1. 4/14/2017
Solutions
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2. solutions
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Solutions are homogeneous liquid mixtures containing completely dissolved components (One-phase system).
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3. Solutions for ORAL dosage
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Solutions for ORAL dosage
Advantages of solutions over a solid DF:
Much easier to swallow (i.e. Ease of taking e.g children, elderly, chronic patients).
Readily absorbed from GIT.
An advantage of solutions over suspensions:
Solutions are homogenous dispersions without the need to shake the bottle.
Disadvantages of solutions:
Bulky, not convenient to carry around.
Less chemically and microbiologically stable.
Drugs with unpleasant taste may not be suitable for administration as oral solutions.
Accuracy of dosage depends on the patient.
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4. Solutions for oral dosage
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The different forms of oral solutions are:
Syrups: which are concentrated, aqueous solutions of sugar or sugar-substitute.
Elixirs: which are clear, sweetened, hydroalcoholic solutions suitable for water insoluble drugs.
Linctuses: viscous liquids used in the treatment of cough. They usually contain a high proportion of sucrose, other sugars or polyhydric alcohol or alcohols.
Mixtures: pharmaceutical oral solutions and suspensions. Examples are chloral hydrate mixture.
Oral drops: are oral solutions or suspensions which are administered in small volumes, using a suitable measuring device. A proprietary example is Abidec® vitamin drops.
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5. Solutions for oral dosage
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Solutions for oral dosage
Containers for dispensed oral solutions:
Plain, amber medicine bottles should be used, with a re-closable child-resistant closure with some exceptions.
A 5 mL measuring spoon or an appropriate oral syringe should be supplied to the patient.
Special labels and advice for dispensed oral solutions:
An expiry date should appear on the label for extemporaneously prepared solutions. Most 'official' mixtures and some oral solutions are freshly or recently prepared.
'Official' elixirs and linctuses and manufactured products are generally more stable, unless diluted.
Diluted products generally have a shorter shelf life than the undiluted preparation.
Linctuses should be sipped and swallowed slowly without the addition of water.
Plain, amber medicine bottles should be used, with a reclos-
able child-resistant closure. Exceptions to this are if the
medicine is in an original pack or patient pack, if there are
no suitable child-resistant containers for a particular liquid
preparation or if the patient requests it, e.g. if they have
severe arthritis in their hands. Advice to store away from
children should then be given. A 5 mL measuring spoon or
an appropriate oral syringe should be supplied to the
patient.
An expiry date should appear on the label for extemporane-
ously prepared solutions. Most 'officia1' mixtures and some
oral solutions are freshly or recently prepared (see Ch. 10).
'Officia1' elixirs and linctuses and manufactured products
are generally more stable, unless diluted. Diluted products
generally have a shorter shelf life than the undiluted prep-
aration. Linctuses should be sipped and swallowed slowly,
without the addition of water.
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6. Solutions for other pharmaceutical uses Mouthwashes and Gargles
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Gargles are used to relieve or treat sore throats
Mouthwashes are used on the mucous membranes of the oral cavity, rather than the throat, to refresh and mechanically clean the mouth.
Both are concentrated solutions, and usually diluted with warm water before use.
Gargles tend to contain higher concentrations of active ingredients than mouthwashes.
They may contain antiseptics, analgesics or weak astringents. The liquid is usually not intended for swallowing.
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7. Solutions for other pharmaceutical uses Mouthwashes and Gargles
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Solutions for other pharmaceutical uses Mouthwashes and Gargles
Containers for mouthwashes and gargles
An amber, ribbed bottle should be used for extemporaneously prepared solutions. Medicine bottles may be used for products which are intended to be swallowed.
Manufactured mouthwashes and gargles are usually packed in plain bottles.
Special labels and advice for mouthwashes and gargles
Directions for diluting the preparations should be given to the patient.
If the preparation is not intended for swallowing, the following label is appropriate: “Not to be swallowed in large amounts ”
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8. Solutions for other pharmaceutical uses Nasal solutions
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Solutions for other pharmaceutical uses Nasal solutions
Most nasal preparations are solutions, administered as nasal drops or nasal sprays.
They are isotonic to nasal secretions and buffered to the normal pH range of nasal fluids (pH ) to prevent damage to ciliary transport in the nose.
The most frequent use of nose drops is as a decongestant for the common cold or to administer local steroids for the treatment of allergic rhinitis.
Nasal route may also be useful for new biologically active peptides and polypeptides which need to avoid the first pass metabolism or GI destruction.
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9. Solutions for other pharmaceutical uses Ear drops
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Solutions for other pharmaceutical uses Ear drops
They may also be referred to as otic or aural preparations.
Ear drops are solutions of one or more active ingredient which exert a local effect in the ear, e.g. by softening earwax or treating infection or inflammation.
Propylene glycol, oils, glycerol (to increase viscosity) and water may be used as vehicles.
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10. Solutions for other pharmaceutical uses Nasal and aural solutions
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Solutions for other pharmaceutical uses Nasal and aural solutions
Containers for nasal and aural preparations:
Extemporaneously: should be packed in an amber, ribbed hexagonal glass bottle (which type?) which is fitted with a teat and dropper.
Manufactured nasal solutions may be packed in flexible plastic bottles which deliver a fine spray to the nose when squeezed, or in a plain glass bottle with a pump spray or dropper.
Manufactured ear drops are usually packed in small glass or plastic containers with a dropper.
Speciallabels and advice for nasal and aural
preparations
Patients should be advised not to share nasal sprays or nose
aod ear drops in order to rninimize contamination and infec-
tion. Manufactured nasal sprays and nose and ear drops will
usually contain instructions for administration. Patients
should be given advice on how to administer extemporane-
ously prepared nose and ear drops, accompanied by written
infonnation if possible (Fig ). For nose drops it may be
easier if the patient is lying flat with the head tilted back as
far as comfortable, preferably over the edge of a bed. The
patient should remain in this position for a few minutes after
the drops have been administered to allow the medication to
spread in the nose.
For ear drops, it may be easier for someone other than the
patient to administer the drops. If desired the drops can be
warrned by holding the bottle in the hands before putting
them in, but they must not be overheated. The ear lobe
should be held up and back in adults, down and back in chil-
dren, to allow the medication to run in deeper. They may
cause some transient stinging. If the drops are intended to
iOften earwax, then the ears should be syringed after use.
Extemporaneous preparations should be labelled with the
appropriate expiry date following the official monographs.
jForexternal use' is not an appropriate label and so .Not to
be taken' is advised.
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11. Solutions for other pharmaceutical uses Nasal and aural solutions
Special labels and advice for nasal and aural prep:
Not to share nasal sprays or nose and ear drops in order to minimize contamination and infection.
Patients should be given advice on how to administer extemporaneously prepared nose and ear drops, accompanied by written information if possible.
Extemporaneous preparations should be labeled with the appropriate expiry date following the official monographs.
“For external use” is not an appropriate label and so ‘Not to be taken” is advised.
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12. Solutions for other pharmaceutical uses Enemas
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Solutions for other pharmaceutical uses Enemas
Enemas are oily or aqueous solutions that are administered rectally.
They are usually anti-inflammatory, purgative, sedative or given to allow X-ray examination of the lower bowel.
Retention enemas are administered to give either a local action of the drug or for systemic absorption. They are used after defecation.
Microenemas are single-dose, small volume solutions. They are packaged in plastic containers with a nozzle for insertion into the rectum.
Large-volume (0.5-1litre) enemas should be warmed to body temperature before administration.
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13. Solutions for other pharmaceutical uses Enemas
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Solutions for other pharmaceutical uses Enemas
Containers for enemas:
If extemporaneously produced, enemas are packed in amber fluted glass bottles.
Manufactured enemas will usually be packed in disposable polythene or polyvinyl chloride bags sealed to a rectal nozzle.
Special labels and advice for enemas:
Patients should be advised on how to use the enema if they are self-administering and the time that the product will take to work.
The label 'For rectal use only' should be used.
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14. EXPRESSION OF CONCENTRATION By percentage strength as %w/v or %v/v,
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EXPRESSION OF CONCENTRATION
By percentage strength as %w/v or %v/v,
In terms of amount of drug contained in 5 mL of vehicle.
FORMULATION OF SOLUTIONS
When compounding a solution:
Information on solubility and stability of each of the solutes ( drug, excipients) must be taken into account.
Chemical and physical interactions that may take place between constituents must also be taken into account.
e.g. Esters of p-hydroxybenzoic acid (parabens) with some flavoring oils.
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15. Solubility
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Saturation solubility: is the maximum concentration of a solution which may be prepared at a given temperature.
Parts of solute in parts of solvent: Grams of solute in ml of solvent
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16. Factors affecting solubility
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Factors affecting solubility
Polarity of the compound
pH of the medium
Temperature of solution
Particle size may affect the rate of solution
Increasing the solubility
Co solvency: ethanol, glycerol, propylene glycol or sorbitol are cosolvents used to increase the solubility of weak electrolytes and non-polar molecules.
Solubilization: surfactants such as polysorbates for oral solutions, soaps for external phenolic preparations.
Polar compounds tend to be more soluble in
polar solvents, such as water and ethanol. The pH will also
affect solubility, as many drugs are weak acids or bases. The
ionized form of a compound will be the most water soluble,
therefore a weakly basic drug will be most soluble in an
aqueous solution that is acidic. Acid or alkali may therefore
be added to manipulate solubility. Most compounds are
more soluble at higher temperatures. Particle size reduction
will increase the rate of solution.
Increasing the solution of compounds
~with low solubility
Cosolvency
The addition of cosolvents, such as ethanol, glycerol, propy-
lene glycol or sorbitol can increase the solubility of weak
electrolytes and non-polar molecules in water. They are dis- ,
cussed in more detail in Aulton (2002).
~: ,
Solubilization ,.
Surfactants may be used as solubilizing agents. Above the
critical rnicelle concentration (CMC) they form rnicelles
which are used to help dissolve poorly soluble compounds.
The dissolved compound may be in the centre of the
micelle, adsorbed onto the rnicelle surface or sit at some
intermediate point depending on the polarity of the com-
pound. Examples of surfactants used in oral solutions are
polysorbates, whilst soaps are used to solubilize phenolic
disinfectants for external use. ~
Preservation of solutions -
Most water-containing pharmaceutical solutions will
support microbial growth unless this is prevented.
Contamination may come from raw materials or be intro- I
duced during extemporaneous dispensing.
Preservatives may be added to the formulation to reduce
or prevent rnicrobial growth. Chloroform is the most widely
used in oral extemporaneous preparations although there are
disadvantages to its use, including its high volatility and
reported carcinogenicity in animals. U se in the UK is limited
to a chloroform content of 0.5% (w/w or w/v). For oral solu-
tions, chloroform at a strength of 0.25% v/v will usually be
incorporated as Chloroform Water BP. Alternatively, double
strength chloroform water may be included in pharmaceuti-
cal formulae as half the total volume of the solution, to effec-
tively give single strength chloroform water in the finished
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17. Vehicles
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A vehicle is the medium which contains the ingredients of a medicine. In solutions, this is the solvent.
The choice of a vehicle depends on:
The intended use of the preparation
The nature and physicochemical properties of the active ingredients.
Water as vehicle
Water is widely available, relatively inexpensive, palatable and non-toxic for oral use and non-irritant for external use. It is also a good solvent for many ionizable drugs.
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18. Vehicles Water Types of water:
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Vehicles Water
Types of water:
Potable water is drinking water, drawn freshly from a mains supply. It should be palatable and 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.
Purified water is prepared from suitable potable water by distillation, by treatment with ion-exchange materials or by any other suitable treatment method such as reverse osmosis. Distilled water is purified water that has been prepared by distillation.
Water for preparations is potable or freshly boiled and cooled purified water, which can be used in oral or external preparations which are not intended to be sterile
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19. 4/14/2017
Vehicle Water
Water for injections is pyrogen-free distilled water, sterilized immediately after collection and used for parenteral products.
Aromatic waters are near-saturated aqueous solutions of volatile oils or other aromatic or volatile substances, and are often used as a vehicle in oral solutions. Some have a mild carminative action. Aromatic waters are usually prepared from a concentrated ethanolic solution, in a dilution of 1 part to 39 parts with water.
Chloroform water is used as an antimicrobial preservative and also adds sweetness to preparations.
P.S. In general, chloroform can be available as:
Chloroform BP = 100% v/v
Concentrated chloroform water BPC = 10% v/v
Single-strength chloroform water = Chloroform water BP= 0.25% v/v
Double-strength chloroform water= 0.5% v/v
Chloroform BP is 100 % v/v
Concentrated chloroform water (CCW) BPC: is 10% v/v.
Single-strength CW (also known as chloroform water BP): is 0.25% v/v
Can be prepared either by dilution of
2.5 ml of chloroform BP in 1000 ml aqueous solution, or
1 part of CCW with 39 parts of water (40 parts solution) or as 2.5 parts of CCW in 100 parts solution.
Double-strength CW: is 0.5% v/v
5 ml of chloroform BP in 1000 ml aqueous solution, or
2 part of CCW with 39 parts of water (40 parts solution) or as 5 parts of CCW in 100 parts solution.
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20. Other vehicles used in pharmaceutical solutions
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Syrup BP is a solution of 66.7% sucrose in water. Promotes dental decay and is unsuitable for diabetic patients. Sweetening agents as mannitol, sorbitol, xylitol, etc. can replace the sucrose to give 'sugar-free' solvents.
Alcohol rarely used for internal and mainly external
Glycerol (glycerin) may be used alone as a vehicle in some external preparations. It is viscous and miscible both with water and alcohol. It may be added as a stabilizer and sweetener in internal preparations. In concentrations above 20% v/v it acts as a preservative.
Propylene glycol is a less viscous liquid and a better solvent than glycerol.
Oils Bland oils such as fractionated coconut oil and arachis oil may be used for fat soluble compounds, e.g. calciferol.
Acetone and solvent ether used as cosolvents in external preparation (limitations of ether).
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21. Preservations of solutions
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Why preservation?
Preservatives are added to the formulation to reduce or prevent microbial growth.
Chloroform:
Chloroform is the most widely used in oral extemporaneous preparations although there are disadvantages to its use. Also used for external preparations
Use in general is limited to a chloroform content of 0.5% (w/w or w/v).
For oral solutions, chloroform at a strength of 0.25% v/v will usually be incorporated as Chloroform Water BP.
Benzoic acid at a strength of
0.1% w/v is also suitable for oral administration, as are
ethanol, sorbic acid, the hydroxybenzoate esters and syrup.
Some of the altemative preservatives have pH-dependent
activity.
Syrups can be preserved by the maintenance of a high
concentration of sucrose as part of the formulation.
Concentrations of sucrose greater than 65% w/w will usually
protect an oralliquid from growth of most microorganisms
by its osmotic effects. A problem with their use occurs when
other ingredients are added to the syrup, as this decreases the
sucrose concentration. This may cause a loss in the pre-
servative action of the sucrose. Accidental dilution by, for
example, using a damp bottle, may have a similar effect.
Preservatives used in extemal solutions include chloro-
cresol (0.1% w/v), chlorbutanol (0.5% w/v) and the para-
hydroxybenzoates (parabens).
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22. Preservations of solutions
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Other preservatives for oral solutions:
Benzoic acid at a strength of 0.1% w/v
Sorbic acid
Para-hydroxybenzoate esters (Parabens).
Ethanol
Syrup: Syrups can be preserved by the maintenance of a high concentration of sucrose 65% w/w .
Some of the alternative preservatives have pH-dependent activity.
Preservatives for external preparations:
Chlorocresol (0.1% w/v)
Chlorbutanol (0.5% w/v)
Parabens
Benzoic acid at a strength of
0.1% w/v is also suitable for oral administration, as are
ethanol, sorbic acid, the hydroxybenzoate esters and syrup.
Some of the altemative preservatives have pH-dependent
activity.
Syrups can be preserved by the maintenance of a high
concentration of sucrose as part of the formulation.
Concentrations of sucrose greater than 65% w/w will usually
protect an oralliquid from growth of most microorganisms
by its osmotic effects. A problem with their use occurs when
other ingredients are added to the syrup, as this decreases the
sucrose concentration. This may cause a loss in the pre-
servative action of the sucrose. Accidental dilution by, for
example, using a damp bottle, may have a similar effect.
Preservatives used in extemal solutions include chloro-
cresol (0.1% w/v), chlorbutanol (0.5% w/v) and the para-
hydroxybenzoates (parabens).
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23. Flavouring agents Why? Selection of flavours:
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Flavouring agents
Why?
Selection of flavours:
To mask particular taste types, e.g. a fruit flavour helps to disguise an acid taste.
The age of the patient should be taken into account when selecting a flavour, as children will tend to enjoy fruit or sweet flavours.
Some flavours are associated with particular uses, e.g. peppermint is associated with antacid preparations.
The flavour and colour should also complement each other.
Extemporaneous medicines tend to use natural flavours added as juices (raspberry ), extracts (liquorice), spirits (lemon and orange), syrups (blackcurrant), tinctures (ginger) and aromatic waters (anise and cinnamon).
Flavouring agents
Flavours added to solutions can make a medicine more
acceptable to take, especially if the drug has an unpleasant
taste. Selection of flavours is a complex process in the phar-
maceutical industry. Flavours should be chosen to mask par-
ticular taste types, e.g. a fruit flavour helps to disguise an acid
taste. The age of the patient should be taken into account
when selecting a flavour, as children will tend to enjoy fruit
or sweet flavours. Some flavours are associated with par-
ticular uses, e.g. peppermint is associated with antacid prep-
arations. The flavour and colour should also complement
each other. Extemporaneous medicines tend to use natural
flavours added as juices (raspberry ), extracts (liquorice ),
spirits (lemon and orange), syrups (blackcurrant), tinctures
(ginger) and aromatic waters (anise and cinnamon). Some
synthetic flavours are used in manufactured medicines.
Sweetening agents
Many oral solutions are sweetened with sugars, including
glucose and sucrose. Sucrose enhances the viscosity of liquids
,n,
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24. Sweetening agents Sugars, including glucose and sucrose.
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Sweetening agents
Sugars, including glucose and sucrose.
Sucrose enhances the viscosity of liquids and also gives a pleasant texture in the mouth.
‘Sugar free’ solutions include sweetening agents such as sorbitol, mannitol, xylitol, saccharin and aspartame as alternatives to sugar (i.e. sucrose, fructose and glucose).
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25. Colouring agents
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Colouring agents are added to pharmaceutical preparations to
Enhance the appearance of a preparation,
Increase the acceptability of a preparation to the patient.
Colour is also useful to give a consistent appearance.
Colours are often matched to the flavour of a preparation.
Colours can give distinctive appearances to some medicines.
Colouring agents should be:
Non-toxic .
Free of any therapeutic activity themselves.
Types of colouring agents:
Natural colourants: derived from animals or plalnts (e.g. carotenoids, chlorophylls, caramel, cochineal, saffron and red beetroot extract).
Mineral pigments: such as iron oxide are not often used in solutions due to their low water solubility.
Synthetic organic dyes such as the azo compounds.
Colours appear in pharmaceutical formulae less often now, especially in children's medicines.
In the EU, A EUROPEAN LIST OF COLOURING AGENTS HAVE THE DISIGNATION ‘E’ with numbers between 100 and 180.
Colouring agents
Colouring agents are added to pharmaceutical preparations
to enhance the appearance of a preparation or to increase the
acceptability of a preparation to the patient. Colours are
often matched to the flavour of a preparation, e.g. a yellow
colour for a banana-flavoured preparation. Colour is also
useful to give a consistent appearance where there is natural
variation between batches. Colours can give distinctive
appearances to some medicines, e.g. the green colour ofthe
Drug Tariff formula of methadone rnixture.
Colouring agents should be non-toxic and free of any thera.
peutic activity themselves. Natura1 colourants are most likely
to meet this criterion and include materials deriyed from
plants and anima1s, e.g. carotenoids, chlorophy1ls, saffron, red
beetroot extract, caramel and cochinea1. As with all natural
agents, the disadvantage is that batches may vary in quality.
Mineral pigments such as iron oxides are not often used in
solutions because of their low solubility in water. Syntheric
organic dyes such as the azo compounds are a1tematives for
colouring pharmaceutica1 solutions as they give a wide range
of bright, stable colours. Colours appear in pharrnaceutical
formulae less often now, especia11y in children's medicines.
Some consumers see their use as unnecessary and some
colouring agents, e.g. tartrazine, have been implicated in
a11ergic reactions and hyperactivity of children. Additionally,
coloured dyes in medicines can lead to confusion when diag.
nosing diseases, e.g. a red dye appearing in vomit could ~
wrongly assumed to be blood. In the European Union, coloun
are selected from a list permitted for medicinal products, with
designated 'E' numbers between 100 and 180.
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26. Those which are added to oral preparations include: Ascorbic acid
Stabilizers
Antioxidants may be used where ingredients are liable to degradation by oxidation, e.g. in oils.
Those which are added to oral preparations include:
Ascorbic acid
Citric acid
Sodium meta bisulphite
sodium sulphite.
These are odourless, tasteless and non-toxic.
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27. Viscosity enhancing agents
Such as syrups, they improve viscosity, palatability, and ease pourability.
Other thickening agents can also be used.
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28. Examples on solution preparations
Ammonium and Ipecacuanha Mixture BP. Mitte 100ml.
Master formula 100ml
Ammonium bicarbonate 200mg 2g
Liquorice liquid extract 0.5ml 5ml
Ipecacuanha tincture 0.3ml 3ml
Concentrated camphor water 0.1ml 1ml
Concentrated anise water ml ml
Double strength chloroform water ml 50ml
Water to 10ml to 100ml
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29. Example on solution preparations
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Example on solution preparations
Action and uses.
Formulation notes.
Method of preparation.
Shelf life and storage.
Advice and labeling.
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30. Rx 10 ml Sodium Bicarbonate Ear Drops BP. Master For formula 10ml
Sodium bicarbonate g mg
Glycerol ml ml
Water to 100ml to 10ml
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31. 200ml Diamorphine linctus Master formula for 200ml
hydrochloride 3mg 120mg
Oxymel ml 50ml
Glycerol ml 50ml
Compound tartrazine
solution ml 2.4ml
Syrup to 5ml to 200ml
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32. 50ml Chloral elixir, paediatric. For an 8-month-old baby.
Master formula for 50ml
Chloral hydrate 200mg 2g
Water ml 1ml
Blackcurrant syrup 1ml 10ml
Syrup to 5ml to 50ml
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33. Rx Compound Sodium Chloride Mouthwash BP. Mitte 500ml Master For
formula ml
Sodium chloride g g
Sodium bicarbonate g 5g
Concentrated peppermint emulsion ml ml
Double strength chloroform water ml ml
Water to 100ml to 500ml
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