1. Liquid dosage forms
Lecture 2

2. Some solvents for liquid preparations
Alcohol, Ethyl alcohol (ethanol)C2H5OH
1. 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%.

3. 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.

4. 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.

5. Polyethyleneglycol, PEG 400
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

6. Miscellaneous solvents
Ethyl ether
Used for extraction of crude drugs
It is used as a co-solvent with alcohol in some collodions
It is not used for internal use
Liquid paraffin
It is unpleasant to use externally
It is used as a solvent for topical application of drugs in emulsion formulations
Dimethylsulfoxide
It is used as a solvent for veterinary drugs
It is used for application to human skin
Miscellaneous solvents
Isopropyl myristate, isopropyl palmitate are solvent for external use, cosmetics
Low viscous, lack of greasiness
Xylene is used in ear drops for human use to dissolve ear wax

7. Chloroform Role of co-solvency
- 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.

8. Types of pharmaceutical water
Purified water, USP
Water for injection
Aromatic water
Physiological compatibility
Lack of toxicity
Possesses a high dielectric constant
ensuring the dissolution of a wide range of ionizable materials
Lack of selectivity

9. 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.

10. Distillation: Purified Water
► Purified water must be used in pharmaceutical preparations. It must have rigid specifications for chemical purity. Such water may be prepared by distillation, by use of ion-exchange resins or reverse osmosis. Such water may be sterile and subjected to a satisfactory sterilization process. Sterile water can be kept sterile if stored properly.
► The major impurities in water are calcium, iron, magnesium, manganese, silica and sodium. The cations usually are combined with the bicarbonate, sulfate or chloride anions. Hard waters are those contain calcium and magnesium cations. Bicarbonates are the major impurity in alkaline water.
► Ultraviolet energy, heat or filtration (Millipore filtration) can be used to remove or kill the microorganisms present in the water.
Distillation:
Conventional distillation can be considered as a method for continuous supply of sterile ultra pure water free of ions.

11. Ion Exchange: Reverse Osmosis: Removal of cation
Ion-exchange (deionization, demineralization) process will remove most of the major impurities in water efficiently and economically. A cation exchanger, in the hydrogen form H2R, first convert bicarbonate, sulfates and chlorides to their respective acids, e.g.
CaSO4 + H2R Ca R + H2SO4
Ca(HCO3)2 + H2R H2CO3
Carbonic acid decomposes to carbon dioxide (can be removed) and water.
The anion exchanger may contain basic anionic resin that can adsorb sulfuric, hydrochloric and nitric acids.
Reverse Osmosis:
The phenomenon of osmosis involves the passage of water from a dilute solution across a semi-permeable membrane to a more concentrated solution. Flow of water can be stopped by applying pressure, equal to the osmotic pressure, to the concentrated solution. The flow of water can be reversed by applying a pressure greater than the osmotic pressure and by this principle reverse osmosis can be utilized to the concentrated solution such as tap water, and pure water may be obtained.
Removal of cation

12. Cellulose acetate is used in the manufacture of semi-permeable membranes for purifying water by reverse osmosis. Why cellulose acetate is used in this process?
Generally salts and higher-valent ions are repelled causing separation of the ions from the water. Organic molecules are rejected based on molecular size and shape.
The selection of water-treatment equipment depends upon the quality of water to be tested, the quality of water required and the specific pharmaceutical purpose of the water. Two or more methods are frequently used to produce the water desired.

13. Water for injection
Must 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.
► They may be prepared by distillation or solution of the aromatic substance with or without the use of dispersing agent such as talc. Concentrated water could be prepared in presence of alcohol with the use of talc. How talc could be used? The aromatic water is prepared by diluting the concentrate with 39 times its volume of water. Aromatic waters such as peppermint, dill, cinnamon and caraway are used. Many synthetic aromatic substances with characteristic odors may be used in preparation of aromatic water such as geranyl phenyl acetate of a honey odor.
► The principal difficulty experienced in compounding prescriptions containing aromatic waters is due to a “salting out” action of certain ingredients such as very soluble salts, on the volatile principles of the aromatic water.

14. 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.

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

16. Additives - Buffers - Isotonicity modifiers - Viscosity enhancement
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 modifiers
Solutions for injection
Application to mucous membrane
Large-volume solutions for ophthalmic application
Most widely used isotonicity modifiers are: dextrose and NaCl
- Viscosity enhancement
It 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

17. Additives Preservatives Preservative used should be:
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

18. 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.

19. Quaternary Ammonium Compounds
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 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.

20. Flavours and perfumes Colours (colorants)
To 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 identification
Ex: 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.

21. Antioxidants
Vitamins, 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 tetra­acetic
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 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.
Ex: sucrose, polyhydric alcohols: sorbitol, mannitol, artificial sweeteners: sodium or calcium salt of saccharin

22. To enhance palatability and to mask the taste of the drugs etc
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 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.

23. Methods of Preparation of Solutions
(a) Simple Solution
(b) Solution by Chemical Reaction
(c) Solution by Extraction
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

24. (b) Solution by Chemical Reaction
These solutions are prepared by reacting two or more solutes with each other in a suitable solvent e.g. Aluminum sulfate
and calcium carbonate used to prepare Aluminum subacetate Topical Solution USP (Burow’s Solution). The preparation has astringent and antibacterial properties and may be used to treat a number of skin conditions such as insect bites, rashes caused by poison. .
(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.