetening power and can be included in the preparations for diabetic use. Maltilol, lactilol, isomalt, fructose, xylitol Artificial sweeteners. E954, E951, E950, E957, E952, E959

Sweetening agents
Sweetener Sucrose Saccharin Sodium cyclamate aspartame 1 =500 =30 =200 Sweetening power Comments Most commonly used Unpleasant aftertaste Banned Not very stable in solution

Flavors and Perfumes

The simple use of sweetening agents may not be sufficient to render palatable a product containing a drug with a particularly unpleasant taste. In many cases, therefore, a flavoring agent can be included Particularly useful in pediatric formulation to ensure patient compliance The inclusion of flavors has the additional advantage of enabling the easy identification of liquid products Can be obtained from either natural or synthetic sources

Suitable Masking Flavors for Various Product Tastes

Salty Apricot, butterscotch, liquorice, peach, vanilla, maple, wintergreen Bitter Anise, chocolate, mint, passion fruit, wild cherry Sweet Vanilla, fruits, berries Sour Citrus fruits, liquorice, raspberry

Colors

Once a suitable flavor has been chosen, it is often useful to include a color associated with that flavor in order to improve the attractiveness of the product Another reason for the inclusion of colors is to enable easy product identification

Colors

Includes lakes and dyes Lakes are pigments that are insoluble in water and which impart color by dispersing and reflecting light, they are not used for aqueous solutions Dyes are water soluble and exhibit color by transmitting light, should be used at the lowest possible concentration required to produce the desired color, higher concentration result in a dull color Most liquid drug products have dye concentrations of less than 0.001%, because dyes are present in trace amounts, they should be dissolved prior to mixing with the bulk of the formulations. This ensures complete dissolution before further processing Factors influencing the shade and stability of dyes in liquid systems: pH, microbiological activity, exposure to light in the final package and compatibility of the dye with other ingredients

Manufacturing Consideration

Raw Materials Equipments Methods of preparation Filling and Sealing

Raw Materials

All raw materials should conform to well thought out specification. These specifications should assure identity, purity, uniformity and freedom from excessive microbial contamination Although purified water (USP) is required in all operations, it is particularly important in liquid manufacturing, if deionized and other water treatment equipment is used, special attention must be given to routine microbiological and chemical testing Storage tanks for glycerin and propylene glycol should be constructed to facilitate examination as well as cleaning

Raw Materials

Aside from active ingredients, water is usually the most important constituent in a liquid product. It should meet the USP requirements for purified water Techniques employed to upgrade the microbial purity of water supply in oral liquid reverse osmosis purification, UV sterilization, membrane filtration, constant circulation in piping system that have no dead ends where microorganism can thrive

Equipments

Simple solutions are most straightforward to scale up, but require tanks of adequate size and suitable mixing capacity Most equipment should have heating and cooling capabilities for rapid dissolution of formulation components Adequate transfer systems and filtration equipments are required, but they must be monitored to ensure that they can clarify the product without removing active or adjuvant ingredients All equipments must be made of suitable, non-reactive, sanitary materials and be designed and constructed to facilitate easy cleaning

Equipments

Liquid pharmaceutical processing includes tanks, kettles, pipes, mills, filter, housing are most frequently fabricated from stainless steel Stainless steel is virtually non-reactive but may react with some acidic pharmaceutical liquids. This problems can be minimized by treating the stainless steel with an acetic acid or nitric acid solution to remove surface alkalinity. This process known as passivation, may be needed at periodic intervals Interaction with metallic surfaces can be minimized by using polytetrafluoroethylene (teflon) liners. Although teflon is inert, these liners have the potential disadvantages of cracking, breaking, flaking and peeling with resulting product contamination

Equipments

Type of equipment used in the manufacture of oral solution consist of mixing tanks, measuring devices for large and small amounts of solids and liquids, filtration system for the final polishing and/or sterilization of the solution All equipments must be thoroughly cleaned, sanitized sterilized if possible before use Equipment and lines can be sterilized by such methods as alcohol, boiling water, autoclaving, steam or dry heat

Methods of Preparation

Dilute solutions of rapidly dissolving materials are prepared by adding the solute to the solvent and agitating until the solution is homogenous Heat maybe required for more concentrated solutions or when the solute is slow to dissolve Excipients are usually added in a specified order to increase the rate of dissolution and facilitate a rapid approach to equilibrium

Methods of Preparation

If the solutes were charged directly to the bulk mixing tank, it would be difficult to detect small amounts of undissolved material at the bottom of the tank As a rule, complete solution should be confirmed at every stage in the manufacture of homogenous liquid. In the laboratory, liquids are usually measured by volume. However, in large scale production, gravimetric means of measurements are used Solutions must be filtered and clarified this stage of process is termed Polishing

Methods of Preparation

Highly polished solution requires the removal of particulate matter down to at least 3 um in size Filters used in the manufacture, processing liquid drug products intended for human use should not release fibers Filter aids are commonly used to improve clarity and increase the flow rate, thus decreasing filtration time Amount and type of filter aid must be determined during the development of the product, the amount usually does not exceed 0.5 g/L. examples of filter aids are diatomaceous earth, carbon, expanded perlite and cellulose

Filling and Sealing

Upon approval by QC liquid may be transported to the filling line, either manually by filling into portable transport tanks or by pumping (gravity flow) through a suitable liquid delivery conduit Method of filling a pharmaceutical liquid depend on the characteristic of the liquid viscosity, surface tension, foam producing, compatibility of the material with the construction of filling machine, type of package (bottle) Small volumes of liquids (usually for pediatric use) are delivered by the stroke of the plunger of a syringe, which forces the liquid through a 2 way valve that provides for alternative filling of the syringe from a reservoir and delivery to a container. For heavy, viscous liquids, sliding piston valve provides more positive action

Filling and Sealing

Large volume filling does not normally require the precision required for small volumes. Therefore, bottles of solution are usually filled by gravity, pressure or vacuum devices Methods of filling gravity filling, pressure pump filling, vacuum filling High viscous solution require specially designed equipment. To obtain a reasonable flow rate, high pressure must be applied or containers with large openings must be used to permit the entry of large delivery tubes. Sometimes, jacketed reservoir tanks can be employed to raise the temperature of the product and thereby lower its viscosity

Filling and Sealing

Excessive foaming is a problem common to all types of machines that fill containers with liquid but is particularly bothersome in high speed automatic equipment. Foaming during the filling operation can be reduced by employing filling equipment that minimizes product turbulence, closed system filling to limit the introduction of air or other gases that cause foaming, mechanical defoaming devices, or reduction in the speed of the filling line Microbial survey should be performed on all packaging materials that come in contact with the product to ensure the absence of microbial contamination

Gravity Filling

Slow but simple process Liquid reservoir is positioned above the filling line, with a hose connection from the reservoir to a shutt off device at the filling line which is usually hand operated, the bottles are filled to a graduation mark

Pressure Pump Filler

Often operated semi-automatically and differs from the gravity filler principally in that the liquid is under pressure It is usually equipped with an overflow tube connected to a receiver to prevent excess filling

Vacuum Filling

Commonly used for large liquid volumes because it is easier adapted to automation Vacuum is produced in a bottle when a nozzle gasket makes seal against the lip of the bottle to be filled Vacuum draws the liquid from reservoir through the delivery tube into the bottle. When the liquid level reaches the level of an adjustable overflow tube, the seal is mechanically loosened and the vacuum is released Any liquid that has been drawn into the vacuum line is collected in a receiver and returned to the reservoir

Procedure for most solutions are classified into the following categories

Simple solutions Solutions of chemical reactions Solution by distillation Solution by extraction (maceration, percolation, digestion, infusion, decoction) Complex solution

Classification of Solutions

Aqueous solutions Non-aqueous solutions

Aqueous solutions

Aromatic waters Aqueous acids Douches Enemas Gargles Washes Juices Sprays

Aromatic waters

Clear, saturated aqueous solutions of volatile oils or other aromatic or volatile substances Do not contain preservatives Prepared by distillation, direct solutions or alternated solutions

Aqueous Acids

Hydracids do not contain oxygen Oxygen containing acid It should be borne in mind that acids are always added to water

Douches

Aqueous solutions used as a cleansing or antiseptic agent directed against a part or into a cavity of the body Most frequently dispensed in the form of powder with directions for dissolving in a specified quantity of water, usually warm

Enemas

Rectal injections employed to evacuate the bowel, to influence the general system by absorption, or to affect locally the seat of disease Possess anthelminthic, nutritive, sedative or stimulating properties, or they may contain radiopaque substances for roentgenographic examination of the lower bowel

Gargles

Aqueous solution used for treating the pharynx and nasopharynx by forcing air from the lungs through the gargle which is held in the throat Must be diluted with water before use

Washes

Aqueous solutions most often used for its deodorant, refreshing or antiseptic effect. May contain alcohol, local anti-infective agents such as hexetidine and cetylpyridinium chloride, glycerin,synthetic sweetners and surface-active, flavoring, coloring agents Listerine, astring-osol and bactidol

Juices

Prepared from fresh ripe fruit, aqueous in character and are used in making syrups which are employed as vehicles Freshly expressed juice is preserved by benzoic acid and is allowed to stand at room temperature for several days, until the pectins which are naturally present are destroyed by enzymatic action of pectinase as indicated by the filtered juice yielding a clear solution with alcohol

Sprays

Solutions of various drugs in aqueous vehicles and are applied to the mucus membranes of the nose and throat by means of nebulizer or atomizer Isotonic with nasal secretions May contain antibiotic, antihistamins, vasoconstritors, alcohol and suitable solubilizing and wetting agents

Sweet or other Viscid Aqueous solutions

Syrups Honeys Mucilages Jellies

Syrups

Concentrated solutions of sugar or sugarsubstitute and intended for oral administration Simple syrup, Medicated Syrup & Flavored Syrup Basic methods solution with heat, agitation without heat, addition of medicating liquids, percolation

Important points to be considered in the manufacture of syrup

Manufacture of syrup must be conducted with care to avoid contamination To prevent bacterial and mold growth, preservatives may be added. Combination of alkyl esters of p-hydroxybenzoic acid are effective inhibitors of yeast Store in tight, light resistance container and in a cool place Cannot be sterilized in an autoclave without some caramelization Glycerin or sorbitol may be added to retard crystallization of sucrose or increase the solubility of added ingredients When heat is employed, invert sugars are produced

Invert Sugars

Dextrose + levulose More readily fermentable than sucrose Tends to darken in color due to levulose Its two reducing sugars are of value in retarding the oxidation of other substances 1.23 times as sweet as sucrose. The relative sweetness of levulose, sucrose and dextrose is 173:100:74

Honeys

Thick liquid preparations somewhat allied to the syrups, differing in the use of honey, instead of syrup, as a base Oxymel and Squill Oxymel BPC

Mucilages

Thick, viscid, adhesive liquids by dispersing gums in water or extracting with water the mucilaginous principles from vegetable substances All prone to decomposition, showing appreciable decrease in viscosity on storage, they should never be made in larger quantities than can be used immediately, unless a preservative is added Primarily used as aid in suspending insoluble substances in liquid

Jellies

Class of gels in which the structural coherent matrix contains a high portion of liquid, usually water

Non-Aqueous Solutions

Alcohol or hydroalcoholic solutions (Elixirs, Spirits) Ethereal Solutions (Collodions) Glycerin Solutions (Glycerites) Oleaginous Solutions (Liniments, Oleovitamins, toothache drops Medicated Solutions for Vaporizations (Inhalations, Insufflations, Inhalants)

Elixirs

Clear, pleasantly flavored, sweetened hydroalcoholic liquids intended for oral use Ethanol, water but glycerin, sorbitol, propylene glycol, flavoring agents, preservatives and syrups Prepared by simple solution or admixture of several ingredients

Spirits

Essences Alcoholic solutions of volatile substances prepared usually by simple solutions, admixture of the ingredients, solution with maceration, chemical reaction and distillation Store in a tight, light resistant containers to prevent loss by evaporation and to limit oxidative changes Flavoring agents while others used for therapeutic effect of the medicinal substances they contain

Collodions

Liquid preparation containing pyroxylin in a mixture of ethyl ether and ethanol Applied to the skin by means of soft brush or other suitable applicator and, when ether and ethanol have evaporated, leave a film of pyroxylin on the surface Made flexible by the addition of castor oil

Glycerites

Solutions or mixtures of medicinal substances in not less than 50% glycerin Hydroscopic and should be stored in tightly closed container Most of them are extremely viscous and some of them are of jelly-like consistency

Liniments

Solutions of various substances in oil, alcoholic solutions of soap or emulsion Usually applied with friction and rubbing of the skin, the oil or soap base providing for case of application and massage Alcoholic liniments are used generally for their rubefacient, counter-irritant, mildly astringent and penetrating effects

Oleovitamins

Fish liver oils diluted with edible vegetable oil of solutions of the indicated vitamins or vitamins concentrates (usually vitamin A and D) in the fish liver oils Popular commercial dosage form is the SOFT Gelatin capsule

Toothache Drops

Preparations used for temporary relief of toothache by application of a small pledget of cotton saturated with the product into the tooth cavity Clove oil and mixtures of phenol with camphor or creosote

Inhalations

Drugs or solutions of drugs administered by the nasal or respiratory route for local or systemic effect Nebulizers are suitable for the administration of inhalation solutions only if they give droplets sufficiently fine and uniform in size so that the mist reach the bronchioles Solutions may be nebulized by the use of inert gas

Insufflations

Consist of finely powdered or liquid drugs that are carried into the respiratory passage by the use of special delivery systems such as pharmaceutical aerosol

Inhalants

Drugs or combination of drugs which by virtue of their high vapor pressure, can be carried by an air current into the nasal passage where they exert their effect Inhaler

LIQUID PREPARATIONS part 2

Marilyn A. Ngo M.S. Pharmacy

Dispersion

Dispersed phase/ internal phase Dispersing phase/dispersion medium/ external phase Types: colloidal dispersion (1 nm to 0.5 um); coarse dispersion (10-50 um); fine dispersion (0.5-10 um)

MIXTURE (2-phase systems)

Suspensions Emulsions

Suspension

2-phase system which consists of a finely divided solid (dispersed phase) dispersed in a solid, liquid or gas (dispersing medium) Dispersed phase with mean particle diameter of up to 1 micrometer is usually termed as colloidal dispersion A solid in liquid dispersion, in which the particles are above colloidal size, is termed coarse suspension

Emulsion

2-phase system in which one liquid is dispersed in the form of small droplets throughout another liquid Stabilized by the presence of an emulsifying agent The dispersed liquid or internal phase usually consists of globules of diameters down to 0.1 micrometer which are distributed within the external or continuous phase

Physical Properties of Well-Formulated Suspensions and Emulsions

Must remain sufficiently homogenous for at least the period between shaking the container and removing the required amount Sediment or creaming produced on storage, if any, must be easily resuspended by moderate agitation of the container The product may be required to be thickened in order to reduce the rate of settling of the particles or the rate of creaming of oil globules Any suspended particles should be small and uniformly sized in order to give a smooth, elegant product, free from gritty texture

Pharmaceutical Applications of Suspensions

Suspensions can be used as oral dosage forms, applied topically to the skin or mucus membranes surfaces, or given parenterally by injection

Formulations of Suspensions

Particle size control Use of wetting agents Flocculated and deflocculated system Viscosity Modifiers

Particle Size Control

To ensure that the drug to be suspended it of a fine particle size prior to formulation To ensure a slow rate of sedimentation of the suspended particles Large particles, if greater than about 5 um diameter, will also impart a gritty texture to the product, and may cause irritation if injected or instilled into the eyes. If there is a temperature fluctuations, degree of crystal growth can occurs on storage. Solubility of the drug may increase as the temperature rises, but on cooling, the drug will crystallize out. This particular problem with slightly soluble drugs such as paracetamol If the drug is polydispersed, then the very small crystals of less than 1 um diameter will exhibit greater solubility than the larger ones. Over a period of time, the small crystals will become even smaller, whereas the diameter of the larger particles will increase

Particle Size Control

Advantageous to use a suspended drug of a narrow size range Inclusion of surface active agents or polymeric colloids, which adsorb on to the surface of each particle, may also help to prevent crystal growth Different polymorphic forms of a drug may exhibit different solubilities, the metastable state being the most soluble Conversion of the metastable form, in solution, to the less soluble stable state, and its subsequent precipitation, will lead to changes in particle size

Use of Wetting Agents

Some insoluble solids may be easily wetted by water and will disperse readily throughout the aqueous phase with only minimal agitation Most, however, will exhibit varying degrees of hydrophobicity and will not be easily wetted Some particles will form large porous clumps within the liquid, whereas others remain on the surface and become attached to the upper part of the container. The foam produced on shaking will be slow to subside because of the stabilizing effect of the small particles at the liquid/air interface

Use of Wetting Agents

To ensure adequate wetting, the interfacial tension between the solid and the liquid must be reduced so that the adsorbed air is displaced from the solid surfaces by the liquid The particles will then disperse readily throughout the liquid, particularly if an intense shearing action is used during mixing Most widely used: surface active agents, hydrophilic colloids, solvents

Surface Active Agents

HLB value between about 7 and 9 Hydrocarbon chains would be adsorbed by the hydrophobic particle surfaces, whereas the polar groups project into the aqueous medium and become hydrated Wetting of the solid occurs as a result of a fall both in interfacial tension between the solid and the liquid and, to a lesser extent, between the liquid and air Concentrations of up to about 0.1%, for oral use, the polysorbates (Tweens) and sorbitan esters (Spans). For external application, sodium lauryl sulfate, sodium dioctylsulphosuccinate and quillaia extract can also be used. For parenteral administration, polysorbates, some of the poloxamers (polyoxyethylene/polyoxy-propylene copolymers) and lecithin Disadvantages in the use of this type of wetting agent include excessive foaming and the possible formation of a deflocculated system, which may not be required

Hydrophilic Colloids

Acacia, bentonite, tragacanth, alginates, xanthan gum and cellulose derivates Will behave as protective colloids by coating the solid hydrophobic particles with the multimolecular layer Will impart a hydrophilic character to the solid and so promote wettings Used as suspending agent, and may, like surfactants, produce a deflocculated system, particularly if used at low concentrations

Solvents

Alcohol, glycerol and glycols, which are water miscible will reduce the liquid/air interfacial tension Solvents will penetrate the loose agglomerates of powder displacing the air from the pores of the individual particles, so enabling wetting to occur by the dispersion medium

Relative Properties of Flocculated and Deflocculated Particles in Suspension

Deflocculated Particles exist in suspension as separate entities Flocculated Particles form loose aggregates

Rate of sedimentation is slow

Sediment is formed slowly Sediment eventually becomes very closely packed Suspension has a pleasing appearance

Rate of sedimentation is high

Sediment is formed rapidly Sediment is loosely packed and possesses a scaffold like structure Suspension is somewhat unsightly

Controlled Flocculation

Achieved by combination of particle size control, use of electrolytes to control zeta potential, and the addition of polymers to enable crosslinking to occur between particles Underflocculation will give those undesirable properties that are associated with deflocculated systems Overflocculated product will look inelegant and, to minimize settling, the viscosity of the product may have to be so high that any necessary redispersion would be difficult

Flocculating Agents

In many cases, after the incorporation of a non-ionic wetting agent a suspension will be found to be deflocculated, either because of the reduction in solid/liquid interfacial tension, or because of the hydrated hydrophilic layer around each particle forming a mechanical barrier to aggregation Use of an ionic surfactant to wet the solid could produce either a flocculated or a deflocculated system, depending on any charge already present on the particles If particles are of opposite charge to that of the surfactant then neutralization will occur High charge density is imparted to the suspended particles then deflocculation will be the result Convert deflocculated to a partially flocculated state, this may be achieved by the addition of electrolytes, surfactants and/or hydrophilic polymers

Electrolytes

Addition of an inorganic electrolyte to an aqueous suspension will alter the zeta potential of the dispersed particles and, if this value is lowered sufficiently, flocculation may occur Scultz- Hardy rule shows that the ability of an electrolyte to flocculate hydrophobic particles depends on the valency of its counter ion. Trivalent ions are less widely used than mono- or divalent electrolytes because they are generally more toxic. If hydrophilic polymers, which are usually negatively charged, are included in the formulation they may be precipitated by the presence of trivalent ions Most widely used: sodium salts of acetates, phosphates and citrates, and the concentration chosen will be that which produces the desired degree of flocculation Care must be taken not to add excessive electrolyte or charge reversal may, occur on each particle, so forming, once again, a deflocculated system

Surfactants

Ionic surface active agents may also cause flocculation by neutralizing the charge on each particle, thus resulting in a deflocculated system Non-ionic surfactants will have a negligible effect on the charge density of a particle but may, because of their linear configurations, adsorb on to more than one particle, thereby forming a loose flocculated structure

Polymers Flocculating Agents

Starch, alginates, cellulose derivates, tragacanth, carbomers and silicates Their linear branched chain molecules form a gel-like network within the system and become adsorbed on to the surfaces of the dispersed particles, thus holding them in a flocculated state Care must be taken to ensure that, during manufacture, blending is not excessive as this may exhibit the crosslinking between adjacent particles and result in the adsorption of each molecule of polymer on to one particle only. If this should occur then a deflocculated system may result, because the formation of the hydrophilic barrier around each particle will inhibit aggregation High concentration of polymer may have similar effect if the whole surface of each particle is coated. It is essential that areas on each suspended particle remain free from adsorbate, so that crosslinking can recur after the product is sheared

Viscosity Modifiers

Polysaccharides acacia, tragacanth, alginates, starch, xanthan gum Water soluble celluloses methylcellulose, hydroxyethylcellulose, carmellose sodium, microcrystalline cellulose Hydrated silicates bentonite, magnesium, aluminum silicate (Veegum), hectorite Carbomers (carboxypolymethylene) synthetic copolymer of acrylic acid and allyl sucrose. Concentration used up to 0.5%, mainly for external application Colloidal silicon dioxide (Aerosil) finely divided product, that is dispersed in water, will aggregate, forming a 3 dimensional network. Concentration used of up to 4%, for external use

Several Preparations which may be classified as Suspensions

Gels Magmas and Milks Lotions Mixtures

Gels

Semisolid systems of either suspensions made up of small inorganic particles or large organic molecules interpenetrated by a liquid Thixotropic, forming semisolid on standing and becoming liquid on agitation To ensure homogeneity, they should be shaken before use Aluminum Hydroxide Gel

Magmas and Milks

Aqueous suspensions of insoluble, inorganic drugs and differ from gels mainly in that the suspended particles are larger Thick and viscous, no need to ass a suspending agents Shaken well before use Freezing must be avoided Prepared by simple hydration (bentonite magma) or by chemical reaction (milk of magnesia and milk of bismuth)

Lotions

Liquid suspensions intended for external application to the body Prepared by triturating the ingredients to a smooth paste and then cautiously adding the remaining liquid phase Usually applied with friction Wide variety of ingredients may be added to the preparation to produce better dispersions or to accentuate the cooling, soothing, drying, moisturizing, or protective properties of lotion Cosmetic aspect is of great importance Tend to separate at long standing, it requires a shake well label. Should be labeled for external use only Care should be taken to avoid contamination during manufacturing, even if preservatives are present

Mixtures

Aqueous liquid preparations which contain suspended, insoluble, solid substances and are intended for internal use Insoluble substance does not make the mixture very viscous and the particles may be suspended by the use of suitable suspending or thickening agents Shake well label affixed to the container Subject to microbial contamination, a preservative should be added to the formulation Kaolin Mixture with Pectin, Brown Mixture

Emulsion

2-phase system in which one liquid is dispersed in the form of small droplets throughout another liquid Dispersed phase is also known as internal or discontinuous phase. Dispersed medium is also known as external or continuous phase If the dispersed globules are of colloidal dimensions (1 nm to 1 micrometer) the preparation, which is quite often transparent or translucent is called MICROEMULSION

Types of Emulsion

Oil in water Water in oil Water in oil in water

Emulsifying agent

3rd basic component of an emulsion Prevent the separation of two phases Classified into: Natural emulsifying agent, Finely divided solids and synthetic emulsifying agent

Natural Emulsifying Agent

Derived from either animal (gelatin, egg yolk, casein, wool fat and cholesterol) and vegetable origin (acacia, tragacanth, choldrus and pectin) 2 disadvantages: they show considerable batch to batch variation in composition and hence in emulsifying properties; and many are susceptible to bacterial or mold growth. For these reasons, they are not widely used in manufactured products requiring a long shelf life, but rather for extemporaneously prepared emulsions designed for use within a few days of manufacture

Natural Emulsifying Agent

Polysaccharides acacia, stabilizes o/w emulsions by forming a strong multimolecular film round each oil globule, and so coalescence is retarded by the presence of a hydrophilic barrier between the oil and water phases. Because of its low viscosity, creaming will occur readily, therefore a suspending agent such as tragacanth or sodium alginate can also be included. Because of its sticky nature, it is limited to products for internal use Semisynthetic polysaccharides several grades of methylcellulose and carmellose sodium. Exert their action similar to acacia

Natural Emulsifying Agent

Sterol-containing substances beeswax, wool fat and wool alcohols. Beeswax is used mainly in cosmetic creams of both o/w and w/o type in conjunction with borax. Because of the systemic toxicity of boric acid and its salts, however, beeswax is used as stabilizer for w/o creams. Wool fat will form w/o emulsions of low dispersed phase concentration, it has characteristic odor and need to incorporate antioxidants, it is not widely used, however, it is found in low concentration in many ointments. The principal emulsifying agent in wool fat is wool alcohols. Wool alcohols does not have the same strong odor as wool fat but does require the presence of antioxidant. It is effective as w/o emulgent

Finely divided solids

Montmorillonite clays (Bentonite and aluminum magnesium silicate) and colloidal silicon dioxide are used mainly for external use Aluminum and magnesium hdroxides are also used internally Can be adsorbed at the o/w interface, forming a coherent film that physically prevents coalescence of the dispersed globules.

Synthetic emulsifying agent

Anionic sodium lauryl sulfate Cationic benzalkonium chloride Nonionic polyethylene glycol 400 monostearate

Anionic Surfactants

Cheap, toxic and used externally Alkali metal and ammonium soaps sodium stearate. These emulgents are incompatible with polyvalent cations, often causing phase reversal, and it is therefore essential that deionized water is used in their preparation Soaps of divalent and trivalent metals will only produce w/o emulsion Amine soaps triethanolamine. It forms stable o/w emulsions. Neutral pH. Restricted to external used. Incompatible with acids and high concentrations of electrolytes Sulphated and sulphonated compounds sodium lauryl sulfate. Widely used to produce o/w emulsions. Because of its high water solubility and its inability to form condensed films

Cationic Surfactants

Quarternary ammonium compounds Widely used for their disinfectant and preservatives Useful in o/w emulsifiers Because of the toxicity, they tend to be used only for the formulation of antiseptic creams Incompatible with anionic surfactants and polyvalent anions, and are unstable at high pH Cetrimide most useful of these cationic emulgents. Used at a concentration of 0.5%

Non-ionic Surfactants

Low toxicity and irritancy, some can therefore be used for orally and parenterally administered preparations Greater degree of compatibility with other materials than do anionic or cationic emulgents, and less sensitive to changes in pH or to the addition of electrolytes Expensive Most non-ionic surfactants are based on: fatty acid or alcohol (usually 12-18 carbons), the hydrocarbon chain of which provides the hydrophobic moiety; an alcohol and/or ethylene oxide grouping, which provide the hydrophilic part of the molecule Best type of non-ionic surfactant to use is one with an equal balance of hydrophilic and hydrophobic groupings. An alternative would be to use two emulgents, one hydrophilic and one hydrophobic. Glycol and glycerol esters glyceryl monostearate; sorbitan esters sorbitan monostearate; polysorbates (Tween); fatty alcohol polyglycol ethers macrogol cetostearyl ether; fatty acid polyglycol estes; poloxalkols; higher fatty alcohols; amphoteric surfactants lecithin (used to stabilize IV fat emulsions)

Methods of preparation (emulsion)

Emulsifier in water method Emulsifier in oil method Continental method Soap method Alternate addition method English Method

Tests for identification of emulsion type

Miscibility tests Conductivity tests Staining test

Equipments for breaking up the internal phase into droplets can be divided into 4 board categories

Agitator or mechanical stirrers Homogenizers Ultrasonifiers Colloid mills

Formulation of Emulsions
-

Choice of emulsion type o/w or w/o emulsion Fats or oils for oral administration, either as medicaments in their own right or as vehicles for oil soluble drugs, are invariably formulated as oil in water emulsions Emulsions for IV administration must be of o/w type, IM administration injections can also formulated as w/o type Choice of oil phase liquid paraffin, castor oil, cod liver oil, arachis oil are for oral administration Cottonseed oil, soya bean oil, safflower oil are used for their high calorific value in emulsions for IV feeding Turpentine oil and benzyl benzoate are for external application

Formulation of Emulsion
-

Emulsion consistency w/o type will have a greasy texture and often exhibit a higher apparent viscosity than o/w emulsion, often used to convey a feeling of richness to many cosmetic formulations O/w emulsion will feel less greasy or sticky on application to the skin, and will be absorbed more readily because of their lower oil content, and can be more easily washed from the skin surface Ideally emulsions should exhibit rheological properties of plasticity or pseudoplasticity and thixotrophy Choice of of emulsifying agent toxicity and irritancy considerations Cationic surfactants in general are toxic even at lower concentration. Limited to externally used preparations Anionic alkali soaps, often have high pH and are thus unsuitable for application to broken skin. Even on normal intact skin, it can cause irritation Parenteral administration non-ionic surfactants such as lecithin, polysorbate 80, methylcellulose, gelatin and serum albumin

Formulation of HLB method

Calculating the relative quantities of these emulgents necessary to produce the most physically stable emulsion for a particular oil/water combination

Other Formulation Additives

Buffers Density modifiers Humectants Antioxidants Flavors, colors and perfumes Sweetening agents

Preservation of Suspensions

Prevent the growth of microorganisms that maybe present in the raw material and/or introduced into the product during use Bentonite, may contain Clostridium tetani, but can be sterilized by heating the dry powder at 160 C for 1 hour or by autoclaving aqueous dispersion

Preservation of Emulsions

Benzoic acid and sorbic acid and their salts, phydroxybenzoic acid esters, chlorocresol, phenoxyethanol, bronopol, quarternary ammonium compounds It must be realized that no single preservative exhibits all of the desirable properties outlined. In many cases, a combination of methyl and propyl p-hydroxybenzoates at a ratio usually of 10:1

Desirable Features of a Preservative Suitable for Use in an Emulsion

Wide spectrum of activity against all bacteria, yeasts and molds Bactericidal rather than bacteriostatic activity Freedom from toxic, irritant or sensitizing activity High water solubility Compatibility with the other ingredients and with container Stability and effectiveness over a wide range of pH and temperature Freedom from color and odor Retention of activity in the presence of large numbers of microorganisms

Physical stability of suspensions

Assessed by the measurement of its rate of sedimentation, the final volume or height of the sediment, and ease of redispersion of the product

Physical Stability of Emulsions

Avoidance of Creaming Prevention of flocculation Coalescence (breaking, cracking)

Creaming and its avoidance

Creaming is the separation of an emulsion into two regions, one of which is richer in the disperse phase than the other. Inelegant. If the emulsion is not shaken adequately, there is a risk of the patient obtaining an incorrect dosage Consideration of the qualitative application of Stokes law will show that the rate of creaming can be reduced by the following methods: production of an emulsion of small droplet size Increase in the viscosity of the continuous phase Reduction in the density difference between the two phases Control of disperse phase concentration

Flocculation Prevention

Flocculation involves the aggregation of the dispersed globules into loose clusters within the emulsion. The individual droplets retain their identities but each cluster behaves physically as a single unit. Increase the rate of creaming Redispersion can easily be achieved by shaking The presence of a high charge density on the dispersed droplets will ensure the presence of a high energy barrier, and thus reduce the incidence of flocculation in the primary minimum Important in formulating emulsions for parenteral nutrition which contain high levels of electrolytes

Coalescence

Resisted by the presence of a mechanically strong adsorbed layer of emulsifier around each globule. This is achieved by the presence of either a condensed mixed monolayer of lipophilic and hydrophilic emulgents or multimolecular film of a hydrophilic material Hydration of either of these types of film will hinder the drainage of water from between adjacent globules which is necessary prior to coalescence. As 2 globules, approach each other their close proximity causes their adjacent surfaces to flatten As a change from a sphere to any other shape results in an increase in surface area and hence in total surface free energy, this globule distortion will be resisted and drainage of the film of continuous phase from between the 2 globules will be delayed The presence of long, cohesive hydrocarbon chains projecting into the oil phase will prevent coalescence in a w/o emulsion

Chemical Instability of Emulsions

Anionic and cationic emulgents are incompatible Presence of electrolyte can influence the stability of emulsion either by reducing the energy of interaction between adjacent globules, or salting out effect, by which high concentrations of electrolytes can strip emulsifying agents of their hydrated layers and so cause their precipitation To precipitate hydrophilic colloids by the addition of alcohol Changes in pH may lead to the breaking of emulsion Oxidation , Microbiological contamination, adverse storage conditions

Oxidation

Resulting rancidity is manifested by the formation of degradation products of unpleasant odor and taste These problems can also occur with certain emulsifying agents, such as wool fat or wool alcohols Oxidation of microbiological origin is controlled by the use of microbial preservatives and atmospheric oxidation by the use of reducing agents or antioxidants

Microbiological Contamination

Contamination of emulsions by microorganisms can adversely affect the physicochemical properties of the product, causing such problems as gas production, color and odor changes, hydrolysis of fats and oils, pH changes in the aqueous phase and breaking of the emulsion Most fungi and many bacteria will multiply readily in the aqueous phase of an emulsion at room temperature and many molds will also tolerate a wide pH range Some hyrophilic colloids, may provide a suitable nutritive medium of use by bacteria and molds Pseudomonas species can utilize polysorbates, aliphatic hydrocarbons and compounds Some fixed oils, including arachis oil, can be used by some Aspergillus and Rhizopus species, and liquid paraffin by some species of Penicillium

Adverse Storage Conditions

Increase temperature will cause an increase in the rate of creaming, owing to a fall in apparent viscosity of the continuous phase Temperature increase will also cause an increased kinetic motion, both of the dispersed droplets and of the emulsifying agent at the o.w interface Increase motion of the emulgent will result in a more expanded monolayer and so coalescence is more likely Freezing of the aqueous phase will produce ice crystals that may exert unusual pressures on the dispersed layer of emulgent. In addition, dissolved electrolyte may concentrate in the unfrozen water, thus affecting the charge density on the globules

Stability Testing of Emulsions

Methods of assessing stability macroscopic examination, globule size analysis, viscosity changes Accelerated Stability tests storage at adverse temperatures, centrifugation, rheological assessment

Manufacture of Suspensions Manufacture of Emulsions

LIQUID PREPARATIONS part 3

Marilyn A. Ngo M.S. Pharmacy

Galenicals (Extractives)

Galen, 2nd Century Greek physician Involves the separation of medicinally active portions of plant or animal tissues from the inactive or inert components by the use of selective solvents in standard extraction procedures Relatively impure liquids, semisolids or powders which may be used per se or may be processed further for oral or external use

Classes of Preparation (Galenicals)

Decoctions Infusions Tinctures Fluidextracts (liquid extracts) Extracts

Decoctions

Preparations containing water-soluble and heat stable constituents extracted from crude drugs by boiling the latter in water

Infusions

Dilute solutions of readily soluble constituents of crude drugs prepared by short maceration of the drugs with either cold or boiling water

Tinctures

Alcoholic or hydroalcoholic solutions prepared from vegetable materials or from chemical substances (eg Iodine Tincture) 10%, 20% Prepared from vegetable drugs are made by 2 processes: Process P & Process M

Fluidextracts (Liquid Extracts)

Liquid preparations of vegetable drugs, containing alcohol as a solvent or as a preservatives, or both, so made that each mL contains the therapeutic constituents of 1 g of the standard drug that is represents Made by percolation with the following variations: Process A, Process E & Process D

Extracts

Concentrated preparations of vegetable or animal drugs obtained by removal of the active constituents of the respective drugs with suitable menstrua, evaporation of all or nearly all of the solvent, and adjustment of the residual masses or powders to the prescribed standards Most extracts are prepared by percolation Forms of extracts are recognized: semiliquids or liquids or syrupy consistency; plastic masses known as pilular or solid extracts; dry powders known as powdered extracts

Compounding Procedure

Rationale for most of the steps in compounding liquid preparations lies in the knowledge of equilibrium solubility Rate at which solution is achieved is influenced by the compounding procedure As an additional aid in formulators, the official compendia provides approximate solubilities of USP/NF articles as indicated by the descriptive terms

Relative Solubilities of USP and NF articles

Descriptive term Very soluble Freely soluble Soluble Sparingly Soluble Slightly Soluble Very Slightly Soluble Practically insoluble Parts of solvent required for one part of solute Less than 1 From 1 to 10 From 10 to 30 From 30 to 100 From 100 to 1000 From 1000 to 10,000 10,000 and over

Compounding Procedure

As the proportion of solvent required increases or when more concentrated solutions are being made, it may be advantageous to employ heat, taking into consideration the thermal stability of the components Solutes present in small concentrations should be pre-dissolved prior to mixing to the 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 through a filtration system with or without prior addition of a filter aid. Polished solution is then stored in a holding tank until released by Quality Control

Sterile Preparations

Distinct class of products introduced into internal body compartments. Because all components and processes are selected and designed to eliminate contamination of all types (physical, chemical and microbiological), maximum compliance to cGMP is mandatory

Classification of Sterile Products based on Route of Administration

Parenteral preparations those intended for injection under or through one or more layers of the skin or mucous membranes. IV, IM, SC, Intradermal, intraspinal Ophthalmic preparations for the eye Otics for the ears Nasal preparations for the nose and throat Irrigating solutions for washing wounds or abraded mucous membranes

Components

Highest quality General characteristics: therapeutically effective, provide maximum safety, function efficiently, free from contamination, physically and chemically stable even after thermal sterilization, produce little or no tissue irritation at site of administration On the basis of their functions, components are classified into the therapeutic or active ingredient, vehicle and additives

Pyrogens

Lipid substances associated with a carrier molecule, which is usually a polysaccharide but may be a protein Product of metabolism of microorganisms such as most bacteria, many molds and viruses Febrile reactions about an hour after injection into man. This is accompanied by chills, body aches, cutaneous vasoconstriction and rise in arterial blood pressure Antipyretics eliminate the fever, but not the systemic effects of pyrogens

Official test for detecting and measuring pyrogens

Bacterial endotoxins test Pyrogen test

Bacterial Endotoxins Test

Test for estimating the concentration of bacterial endotoxins that may be present in sample using Limulus Amebocyte Lysate (LAL) which has been obtained from the aqueous extracts if the circulating amebocytes of the horseshoe crab, Limulus polyphenus, and which has been prepared and characterized for use as an LAL reagent for gel-clot formation Endotoxin units Procedures include incubation for preselected time of reacting endotoxin and control solutions with LAL reagent and reading of the spectrophotometric light absorbance at suitable wavelength

Pyrogen Test

Designed to limit to an acceptable level the risks of febrile reaction in the patient to the administration, by injection, of the product concerned. Involves measuring the rise in temperature of rabbits following the IV injection of a test solution and is designed for products that can be tolerated by the test rabbit in a dose not to exceed 10 mL/kg injected IV within a period of not more than 10 minutes If no rabbit shows an individual rise in temperature 0.6 oC or more above its respective control temperature, and if the sum of the 3 individual maximum temperature rises does not exceed 1.4 oC, the product meets the requirements for the absence of pyrogens

Pyrogen tests

May be destroyed or eliminated through physical, chemical or combination of both means

Depyrogenation Method

Adequate washing with detergent treatment followed by dry heat sterilization is recommended for glasswares and equipment. Optimum temperature is 250 oC for 45 minutes or 180 oC for 3 to 4 hours. Autoclaving temperatures will not destroy pyrogens during normal cycle Distillation is the most reliable method of eliminating pyrogens from water. Pyrogenic substances are not volatile and thus will remain in the distilland Removal of pyrogens by select adsorbents has limited use because of the concurrent phenomenon of adsorption of solute ions of molecules

Vehicles

Water for injections Prepared by distillation or by reverse osmosis Non-aqueous solvents (polyethylene glycol, propylene glycol and fixed oils) solubility factors or hydrolytic reactions Must not be toxic, irritating or sensitizing and must not exert an adverse effect on the ingredients of the formulation

Additives

Essential for almost every product to enhance its stability Must exhibit the following characteristics:

Perform its function throughout the useful life of the product Must be non-toxic and non-irritating Must not exert any adverse effect on the product Must not interfere with therapeutic efficacy or assay of the active therapeutic compound

Includes solubilizers, antioxidants, chelating agents, buffers, antimicrobial agents, tonicity contributors, hydrolysis inhibitors, antifoaming agents and numerous other substances for specialized purposes

Additivies Antibacterial/Antifungal Agents

USP states that antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to preparations contained in multiple dose containers Must be present in adequate concentration at the time of use to prevent the multiplication of microorganisms inadvertently introduced into the preparation while withdrawing a portion of the contents with a hypodermic needle and syringe Two mercurials, phenylmercuric nitrate and thimerosal, the four homologous esters of p=hydroxybenzoic acid, phenol, benzyl alcohol, and chlorobutanol

Additives- Antioxidant

Oxidation is one of the pathways of degradation which can be accelerated during thermal sterilization To protect a therapeutic agent susceptible to this reaction, antioxidants are required. Antioxidants used in sterile products are classified into: reducing agents, blocking agents, synergists, chelating agents, inert gases

Reducing agents

Antioxidants which function by being preferentially oxidized Ascorbic acid, sodium bisulfite and metabisulfite, sodium formaldehyde sulfoxylate, thiourea

Blocking agents

Antioxidants which block an oxidative chain reaction in which they are nor usually consumed Ascorbic acid esters, butyl hydroxytoluene (BHT), and tocopherols

Synergists

Compounds increase the effectiveness of antioxidants, particularly those blocking oxidative reactions Ascorbic acid, citric acid, citraconic acid, phosphoric acid and tartaric acid

Chelating agents

Those that complex with catalysts which otherwise would accelerate the oxidative reaction Ethylenediaminetetraacetic acid salts

Inert gases

Nitrogen and carbon dioxide have been used to displace oxygen from a solution and reduce the possibility of oxidative changes in the formulation

Additives - Buffers

Added to maintain the required pH for many products A change in pH may cause significant alterations in the rate of degradation reactions. Changes in pH may occur during storage as a result of : 1. Dissolving of glass constituents in the product; 2. Release of constituents from rubber closures or plastic components in contact with the products; 3. Dissolving of gases and vapors from the air space in the container or by diffusion through the rubber or plastic component; 4. Reactions within the products Acetates, citrates and phosphates

Additivies Tonicity Contributors

Compounds contributing to the isotonicity of a product reduce the pain of injection in areas with nerve endings Buffers may serve as tonicity contributors as well as stabilizers for the pH

Containers

Containers for sterile products are made of glass or plastic Glass is still preferred for injectable products, and composed principally of silicon dioxide tetrahedron, modified physiochemically by such oxides as those of sodium, potassium, calcium, magnesium, aluminum, boron and iron 2 general types of glass are soda lime and borosilicates

Based on its chemical resistance, glass compounds are classified into 4 types

Type Type Type Type

I highly resistant borosilicate glass II treated soda lime glass III soda lime glass NP general purpose soda lime glass

Containers

Glass containers like ampule cartridges and vials may be manufactured from glass tubings or by blow molding Rubber closures are used to seal the openings of cartridges, vials and bottles, providing a material soft and elastic enough to permit entry and withdrawal of a hypodermic needle without loss of the integrity of the sealed containers Accessories used in conjunction with closures are aluminum caps with or without flif-off seals

Production of a sterile preparation consists of the following steps

Compounding Filtration Filling Sealing Sterilization

Compounding

Processing of sterile preparations follow normal manufacturing procedures which must be done in aseptic condition based on the cGMP All conditions must be carefully designed and controlled to prevent the entrance of microorganisms to a product. Good environmental control. Good hygiene. All equipments and materials used whenever possible must be sterile

Filtration

Membrane filters, with a porosity ratings of 0.22 or 0.45 microns are usually specified for sterile filtration Larger size has a faster flow rate (8 times) but would require the use of a prefilter to remove some colloidal matter which cause rapid clogging and thus reduce the filtration cycle The process removes particulate matter down to at least 3 microns in size The efficiency of membrane filters is tested by Bubble test

Filling

Bulk preparations are subdivided into unit dose containers during filling Process forces a measured volume of the preparation through the orifice of a delivery tube designed to enter the constricted opening of a container by means of Gravity, Vacuum or with the aid of Pressure Pump Method selected for filling sterile preparations should provide the degree of accuracy and precision required by the nature of the product Slight excess is required in each container provide loss that will occur at the time of administration by adherence to the wall of the container and retention in the syringe and hypodermic needle lumen

Sealing

Will retain the contents of a sterile product and will assure a tamper proof presentation Containers should be sealed in an aseptic area adjacent to the filling machine Ampuls are sealed by heating with a high temperature gas-oxygen flame to form: Tip seals & Pull seals Sometimes, it is necessary to displace the air in the space within the ampul above the product to prevent decomposition. Stream of inert gas, such as nitrogen or carbon dioxide is introduced during or after filling with the product and the ampul is sealed immediately before the gas can diffuse to the outside

Sealing

Dye leakers test is useful method for evaluating the efficiency of sealing process of ampuls. Methylene blue is used. Vials and bottles are NOT subjected to a dyeleakers test Bottles, cartridge and vials are stoppered by rubber closures held in place by aluminum caps Bottom edge of these caps are bent (crimped) around and under the tip of the glass container. It offers a tamper-evident presentations since the cap cannot be removed without destroying the cap. Perforations permit tearing away the portions of the cap to be discarded preparatory to use

Sterilization

Complete destruction or elimination of microbial life Choice of most effective sterilization procedure is dependent on: 1. Compatibility of the process with the preparation; 2. Successful validation of the process 2 main divisions of sterilization procedures are physical processes and chemical processes

Physical Processes of Sterilization

Thermal methods Non-thermal methods

Thermal Methods

Microorganisms are killed by heat by what is thought to be coagulation of the protein of a living cell Lethal effectiveness of heat is dependent on: degree of heat, exposure period and moisture present Within the range of sterilizing temperatures, the time required to produce a lethal effect is inversely related to the moisture present. For these reasons dry heat or moist heat are used as the conditions require

Non-thermal Methods

Ultraviolet light Ionizing Radiations Filtration Aseptic Processing

Non-Thermal Methods UV light

Commonly employed to aid in the reduction of airborne contamination and to attempt to sterilize surfaces within the processing environment Germicidal light produced by mercury vapor lamps is emitted at a wavelength of 2537 Angstrom units (253.7 millimicrons). Function of the intensity of radiation and time of exposure. It also varies with the susceptibility of the organisms Organisms dies or is unable to reproduce

Non-Thermal Methods- Ionizing Radiations

High energy radiations emitted from radioactive isotopes such as Cobalt 60 (gamma rays) or produced by mechanical acceleration of electrons to very high velocities and energies (cathode rays, beta rays) Destroy microorganisms by stopping reproduction as a result of lethal mutations

Non-Thermal Methods - Filtration

Non-thermal method for the sterilization of select solutions by removing microorganisms fro the solution while permitting the passage of all the desired components of the solution and imparting no undesirable components from the filter

Non-Thermal Methods Aseptic Processing

Closely involved with sterilization although it is technically not a sterilization process Condition and manipulations followed gives the assurance that microorganisms do not enter a product Used for products that cannot terminally sterilized after they have been sealed in the final container

Chemical Processes of Sterilization

Gas sterilization Surface Disinfection

Chemical Processes Gas Sterilization

Ethylene oxide is believed to exert its lethal effect upon microorganisms by alkylating essential metabolites, affecting particularly the reproductive process Ethylene dioxide sterilization is the acceptable practical method for sterilizing plastic. Other gases used are beta propiolactone, formaldehyde, sulfur dioxide

Chemical Processes Surface Disinfection

Disinfectants do not sterilize a surface, however, as adjuncts to thorough cleaning of surfaces, disinfectants properly used may be expected to provide an aseptic condition of the surfaces involved

Sterility test

Performed on products and materials subjected to previously validated sterilization procedures USP provides 2 basic methods for sterility testing: 1. Direct inoculation of test samples on culture media; 2. Membrane filtration technique which involves filtering test samples through membrane filters, washing the filters with fluids to remove inhibitory properties and transferring the membrane aseptically to appropriate culture media

Air Control

HEPA (high efficiency particulate air) filter composed of glass and asbestos or electrostatic precipitators. Effectiveness of HEPA filters is tested by DOP (dioctylphthalate) test method Laminar Airflow Devices in the form of rooms, cabinets or benches are based on the procedure discovered by Whitfield in 1961. Horizontal air flow appears to be the most superior of the other flow hoods.

Production Facilities

Clean up area Preparation area Aseptic area Quarantine area Finishing or packaging area

Personnel

Good health and free from dermatological conditions that might increase the microbial load Neat, orderly and reliable Uniforms used in the aseptic areas should be Sterile. Uniforms usually consists of coverall for both men and women, hoods to completely cover the hair, face masks, and cloth or plastic hoods. Sterile rubber gloves are also required for most aseptic operations, preceded by thorough scrubbing of the hands with a disinfectant soap. The uniform is designed to confine the contaminants discharged from the body of the operator, thereby preventing their ingress into the product