LIQUID PREPARATIONS

Objectives:

•Discuss the advantages and disadvantages of solutions

•Identify the sources of instability.

•Discuss the pharmaceutical considerations of solutions

•Discuss different classifications of Solutions

•Solutions, Emulsions, Suspensions

Prepared by dissolving the active ingredients in an aq. solvent

Suspending the drug in an appropriate medium or by incorporating the agent into one phase or 2 phase of an o/w system

Advantages:

• Readily available for absorption

• Easier to swallow

• Homogenous

• Reduced gastric irritation caused by certain solid doses from drugs

• Formulated for different routes

• Can be easily adjusted by dilution

Disadvantages

• Less stable

• Susceptible to microbial contamination

• Unpleasant taste or odor are difficult to mask

• Bulky

• Less precise in dosage administration

• Suspension & emulsions have the added drawback thoroughly shaken to allow accurate dosing

Sources of Instability of Liquid Preparations

•pH

•Temperature

•Concentration of reactants

•Light or radiation

•Packaging components

Considerations in the Formulations of Liquids

1.SOLUBILITY

2.STABILITY

3.PRESERVATIVE

4. SWEETENING AGENTS

5.VISCOSITY

6.FLAVORS

7.COLORING AGENTS

8.APPEARANCE

SOLUBILITY

• Can be increased by pH control or by the addition of buffer – w/c will not affect the stability of the product & organoleptic characteristics

Co-solvents can be used

Alcohol

Sorbitol

Glycerin PG

STABILITY

• A solution must retain its clarity, color, odor, taste and viscosity over its shelf life.

Consider the package and the effect of

the package

Stability of the active ingredient in the final

product

PRESERVATIVESolution may become contaminated for a number of reasons:

1.Raw materials used in the manufacture of solutions are excellent growth media for bacterial substances such as gums, dispersing agents, sugars and flavors

2.Equipment, environment and personnel contribute to product contamination.

3. Consumer use may result in the

introduction of microorganism.

➔ a preservative should be added to

the product

PRESERVATIVE

Preservative should be:

1.Effective against a wide spectrum of microorganisms

2.Stable for its shelf life

3.Non toxic, non sensitizing

4.Compatible with the ingredients in the dosage form

5.Free of taste and odor

ACIDIC NEUTRAL MERCURIAL QUATERNARY AMMONIUM COMPOUNDS

PHENOL (0.2-0.5%)

CHLOROBUTANOL(0.5%)

THIOMEROSAL (0.001-0.1%)

BENZALKONIUM CHLORIDE (0.004-0.02%)

CHRLOROCRESOL(.05-0.1%)

BENZYL ALCOHOL (1.0%)

PHENYL MERCURIC ACETATE & NITRATE (0.002-0,005)

CETYLPYRIDINIUM CHLORIDE (0.01-0.02%

O-PHENYL-PHENOL (0.005-0.01%

A-PHENYL ETHYL ALCOHOL (0.2-1.0%)

NITROMERSOL (0.001-0.1%

ALKYL ESTERS OF PARAHYDROXYBENZOIC ACID (0.001-0.2%)

BENZOIC ACID and SALTS (0.1-0.3%)

BORIC ACID (0.5-1.0%)

SORBIC ACID (0.05-0.2%)

Preservatives may be used alone or in combination to

prevent the growth of microorganisms.

Alcohols

Ethanol is useful as a preservative when it is used as a solvent.

It needs a relatively high concentration (> 10%) to be effective.

Propylene glycol also used as a solvent in oral solutions and

topical preparations. It can function as a preservative in the

range of 15 to 30%. It is not volatile like ethanol.

Acids

Benzoic acid and sorbic acid have low

solubility in water.

They are used in a concentration range

from 0.1 % to 0.5%.

Only the non-ionized form is effective

and therefore its use is

restricted to preparations with a pH

below 4.5

Esters

Parabens are esters (methyl, ethyl, propyl and butyl) of p-

hydroxybenzoic acid.

They are used widely in pharmaceutical products and are

effective and stable over a pH range of 4 to 8.

They are employed at concentrations up to about 0.2%.

Frequently 2 esters are used in combination in the same

preparation WHY?

- To achieve a higher total concentration

- To be active against a wider range of microorganisms.

Quaternary Ammonium Compounds

Benzalkonium chloride is used at a relatively low

concentration 0.002 to 0.02%.

This class of compounds has an optimal activity over the

pH range of 4 to 10 and is quite stable at most

temperatures.

Because of the cationic nature of this type of preservative

it is incompatible with many anionic compounds.

SWEETENING AGENTS

•Sucrose is the most widely used sweetening agent.

Advantages: Colourless, highly water soluble, stable over a wide pH range (4-8), increase the viscosity, masks both salty and bitter taste, has soothing effect on throat.

•Polyhydric alcohols (sorbitol, mannitol and glycerol) possess sweetening power and can be

used for diabetic preparations.

•Saccharin. Used to supplement sugars and polyols as sweeteners• Approx 250 to 500 x as sweet as sugar• Have a bitter aftertaste if not properly used in the

formula.

•Aspartame. A synthetic sweetener that is 200

times sweeter than sucrose and no aftertaste

VISCOSITY-ENHANCING AGENTS

•Used to improve palatability and ease of pourability

•Can be achieved by increasing the sugar concentration or incorporating viscosity controlling agents • Polyvinylpyrrolidone (PVC)• Cellulosic derivatives (methyl cellulose, CMC)

FLAVORS

Mask unpleasant taste or odour

Enable the easy identification of the product.

Natural products: fruit juices, aromatic oil (peppermint, lemon)

Artificial perfumes are cheaper, more readily available and more stable than natural products.

FLAVORS

•Fruit flavors• Disguise acid or sour taste

•Butterscotch, liquorice, cinnamon• Effective w/ salty taste

•Salty taste, chocolate, anise and fruit flavor• Mask bitter taste

•Chloroform, menthol• Mild local anesthetic, and soothing effect

Flavors may be chemically unstable because of oxidation, reduction, or hydrolysis and stability may be affected

COLORING AGENTS

•To mask unpleasant appearance or increase the acceptability of the preparation to the patient

•Acceptability may be enhanced by inclusion of a color that is closely associated with the flavor.

Requirements for dyes:

• Non toxic

• Non irritant

• Compatible with the active and other ingredients of the preparation

• Solubility

• Stability and compatibility

3 categories:

1. Mineral pigments❑ Iron oxide – used in solid pharmaceutical dosage form

and preparation for external use❑ Low solubility in liquids

2. Natural colorants❑ Anthocyanins, carotenoids, chlorophylls, xantophylls,

riboflavin, saffron and caramel❑ Used for oily or fatty products

3. Synthetic organic dyes

3. Synthetic Organic dyes❑Commonly known as “coal tar” dyes❑Preferred to natural colorants because they

provide a wider range of bright and stable colors

APPEARANCE

• Overall – depends on the color and clarity

• Purification step is required to achieve maximum clarity

• “polishing” – removal of particulate matter may be accomplished by:1. Settling and subsequent decantation2. Centrifugation3. Filtration – practical method when large volume are

involved

MANUFACTURING CONSIDERATIONS

RAW MATERIALS

EQUIPMENT

COMPOUNDING PROCEDURE

PACKAGING

Raw Materials

• Should conform to specification which should assure identity, purity, uniformity and freedom from excessive microbial contamination.

• Incoming raw materials – should be impounded and thoroughly tested before they are release

• Water is most important constituent as a vehicle

WATER

Water is used both as vehicle and as a solvent for the desired

flavoring or medicinal ingredients.

Advantages: Tasteless, odourless, lack of pharmacological

activity, neutral and very cheap

Tap Water

It is not permitted to use tap water for the dispensing of

pharmaceutical dosage forms due to its possible bacterial

contamination and the presence of dissolved salts that destroy the

active ingredients or enhance their decomposition.

Freshly Boiled and Cooled Water

Boiling is seldom used to destroy

vegetative bacteria. But, on storage for

long time spores may yield vegetative

microorganism.

Purified Water

Must be used for most pharmaceutical operations

and in all the tests and assays.

Such water is prepared by distillation, deionization or

reverse osmosis.

"Hard" waters are those that contain the Ca and Mg

cations.

“Alkaline" waters are those that contain bicarbonates

as the major impurity.

Ultraviolet energy, heat or filtration (Millipore filtration)

can be used to remove or kill the microorganisms

present in the water.

Water for injection

Must be used for the formulation of

parental solutions.

It is obtained by sterilizing pyrogen-free

distilled water.

Techniques employed for purification of water

•Reverse osmosis

•Purification

•UV sterilization

•Membrane filtration

EQUIPMENT

•Mixing tanks equipped with a means of agitation, measuring devices and filtration system, sterilization

PACKAGING

• The specific method used for filling a pharmaceutical liquid varies greatly depending on the characteristic of a liquid (viscosity, surface tension, foam producing qualities and compatibility with the materials used in the construction of the filling machine.

Three basic filling methods

1. Gravimetric

2. Volumetric

3. Constant level

Gravimetric method

•Limited to large containers or to highly viscous products.

Volumetric method

•Accomplished by the pumping of a liquid at a constant pressure through an orifice of constant size

Constant level filling

•Uses the containers as the means of controlling the fill of each unit.

Common problem encountered in filling liquids

Excessive foam

Foaming during the filling operation

often can be decreased by filling

equipment that minimizes product

turbulence, closed system filling to limit

the introduction of air or gases

Addition of defoaming device

SOLUTIONS

•Homogenous mixture prepared by dissolving a solid, liquid, or gas in another liquid

Classification of Solutions According to Vehicle

(a) Aqueous solutions

(b) Non-aqueous solutions

Aqueous Solutions

Aqueous solutions are homogeneous mixtures that are

prepared by dissolving a solid, liquid or gas in an aqueous

medium (vehicle).

Vehicle: This may be water, aromatic water or extracts.

Pharmaceutical Solutions

Aqueous1. Douches

2. Enemas

3. Gargles

4. Mouthwashes

5. Nasal washes

6. Juices

7. Sprays

8. Otic solutions

9. Inhalations

Sweet &/or Viscid

1.Syrups

2.Honeys

3.Mucilages

4.Jellies

Nonaqueous

1.Elixirs

2.Spirits

3.Collodions

4.Glycerins

5.Liniments

6.Oleo Vitamin

Douches

Douche is an aqueous solution, which is directed against a part

or into a cavity of the body.

It functions as a cleansing or antiseptic agent.

Douches most frequently dispensed in the form of a powder

with directions for dissolving in a specified quantity of water.

Enemas

These preparations are rectal injections employed to:

▪ evacuate the bowel (evacuation enemas),

▪ influence the general system by absorption (retention

enemas) e.g. nutritive, sedative or stimulating properties

▪ affect locally the site of disease (e.g. anthelmintic property)

▪ they may contain radiopaque substances for

roentgenographic examination of the lower bowel.

Retention enemas are used in small quantities (about 30ml)

and are thus called retention microenema.

Gargles• Aq solutions frequently containing antiseptics,

antibiotics or anesthetics used for treating the pharynx and nasopharynx by forcing air from the lungs through the gargle that is held in the throat.

Mouthwashes

•Aq. solutions often in concentrated form containing one or more active ingredients and excipients.

•Used by swishing the liquid in the oral cavity. Used for 2 purpose: therapeutic & cosmetic

These include Syrups, Honeys, Mucilages, and

Jellies. All of these preparations are viscous

liquids or semisolids. The sweetness and viscid

appearance are given by sugars, polyols, or

polysaccharides (gums).

SYRUPS Syrups are concentrated solutions of sugar such as sucrose in

water or other aqueous liquid.

simple syrup: when water is used alone for making syrup.

medicated syrup: when the aqueous preparation contains

some added medicinal substance

flavored syrup: which contains aromatic or pleasantly

flavored substances and is intended to be

used as a vehicle or flavor for prescriptions

HONEYSAre thick liquid preparations. At one time, before sugar was available, honey

was used as a base, instead of syrup.

MUCILAGES

▪ The official mucilages are thick viscid, adhesive liquids, produced by

dispersing gum (acacia or tragacanth) in water.

▪Mucilages are used as suspending agents for insoluble substances in

liquids; their colloidal character and viscosity prevent immediate

sedimentation.

▪ Synthetic agents e.g. carboxymethylcellulose (CMC) or polyvinyl alcohol are

non-glycogenetic and may be used for diabetic patients.

Jellies

▪ A class of gels in which the structural coherent matrix

contain high portion of liquid, water.

▪ Preparations having a jelly-like consistency. They are

prepared also from gums.

▪ Are used as lubricants for surgical gloves and catheters

▪ Lidocaine HCl Jelly USP is used as a topical

anaesthetic.

Advantages

▪ If the drug is not completely soluble or unstable in

aqueous medium it may be necessary to use an

alternative non-aqueous solvent.

▪Oily solutions of drugs are often used for depot therapy

e.g. in muscles (Depo Provera and haloperidol

decanoate.)

▪Note: depot therapy is in Long-acting forms of

subcutaneous/intramuscular injections

This section is devoted to four groups of non-

aqueous solutions:

1. alcoholic or hydroalcoholic solutions, e.g. elixirs and

spirits,

2. ethereal solutions, e.g. the collodions

3. glycerin solutions, e.g. the glycerites,

4. oleaginous soIutions e.g. the liniments, medicated oils,

oleo-vitamins, sprays, and toothache drops.

ELIXIRS

▪ Are clear, pleasantly flavored, sweetened hydroalcoholic

liquids intended for oral use.

▪ They are used as flavors and vehicles e.g. Dexamethasone

Elixir USP and Phenobarbital Elixir USP.

▪The main ingredients in elixirs are ethanol

and water but glycerin, sorbitol, propylene

glycol, flavoring agents, preservatives, and

syrups are often used in the preparation of the

final product.

▪EIixirs contain ethyl alcohol, however, the

alcoholic content will vary greatly, from elixir

containing only a small quantity to those that

contain a considerable portion as a necessary

aid to solubility

SPIRITS

▪Alcoholic or hydroalcoholic solutions of volatile substances. The

active ingredient may be gas, liquid or solid.

▪Spirits may be used internally for their medicinal value, by

inhalation but is mostly used as flavouring agents.

▪Spirits should be stored in tight, light-resistant containers and in

a cool place,

▪Spirits are preparation of high alcoholic strength and when

diluted with aqueous solutions or liquids of low alcoholic content

turbidity may occur.

COLLODIONS

▪Are liquid preparations containing pyroxylin (a

nitrocellulose) in a mixture of ethyl ether and ethanol.

▪ They are applied to the skin by means of a soft brush or

other suitable applicator and, when the ether and

ethanol have evaporated, leave a film of pyroxylin on the

surface.

GLYCERINS

▪Glycerins or glycerites are solutions or mixtures of

medicinal substances in not less than 50% by weight of

glycerin.

▪Most of the glycerins are extremely viscous.

▪Glycerin is a valuable pharmaceutical solvent forming

permanent and concentrated solutions not otherwise

obtainable.

▪Glycerins are hygroscopic and should be: stored in

tightly closed containers.

LINIMENTS

▪ Are alcoholic or oil-based solutions or emulsion containing

therapeutic agents intended for external application

▪ They are applied with rubbing to the affected area,

embrocations

▪ Alcoholic liniments are used generally for their rubefaciant

and counterirritant effects. Such liniments penetrate the skin

more readily than do those with an oil base.

▪ Oily liniments, have milder action but are more useful when

massage is required.

Rubefacient

a substance for external application that

produces redness of the skin e.g. by causing

dilation of the capillaries and an increase in

blood circulation.

Counterirritant

a medicine applied locally to produce superficial

inflammation in order to reduce deeper

inflammation

OLEO VITAMINS

▪ Oleo vitamins are fish liver oils diluted with edible

vegetable oil or solutions of the indicated vitamins

(usually vitamins A and D).

▪ The indicated vitamins are unstable in the presence of

rancid oils and, therefore, those preparations, should

be stored in small, tight containers, preferably under

vacuum or under an atmosphere of an inert gas,

protected from light.