Liquid dosage forms

Lecture 2

Solubility

●To hasten dissolution, a pharmacist may employ one of several techniques such as applying heat, reducing the particle size of the solute, using a solubilizing

agent, or subjecting the ingredients to vigorous agitation .

●Most chemical agents are more soluble at elevated temperatures than at room temperature or below because an endothermic reaction between the solute and the solvent uses the energy of the heat to enhance dissolution. However, elevated temperatures cannot be maintained for pharmaceuticals, and the net effect of heat is simply an increase in the rate of solution rather than an increase in solubility.

●In addition to or instead of raising the temperature of the solvent to increase the rate of solution, a pharmacist may choose to decrease

The particle size of the solute (grinding of a solid to a fine state of subdivision). The reduced particle size increases the surface area of the solute.

IMPORTANCE OF SOLUBILITY

-A solution is a chemically and physically homogenous mixture of two or more substances.

-The dispersed phase or the solute that is present in smaller proportion is found at ionic or molecular dimensions as in case of sodium chloride or sucrose in water. True solution

1 .Assess the purity of the drug2 .Determine the possible dosage form

3 .Qualitatively and quantatively analyses the drug in the dosage form4 .Expect bioavailability of drugs from solid dosage forms since the most important

stage is the dissolution of solid drug particles to for a solution in the gastrointestinal tract.

Some solvents for liquid preparations

Alcohol, Ethyl alcohol (ethanol)C2H5OH1 .Next to water, alcohol is the most useful solvent in pharmacy. It is used as a primary

solvent for many organic compounds.

2 .It forms hydroalcoholic mixture with water that dissolves both alcohol-soluble and water-soluble substances

3 .Alcohol has been well recognized as a solvent and excipient in the formulation of oral pharmaceutical products. Alcohol is often preferred because of its miscibility with water and its ability to dissolve many water-insoluble ingredients, including drug substances,

flavorants, and antimicrobial preservatives .

4 .It is also used in liquid products as an antimicrobial preservative alone or with parabens, benzoates, sorbates, and other agents.

5 .Toxicity of ingested alcohol particularly for children. For OTC oral products intended for children under 6 years of age, the recommended alcohol content limit is 0.5%, for products intended for children 6 to 12 years old, the recommended limit is 5% and for children over 12 years and adults, the recommended limit is 10%.

Diluted alcohol - Is prepared by mixing equal volumes of alcohol and purified water (50%).- Diluted alcohol is a useful hydroalcoholic solvent in various pharmaceutical processes and preparations.

•Alcohol, Rubbing (alcohol rubbing compound)• -It contains about 70% ethyl alcohol by volume.

• -It is employed as a rubefacient externally and as soothing rub for bedridden patients, a germicide for instruments

• -As vehicle for topical preparation• -As skin cleanser before injection

Isopropyl rubbing alcohol

It has the advantage over ethyl alcohol in that the commonly available product contains not over 1% of water, while ethyl alcohol contains about 5% water, which often a disadvantages.

Is about 70% by volume isopropyl alcohol, with or without colour additives, stabilizers and perfume oils

-It is used externally as a rubefacient and soothing rub and for topical products

-The commercially available 91% isopropyl alcohol solution are commonly employed by diabetic patients in preparing needles and syringes for hypodermic injections of insulin and for disinfecting the skin.

Glycerin, Glycerol -It is a clear syrupy liquid with sweet taste

-It is miscible with water and alcohol -As solvent it is comparable with alcohol, but because of its viscosity, solutes

are slowly soluble in it unless it is rendered less viscous by heating. -It is used as a stabilizer and as auxiliary solvent in conjunction with water or

alcohol. -It has preservative qualities

-It is used in internal preparations -It dissolves the fixed alkalies, a large number of salts and vegetable acids,

pepsin, tannin, some active principals of plants, etc. -It also dissolves gum, starch, etc.

Propylene glycol -A viscous liquid, miscible with water, with acetone and with chloroform in

all proportions. -It is soluble in ether and will dissolve many essential oils but is immiscible

with fixed oils. -It is a useful solvent with wide range of application

-It is substituted for glycerol in modern pharmaceutical preparations -It is used for formulation of digoxin, diazepam, phenobarbital injection

-As diluent for ear drops

Polyethyleneglycol, PEG 400 - It is miscible with water, acetone, alcohol and other glycols.

- It dissolves many water-soluble organic compounds as well as certain water insoluble substances such as acetylsalicylic acid and theophyllin.

-Is used as a solvent in topical solution -Used as co-solvent with alcohol and water

-Can be used for extraction processes -In the formulation of veterinary solutions

Ethyl etherUsed for extraction of crude drugs

It is used as a co-solvent with alcohol in some collodionsIt is not used for internal use

Liquid paraffinIt is unpleasant to use internally

It is used as a solvent for topical application of drugs in emulsion formulations

DimethylsulfoxideIt is used as a solvent for veterinary drugsIt is used for application to human skin

Miscellaneous solventsIsopropyl myristate, isopropyl palmitate are solvent for external use, cosmeticsLow viscous, lack of greasiness

Xylene is used in ear drops for human use to dissolve ear wax

Chloroform -It is miscible with alcohol, ether, benzene, solvent hexane and both fixed and

volatile oils.

It dissolves polar solutes through the formation of hydrogen bonds.

It is possible to dissolve alkaloids in chloroform.

Role of co-solvency Weak electrolytes and non-polar molecules frequently have poor water solubility

Their solubility usually can be increased by the addition of a water-miscible solvent in which the drug has good solubility.

This process is known as co-solvency, and the solvents used in combination to increase the solubility of the solute are known as co-solvent

Co-solvents are employed not only to affect solubility of the drug, but also to improve the solubility of volatile constituents used to impart a desirable flavor and odour to the product.

Types of pharmaceutical water

Purified water, USPWater for injectionAromatic water

Physiological compatibilityLack of toxicityPossesses a high dielectric constant ensuring the dissolution of a wide range of ionizable materialsLack of selectivity

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 (ion exchange method) 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 injectionMust be used for the formulation of parental solutions.It is obtained by sterilizing pyrogen-free distilled water.

Aromatic Waters 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.

The strengths of pharmaceutical preparations are usually expressed in terms of percent strength, although for very dilute preparations, expressions of ratio strength may be used.

Percentage(%) %w/v (e.g., 1%w/v =1g constituent in 100 mL preparation)

%v/v (e.g., 1%v/v = 1mL constituent in 100 mL preparation) %w/w (e.g.,1%w/w=1 g constituent in 100 g preparation)

Ratio strengthweight in volume (e.g., 1:1000 w/v= 1g constituent in 1000 mL

preparation)volume in volume (e.g., 1:1000 v/v = 1ml constituent in 1000 mL

preparation)weight in weight (e.g., 1:1000 w/w = 1 g constituent in 1000 g

preparation)

Additives

-Buffers Injection, eye drops and nasal drops should be buffered at pH 7.4

Ex: carbonates, citrates, phosphate, lactates, gluconates, tartarates, borates (external). Its presence in solution resists any changes in pH upon dilution or

addition of small quantities of acid or base. The usual buffering agents used in oral liquid preparations are acetate and phosphate buffer. The buffer increase the stability of the drug in solution.

-Isotonicity modifiersSolutions for injectionApplication to mucous membraneLarge-volume solutions for ophthalmic applicationMost widely used isotonicity modifiers are: dextrose and NaCl

-Viscosity enhancementIt is difficult for aqueous-based topical solutions to remain on the skin or in the eye (why?) therefore low concentrations of jelling agents are added to increase the viscosity of the product. Low conc., of gelling agents can be used to increase the apparent viscosity of the product. Ex: Povidone, Carbomer, Hydroxyethylcellulose

AdditivesPreservatives

Solution may become contaminated for a number of reasons: Raw materials used in the manufacture of solutions are excellent growth media for

bacterial substances such as (1) 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 Ex: parahydroxybenzoic acid

esters (Parabens).Preservative used should be:

-effective against a wide spectrum of microorganisms -stable for its shelf life

-non toxic, non sensitizing -compatible with the ingredients in the dosage form

-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 (mostly used) 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 (WHY?) .

-Phenol -Alkylester parahydroxy benzoic acid (methyl and propyl paraben) which

are mostly used, adequately soluble in water antifungal and antibacterial activity.

-Sorbic acid and its salts have antibacterial action and antifungal action.

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. Not used in oral preparations but used in ophthalmic, nasal and parenteral solutions. They are inactivated by variety of anionic substances.

•Flavours and perfumesTo mask the unpalatable taste, ex: fruit juices, aromatic oils, herps 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.

•Colours (colorants)To improve the attractiveness of the product and to enable ease of identificationEx: carotenoids, chlorophyll, riboflavines, coal tar dyes (amaranth). The colorant used is generally water soluble, non-reactive with other components, and color-stable at the pH range and under intensity of light that the liquid preparation is likely to be exposed during its shelf-life. It must be

Harmless, no physiological activity and its coloring power should be high so that only small quantities are required.

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. Reducing agent and antioxidants Ex: sodium metabisulphite, butylated hydroxyanisole or butylated hydroxytoluene

Sweetening agentsSucrose 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 .

Ex: sucrose, polyhydric alcohols: sorbitol, mannitol, artificial sweeteners: sodium or calcium salt of saccharin

To enhance palatability and to mask the taste of the drugs etc. sweeteners are used. Example sucrose (sugar), saccharin, aspartame, liquid glucose.

Sucrose is soluble in aqueous medium and it is available in highly purified form at reasonable price. It is chemically and physically stable in the pH range of 4 to 8. It is frequently used in conjunction with sorbitol, glycerin and other polyols.

Liquid glucose such as dextrose and maltose

Saccharin is used to supplement sugars and polyols as sweeteners. It is approximately 250-500 times as sweet as sugar. It has no calorie value hence can be given to obese and diabetic patients. It has a bitter after taste.

Aspartame (methylester of aspartic acid and phenylalanine) is approximately 200 times sweeter than sugar. No bitter after taste. Solubility in water is adequate for formulation purpose. Its stability in aqueous solution is pH and temperature dependant. It is stable at pH 3.4 and 5 and at refrigerated temperature.

Methods of Preparation of Solutions

(a )Simple Solution (b )Solution by Chemical Reaction

(c )Solution by Extraction(a )Simple Solution

Solutions of this type are prepared by dissolving the solute in a suitable solvent (by stirring or heating) .

The solvent may contain other ingredients which stabilize or solubilize the active ingredient e.g. solubility of Iodine is 1: 2950 in water however, it dissolves in presence of KI due the formation of more soluble polyiodides (KI.I2 KI.2I2 KI3.I3 KI.4I4) .[ Strong Iodine Solution USP (Lugol's SoIution)] is prepared by dissolving 50g of iodine in 100 ml of purified water containing 100g of potassium iodide. Sufficient purified water is then added to make 1000 ml of solution.

Calcium hydroxide solution USP (lime water) is prepared by vigorusly agitating 3g of calcium hydroxide with 1000 ml of cool purified water. The solution must kept in well-filled tight closed container (to avoid .interaction with C02 of the atmosphere) at 25°C

(b )Solution by Chemical ReactionThese solutions are prepared by reacting two or more solutes with each other in a suitable solvent e.g. Aluminum sulfateAnd calcium carbonate used to prepare Aluminum subacetate

solution USP .(c )Solution by Extraction

Plant or animal products are prepared by suitable extraction process. Preparations of this type may be classified as

solutions but more often, are classified as extractives .