Solutions are:

Solution Dosage forms are prepared by dissolving the active ingredient(s) in an

aqueous or non aqueous solvent.

Solutions can be formulated for different routes of administration

Orally: Syrups, elixirs, drops

In mouth and throat: Mouth washes, gargles, throat sprays.

In body cavities: Douches, enemas, ear drops, nasal sprays.

On body Surfaces: Collodions, lotions.

Advantages of SoIutions (1) Easier to swallow therefore easier for: children - old age - unconscious people.

(2) More quickly effective than tablets and capsules.

(3) Homogenous therefore give uniform dose than suspension or emulsion which need shaking.

(4) Dilute irritant action of some drugs (aspirin, Kl, KBr) minimize adverse effects in the GIT like KCl.

Disadvantages of SoIutions

(1) Bulky therefore difficult to transport and store.

(2) Unpleasant taste or odours are difficult to mask.

(3) Needs an accurate spoon to measure the dose.

(4) Less stable than solid dosage forms.

(5) Solutions often provide suitable media for microbial

growth.

Formuation of Solutions

(Aqueous Solutions):

√ H2O is the most widely used solvent for use as vehicle because its lack of toxicity, physiological compatibility and ability to dissolve a wide range of materials.

√ At least Purified water BP should be used in all sort of solutions.

√ Water for injections must be used in case of parenteral solutions and it must be pyrogen free.

√ For CO2 sensitive drugs (phenobarbitone-Na, or aminophylline) or oxidation sensitive drugs (apomorphine, ergotamine) CO2 or airfree water for injection must be used.

Approaches to Improve Aqueous Solubility

The following methods may be used in order to improve aqueous solubility.

(1) Cosolvency: Vehicles used in combination with water to improve

the solubity of of the drug are called cosolvents.

For example,

a blend of propylene glycol and water is used to improve

the solubility of cotrimoxazole.

Paracetamol elixir is formulated as an elixir by the use of propylence

glycol and syrup.

(2) pH control:

■ The solubility of a weak base can be increased by lowering the

pH of its solution whereas the solubility of a weak acid is

improved by a pH increase.

■ The chemical stability of a drug may also depend on pH.

So it must be carefully controlled.

■ The solutions for parenteral, opthalmic and mucous

membrane use must be carefully controlled to avoid pain and

irritiation.

■ The bioavailability of drugs may be influenced by the pH

of their solution.

(3) Solubilization

■ The solubility of insoluble or poorly soluble drugs in water can be

improved by the addition of surface active agents.

■ The hydrophillic surfectants possessing HLB values above 15

are usually used as solubilizing agent.

■ The surfectant chosen must be nontoxic, nonirritant, miscible

with solvent systems and compatible with other ingredients,

free from disagreable odour and taste.

■ For example, the solubilization of iodine to produce iodophores

is achieved by use of macrogel ethers.

(4) Complexation.

■ Poorly soluble drugs sometimes interact with a soluble material

to form a soluble intermolecular complex. This complex could

not cross lipid membrane. So a device must be developed to

release drug from the complex before contact with biological fluids.

■ Hydrotropy; the increase in aqueous solubility of material

by inclusion of additives. This method could also be used for

complexation.

■ For example, complexation of iodine with a 10-15% solution

of polyvinylpyrrolidone to improve the aqueous solubility

of the active agent.

(5) Chemical Modification:

■ Chemical modification of drug may be necessary in order to

produce a water soluble derivative.

■ For example, the synthesis of the sodium phosphate salts

of hydrocortisone, prednisolone and betamethasone.

(6) Particle Size Control:

■ As particle size decreases solubility will increases.

■ This phenomenon is very important for suspension

formulation rather than solution.

Formulation of SolutionNon-aqueous solutions

The use of alternative solvents : If complete solution of the active

ingredients is not possible at all storage temperatures or if the drug is

unstable in aqueous systems it may be necessary to use alternative

solvent.

For example, IM injection of solutions of drugs in oils is often used for

depot therapy and some drugs (propionate and benzoate esters of

testesterone and oestradiol) are specially synthesized to improve their

oil solubilities.

Fixed Oils & Vegetable Origin: These are nonvolatile oils which

consist of fatty acid esters of glycerol. Olive oil, sesame oil, maize oil,

cottonseed oil, soya oil and castor oil are suitable for parenteral use.

For example, almond oil consists of glycerides mainly of oleic acid

is used as solvent for oily phenol injection BP.

Some fixed oils are sufficiently tasteless and odourless to be suitable

for oral use as solvents of Vitamin A & D.

Alcohols: Ethyl alcohol is the most widely used solvent in this class

specially for external application. For example, Salicylate lotion BP.

At concentration above 15%, it exhibits antimicrobial activity. Usually

it is used as cosolvent with water.

If required for external use then industrial methylated spirit (IMS) is

usually included rather than the more expensive ethanol.

An alcohol possessing similar properties is isopropyl alcohol, is used

as a solvent for dicophane.

Polyhydric Alcohols: Alcohols having two hydroxyl groups are known

as glycols but due to their toxicity they are rarely used internally.

Propylene glycol is an exception often used in conjunction with water

or glycerol as a cosolvent

It is used in formulation of Digoxin Inj BP, Phenobarbitone Inj. BP,

Cotrimoxazole IV inj BP.

Dimethylsulfoxide (DMSO)

This is a highly polar compound and is thought to aid the penetration of drugs through the skin.

For example, DMSO is used as a carrier for idoxuridine (antiviral agent) for application to human skin.

Ethyl Ether: It is used as a cosolvent with alcohol in some collodions.

Liquid Paraffin: The oily nature of this material makes it unpleasent to use externally, although it is often used as a solvent for the tropical application of drugs in emulsion formulations.

Isopropyl myristate and isopropyl palmitate are oily materials, used as solvents for external use particularly in cosmetics.

Formulation Additives• Buffers

To resist any change in pH. It must be compatible with other excipients and

have low toxicity. Most pharmaceutically acceptable buffer systems are carbonates, citrate, gluconates, lactates, phosphates and tartarates.

• Isotonicity modifiers• Solutions for injection• Application to mucous membrane• Large-volume solutions for ophthalmic applicationmust be made isotonic to avoid pain and irritation.

Most widely used isotonicity modifiers are: dextrose and NaCl

• Viscosity enhancementIt is difficult for aqueous-based topical solutions to remain on the skinor in the eye; therefore low concentrations of jelling agents are added to increase the viscosity of the product.

• PreservativesSolution 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. 4. Consumer use may result in the introduction of microorganism. so a preservative should be added to the product

Preservative used 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 odour

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 ascorbic 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 .

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.

•AntioxidantsVitamins, essential oils & almost all fats and oils can be oxidized.

Oxidation reaction can be initiated by:

1. heat: maintain oxidizable drugs in a cool place

2. light: use of light- resistant container

3. heavy metals (e.g. Fe, Cu): effect of trace metals can be

minimized by using citric acid or ethylenediamine tetra acetic

acid (EDTA) i.e. sequestering agent .

Antioxidants as propyl & octyl esters of gallic acid, tocopherols or

vitamin E, sodium sulfite, ascorbic acid (vit. C) can be used.

•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.

• Flavours and perfumes

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.

Pharmaceutical Solutions

Aqueous

1.Douches2.Enemas3.Gargles4.Mouthwashes5.Nasal washes6.Juices7.Sprays8.Otic solutions9. Inhalations

Sweet &/Viscid1.Syrups2.Honeys3.Mucilages4.Jellies

Nonaqueous

1.Elixirs2.Spirits3.Collodions4.Glycerins5.Liniments6.Oleo Vitamin

Syrups:

Concentrated viscous liquid prepn containing

large amount of dissolved sugar (or sugar

substituent) with or without added flavouring

agents and medicinal substances.The concn

of sugar in syrup should be 66.7%.

Syrups are two types:

1)Non-medicated syrup: contain flavouring agents but not

medicinal substances.

For example, Cherry syrup. Cocoa syrup, orange syrup,

raspberry syrup etc.

2) Medicated syrup: contain therapeutic agents. Now these

syrups are used to extremporneous preparation of liquid

dosage forms of medicines.

Medicated syrup is formulated by the components ; sucrose,

purified water, flavouring agent & other excipients.

Components of Syrup

► Sucrose or sucrose substitutes: provide sweeting effects

and viscosity.

► Antimicrobial preservatives

► Flavourants

► Colourants.

Medicated syrups contain special solvents, solubilizing agents,

thickeners or stabilizers along with active ingredients.

Sugar used in Syrup: Sucrose is the most frequently used sugar

substance in syrups. Dextrose is also used as sugar substituent.

Non-sugar substance: Sorbitol, glycerin and propylene glycol (PEG).

Artificial sweeteners: Saccharin, Aspartame, Neotame etc.

Why most syrups contain sucrose of 60-80%?

Most syrups contain sucrose of 60-80%,

► not only because of the desirable sweetness and viscosity but also

to enhance stability in contrast to unstable character of dilute

sucrose solutions.

► Aqueous dilute sugar medium is an efficient nutrient medium for

microbial growth particularly yeasts and molds. But concentrated

sugar solutions are resistant to microbial growth.

Antimicrobial Preservatives:

Amount of preservative required to protect a syrup against microbial

growth varies with the proportion of water available, the nature and

inherent preservative activity of some formulative materials and the

capability of the preservative itself.

E.g. benzoic acid (0.1 to 0.2%), Na-benzoate(0.1 to 0.2%) and various

combinations of methyl, propyl and butylparabens.

Flavourant

Most syrups are flavoured with synthetic flavourants or with naturally

occuring materials as volatile oils (e.g. orange oil), vanillin and others

to render the syrup pleasant testing.

Colorants

To enhance the appeal of the syrup, a colouring agent is generally

used which correlates with flavourant (e.g. green with mint, brown

with chocolate etc).The colorant should be water soluble, nonreactive

and color stable at different pH range.

Advantages and Syrup

1.Syrups retard oxidation because it is partly hydrolysed into reducing sugar such as levulose and dextrose.

2. It prevents decomposition of many vegetable substances, syrups have high osmotic pressure which prevents microbial growth.

3. They are palatable due to presence of sugar, suitable vehicle for administration of bitter and bad odorous substances.

4. They are more quickly effective than solid dosages (e.g. tablet, capsule etc.) 5. They are homogenous formulation so the active ingredients are also homogenously distributed.

6. This is a suitable formulation for pediatric and geriatric patients.

Disadvantages of Syrup

1.It is possible in a closed container of syrup for surface dilution

due to solvent evaporation.

2. Solvent evaporation condenses upper internal surface of the

container and then flows back on to the surface of the product

which provide an ideal medium for the growth of certain

microorganism.

3. During storage and use of syrup involves crystallization of the

sugar within the screw cap. This problem is solved by addition of

polyhydric alcohols.

Elixirs

Elixirs are clear, sweetened, hydroalcholic solutions intended for

oral use and are usually flavoured to enhance their palatability.

Nonmedicated elixirs are employed as vehicles and medicated

elixirs for the therapeutic effect of the medicinal substances they

contain.

Difference between Syrup and elixirsSyrup Syrups are concn aq,

prepn of sugar or nonsugar substitute with or without added of flavouring agent and also the medicaments.

Usually more sweet than elixir.

More viscous than elexir. More effective than elixir.

Elixir Elixirs are clear, sweetened,

hydroalcoholic solutions intended for oral use, are usually flavoured to enhance their palatability.

Less sweet than syrup. Less viscous due to

containing lower proportion of sugar.

Less effective than syrup.

Difference between Syrup and elixirs

Syrup Syrups are unable to

maintain alcohol soluble components in solution.

From a manufacturing stand point, syrups are not preffered over elixir.

Syrup containing over 60-80% of sugar were usually self preserving.

Elixir Elixirs are better able to

maintain both water soluble acid, alcohol soluble components in solution

Elixirs are preffered over syrup.

Elixir containing over 10-20% of alcohol are usually self preserving.

Formulation of Elixir

(1)Vehicles:

■ The elixirs are usually prepared by using water, alcohol, syrup

glycerin, sorbitol, propylene glycol as vehicle. Among them water is

used to dissolve the majority of ingredients.

■ The flavouring agents containing essential oils are soluble in

alcohol. Certain ingredients of elixir are easily soluble in alcohol. In

this case concn of alcohol is 5-40% (to make a clear soln).

■ Glycerin, sorbitol and propylene glycol are used as a vehicle for

many ingredients which are not soluble in water and alcohol.

(2) Adjuvents:

■ Chemical Stabilizers: The various chemicals or solvents are used

to make stable elixirs. For example, in neomycin elixir, citric acid

is added to adjust the pH between 4 to 5 to prevent darkening of

elixir on storage.

■ Colourant:

The coalter dyes are commonly used in elixir. For example,

amaranth compound, tartrazine, green sulphur.

■ Flavourant:

The colourants used in elixirs are Raspberry syrup, lemon syrup,

orange syrup etc.

■ Preservatives:

The mould growth and fermentation in elixirs are inhibited by using

alcohol 20% or more, propylene glycol, glycerol as a vehicle. The high

osmotic pressure of elixir prevents the growth of microorganism.

Benzoic acid, methyl paraben, propyl paraben etc are also used

as preservatives in many elixirs.

(3) Container: Elixirs are dispensed in well closed, airtight glass bottles having screwcaps.

(4) Storage:Elixirs are required to be stored in a cool place protected from light.

Why preservatives are added in the syrup?

Although syrups have 66.7% sugar content, it require addition of

preservatives for following reasons;

(1)Solvent evaporation of syrup some times cause flow back of the

evaporated solvent to the upper layer of syrup producing a dilute

layer which provides an ideal media for microbial growth. This is

why preservative is essential in syrup.

(2) Syrups are usually formulated in a temperature controlled

environment. These may be transferred to other region of

uncontrolled temperature, it may cause the crystallization of the

sugar molecule and may remain as sediment to the solution. Thus

two layers are formed upper layer remain as solvent and the

lower layer remain as solute. Since the solvent layer is less

sugar content, it may be easily attacked by the microorganisms.

This is why preservatives are added to the syrup formulation.

Concentration of Sucrose controlling in Syrup Why is so important?

In dilute solutions sucrose provides an excellent nutrient for

molds, yeasts, and other microorganisms.

In concentration of 65 % by weight or more the solution will

retard the growth of such microorganisms.

A saturated solution may lead to crystallization of a part of

the sucrose under conditions of changing temperature.

How heat may cause the Deterioration of Syrup?When heat is used in the preparation of syrups, there is almost certain to be an inversion of a slight portion of the sucrose.

C12H22O11 2 C6H12O6

Sucrose heat & acid Invert sugar (dextrose and levulose)

The speed of inversion is greatly increased by acids; the hydrogen ion acts as a catalyst in this hydrolytic reaction.

Invert sugar♣ is more readily fermentable than sucrose♣ tend to darken in color♣ retard the oxidation of other substances.

The levulose formed during inversion is sweeter than sucrose; therefore the resulting syrup is sweeter than the original syrup.

When syrup is overheated it caramelizes.

Manufacturing of Solutions

■ Very simple equipments like mixing vessels, agitation system and

filtration system is necessary for formulation of syrup. Solutes are

simply added to the solvent in a mixing vessel and stirring is continued

until dissolution is complete.

■ Heat may be necessary in some cases for complete dissolution of materials. Care must be taken also for volatile and thermolabile materials.

■ Size reduction of solid materials may speed up the solution process.

■ Solutes needed in low concn are often predissolved in a small volume of the solvent and then added to the bulk.

■ Volatile materials such as flavours and perfumes are added at the end of a process and after cooling if necessary to reduce evaporation.

■ Finally the formulation is filtered for final clarification.

Stability of Solutions

Both the chemical and physical stability of solutions in their container

are important. A solution must retain its initial clarity, colour, odour,

taste and viscosity over its allocated shelf life.

Major signs of instability are

colour change,

precipitation

microbial growth

chemical gas formation

Clarity can be easily assessed by visual examination or optical

density measurement after agitation. Colour may be assessed by

visually or spectrophotometrically. The stability of flavours and

perfumes is difficult to assess but now a days chromatographic

methods are used.

Organoleptic powers are screened by a panel accessors. If a suitable

majority of the panel members are unable to detect a difference

between stored sample and freshly prepared reference material,

it may be assumed that the taste and odour of the sample has not

significantly changed.

Different Types of solutions

(a)Mixtures: Mixures are aqueous prepn either solution or suspension.

Most mixture prepn are manufactured on a small scale and allocated

shelf life of a few weeks before dispensing.

(b) Draughts: A draught is a mixture of only one or two large doses of

about 50 ml of solutions.

(c) Linctuses: A linctus is a viscous preparation usually prescribed for the

relief of cough. It is usually consists of a simple solution of the active

agent in a high concentration of sucrose often other sweetening

agents.

(d) Mouthwashes and Gargles: Aqueous solutions for the prevention

and treatment of mouth and throat infections can contain antiseptics,

analgesics and astringents. They should be diluted with warm water

before use.

(e) Nasal Products

Small volume solutions in an aqueous vehicle formulated at pH of

6.8 to avoid irritation in nasal mucous. Made isotonic with nasal

secretions using NaCl. Viscosity is controlled by cellulose derivatives

due to low buffering capacity of nasal mucous membrane.

Active ingredients include antibiotics, antiinflammatories and

decongestants.

(f) Ear Drops

These are simple solutions of drugs in either water, glycerol, propylene

glycol or alcohol/water mixtures for local use and include antibiotics,

antiseptics, cleansing solutions and wax softeners.

(g) Enemas

Aqueous or oily solutions, emulsions and suspensions available for

the rectal administration of medicaments for cleansing, diagnostic or

therapeutic purposes.

(h) Lotions:

A solution, designed to apply to the skin without friction. It may contain

humectants so moisture is retained on the skin after application or alcohol

which evaporates quickly imparting cooling effect on skin.

(i) Liniments:solutions or mixtures of various substances in oil, alcoholic solutions

of soaps, or emulsions.

They are intended for external application and should be so labeled.

They are applied with rubbing to the affected area, the oil or soap base

providing for ease of application and massage.

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.

(j) Paints:

Liquid prepn for application to the skin or mucous membrane, often

applied with a small brush. The solvents (e.g. alcohol, acetone)

evaporates quickly leaving a film on the skin containing active agents.

(k) 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.

The official medicated collodion, Salicylic Acid Collodion USP, contains 10 % w/v of Salicylic Acid in Flexible Collodion USP and is used as a keratolytic agent in the treatment of corns and warts.

(l) Aromatic Water:

Aromatic waters (medicated waters) are clear, saturated aqueous solution

of volatile oils or other aromatic or volatile substances. ■ They are used principally as flavored or perfumed vehicles.

■Volatile oils solutions represent an incompatibility problem of salting out.

This occurs after the incorporation of a very soluble salt in their solution.

■ Aromatic water will deteriorate with time therefore should be made in small quantities

- protected from intense light and excessive heat by storing in air

tight, light resistant containers.

■ If they become cloudy or otherwise deteriorate; they should be

discarded. Deterioration may be due to volatilization, decomposition or

mould growth.

There are 2 official methods of preparation:

(a)Distillation process (Stronger Rose Water NF) Adv.: most satisfactory method Dis.: slow and expensive

The drug should be coarsely ground and mixed with sufficient

quantity of purified water in the distillation unit.

After distillation any excess oil in the distillate is removed by

filtration.

Drug should not be exposed to the action of direct heat during

distillation; otherwise, the odour of the carbonized substance

will be noticeable in the distilled aromatic water.

If the volatile principle in the water are present in small quantities

the distillate is returned several times to the still with fresh portions of

drug.

(b) Solution process (Peppermint water)

Aromatic water may be prepared by shaking volatile substance

with purified water. The mixture is set aside for 12 hours &

filtered. Talc (inert) may be used to increase the surface of the

volatile substance, ensure more rapid saturation of the water

and act as a filter aid.

(m) Infusions

Infusions are concentrated solutions of active principles from animal

or vegetable sources. These are prepared by extracting the drug

using 25% alcohol but without application of heat. This is then

diluted 1 to 10 in the final product.

(n) Extracts: These similar product of infusions but concentrated by evaporation.

(p) Tinctures:

Alcoholic extracts of drugs but are relatively weak compared with

extracts.

(q) Spirits:

Alcoholic solutions but of volatile materials which are used as

flavoring agent.