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Solutions: Definition
Pharmaceutical solutions are extensively used as dosage forms for
the oral administration of therapeutic agents.
Pharmaceutical solutions defined as liquid preparations in which the
therapeutic agent and the various excipients are dissolved in the
chosen solvent system.
Pharmaceutical solutions are homogeneous, i.e. the therapeutic
agent(s) and excipients are dissolved in the vehicle.
Pharmaceutical solutions for oral administration are in non-sterile
dosage forms.
Pharmaceutical sol. classified according to their intended use as
Oral solution, - Otic solution
Ophthalmic solution, - Topical solution.
Parenteral preparations
Sol. categorized by a traditional name related to the solvent system
used and/or their intended function (e.g. Spirits, Syrups Tinctures,
Aromatic waters, and Elixirs).
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Disadvantages of solutions
1.Drug stability is reduced in Sol by hydrolysis or oxidation.
For this reason, Sol. is commonly has a shorter expiry date
than equivalent solid dosage forms.
2.It is difficult to mask unpleasant tastes.
3.A major disadvantage ; they are much larger & more bulky,
difficult to transport.
Liquids packed in glass bottles are obviously prone to breakage
and cause loss of the preparation.
4.Technical accuracy is needed to measure the dose on admin.
patient accuracy in measuring a dose is required
5.Some drugs are poorly soluble so it is necessary to alter
vehicle or drug form in order to formulate a convenient prep.
6.A measuring device is needed for admin. so need to be
supplied to the patient to be able to measure an accurate dose 6
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Drug Solubility
• In pharmaceutical sols both therapeutic drugs and the
excipients are required to be present in sol over the shelf-life.
• As a result solutions are termed homogeneous.
• 1.IF the aqueous solubility of drug is high at the selected pH of
formulation, → therapeutic drug is readily incorporated into
vehicle and formulated as oral sol.
• 2.IF aqueous solubility of drug is moderate at selected pH , i.e.
aqueous solubility is less than requested conc. of drug→ the
solubility of drug in sol. must be enhanced using co-solvents.
• 3.IF aqueous solubility of drug is low at selected pH of
formulation. The difference between aqueous solubility of drug
and the required conc. is too great to the use of cosolvents or
surfactants in the solubilised form & toxic when administered
orally. The drug therefore formulated as a suspension
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• 2- Temperature:
• Most compounds are more soluble in higher temperature.
• 3- pH
• The vast majority of drug subs. are either acids or bases .
• The solubility of therapeutic agents are pH-dependent.
• The solubility of acids & bases increases as the degree of
ionization increases.
• The solubility of acidic compounds increases as the pH
of the sol. is increased (above the pKa) & solubility of
basic comps increase as the pH is lowered below the pKa
4. Polarity:
Polar comp. more soluble in Polar solvents as water & ethanol .
Non polar comps more soluble in non polar solvents as chloroform
Conc. acid or alkali added to form water- soluble salts.
Conversilly,The organic bases more soluble in organic
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solvents than the corresponding salt forms.
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3. Use of co-solvents :
Co-solvents are liquid components incorporated into a
formulation to enhance the solubility of poorly soluble drugs.
The Commonly employed co solvents include , glycerol,
propylene glycol, ethanol and polyethylene glycol.
The final choice of the co-solvent system for a particular
formulation involves consideration of the solubility of the
therapeutic agent in the vehicle, the toxicity of the vehicle
and the cost of formulation.
The range of concentrations of each co-solvent used in oral
formulations is primarily limited by concerns regarding
toxicity.
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Types of water
1.Potable water : drinking water, should be palatable &
safe for drinking, Its chemical composition may include
mineral impurities which could react with drugs, e.g. the
presence of calcium carbonate in hard water.
2.Purified water USP, obtained from potable water by
distillation, ion exchange treatment,or reverse osmosis.
Distilled water is purified water prepared by distillation.
Compared with ordinary drinking water:
Purified Water, more free of solid impurities.
When evaporated to dryness, not yield greater than
0.001% of residue (1 mg of total solids /100 mL of sample
evaporated).
Purified Water is intended for use in preparation of
aqueous DF, except those intended for Parenteral
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administration (injections).
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Water as a vehicle
3.Water for preparations : potable or freshly boiled and cooled
water, used in oral or external LDF not intended to be sterile.
4.Water for injections: is pyrogen-free distilled water, sterilized
immediately after collection and used for Parenteral
preparations.
5. Chloroform water : used as antimicrobial preservative and
also adds sweetness to preparations. chloroform available as:
Chloroform BP = 100% v/v
6. Aromatic water : saturated solution of volatile oils in water
and are used to provide a pleasant flavor or aroma, e.g.
Peppermint Water, USP.
Used as a vehicle in oral sol. Some have mild carminative action
For example diluted Aromatic waters are usually prepared from
a conc. ethanolic sol. in a dilution of 1 part to 39 parts with water.
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• II. Co-solvents
• Employed to increase the solubility of therapeutic agent
within the formulation.
• Co-solvents used in the formulation of oral solutions are :
• Glycerol (also termed glycerin)
• Glycerol is a clear odorless, viscous liquid, with a sweet taste
, and miscible with both water and alcohol.
• Its co-solvency properties due to the presence of three
hydroxyl gps;oH. It has similar co-solvency properties to ethanol
• Alcohol USP (CH3CH2OH)
• Contain between 94.9 and 96.0% v/v ethyl alcohol(ethanol).
• Commonly used as a co-solvent, both as a single and with
other co-solvents, e.g. glycerol.
• The known pharmacological & toxicological effects of alcohol
have compromised its use in pharmaceutical preparations. 18
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Surface-active agents
• As the conc. increased, the interface will become saturated with
surface-active agent & the molecules that are present in the
bulk aqueous phase will orient themselves to shield the
hydrophobic regions of surface-active agent.
• This orientation is referred to as a micelle ةليذمﻼ.
• The conc. of surface-active agent at this occurs is termed the
critical micelle concentration (CMC).
• In this the core of the micelle represents a hydrophobic
region into which the poorly water-soluble drugs partition.
• For example, if the therapeutic agent is poorly soluble, the
molecule will locate exclusively within the micelle.
• if the drug is water-insoluble but contains polar groups, the
molecule will orient within the micelle, w & drug solubilised
within the colloidal micelles; due to their small size →the
resulting sol. appears homogeneous to the naked eye. 20
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B. Complexation
• Complexation refers to the interaction of a poorly
soluble therapeutic agent with an organic molecule,
e.g. surface-active agents, hydrophilic polymers to
generate a soluble intermolecular complex.
• One particular concern regarding the use of solution of
drug complexes is the ability of the complex to dissociate
following administration.
• This is particularly important in situations where the
complexing agent is a hydrophilic polymer, as the
high molecular weight of the drug–polymer complex
would prevent drug absorption across biological
membranes.
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Sweetening Agents
• Sweetening agents are employed in liquid formulations
designed for oral administration specifically to increase
the palatability of the therapeutic agent.
• The main sweetening agents employed in oral
preparations are sucrose, liquid glucose, glycerol,
sorbitol, saccharin sodium and aspartame.
• The use of artificial sweetening agents in formulations
is increasing and, in many formulations, saccharin
sodium is used either as the sole sweetening agent or in
• combination with sugars or sorbitol to reduce the sugar
• concentration in the formulation.
• The use of sugars in oral formulations for children and
patients with diabetes mellitus is to be avoided. 24
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Antioxidants
• Antioxidants included in pharm. Sol. to enhance the stability of
drugs that susceptible to chemical degradation by oxidation.
• Antioxidants are compounds that inhibit free radical-induced
drug decomposition.
• Both water-soluble & water-insoluble antioxidants are available.
• Antioxidants for aqueous formulationse eg; Sodium sulphite,
sod. metabisulphite, sod. formaldehyde sulphoxylate and
ascorbic acid.
• Antioxidants used in oil-based solutions e.g; butylated
hydroxytoluene (BHT), butylated hydroxyanisole (BHA) and
propyl gallate.
• Antioxidants employed in low concentrations ( ˂ 0.2% w/w) .
• Antioxidants employed in conjunction with chelating agents,
e.g. ethylenediamine tetraacetic acid, that act to form
complexes with heavy-metal ions. 26
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Preservatives
• Preservatives are included in pharmaceutical solutions to
reduce or prevent the microbial growth of the formulation.
• Ideally, preservatives should exhibit the following properties:
• 1. possess a broad spectrum of antimicrobial activity
includes Gram-positive,Gram-negative bacteria & fungi.
• 2.be chemically and physically stable over the shelf-life
of the product. 3. have low toxicity.
• Preservatives for use in oral pharmaceutical solutions :
• ■ benzoic acid and salts (0.1–0.3%).
• ■ sorbic acid and its salts (0.05–0.2%).
• ■ Alkyl esters of parahydroxybenzoic acid (0.001-0.2%).
• A combination of two preservatives employed in solutions
to enhance the antimicrobial spectrum.
• Methyl & propyl parahydroxybenzoates (in a ratio 9:1). 27
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Flavour Adjuncts
• Certain excipients added to oral solution formulations, referred
to as flavour adjuncts (e.g. menthol, chloroform).
• flavour adjuncts add flavor to formulation and in addition, act to
desensitise the taste receptors.
• These agents augment the taste-masking properties .
• Colourants:
• Colours are pharmaceutical ingredients that impart the preferred
colour to the formulation.
• When used in combination with flavours, the selected colour
should ‘match’ the flavour of the formulation,
• e.g. green with mint-flavoured solutions,
• red for strawberry-flavoured formulations.
• Although colours is not a prerequisite for all pharmaceutical sol.,
certain categories of solution (e.g. mouthwashes/gargles) are
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normally coloured.
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Oral solutions
• Oral solutions are administered to the GIT to provide systemic
absorption of the therapeutic agent.
• Oral solutions formulated over a broad pH range due to the
flexibility of GI environment.
• The usual pH of oral solutions is about 7.0, unless there are
issues regarding the solubility or stability of drug.
• Typically the following excipients used in the formulation:.
• ■ Buffers (e.g. citrate, phosphate)
• ■ Preservatives (e.g. parabens, benzoic acid, sorbic acid).
• ■ Antioxidants (water-soluble antioxidants used, e.g.
sodium metabisulphite 0.01–1.0% w/w)
• ■ Flavours and colours.
• ■ Viscosity-modifying agents (to affect the pourability of the
Formulation, hydrophilic polymers are used, e.g. sodium
alginate, hydroxyethylcellulose). 31
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Oral syrups
• Syrups are highly concentrated, aqueous sols of sugar or a
sugar substitute that contain a flavouring agent, e.g.
• cherry syrup, orange syrup, raspberry syrup.
• Unflavored (Traditional syrup) composed of aqueous sol.
containing 85% sucrose.
• It is important to ensure that:
• 1.The drug substance soluble within the syrup base.
• 2. The syrup vehicle is appropriate to physicochemical
properties of drug subs. For example, cherry syrup &
orange syrup are acidic, therefore solubility of acidic drugs
lowered & resulting in precipitation of drug subs.
• The use of acidic syrups additionally result in reduced
chemical stability for acid-labile therapeutic agents.
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Preservatives
• Preservatives are not required in traditional syrups containing
high conc. of sucrose.
• Addition of preservatives is required in: 1. sugar-free syrups,
2. syrups in which sucrose substituted by polyhydric alcohol.
3. traditional syrups contain lower conc. of sucrose,
• Examples of commonly used preservatives include:
• Mixtures of parahydroxybenzoate esters (methylhydroxy
benzoate and propylhydroxybenzoate in a ratio of 9:1).
• The typical concentration range is 0.1–0.2% w/v.
• The preservative efficacy decreased in the presence of
hydrophilic polymers (generally employed to enhance
• viscosity), due to interaction of preservative with polymer.
• Other preservatives include benzoic acid (0.1–0.2%) or
sodium benzoate (0.1–0.2%). 35
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Flavours
• Flavours employed to the unpalatable taste of a therapeutic agent
even in presence of the sweetening agents.
• The conc. of flavour in oral syrups is that which required to
provide the required degree of taste-masking effectively.
• 1.The flavours of natural origin (e.g. peppermint, lemon, herbs )
and available as oils, extracts, spirits or aqueous sol.
• 2. synthetic flavours:
• Certain flavors also associated with a (mild) therapeutic activity,
e.g; antacids contain mint due to the carminative effect.
• flavours offer a taste-masking effect by eliciting a mild local anesthetic
effect on the taste receptors,e.g;peppermint oil, chloroform, menthol.
• ■ Colours :natural or synthetic water soluble, photo-stable
ingredients that selected according to flavour of preparation.
• E.g;, mint-flavoured formulations with a green colour, banana-
flavoured sol. with a yellow colour . Must not chemically or
physically interact with the other components of the formulation.
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Oral elixirs
• Elixir is a clear, hydroalcoholic sol. formulated for oral use.
• The presence of alcohol in elixirs cause a problem in paediatric
formulations and, for adults who wish to avoid alcohol.
• The typical components of an elixir are as follows:
• ■ Purified water.
• ■ Alcohol: employed as a co-solvent to ensure solubility of all
ingredients. the conc. Of alcohol varies depending on formulation.
• Generally, Alcohol conc. is greater than 10% v/v; however, in
some preparations, alcohol conc. greater than 40% v/v.
• ■ Polyol co-solvents. e.g. propylene glycol, glycerol, employed
in elixirs to enhance the solubility of drug subs. & excipients.
• The inclusion of co-solvents enable the alcohol conc. to be
reduced. The conc. of co-solvents is dependent on conc. of
alcohol present;e.g; in USP: Phenobarbital Elixir & Theophylline
Elixir 37
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• 1. Phenobarbital Elixir:
• Phenobarbital (therapeutic agent) 0.4% w/v
• Orange oil (flavour) 0.025% v/v
• Propylene glycol (co-solvent) 10% v/v
• Alcohol 20% v/v
• Sorbitol solution (sweetener) 60% v/v
• Colour As required
• Purified water ad 100%
• 2. Theophylline Elixir
• Theophylline (therapeutic agent) 0.53% w/v
• Citric acid (pH regulation) 1.0% w/v
• Liquid glucose (sweetening agent) 4.4% w/v
• Syrup (sweetening agent) 13.2% v/v
• Saccharin sodium (sweetening agent) 0.5% w/v
• Glycerin (co-solvent) 5.0% v/v
• Sorbitol solution (co-solvent) 32.4% v/v
• Alcohol 20% v/v
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• Lemon oil (flavour) 0.01% w/v
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Linctuses
• A liquid oral preparation used for a demulcent,
expectorant or sedative effect in treatment of cough.
• Linctuses are viscous preparations that contain the
therapeutic agent dissolved in a vehicle composed of a
high percentage of sucrose and, if required, other
sweetening agents.
• These formulations are administered orally.
• Primarily employed for treatment of cough, due to their
soothing actions on the inflamed mucous membranes.
• Linctuses also be formulated as sugar-free alternatives
in which sucrose is replaced by sorbitol and the required
Conc. of sweetening agent.
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Mouthwashes /gargles
• Mouth washes/gargles are designed for the treatment of
infections and inflammation of the oral cavity.
• Formulations designed for this purpose employ water as
the vehicle, although a co-solvent, e.g. alcohol, may be
employed to solubilise the active agent.
• The use of alcohol as a co-solvent act to enhance the
antimicrobial properties of the therapeutic agent.
• Other formulation components are frequently required to
enhance the palatability and acceptability of preparation.
• These include preservatives, colours, flavouring agents
and non-cariogenic sweetening agents.
• Oral drops: oral solutions or suspensions administered in
small volumes, using a suitable measuring device.
• E.g.; Abidec® vitamin drops. 40
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