Pharm Technol Hosp Pharm 2018; 3(2): 113–119
Opinion Paper
Cornelia Bruns* and Michael Ober
Development and Preparation of Oral Suspensions
for Paediatric Patients – a Challenge for
Pharmacists
https://doi.org/10.1515/pthp-2018-0008
Received February 17, 2018; revised April 5, 2018; accepted April 6,
2018
Abstract: The preparation of liquid oral dosage forms for
paediatric patients may pose a challenge on pharmacies.
Marketed ready-to-use suspension vehicles do have advan-
tages and disadvantages. In order to overcome the disadvan-
tages a dedicated suspension vehicle, which can be prepared
by every pharmacy, was cooperatively developed by phar-
macist specialists on a national level in Germany. Marketed
as well as pharmacy prepared suspension vehicles provide
added value for pharmacy preparations for the special need
of paediatric patients of different age groups.
Keywords: Oral suspensions, suspending vehicles,
extemporaneous preparation, paediatric dosage forms,
appropriate excipients
Introduction
Licensed medicinal products manufactured by the pharma-
ceutical industry are often not appropriate for the safe use
in paediatric patients. Since the Paediatric Regulation came
into effect in 2007, applications for marketing-authorisation
of new medicinal products have to come along with a
paediatric investigation plan (PIP). Of note, this refers
only to medicinal products containing new active pharma-
ceutical ingredients (API) and has been successfully
performed in some cases. By contrast, the marketing-
authorisation of PUMA (paediatric-use marketing authori-
sation) has not reached the expected level [1]. Therefore
pharmacists have to fill the gap in order to ensure the
*Corresponding author: Cornelia Bruns, Gesundheit Nord gGmbH,
Clinical Center Bremen-Mitte, Pharmacy Department, St.-Jürgen-
Straße 1, 28177 Bremen, Germany,
E-mail: cornelia.bruns@klinikum-bremen-mitte.de
Michael Ober, Heidelberg University Hospital, Pharmacy
Department, Im Neuenheimer Feld 670, 69120 Heidelberg, Germany,
E-mail: michael.ober@med.uni-heidelberg.de
supply of appropriate dosage forms for paediatric patients.
Innovative dosage forms, like orodispersible mini-tablets or
orodispersible films, provide fixed single doses. The fixed
single doses are a major drawback of these dosage forms
because the administered dose depends on the weight and
age of the patients. Mini-tablets may improve the flexibility
in dosing by multiplying the number of single doses [2].
Nevertheless, oral liquid dosage forms represent the gold
standard for paediatric patients because they allow appro-
priate dosing by means of withdrawing the appropriate
volume from a multiple dose container.
Discussion
Prior to the preparation the added value of the pharmacy
preparations prepared for the specific need of the patients
has to be determined. Pharmacy preparations have to be
prepared according to the regulations and an appropriate
quality assurance system. Efficacy, safety and quality are
essential objectives of the specific dosage forms prepared
in pharmacies. Two-phase systems like suspensions pre-
sent one of the most challenging dosage forms.
Basic considerations
The challenge for pharmacists is to prepare stable sus-
pensions of appropriate concentrations, which allow safe
and easy administration of the prescribed dose in each
paediatric patient of the different age groups [3, 4].
The aim should be the limitation of excipients, because
they may cause adverse effects. Issues to be regarded are:
– Availability of the active pharmaceutical ingredient (API)
fulfilling the specifications of the Pharmacopoeia or
availability of solid dosage forms, such as tablets or
capsules to be used as starting material
– Stability of the API in the suspension vehicle (e.g. low
solubility to avoid crystal growth of suspended
114 C. Bruns and M. Ober: Development and Preparation of Oral Suspensions
particles, concentration of API in the dissolved phase
of suspensions)
– Compatibility of the excipients and stability of the
formulation
– Appropriate particle size of the API
– Slow settling and, when shaken, readily dispersed
– Availability of toxicological data regarding the exci-
pients and suitability for formulations for paediatric
use
– Choice of preservatives
– Choice of thickening agents
– Choice of sweetener
– Avoidance of additional wetting agents, e.g. polysor-
bate or polyvidone
– Avoidance of flocculating agents, because the choice
depends on the API and its concentration
– Avoidance of flavouring agents due to their indivi-
dual acceptance and age-appropriate use.
Furthermore the choice would depend on the taste
of the API
– Setting to the desired pH-value
– Palatability and acceptability
Preservatives
The most common preservatives used in liquid formulations
are sodium benzoate, sorbic acid/potassium sorbate,
methyl-4-hydroxybenzoate and propyl-4-hydroxybenzoate
[5–7]. Clinical data about the toxicity of the compounds are
rare. Some recommendations are made by the European
Medicines Agency for the use of preservatives in children.
Sodium benzoate and benzoic acid may displace bilirubin
from albumin. Especially in newborns up to the age of eight
weeks benzoic acid can accumulate and lead to clinical
jaundice. Methyl-4-hydroxybenzoate and propyl-4-hydroxy-
benzoate may cause allergic reactions. The latter one binds
to the oestrogen receptor and influence the maturation of the
reproductive system. However, the hydroxybenzoates are
widely used because they are effective in the pH interval of
1 to 8.5. Propylene glycol is sometimes used as preservative
in oral formulations. Pharmacokinetic in neonates differs
significantly from adult values leading to its accumulation
following repeated administration and can cause alcohol-
like symptoms. For children up to 5 years the maximum daily
intake must be under 50 mg/kg/day and 1 mg/kg/day for
pre-term and term neonates [8]. Comparing the
risks and suitability of these preservatives (see Table 1),
potassium sorbate shows the best risk-benefit-relationship
but the effectiveness is limited to a pH-range of 3.5 to 5.5.
Thickening agents
Oral liquids containing active substances with low aqueous
solubility often result in two-phase systems (solid particles
dispersed in the liquid). Thickening agents increase the
viscosity of the aqueous solution and prevent fast sedimen-
tation of suspended particles and caking. Some of these
substances may also increase the stability of suspensions
due to their surfactant activity. Well-known thickening
agents are semi-synthetic polysaccharides, e.g. hydro-
xyethylcellulose or hypromellose, and natural polysacchar-
ides such as tragacanth and xanthan gum (see Table 2).
Unfortunately, xanthan gum is not marketed in small quan-
tities appropriate for pharmacies and with certified pharma-
ceutical quality. Raw-material suppliers in small amounts
deliver tragacanth, but the microbiological burden must be
considered and eventually the suspension vehicle has to be
sterilized. Hydroxyethylcellulose (HEC) does not cover the
bitterness of active substances such as tragacanth does.
However, HEC is readily available on the market in assured
quality, can be used in a wide pH-range, shows solubility in
hot or cold water and exhibit the above-mentioned surfac-
tant activity. These characteristics qualify HEC as advanta-
geous thickening agent. One of the marketed suspension
vehicles contains pregelatinised starch as thickening agent.
This excipient is rather unknown and not available in certi-
fied pharmaceutical quality for pharmacy use [9–11].
Sweeteners
Sucrose is hydrolysed in the intestine to the monosac-
charides glucose and fructose, which should avoided for
paediatric patients suffering from fructose intolerance.
Sorbitol and Sorbitol solution are also contraindicated
to these patients and may cause osmotic diarrhoea,
whereas an acceptable daily intake for artificial sweet-
eners like sodium saccharin, sodium cyclamate or aspar-
tame must be appropriately taken into consideration. At
high concentrations they may evolve a bitter aftertaste
[12]. Therefore, glucose monohydrate seems to be the
most suitable sweetener in spite of its caloric value and
its risk to promote dental caries.
Stability
Undissolved substances are not subject to degradation
and hydrolysis as if they are dissolved.
 C. Bruns and M. Ober: Development and Preparation of Oral Suspensions 115

Table 1: Characteristics of preservatives used in liquid oral dosage forms.

Preservative Concentration pH- Risk Recommendation

range

Sodium benzoate . – . % <  May increase the risk of jaundice in There are adequate data to establish an
newborn babies. overall no-observed-adverse-effect level
(NOAEL) of  mg/kg bw/day. Therefore
the acceptable daily intake (ADI) for benzoic
acid and its salts has been established to
– mg/kg bw/day. []
Potassium sorbate , % (. %) .–. There are no data showing any risk Recommended acceptable daily intake for
(sorbic acid) by using recommended concentrations. sorbic acid and its salts are  mg/kg bw/
day. []
Methyl-- . – . %  – . May cause allergic reactions The use of MHP in oral formulations up to
hydroxybenzoate (possibly delayed). . % of the product (as within the
(MHB) recommended effective concentrations as a
preservative) is not a concern for humans
including the paediatric population. []
Propyl-- . – . %  – . May cause allergic reactions (possibly A permitted daily exposure (PDE) value of
hydroxybenzoate delayed).Propyl--hydroxybezoate binds to  mg/kg/day can be calculated for the use of
(PHB) oestrogen receptors but with a much PHB in adults and children older than 
weaker affinity than the natural ligand [] years with mature metabolic capacity.For
children below  years a PDE for PHB cannot
be determined because of uncertainty
related to the maturation of the enzymes that
metabolize PHB as well as the limitation of
the available animal data corresponding to
the youngest children. [, ]
Propylene glycol – % – May cause alcohol-like symptoms. [] In the absence of compelling data the
maximum daily intake is  mg/kg/day in
children less than  years old, and  mg/
kg/day in pre-term and term neonates due
to known immaturity of both metabolic and
renal clearances of propylene glycol in
these populations. []

Table 2: Characteristics of thickening agents used in liquid oral dosage forms.

Thickening agent Concentration Applicable Advantages Disadvantages

pH-range

Hydroxyethylcellulose . –  %  –  Wide pH-range, availability, solubility in cold and hot Sometimes musty taste,
[–] water, surfactant activity type dependent
viscosity
Hypromellose [–] . – , % – Wide pH-range, availability, surfactant activity Unsoluble in hot water,
coagulation by heat
Tragacanth [–] . –  % – Covers the taste of other excipients Narrow pH-range,
microbiological quality
Xanthan Gum [–]  – % – Wide pH-range, high viscosity, solubility in water, Lack of availability
compatibility with high salt concentrations
116 C. Bruns and M. Ober: Development and Preparation of Oral Suspensions
In suspensions, on the other hand, the particle size plays
a significant aspect in physical stability. In order to
influence the sedimentation rate the density and the
viscosity of the medium should be adjusted to the particle
size, as well as a narrow and small particle size distribu-
tion should be preferred.
Experimental stability testing is required to validate the
preparation, distribution and the determination of the
maximum shelf life and in-use stability after opening
the container
Occasionally the lack of active pharmaceutical ingredients
requires the use of tablets or capsules as starting material. In
these cases the impact of the excipients contained in the
solid oral dosage forms on the compatibility and stability of
the resulting suspension must be considered. Furthermore
the API content of the tablets and capsules used as starting
material determines the content of the API in the extempora-
neous preparation and has to be checked.
Marketed suspension vehicles
In Germany, a composition of a suspension vehicle, which
can prepared in pharmacies, was published in 2001[13].
However, many pharmacies use industrially manufactured
suspension vehicles [14], because they allow quick and
easy preparation of oral formulations (see Table 3). The
most important advantage of ready-to-use-vehicles is the
proven stability of the products and provision of stability
data for a huge number of APIs by the manufacturers of
the suspension vehicles. This allows quick and easy pre-
paration of oral liquid suspensions of many different APIs
in every pharmacy. On the other hand marketed suspen-
sion vehicles can cause a relationship of dependence and
may be subjected to product recalls and supply shortages.
Such a recall and failure of deliver occurred in Germany at
the end of 2017 for one of these products and caused a
state of emergency especially in local pharmacies.
Alternatives were not readily available and the company
not able to predict the renewed availability.
Another disadvantage of the marketed suspension
vehicles are the different and sometimes non-suitable
ingredients for patients of special age groups. Some pre-
servatives used in these products are not appropriate for
the use in new-born or premature infants. Of note, vehi-
cles without preservatives are problematic because of the
microbiological instability of the multiple dosage form.
Development of an alternative
compounded suspension vehicle
In order to overcome these disadvantages a dedicated
suspension vehicle, which can be prepared by every
pharmacy or ordered as ready-to-use vehicle from a phar-
maceutical manufacturer, was developed in a joint pro-
ject of Deutscher Arzneimittel-Codex/Neues Rezeptur-
Formularium (DAC/NRF) and other groups, e.g. hospital
pharmacists. Currently stability studies of this particular
suspension vehicle are performed with the 10 most often
used APIs in paediatric patients [15].
Conclusion
In spite of new regulations and the development of pro-
mising new dosage forms, the preparation of suspensions
for the special needs of paediatric patients remains an
important assignment in pharmacies. Whenever a mar-
keted suspension vehicle is not available or not suitable,
e.g. for newborn, pharmacies should be able to prepare a
preparation for the particular needs. Due to the different
components contained in suspensions stability testing
and validation is commonly performed by validated
high performance liquid chromatography (HPLC).
Therefore sharing of information and cooperation in the
development and analytics of suitable formulas are
essential both on the national and international level of
the professional bodies.
Acknowledements: We are grateful to Prof. Dr. Irene
Krämer head of the Special Interest Group Pharmacy
preparation and quality control of the German Society
of Hospital Pharmacists ADKA e.V. for taking the initia-
tive and fruitful discussions.
Conflict of interest statement: The authors state no con-
flict of interest. The authors have read the journal’s
Publication ethics and publication malpractice statement
available at the journal’s website and hereby confirm that
they comply with all its parts applicable to the present
scientific work.
Table 3: Characteristics of suspension vehicles.
Suspension vehicle Type Composition
Ora-Plus® Marketed Water, microcrystalline
cellulose,
carboxymethylcellulose
sodium, xanthan gum,
carrageen, calcium sulphate,
trisodium phosphate, citric
acid, sodium phosphate,
dimethicone antfoam
emulsion, methylparaben,
potassium sorbate
Ora-Sweet® Marketed Water, sucrose, glycerin,
sorbitol, citric acid, sodium
phosphate, methylparaben,
potassium sorbate,
flavouring
Ora-Sweet SF® Marketed Water, glycerin, sorbitol,
sodium saccharin, xanthan
gum, flavouring, citric acid,
sodium citrate,
methylparaben, potassium
sorbate, propylparaben
Ora-Blend® Marketed Water, sucrose, glycerin,
sorbitol, flavouring,
microcrystalline cellulose,,
carboxymethylcellulose
sodium, xanthan gum,
carrageen, calcium sulphate,
trisodium phosphate, citric
acid, sodium phosphate,
dimethicone antifoam
emulsion, methylparaben,
potassium sorbate
Advantages
Composition meets USP monograph,
can be combined with Ora-Sweet®,
Ora-Sweet SF® or water, numerous
formulations published, low
osmolarity
Can be combined with Ora-Plus® or
water,
numerous formulation published
Can be combined with Ora-Plus® or
water, numerous formulations
published
Numerous formulations published
Disadvantages Formulations
Complex composition makes stability Stability data for many APIs published in
tests difficult and increases API – different professional journals and books
excipient interactions,, incompatible
with positively charged APIs
Contains flavouring, complex Stability data for many APIs published in
composition makes stability tests different professional journals and books
difficult and increases API – excipient
interactions, high osmolarity
Contains flavouring and Stability data for many APIs published in
propylparaben, complex composition different professional journals and books
makes stability tests difficult and
increases API – excipient interactions,
high osmolarity
Contains flavouring, complex Stability data for many APIs published in
composition makes stability tests different professional journals and books
difficult and increases API – excipient
interactions, incompatible with
positively charged APIs, high
osmolarity
(continued )
C. Bruns and M. Ober: Development and Preparation of Oral Suspensions
117
Table 3: (continued )
Suspension vehicle Type Composition
Ora-Blend SF® Marketed Water, sorbitol, glycerin,
flavouring, microcrystalline
cellulose,
carboxymethylcellulose
sodium, xanthan gum, car-
rageenan, calcium sulfate,
trisodium phosphate sodium
saccharin, sodium
phosphate, citric acid,
sodium citrate, dimethicone
antifoam emulsion,
methylparaben,
propylparaben, potassium
sorbate
In-Orpha® Marketed Water, glycerin,
hydroxyethylcellulose, citric
acid, sodium citrate, bitter
blocker, toffee flavouring,
sucralose, potassium sorbate
SyrSpend® SF PH liquid Marketed Water, preaggluginated
starch, sodium citrate, citric
acid, malic acid, sodium
benzoate, sucralose,
simethicone (flavoured or
unflavoured)
SyrSpend® SF PH powder Marketed Preaggluginated starch,
sodium citrate, citric acid,
sucralose
SyrSpend® SF Alka powder Marketed Preaggluginated starch,
calcium carbonate, sucralose
Basissuspensionsmedium Compounded Water, glucose monohydrate,
[] sodium chloride, citric acid,
tragacanth (potassium
sorbate is added to final
suspension, the preservative-
free vehicle is sterilized)
Grundlage für Compounded Water, glucose monohydrate,
Suspensionen zum and marketed citric acid, potassium
Einnehmen DAC/NRF® sorbate,
(utility model hydroxyethylcellulose
No.    )
Advantages
Numerous formulations published,
medium osmolarity
Hydroxyethylcellulose exhibit
surfactant activity and inured to salts, blockers, glycerin may cause adverse
preservative appropriate for
paediatric patients, low osmolarity
Low osmolarity
Preservative-free, low osmolarity
Preservative-free, low osmolarity
Tragacanth can cover poor taste of
APIs and may act as wetting agent,
excipients in small amounts available,
preservative appropriate for
paediatric patients
Excipients in small amounts available,
hydroxyethylcellulose exhibit
surfactant activity and inured to salts,
preservative appropriate for
paediatric patients, medium
osmolarity
118
Disadvantages Formulations
Contains flavouring and Stability data for many APIs published in
propylparaben, complex composition different professional journals and books
makes stability tests difficult and
increases API – excipient interactions,
incompatible with positively charged
APIs
Contains flavouring and bitter Stability data for only a few APIs
affects
Contains sodium benzoate, lack of Stability data for many APIs
information relating to sucralose for
the use in paediatrics
Microbiological risk, lack of Stability data for many APIs
C. Bruns and M. Ober: Development and Preparation of Oral Suspensions
information regarding to the use of
sucralose in paediatrics
Microbiological risk, lack of Stability data for relevant APIs
information regarding to the use of
sucralose in paediatrics
Microbiological quality of tragacanth, Stability data for only a few APIs:
high osmolarity Hydrochlorothiazide Suspension  mg/ml -
shelf life  month, after opening  weeks
Spironolactone Suspension  mg/ml - shelf
life  month, after opening  month
Naproxen Suspension  mg/ml - shelf life
 month, after opening  month
Stability studies are currently performed
 C. Bruns and M. Ober: Development and Preparation of Oral Suspensions 119

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