Transcript Liquid dosage forms

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.
- 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
IMPORTANCE OF SOLUBILITY
1. Assess the purity of the drug
2. Determine the possible dosage form
3. Qualitatively and quantatively analyses the drug in the dosage form
4. 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)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%.
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
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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.
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Propylene glycol
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- 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
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- 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 
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Ethyl ether
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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
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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
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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, 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
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
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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.
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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 injection 
Must be used for the formulation of parental solutions.
It is obtained by sterilizing pyrogen-free distilled water.
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Aromatic Waters
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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
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- protected from intense light and excessive heat by storing
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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.
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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)
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 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
Additives
Preservatives
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Solution may become contaminated for a number of reasons:
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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:
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- 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 
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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
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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.
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Flavours and perfumes
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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)
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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 colorstable 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.
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
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 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
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.