Tuesday, July 14, 2009


Liquid preparations for oral use are usually solutions, emulsions or suspensions containing one or
more active ingredients in a suitable vehicle; they may in some cases consist simply of a liquid
active ingredient used as such. Liquid preparations for oral use are either supplied in the finished
form or, with the exception of Oral emulsions, may also be prepared just before issue for use by
dissolving or dispersing granules or powder in the vehicle stated on the label.
The vehicle for any liquid preparation for oral use is chosen having regard to the nature of the
active ingredient(s) and to provide organoleptic characteristics appropriate to the intended use of the
preparation. Liquid preparations for oral use may contain suitable antimicrobial preservatives,
antioxidants and other excipients such as dispersing, suspending, thickening, emulsifying,
buffering, wetting, solubilizing, stabilizing, flavouring and sweetening agents and authorized
colouring matter.
Liquid preparations for oral use may be supplied as multidose or as single-dose preparations. Each
dose from a multidose container is administered by means of a device suitable for measuring the
prescribed volume. The device is usually a spoon or a cup for volumes of 5 ml or multiples thereof,
or an oral syringe for other volumes or, for Oral drops, a suitable dropper.
Additional information. Liquid preparations for oral use are often the dosage form of choice for
paediatric use.

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Owing to the wide range of liquid preparations for oral use and their long history of use, a variety
of terms has been used to describe different members of this category of preparation. These terms,
which are not mutually exclusive and the definitions of which have changed over time, include
elixirs, linctuses, milks, mixtures and syrups. Such terms are still used within the titles of certain
specific, long-established, traditional preparations (for example, ephedrine elixir, codeine linctus,
acid gentian mixture). With such exceptions, however, it is recommended that the titles of liquid
dosage forms for oral use are based on the terms used as sub-monograph headings in this general
monograph. The term syrup (denoting a solution containing a high proportion of sucrose) is used,
inter alia, for certain solutions (for example, black currant syrup, lemon syrup) that are used as
vehicle ingredients for their sweetening and flavouring properties. Such syrups are not dosage forms
in the pharmacopoeial sense: they do not contain any active ingredient and are not intended to be
administered as such.
Oral solutions containing one or more active ingredients dissolved in a vehicle containing a high proportion of
sucrose or a suitable polyhydric alcohol or alcohols and which may contain ethanol have traditionally been called
elixirs. Viscous oral solutions containing one or more active ingredients dissolved in a vehicle containing a high
proportion of sucrose, other sugars or a suitable polyhydric alcohol or alcohols and which are intended for use in
the treatment or relief of cough have traditionally been called linctuses. They are intended to be sipped and
swallowed slowly without the addition of water.
The manufacturing process for liquid preparations for oral use should meet the requirements of
Good Manufacturing Practice.
The following information is intended to provide broad guidelines concerning the critical steps to be
followed during production of liquid preparations for oral use.
In the manufacture of liquid preparations for oral use, measures are taken to:
• ensure that all ingredients are of appropriate quality
• minimize the risk of microbial contamination (see recommendations described under 3.3
Microbial quality of pharmaceutical preparations);
• minimize the risk of cross-contamination
During the development of a preparation, the formulation for which contains one or more
antimicrobial preservatives, the effectiveness of the chosen preservative system shall be
demonstrated to the satisfaction of the relevant regulatory authority.
Appropriate measures should also be taken to optimize the stability of the active ingredient(s) in
liquid formulations including those prepared from powder or granules. Additional measures should
be taken so that, when stored under the conditions stated on the label, oral solutions are not subject
to precipitation and oral suspensions are not subject to fast sedimentation, lump formation or
During development of a single-dose liquid preparation for oral use it shall be demonstrated that
the nominal content can be withdrawn from the container.

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In the production of liquid preparations for oral use containing dispersed particles, measures are
taken to ensure a suitable and controlled particle size and, where appropriate, crystal structure
(polymorphic and/or solvated forms) with regard to the intended use.
Throughout manufacturing, certain procedures should be validated and monitored by carrying out
appropriate in-process controls. These should be designed to guarantee the effectiveness of each
stage of production. In-process controls during the manufacture of oral liquids should include pH
and fill volume. The validation of the manufacturing process and the in-process controls are
Safety concerns
An important aspect of Good Manufacturing Practice for all pharmaceutical products is
assuring the quality of all the starting materials used. The need for analytical testing to check
the identity and quality of starting materials is explained in detail in (section 14 of ) the
current WHO GMP guidelines1. Failure to ensure that starting materials are of the required
quality can have very serious consequences.
Increasingly countries are dependent on the importation of starting materials for use in the
production of medicines. Starting materials often change hands many times before reaching
the manufacturer of the final marketed product and there are many opportunities for the
material to undergo relabelling along the distribution and trade chain (see WHO Guideline on
Good Trade and Distribution Practices for Pharmaceutical Starting Materials1). As a result,
starting materials required for production of pharmaceutical products can become
contaminated or materials may be supplied that no longer correspond to what is stated on the
label in terms of quality or identity, either accidentally or as a result of negligence and
sometimes fraud.
The most documented incidents of contamination involve liquid preparations for oral use
manufactured with excipients such as glycerol and propylene glycol that have been
contaminated, adulterated or mixed up with diethylene glycol. Such incidents have been
responsible for hundreds of deaths throughout the world (see, for example, editorial in WHO
Bulletin 2001, 79(2)). Ingestion of diethylene glycol often leads to death through kidney
1For current edition of WHO guidelines, please consult the WHO Medicines website
Uniformity of mass
Liquid preparations for oral use that are presented as single-dose preparations comply with the
following test. Weigh individually the contents of 20 containers, emptied as completely as possible,
and determine the average mass. Not more than 2 of the individual masses deviate by more than
10% from the average mass and none deviates by more than 20%.

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Uniformity of mass of doses delivered by the measuring device. The measuring device provided
with a multidose liquid preparation for oral use complies with the following test. Weigh
individually 20 doses taken at random from one or more multidose containers with the measuring
device provided and determine the individual and average masses. Not more than two of the
individual masses deviate by more than 10% from the average mass and none deviates by more than
The containers should be made of material that will not adversely affect the quality of the
preparation by, for example, leaching or sorption. Liquid preparations for oral use that contain
light-sensitive active ingredients are supplied in containers that are light-resistant.
Except where indicated in the individual monograph, containers should be made from material that
is sufficiently transparent to permit the visual inspection of the contents.
If the preparation contains volatile ingredients, the liquid preparation for oral use should be kept in
a tightly closed container.
Every pharmaceutical preparation must comply with the labelling requirements established under
Good Manufacturing Practice.
The label should include:
(1) the name of the pharmaceutical product;
(2) the name(s) of the active ingredients; INNs should be used wherever possible;
(3) the amount of active ingredient in a suitable dose-volume;
(4) the name and concentration of any antimicrobial preservative and the name of any other
(5) the batch (lot) number assigned by the manufacturer;
(6) the expiry date and, when required, the date of manufacture;
(7) any special storage conditions or handling precautions that may be necessary;
(8) directions for use, warnings, and precautions that may be necessary;
(9) the name and address of the manufacturer or the person responsible for placing the product
on the market.

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If the Liquid preparation for oral use is supplied as granules or powder to be constituted just before
issue for use, the label should include:
(1) that the contents of the container are granules or powder for the preparation of an oral liquid;
(2) the strength as the amount of the active ingredient in a suitable dose-volume of the
constituted preparation;
(3) the directions for preparing the oral liquid including the nature and quantity of liquid to be
(4) the storage conditions and shelf-life of the constituted preparation.

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