Solution dosage formSolution dosage form

Lecture 3Lecture 3

Oral solutionsOral solutions

Dry mixtures for solutionDry mixtures for solution - -Certain antibiotics have insufficient stability in aqueous Certain antibiotics have insufficient stability in aqueous

solution to meet extended shelf life periodssolution to meet extended shelf life periods.. - -They are provided in dry powders or granules for They are provided in dry powders or granules for

reconstitution with a prescribed amount of purified reconstitution with a prescribed amount of purified water immediately before dispensing to the patientwater immediately before dispensing to the patient . .

- - -Once reconstituted, the solution remain stable in the Once reconstituted, the solution remain stable in the refrigerator for the labeled period usually 7-14 days refrigerator for the labeled period usually 7-14 days depending on the preparationdepending on the preparation..Examples: Penicillin V Potasium for oral solution, USPExamples: Penicillin V Potasium for oral solution, USP

Cloxacillin Sodium for oral solution, USPCloxacillin Sodium for oral solution, USP

Oral rehydration solutionsOral rehydration solutionsAre usually effective in treatment of Are usually effective in treatment of diarrheadiarrhea and mild volume depletion (5-10% of and mild volume depletion (5-10% of body weight). These are available OTCbody weight). These are available OTCA liter of typical oral rehydration solution contains: 45mEq NaA liter of typical oral rehydration solution contains: 45mEq Na++, 20 mEq K, 20 mEq K++, 35 , 35

mEq CLmEq CL--

, 30 mEq citrate, 25 g dextrose., 30 mEq citrate, 25 g dextrose.These formulations are available in liquid or powder packets form for reconstitutionThese formulations are available in liquid or powder packets form for reconstitutionThese products should not be mixed with milk or fruit juiceThese products should not be mixed with milk or fruit juice

Oral colonic lavage solutionOral colonic lavage solution Used for preparation of the bowel for colonoscopy, administration of a clear Used for preparation of the bowel for colonoscopy, administration of a clear

liquid diet for 24 to 48 hours preceding the procedure, administration of an oral liquid diet for 24 to 48 hours preceding the procedure, administration of an oral laxative such as magnesium citrate the night before, and a cleansing enema laxative such as magnesium citrate the night before, and a cleansing enema administered 2 to 4 hours prior to the procedureadministered 2 to 4 hours prior to the procedure..

Oral administration Oral administration of a balanced electrolytes with PEG-3350of a balanced electrolytes with PEG-3350 . . Before dispensing it to the patient, the solution is reconstituted with water, Before dispensing it to the patient, the solution is reconstituted with water,

creating an iso-osmotic solution having a mildy salty taste. PEG is an osmotic creating an iso-osmotic solution having a mildy salty taste. PEG is an osmotic agent in the GITagent in the GIT

The formulation is as followsThe formulation is as follows : :PEG-3350; Sodium sulfate; sodium bicarbonate; sodium chloride; potassium PEG-3350; Sodium sulfate; sodium bicarbonate; sodium chloride; potassium

chloride 240 ml every 10 min (total 4 L)chloride 240 ml every 10 min (total 4 L)..

SyrupsSyrups

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

Syrups Syrups Syrups are concentrated aqueous preparations of a sugar substitute with or without Syrups are concentrated aqueous preparations of a sugar substitute with or without flavoring agents and medicinal substances. Syrups containing flavoring agents but flavoring agents and medicinal substances. Syrups containing flavoring agents but not medicinal substances are called nonmedicated or flavored vehicles (syrups) not medicinal substances are called nonmedicated or flavored vehicles (syrups) such as cherry syrup, orange syrup and Raspberry syrup. These syrups are such as cherry syrup, orange syrup and Raspberry syrup. These syrups are intended to serve as pleasant-tasting vehicles for medicinal substancesintended to serve as pleasant-tasting vehicles for medicinal substances..

Medicinal syrups are commercially prepared from the starting materials , that is by combining each of the individual components of the syrup, such as sucrose, purified water, flavoring agents, coloring agents, the therapeutic agent, and other necessary and described ingredients. Naturally, medicated syrups are employed in therapeutics for the value of the medicinal agent present in the syrup.

Components of syrupsThe sugar, usually sucrose or sugar substitute used to provide sweetness and viscosity.

Antimicrobial preservativesFlavorants and colorantsAlso, many syrups contain special solvents, solubilizing agents, thickeners or stabilizer.

- -Sucrose is the sugar most frequently employed in syrups it may be replaced by other sugars or substances Sucrose is the sugar most frequently employed in syrups it may be replaced by other sugars or substances such as sorbitol, glycerin and propylene glycolsuch as sorbitol, glycerin and propylene glycol..

- -In some instances, all glycogenetic substances (materials converted to glucose in the body) are replaced In some instances, all glycogenetic substances (materials converted to glucose in the body) are replaced by nonglycogenetic substances such as methylcellulose or hydroxy ethylcellulose. These two materials by nonglycogenetic substances such as methylcellulose or hydroxy ethylcellulose. These two materials are not hydrolyzed and absorbed into the blood stream, and their use results in excellent syruplike are not hydrolyzed and absorbed into the blood stream, and their use results in excellent syruplike vehicle for medications intended for use by diabetic patientsvehicle for medications intended for use by diabetic patients..

- - -Most syrups contain a high proportion of sucrose, usually 60 to 80% not only because of the desirable Most syrups contain a high proportion of sucrose, usually 60 to 80% not only because of the desirable sweetness and viscosity of such solutions but also because of their inherent stability in contrast to sweetness and viscosity of such solutions but also because of their inherent stability in contrast to unstable character of dilute sucrose solutions. Additionally, the concentrated sugar solution are quite unstable character of dilute sucrose solutions. Additionally, the concentrated sugar solution are quite resistant to microbial growthresistant to microbial growth..

- -Simple syrup Syrup, NFSimple syrup Syrup, NF, , is prepared by dissolving 85g of sucrose in enough purified water to make 100 is prepared by dissolving 85g of sucrose in enough purified water to make 100 ml of syrup. Syrup has a specific gravity of about 1.313ml of syrup. Syrup has a specific gravity of about 1.313..

- -The slight excess of water permits the syrup to remain physically stable in varying temperatures. If the The slight excess of water permits the syrup to remain physically stable in varying temperatures. If the syrup were completely saturated with sucrose, in cool storage some sucrose might crystallize from syrup were completely saturated with sucrose, in cool storage some sucrose might crystallize from solutionsolution..

As formulated, the official syrup is both stable and resistant to crystallization and microbial growthAs formulated, the official syrup is both stable and resistant to crystallization and microbial growth..

•The amount of preservative required to protect a syrup against microbial The amount of preservative required to protect a syrup against microbial growth varies with the proportion of water available for growthgrowth varies with the proportion of water available for growth

•Preservative commonly used in syrups : benzoic acid 0.1-0.2%, sodium Preservative commonly used in syrups : benzoic acid 0.1-0.2%, sodium benzoate 0.1-0.2%, parabens (0.1%)benzoate 0.1-0.2%, parabens (0.1%)

•To enhance the appeal of the syrup, a coloring agent that correlates with the To enhance the appeal of the syrup, a coloring agent that correlates with the flavorant employed (green with mint, brown with chocolate)flavorant employed (green with mint, brown with chocolate)..

•Most syrups are flavored with synthetic flavorants or with naturally occurring Most syrups are flavored with synthetic flavorants or with naturally occurring materials, such as volatile oils (orange oil), vanilinmaterials, such as volatile oils (orange oil), vanilin

•Colorant to enhance the appeal of the syrup may be addedColorant to enhance the appeal of the syrup may be added•Sucrose-based syrup may be substituted by a polyol, such as sorbitol solution Sucrose-based syrup may be substituted by a polyol, such as sorbitol solution

USP, 64%USP, 64% Examples of medicated syrupExamples of medicated syrup::

AnalgesicAnalgesicAnticholenergicAnticholenergic

AntiemeticsAntiemeticsAnticonvulsantAnticonvulsant

AntihistamineAntihistamineAntiviralAntiviral

AntitussivesAntitussivesExpectrorantExpectrorant

BronchodilatorsBronchodilatorsFecal softenerFecal softener

Polyols (e.g. glycerin or sorbitol) may be added to - retard crystallization of sucrose or - increase the solubility of added ingredients.

Alcohol often is included as - preservative- solvent for volatile oils.

Syrups possess remarkable masking properties for bitter and saline drugs.

It is important that the concentration of sucrose approaches

but not quite reach the saturation point, WHY?

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 (WHY?).

A saturated solution may lead to crystallization of a part of the sucrose under conditions of changing temperature.

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 (why ?);

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.

Invert Syrup:

It is prepared by hydrolyzing sucrose with hydrochloric acid and neutralizing the solution with Ca or Na carbonate.

The sucrose in the 66.7% w/w solution must be at least 95% inverted.

The invert syrup, when mixed in suitable proportions with syrup, prevents the deposition of crystals of sucrose under most conditions of storage.

Invert Syrup:

It is prepared by hydrolyzing sucrose with hydrochloric acid and neutralizing the solution with Ca or Na carbonate.

The sucrose in the 66.7% w/w solution must be at least 95% inverted.

The invert syrup, when mixed in suitable proportions with syrup, prevents the deposition of crystals of sucrose under most conditions of storage.

Preparation of Simple Syrup

(a) Solution with heat This is the usual method of making syrups:

in the absence of volatile agents or those injured by heat when it is desirable to make the syrup rapidly.

The sucrose is added to the purified water or aqueous solution and heated until dissolved, then strained and sufficient purified water added to make the desired weight or volume.

Excessive heating in the preparation of syrups must be avoided to prevent inversion of sucrose, with increased tendency to fermentation. Syrups cannot be sterilized by autoclaving without caramelization (yellow color).

The specific gravity of syrup is an important property to identify its concentration. Syrup has a specific gravity of about 1.313, which means that each 100 ml of syrup weighs 1313 g.

(b) Agitation without Heat

This process is used in those cases where heat would cause loss of valuable volatile constituents.

The syrup is prepared by adding sucrose to the aqueous solution in a bottle of about twice the size required for the syrup. This permits active agitation and rapid solution.

The stoppering of the bottle is important, as it prevents contamination and loss during the process.

(c) Addition of a Medicating Liquid to syrup

This method is resorted to in those cases in which fluid extracts, tinctures, or other liquids are added to syrup to medicate it.

Syrups made in this way usually develop precipitates since alcohol is often an ingredient of the liquids thus used and the resinous and oily substances dissolved by the alcohol precipitate when mixed with syrup.

A modification of this process consists of mixing the fluid extract or tincture with the water, allowing the mixture to stand to permit the separation of insoluble constituents, filtering & and then dissolving the sucrose in the filtrate.

This procedure is not permissible when the precipitated ingredients are the valuable medicinal agents.

(d) Percolation

In this procedure, purified water or an aqueous solution is permitted to pass slowly through a bed of crystalline sucrose, thus dissolving it and forming a syrup a pledget of cotton is placed in the neck of the percolator

If necessary, a portion of the liquid is repassed through the percolator to dissolve all of the sucrose.

This method is used for the preparation of Syrup USP.

Preservation of Syrups

The USP suggests that syrups be kept at a temperature not above 25°C.

Preservatives such as glycerin, methyl paraben, benzoic acid and sodium benzoate may be added to prevent bacterial and mold growth, particularly when the concentration of sucrose in the syrup is low.

The concentration of preservative is proportional to the free water.

The official syrups should be preserved in well dried bottles and stored in a cool dark place.

Dextrose-Based Syrups

Dextrose may be used as a substitute for sucrose (WHEN?) in syrups containing strong acids in order to eliminate the discoloration associated with inversion.

Dextrose forms a saturated solution in water at 70% w/v, which is less viscous than simple syrup.

It dissolves more slowly than sucrose and is less sweet Preservatives are required to improve the keeping qualities of such syrups. Glycerin is added in 30% to 45% v/v as preservative.

Artificial Syrups (Non-Nutritive Syrups)

intended as substitutes for syrups and are to be administered to persons who must regulate their sugar and/or calorie intake accurately. e.g. persons suffering from diabetes mellitus.

Some early formulae included glycerin, however, glycerin and propylene glycol are glycogenetic substances, i.e. they are materials which are converted into glucose in the body.

An example of non–nutritive syrup is “Diabetic Simple Syrup”. It contains compound sodium cyclamate (6% cyclamate sodium and 0.6% saccharin sodium)

However, the cyclamate studies showed that the sweetener could produce cancer in animals and, as a result, this substance was removed from a wide variety of products. Similar studies have been carried out on saccharin. Much research has been done to find a safe synthetic substitute for sucrose. As a result, aspartame which is about 200 times sweeter than sucrose, is being used now in many commercial preparations as the sweetening agent.

Sorbitol-Based Syrups

Sorbitol which is hexahydric alcohol made by hydrogenation of glucose has been used in the preparation of syrup.

It is used mostly in the form of a 70% w/w aqueous solution.

Sorbitol solution is not irritating to the membrane of the mouth and throat and does not contribute to the formation of dental carries.

Sorbitol is metabolized and converted to glucose; however, it is not rapidly absorbed from the GlT as sugars. No significant hyperglycemia has been found (WHY?); it may be used as component of non-nutritive vehicles.

Sorbitol solution does not support mold growth. Preservative should be used in solution containing less than 60% w/w sorbitol.

It is chemically stable and inert with respect to drugs and other ingredients used in pharmaceutical perpetration.

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

It is essential to test:toxicity – irritancy – flammability – cost – stability and compatibility

of solvents to avoid problems

Solvents such as acetone, benzene and petroleum ether are not used for internal products.

Internal products may contain ethanol, glycerol, propylene glycol certain oils.

For parental products the choice is very limited

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 and usually flavored to enhance their palatability.

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

An elixir may contain water and alcohol soluble ingredients.

ElixirsElixirs

Compared with syrups, elixirs are usually less sweet and less Compared with syrups, elixirs are usually less sweet and less viscous because they contain a lower proportion of sugar viscous because they contain a lower proportion of sugar and consequently are less effective than syrups in masking and consequently are less effective than syrups in masking the taste of medicinal substancesthe taste of medicinal substances..

Non-medicated elixirs are employed as vehiclesNon-medicated elixirs are employed as vehicles . .

In addition to alcohol and water, other solvents, such as In addition to alcohol and water, other solvents, such as

glycerol and propylene glycol are frequently employed in glycerol and propylene glycol are frequently employed in

elixirs as adjunctive solventselixirs as adjunctive solvents . .

Elixirs are Elixirs are sweetened sweetened with sucrose, sorbitol, glycerol, and/or with sucrose, sorbitol, glycerol, and/or artificial sweetenersartificial sweeteners

Elixirs having a high alcoholic content usually use artificial Elixirs having a high alcoholic content usually use artificial sweetener such as saccharinsweetener such as saccharin..

Most elixirs have Most elixirs have coloring agents coloring agents to enhance their appearanceto enhance their appearanceElixirs containing more than 10-12% alcohol are usually self-Elixirs containing more than 10-12% alcohol are usually self-

preservingpreserving Because of their usual content of volatile oils and alcohol, elixirs Because of their usual content of volatile oils and alcohol, elixirs

should be stored should be stored in tight, light-resistant containers and protected in tight, light-resistant containers and protected from excessive heatfrom excessive heat

Antihistamine ElixirAntihistamine Elixir: Diphenhydramine HCl: Diphenhydramine HClAnalgesic ElixirAnalgesic Elixir: acetominophen: acetominophen

Cardiotonic ElixirCardiotonic Elixir: digoxin: digoxinAntispasmodic ElixirAntispasmodic Elixir: hyoscyamine sulfate: hyoscyamine sulfate

Sedative ElixirSedative Elixir: phenobarbital: phenobarbital

Tinctures

•In In medicine, a tincture is an , a tincture is an alcoholic extract (e.g. (e.g.

of leaves or other plant material) or of leaves or other plant material) or solution of a of a

non-non-volatile substance; e.g. of substance; e.g. of iodine , ,

mercurochrome .( .(•Tinctures contain alcohol in amounts ranging from Tinctures contain alcohol in amounts ranging from

approx. 15-80%. The alcohol content protects approx. 15-80%. The alcohol content protects against microbial growthagainst microbial growth

•Other solvent, such as glycerol, may be employedOther solvent, such as glycerol, may be employed•Tincture must be tightly stopered and not exposed Tincture must be tightly stopered and not exposed

to excessive temperatureto excessive temperature

Many tinctures must be stored in light-resistant Many tinctures must be stored in light-resistant containers and protect from sunlightcontainers and protect from sunlight..

Some examples that were formerly common in Some examples that were formerly common in medicine includemedicine include::

Tincture of Cannabis sativaTincture of BenzoinTincture of Benzoin Tincture of cantharidesTincture of cantharides

Tincture of green soap (which contains also lavender)Tincture of green soap (which contains also lavender) Tincture of iodineTincture of iodine

Tincture of opium (laudanum)Tincture of opium (laudanum)Camphorated tincture of opiumCamphorated tincture of opium (paregoric)(paregoric)

Tincture of iodine is often found in emergency survival Tincture of iodine is often found in emergency survival kits, used both to disinfect wounds and to sanitize kits, used both to disinfect wounds and to sanitize surface water for drinkingsurface water for drinking..

When an alcohol solution is not desirable, Lugol's When an alcohol solution is not desirable, Lugol's iodine, an aqueous solution of iodine in potassium iodine, an aqueous solution of iodine in potassium iodide solution, or povidone iodine (Betadine), a PVP iodide solution, or povidone iodine (Betadine), a PVP solution, can be usedsolution, can be used..

Other names for Lugol's solution are Other names for Lugol's solution are II22KIKI (Iodine- (Iodine-

Potassium Iodide); Markodine, Strong solution Potassium Iodide); Markodine, Strong solution (Systemic); Aqueous Iodine Solution BP(Systemic); Aqueous Iodine Solution BP..

Topical tincturesTopical tincturesIodine TinctureIodine Tincture

It is a reddish-brown colour tinctureIt is a reddish-brown colour tincture It is prepared from 2% iodine crystal and 2.4% sodium iodide in a vehicle It is prepared from 2% iodine crystal and 2.4% sodium iodide in a vehicle

alcohol/water (44-50% alcohol)alcohol/water (44-50% alcohol)It is a popular local anti-infective agent applied to the skin in general household It is a popular local anti-infective agent applied to the skin in general household

first aidfirst aidCompound Benzoin tinctureCompound Benzoin tincture

It is prepared from 10% benzoin and lesser amounts of aloe, storax and tolu It is prepared from 10% benzoin and lesser amounts of aloe, storax and tolu balsambalsam

The mixture is macerated in alcoholThe mixture is macerated in alcoholIt is used to protect and toughen skin in the treatment of bedsores, ulcers, It is used to protect and toughen skin in the treatment of bedsores, ulcers,

cracked nipples, and fissures of the anuscracked nipples, and fissures of the anusAlso used in treatment of venereal wartsAlso used in treatment of venereal warts

It is also used as an inhalent for bronchitis and other respiratory conditionsIt is also used as an inhalent for bronchitis and other respiratory conditionsIt is best stored in tight, light-resistant containersIt is best stored in tight, light-resistant containers

Thimerosal TinctureThimerosal TinctureThe vehicle is water, acetone and 50% alcoholThe vehicle is water, acetone and 50% alcohol

It must be manufactured and stored in glass or suitably resistant It must be manufactured and stored in glass or suitably resistant containerscontainers

Ethylenediamine is used as stabilizer in the official solution and Ethylenediamine is used as stabilizer in the official solution and tincturetincture

The commercial preparation is colored orange red, the colour The commercial preparation is colored orange red, the colour defines the area of applicationdefines the area of application

It is a commonly used household It is a commonly used household antisepticantiseptic for application to the for application to the skin abrasions and cuts and in preparation of patients for surgeryskin abrasions and cuts and in preparation of patients for surgery

Green Soap tinctureGreen Soap tincture65%65% of active constituent in alcoholof active constituent in alcohol

Also contains 2% lavender oil as perfumeAlso contains 2% lavender oil as perfumeUsed as Used as detergentdetergent