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 pH Usual conc (%)

Acetic acid and a

salt

3.5-5.7 1-2

Citric acid and a

salt

2.5-6 1-3

Glutamic acid 8.2-10.2 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 p-hydroxybenzoic 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 Sweetening

power

Comments

Sucrose 1 Most commonly

used

Saccharin =500 Unpleasant

aftertaste

Sodium

cyclamate

=30 Banned

aspartame =200 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 sugar-

substitute 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 Flocculated

Particles exist in suspension as

separate entities

Particles form loose aggregates

Rate of sedimentation is slow Rate of sedimentation is high

Sediment is formed slowly Sediment is formed rapidly

Sediment eventually becomes

very closely packed

Sediment is loosely packed and

possesses a scaffold like

structure

Suspension has a pleasing

appearance

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, p-hydroxybenzoic 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 Stoke’s 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 anti-

oxidants

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 Parts of solvent required for

one part of solute

Very soluble

Freely soluble

Soluble

Sparingly Soluble

Slightly Soluble

Very Slightly Soluble

Practically insoluble

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 anti-

oxidants, 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 I – highly resistant borosilicate glass

Type II – treated soda lime glass

Type III – soda lime glass

Type 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 dye-leakers 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 (dioctyl-

phthalate) 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