Liquid preparations for oral use
This
monograph does not apply to liquids intended for oromucosal administration (for
example, gargles and mouthwashes).
Definition
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.
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.
Manufacture
The manufacturing process for liquid preparations for oral use
should meet the requirements of Good Manufacturing Practice (GMP).
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
in chapter MICROBIOLOGICAL QUALITY
OF NON-STERILE PRODUCTS: RECOMMENDED ACCEPTANCE CRITERIA FOR PHARMACEUTICAL
PREPARATIONS of the supplementary information
section.);
• 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 caking.
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.
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 documented.
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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 failure.
For
the current edition of WHO guidelines, please consult the WHO Medicines web
site:
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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%.
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 20%.
Containers
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. Labelling
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 excipient;
(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.
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 used;
(4)
the
storage conditions and shelf-life of the constituted preparation. Requirements for specific types of liquid
preparations for oral use
Oral solutions
Definition
Oral
solutions are clear Liquid preparations for oral use containing one or more
active ingredients dissolved in a suitable vehicle.
Visual inspection
Inspect the solution. It should be clear and free from any
precipitate. A change in colour or cloudiness of solutions may indicate
chemical degradation or microbial contamination.
Oral
suspensions
Definition
Oral suspensions are Liquid preparations for oral use containing
one or more active ingredients suspended in a suitable vehicle. For oral
suspensions containing more than one active ingredient, some of the active
ingredients may be in solution.
Oral suspensions may show a sediment which is readily dispersed on
shaking to give a uniform suspension which remains sufficiently stable to
enable the correct dose to be delivered.
Visual inspection
Inspect the suspension. Evidence of physical instability is
demonstrated by the formation of flocculants or sediments that do not readily
disperse on gentle shaking. A change in colour may indicate chemical
degradation or microbial contamination.
Uniformity of content. For oral suspensions that are presented as single-dose preparations and that contain
less than 5 mg of active
ingredient per dose or in which the active ingredient is less than 5% of the total weight per dose, carry out the following
test. Shake and empty each container as completely as possible and carry out
the test as described under 5.1 Uniformity of content for single-dose preparations. In such cases,
the test for Uniformity of mass prescribed above is not required.
Labelling
The label on the container should
include a direction that the bottle should be shaken before use.
Oral
emulsions
Definition
Oral emulsions are Liquid preparations for oral use containing one
or more active ingredients. They are stabilized oil-in-water dispersions,
either or both phases of which may contain dissolved solids. Solids may also be
suspended in Oral emulsions.
Oral emulsions may show evidence of
phase separation but are readily redispersed on shaking. Visual inspection
Inspect the emulsion. Evidence of physical instability is
demonstrated by phase separation that is not readily reversed on gentle
shaking. A change in colour of emulsions may indicate chemical degradation or
microbial contamination.
Containers
When
issued for use, Oral emulsions should be supplied in wide-mouthed bottles.
Labelling
The
label on the container should include a direction that the bottle should be
shaken before use.
Oral
drops
Definition
Oral drops are Liquid preparations for oral use that are intended
to be administered in small volumes with the aid of a suitable measuring
device. They may be solutions, suspensions or emulsions.
Visual inspection
Inspect the drops. Drops that are solutions should be clear and
free from any precipitate. Evidence of physical instability of drops that are
suspensions is demonstrated by the formation of flocculants or sediments that
do not readily disperse on gentle shaking. Evidence of physical instability of
drops that are emulsions is demonstrated by phase separation that is not
readily reversed on gentle shaking. A change in colour (or cloudiness of
solutions) may indicate chemical degradation or microbial contamination of the
drops.
Dose and uniformity of dose of oral
drops
Into a suitable, graduated cylinder, introduce by means of the
dropping device the number of drops usually prescribed for one dose or
introduce by means of the measuring device the usually prescribed quantity. The
dropping speed does not exceed 2 drops per second. Weigh the liquid, repeat the
addition, weigh again and carry on repeating the addition and weighing until a
total
of 10 masses are obtained. No single mass deviates by more than 10%
from the average mass. The total of 10 masses does not differ by more than 15%
from the nominal mass of 10 doses. If appropriate, measure the total volume of
10 doses. The volume does not differ by more than 15% from the nominal volume
of 10 doses.
Containers
Oral drops are normally supplied in suitable multidose containers
that allow successive drops of the preparation to be administered.
Powders
for oral solutions, oral suspensions or oral drops
Presentations of powder (usually single-dose presentations, for
example, a small sachet) that are intended to be issued to the patient as a
powder, to be taken in or with water or another suitable liquid, are outside
the scope of this general monograph. Such preparations are controlled by the
monograph for Oral powders.
Definition
Powders for oral solutions, suspensions or drops are multidose
preparations consisting of solid, loose, dry particles of varying degrees of
fineness. They contain one or more active ingredients, with or without
excipients and, if necessary, authorized colouring matter and flavouring substances.
They may contain antimicrobial preservatives and other excipients in particular
to facilitate dispersion or dissolution and to prevent caking.
After dissolution or suspension in the prescribed liquid, they
comply with the requirements for Oral solutions, Oral suspensions or Oral
drops, as appropriate.
Manufacture
In the manufacture of powders for oral solutions, suspensions or
drops, the components of the powder mixture are passed through a sieve to
remove lumps and particle aggregates. The weighed masses of the sieved
components, preferably of a narrow particle size distribution, are then
transferred to a suitable mixer. The greatest risk of segregation of the powder
mixture usually occurs when emptying the mixer container and when the powder mixture
is dosed into the containers. Ensuring the suitability of the mixing equipment
and the dosing devices is, therefore, critical.
Visual inspection
Inspect the powder. Evidence of physical instability is
demonstrated by noticeable changes in physical appearance, including texture
(for example, clumping). A change in colour may indicate chemical degradation
or microbial contamination.
Granules
for oral solutions or suspensions
Presentations of granules that are intended to be issued to the
patient as granules to be swallowed as such, to be chewed, or to be taken in or
with water or another suitable liquid, are outside the scope of this general
monograph.
Definition
Granules for oral solutions or suspensions are multidose
preparations consisting of solid, dry aggregates of powder particles
sufficiently resistant to withstand handling. They contain one or more active
ingredients with or without excipients and, if necessary, authorized colouring
matter and flavouring substances. They may contain antimicrobial preservatives
and other excipients in particular to facilitate dispersion or dissolution and
to prevent caking.
After dissolution or suspension in the prescribed liquid, they comply
with the requirements for Oral solutions or Oral suspensions, as appropriate.
Visual inspection
Inspect the granules. Evidence of physical instability is
demonstrated by noticeable changes in physical appearance, including texture
(for example, clumping of granules, presence of loose powder). A change in
colour may indicate chemical degradation or microbial contamination.
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