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Drug Dev Ind Pharm, Early Online: 1–17


! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/03639045.2013.850713

REVIEW ARTICLE

Pediatric drug development: formulation considerations


Areeg Anwer Ali1, Naseem Ahmad Charoo2, and Daud Baraka Abdallah3
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1
Department of Clinical Pharmacy and Pharmacology, RAKCOPS, RAK Medical and Health Sciences University, Ras Al Khaimah, UAE, 2Xepa, Soul
Pattinson Sdn Bhd, Melaka, Malaysia, and 3Department of Pharmaceutics, Faculty of Pharmacy, Al Ribat University, Khartoum, Sudan

Abstract Keywords
Absence of safe, effective and appropriate treatment is one of the main causes of high mortality Clinical studies, excipients, formulation
and morbidity rates among the pediatric group. This review provides an overview of development, pediatric formulations,
pharmacokinetic differences between pediatric and adult population and their implications in pharmacokinetics, taste masking
pharmaceutical development. Different pediatric dosage forms, their merits and demerits are
discussed. Food and Drug Administration Act of 1997 and the Best Pharmaceuticals for Children History
Act 2002 added 6 months patent extension and exclusivity incentives to pharmaceutical
companies for evaluation of medicinal products in children. Prescription Drug User Fee Act and Received 22 June 2013
Food and Drug Administration Amendments Act of 2007 made it mandatory for pharmaceutical Revised 16 September 2013
companies to perform pediatric clinical studies on new drug products. Drug development Accepted 19 September 2013
program should include additional clinical bridge studies to evaluate differences in pharmaco- Published online 31 January 2014
For personal use only.

kinetics and pharmacodynamics of drugs in adult and child populations. Additionally,


pharmaceutical development should consider ease of administration, palatability, appropriate
excipients, stability and therapeutic equivalency of pediatric dosage forms. Pediatric population
is diverse with individual preferences and demand for custom made dosage formulations.
Practically it is not feasible to have different pharmaceutical dosage forms for each group. Hence,
an appropriate dosage form that can be administered across pediatric population is warranted.

Introduction study. The products to be studied in the pediatric population are


categorized into four classes1, as shown in Figure 1.
In the absence of specific pediatric medicines, their huge demand
Oral route is by far the most preferred route for children
is met by extemporaneously prepared products. Upward shift in
46 years. The target product profile of pediatric formulations by
such prescriptions justifies the ‘‘Make Medicine Child Size’’
this route of administration will have additional critical quality
initiative. It resonated well with the wishes of the wider scientific
attributes (CQAs) in the form of organoleptic characteristics,
community that children should benefit from recent scientific
palatability, dosing flexibility, safety, ease of administration,
developments and improving access to medicines can be a leap
pharmacokinetics and stability.
forward. Extemporaneously prepared preparations are generally
Liquid dosage forms are preferred among children 55 years of
viscous dispersions prepared from tablets by incorporating other
age for their ease in swallowing and dose adjustment. Children in
excipients like antimicrobial preservatives and viscosity modi-
school age can be administered solid dosage forms. The dose
fiers. With little or no regard for drug – excipient compatibility
accuracy and ease with which taste can be masked makes tablets
and effect of these additional excipients or processes on critical
and capsules popular among children and caregivers. Taste needs
quality attributes, such preparations are a threat to safety, efficacy
a special mention, for good medication with disagreeable taste
and quality.
will lead to noncompliance with the dosing regimen. Therefore,
The pediatric age group is so diverse that due to their
organoleptic additives form an integral component of pediatric
individual preferences, it is challenging to develop a single
formulations.
formulation which is accepted across this group. Adding further to
this complexity are rapid anatomical and physiological changes Regulatory perspective
that this group undergoes making it further difficult to find the
The number of product labels not bearing pediatric use informa-
right dose. The group being highly vulnerable presents several
tion has gone down from 76% to 67%, during 1997–2012 period,
ethical challenges in performing clinical studies on children.
respectively2. Yet, two-third of medicinal products prescribed to
Clinical studies must be balanced to obtain needed information
children have not been evaluated clinically and labeled for
against the ethical obligations to protect children through the
pediatric use (Figure 1). As a consequence, off-label use of these
medicines has resulted in their use for unapproved indications.
The widespread use of unauthorized medicinal products in
Address for correspondence: Naseem Ahmad Charoo, Xepa, Soul
Pattinson Sdn Bhd, 1-5 Cheng Industrial Estate, 75250 Melaka, Malaysia. children was a precursor for release of concept paper ‘‘Better
Tel: +606 335 1515. Fax: +606 335 5829. E-mail: naseem102@yahoo medicines for children – proposed regulatory actions on pediatric
.com medicinal products’’3.
2 A. A. Ali et al. Drug Dev Ind Pharm, Early Online: 1–17
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Figure 1. Clinical studies in pediatric population.

The adoption of the4 Food and Drug Administration (FDA) determine drug absorption through this route. The developmental
Modernization Act of 1997 and the Best Pharmaceuticals for differences in gastrointestinal conditions between child and adult
Children Act in 2002 (BPA 2002)5 added incentives for pharma-
For personal use only.

population groups can manifest in drug bioavailability difference


ceutical companies in terms of market exclusivity extension to 6 in these two groups. The changes in gastric pH taking place
months and/or patent extension for performing additional clinical during the development stages of a child are shown in Table 1. In
studies to evaluate these medicinal products in pediatric popula- infants, the gastric pH ranges from 6 to 8 but reaches to adult
tion. Similarly, the European Commission also took the initiative value by the age of 3 years23. This difference is manifested in
in 1997 by introducing incentives for pediatric formulation faster absorption of acid labile drugs (penicillin) in neonates and
development6. infants as compared to adult population24–26. The absorption of
ICH (International Conference on Harmonisation) guidance weak acid drugs (Phenobarbital)27 is decreased whereas absorp-
document E11 on7 ‘‘Clinical investigation of medicinal products tion of basic drugs is increased13.
in the pediatric population’’ was finalized in 2000. Pediatric Gastric emptying is slow and reaches adult value within 6–8
Research Equity Act in 2003 authorized FDA to make pediatric months28. The small intestine is the major site for absorption and
studies mandatory for products that would be used in pediatric slow gastric emptying decreases the absorption of drugs (chlor-
patients and extend clinical data obtained in adults to approve amphenicol and amoxicillin) in infants29,30. Fatty foods such as
pediatric medicines in certain situations8. children formulas/milk further reduce gastric emptying and may
Prescription Drug User Fee Act and Food and Drug delay onset of drug action31. Solid and liquid foods trigger
Administration Amendments Act (FDAAA) of 2007 (FDA2007) peristaltic waves and increase the gastric emptying rate.
further encouraged the pediatric drug development (US Govt Generally, liquids empty faster than solids and this may be one
accountability office) by extending incentives and improving important criterion for selecting suspension dosage formulation
review process for pediatric studies9. Food and Drug over tablet dosage forms31,32. Faster intestinal transit time in
Administration Amendments Act (FDAAA) of 2007 required children may result in incomplete absorption of some controlled
future applications to be submitted with safety and efficacy data release dosage forms33.
in all pediatric age groups with provision for extrapolation of
clinical findings from studies performed on adults or from one Distribution
pediatric age group to another when appropriate. In Europe,
pediatric regulation governing development and authorization of In addition to the physiological factors, the drug distribution is
medicines for pediatric use was implemented10 in 2007. These determined by its physicochemical properties such as pKa,
acts made it mandatory for pharmaceutical companies to perform partition coefficient, molecular weight and solubility. When
clinical studies in pediatric population on new drug products to compared to adults, plasma protein binding and partitioning are
evaluate the feasibility of their use in children11. different in the pediatric population and fluctuate continuously
during the early years. The high volume of distribution of
Pharmacokinetics differences between pediatric water-soluble drugs (linezolid and gentamicin) is caused by high
population and adults extracellular and total body water16,17. Further, the concentration
of binding proteins, their binding capacity and affinity to drug
Absorption
molecules is low in neonates and infants34,35. The plasma protein
The oral route is the most common and preferred route of drug binding of drugs such as phenobarbital18, salicylates and pheny-
administration. pH-mediated drug diffusion, gastric emptying toin is significantly reduced in neonates36. Consequently,
time and intestinal transit time are essential characteristics that these drugs need a higher loading dose to achieve therapeutic
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Table 1. Summary of developmental changes in physiological and pharmacokinetic parameters.

Physiological parameter Birth 24 h 10–30th day 1st year 3rd year Adults References
DOI: 10.3109/03639045.2013.850713

Gastric pH 6–8 1–3 6–8 1–2 1–2 (same as adults) 1–3.5 [12,13]

Gastric emptying Slow and linear Similar to adult biphasic [12]


(rapid and slow phase)

Intestinal transit Prolonged Reduced (incomplete absorption [14]


–Intestinal motility and proteolytic enzymatic activity: low of sustained release formulations)
–IgA secretion: low
–Intestinal permeability: high
–Protein digestion: incomplete
–Protein, carbohydrate absorption: high

Bile salt pool Inadequate [fat soluble substances (Vitamins D and E)-poorly absorbed]

Membrane permeability Blood Brain Barrier: higher permeability [15]

Plasma protein binding Unbound drug fraction: high [16]

Body water 80–90% body weight; low fat content water soluble drugs: large volume [16–18]
of distribution, e.g. phenobarbital

Hepatic enzyme activity Low [17,19–21]

Microsomal enzymatic systems Activities increase

Hepatic phase I reactions Develop rapidly

Phase II reactions Reduced

Renal blood flow 5–6% of cardiac output 15–20% of cardiac output [22]

Reaches to adult value


Pediatric drug development
3
4 A. A. Ali et al. Drug Dev Ind Pharm, Early Online: 1–17

plasma/serum concentration37,38. However, higher level of free The oral route is the preferred mode of drug administration in
drug in plasma has the potential to cause toxic effects39. The adults and children 46 years of age. Children 56 years find it
permeability of blood brain barrier (BBB) in neonates is also difficult to swallow a solid dosage form and therefore liquid
superior which many low penetrating drugs can easily breach to dosage formulations are used to administer drugs to this group.
elicit serious adverse effects15. Their preference for oral route can be gaged by the fact that over
90% of pediatric dosage forms are administered by oral route. The
Metabolism majority of these are supplied as liquid dosage forms44 because
they are easy to swallow and their dose can be easily adjusted
In metabolism, the structure of the drug is changed to the form
according to the body weight or surface area. Further, the drug
that can be easily eliminated by the body. The main organ
being already in solution form facilitates faster onset of action.
responsible for metabolism of drugs is the liver and it also
The desired features and challenges offered by solid and liquid
undergoes developmental changes with age. Newborn neonates
dosage forms are shown in Figure 2.
metabolize drugs at a rate several times lower than adults due
The Biopharmaceutics Classification System (BCS) based on
to the relative lack of mature metabolic enzymes (phase I),
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solubility and permeability categorizes drugs into four main


particularly oxidative and conjugative systems. For example, the
classes45. Class I drugs (High soluble/high permeable), class II
oxidative metabolism of phenobarbital and phenytoin is
(low soluble/high permeable), class III (high soluble/low perme-
severely impaired in infants21. The glucuronidation pathway
able) and class IV (low soluble/low permeable). High soluble
(phase II enzyme reactions) is also relatively un-developed in
drug has dose/solubility ratio 250 ml in aqueous media at 37  C
newborns. The insufficient metabolism of chloramphenicol by
over the pH range of 1.2–6.8 and high permeable drug shows
glucuronyl transferases to the inactive glucuronide metabolite
extent of absorption over 90%. WHO (World Health Organisation)
caused famous Gray Baby Syndrome in newborn infants19 and
technical report series provides the BCS classification of drugs
the low activity of cytochrome P-450 3A resulted in higher
present in the WHO Model List of Essential Medicines46. BCS is
midazolam blood levels in term infants40. Low first pass
an important pharmaceutical tool used in developing bioequiva-
metabolism in neonates may lead to higher blood levels of
lent formulations and obtaining science based biowaivers for
certain drugs such as zidovudine20.
dosage forms. However, its application in pediatric population is
Although most drugs are metabolized to less active forms,
questionable mainly due to the higher permeability of the
some may be transformed to active metabolites. An example is
intestinal mucosa of infants and young children in comparison
the conversion of theophylline to caffeine by the methylation
to adults. Also physiological parameters like gastrointestinal pH,
reaction which is generally low in adults but high in term
gastrointestinal motility, gastric emptying time and intestinal
infants41. Sulfate conjugation reactions are well developed in
transport systems are different in children and adult popula-
For personal use only.

infants and children39.


tion12,18,23. Due to their low solubility, the absorption of Class II
Hepatotoxicity of acetaminophen, excreted via sulfate conju-
and IV drugs is dissolution rate limited. Various strategies such as
gation pathway in children, is considerably reduced in comparison
particle size reduction, polymorphic form and addition of
to adults (adults use glucuronide conjugate pathway for its
solubility enhancer to overcome poor solubility are considered.
excretion)42.
The quality target product profile (QTPP) for a typical
pediatric oral solid dosage formulation is depicted in Table 2.
Excretion
Critical quality attributes based on QTPP for a pediatric dosage
Elimination of drugs generally depends on kidney function, which formulation will be appearance, identification, weight/dosing
also undergoes developmental changes in early childhood. volume, assay, content uniformity, taste, stability (physical,
Decreased clearance of drugs in newborn babies relative to chemical, microbiological), impurities and dissolution.
adults is primarily caused by reduced renal tubular function,
blood flow and the glomerular filtration22. The immature renal Liquid formulations
elimination system leads to accumulation of aminoglycosides and
penicillins which necessitates less frequent dosing intervals43. Liquid formulations contain drug either in solution or in
Overall kidney function increases with age. Therefore, as the dispersion form in the vehicle and may be supplied as solutions,
kidney function matures, there may be a shift from potential drug suspensions, emulsions, elixirs, syrups, spirits, tinctures, lini-
over-dose to potential under-dose for some drugs, such as ments, sprays, aromatic waters or aerosols. Water is physiologic-
theophylline. Urinary pH values differ too which may influence ally compatible, devoid of toxicity and has high dielectric
re-absorption of drugs22. constant which is essential for dissolution of ionizable drugs.
Therefore, water is the preferred vehicle for drug substances with
high solubility and agreeable taste. Other solvents/vehicles that
Formulation development
are used include mineral oil, polyethylene glycol, glycerine and
The focus area of a drug in a clinical set up is its clinical effect, alcohols. Usually, alcohols are avoided in pediatric formulations
dose, drug interaction and adverse effects. The mode of its due to their toxicity. FDA recommends an alcohol limit of 0.5%
delivery to the pediatric patient is paid less attention. The path to and 5% for patients under 6 years of age and between 6 and 12
dosage formulation development for adults is straightforward in years of age, respectively47. There are safety concerns with the
that solid dosage forms are acceptable to the majority of adult use of other solvents which are listed in Table 3. The intrinsic
patients. Pediatric population is diverse (neonates, newborn, solubility of many drugs is low and cannot be formulated in liquid
toddlers, young children and adolescents) with individual prefer- dosage forms at the required dosage strength. Many approaches
ences and demand for custom made dosage formulations. The are available to increase the aqueous solubility including pH
desired attributes for these pharmaceutical dosage forms tailoring control48, use of cosolvents49–52, complexation53, solubilization52,
to individual pediatric population group needs are varied. chemical modification54,55 and particle size reduction56.
However, practically, it is not feasible to have different pharma- Suspension formulations should be considered when solubility
ceutical dosage forms for each group. Hence, an appropriate cannot be modulated. By minimizing drug in solution form,
dosage form that can be administered across pediatric population suspensions improve palatability and allow increased drug load in
is warranted. reduced dose volume. The drug release can also be modified in
DOI: 10.3109/03639045.2013.850713 Pediatric drug development 5
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Figure 2. Features of solid and liquid dosage forms.

suspension formulations. The oral bioavailability of efavirenz is the drug stability. For example, the hydrolysis of furosemide is pH
only 40–45% and administration of higher doses is required to dependent. In spite of being present in solid state, it hydrolyzed in
achieve therapeutic effect. A concentrated, taste masked stable acidic conditions but was more stable in alkaline conditions even
aqueous formulation of efavirenz was developed for the manage- though it was present in solution form60.
ment of pediatric anti-HIV therapy and to prevent mouth burning The liquid dosage forms have several limitations. They are
syndrome associated with its use57. bulky and difficult to transport, require careful handling and have
In certain instances presence of drug in solid state in special storage requirements. In liquid state drug is more
suspension formulations imparts more chemical stability to drug susceptible to degradation and has a lesser shelf life than solid
substances such as acetazolamide and chlorothiazide than the dosage forms. Also, liquid dosage forms are prone to microbial
solution form58,59. However, there are other factors that determine growth. In addition to being a risk to the health, microbial
6 A. A. Ali et al. Drug Dev Ind Pharm, Early Online: 1–17

Table 2. Quality target product profile of pediatric dosage form.

QTPP (quality target product profile)


Attribute TPP (target product profile) TPQP (target product quality profile) Significance
Dosage form Liquid dosage form Palatable Ensures complete dispersion,
Dispersible tablet DT (53 min) release of drug, efficacy and
Powder for oral Palatable, redispersible, stable ease of administration
suspension
ODT DT 530 s, palatable, mouth feel
Chewable tablets Palatable, mouth feel
Weight/dosing volumes Ingestible 51000 mg in fixed dose combinations Ease of swallowing
53 mm in mini tabs
55 ml (children 55 years) and 510 ml
(children over 5 years).
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Appearance Elegant Attractive color, shape, size, flavor and taste Patient acceptability and
compliance
Strength – Identification, assay, compliance to Efficacy
content uniformity limits
Route of administration Oral Palatable Ease of dosing and Patient
compliance to therapy
Indications Disease treatment Dissolution, bioavailability and bioequivalence Ensure therapeutic efficacy
Impurities – Comply with necessary guidance documents Safety
Bioavailability/Bioequivalence – Bioequivalent to reference listed drug Safety and efficacy
(for generics)
Stability Physical, chemical and 424 months To be commerciable
microbial stability

contamination may cause changes in pH, appearance, odor, smell practitioners usually fill this gap by extemporaneously preparing
and palatability of the preparation. Therefore, preservatives are products to suit pediatric patients. Through the use of these
usually added. unlicensed preparations the prescribers try to overcome the
For personal use only.

The accurate dose measurement is another serious concern shortage of approved medicines for children63. However, there is a
especially with potent drugs. In order to be measurable, the dose serious concern about their safety, efficacy and quality. These
volume for liquid formulations are generally kept 55 ml (children preparations are generally prepared by modifying commercially
55 years) and 510 ml (children over 5 years)61. Bad taste is more available dosage forms. The most commonly prepared extempor-
pronounced in liquid formulations and thus sweeteners are aneous preparations are suspensions usually prepared from tablets
required. with the use of excipients such as antimicrobial preservatives,
The stability problems encountered in liquid dosage forms are suspending agents and flavoring agents. Such preparations should
color change, decrease in potency, increase in degradation be easily and uniformly dispersible with gentle shaking. The
impurities, clarity changes, difficulty in re-dispersion of settled selection of vehicle is of primary importance in achieving this
particles in suspension, polymorph changes, microbial growth, critical quality attribute. Methyl cellulose in syrup or glycerol
creaming and breaking in emulsions. The instability is primarily base is commonly used vehicle. Sometimes alcohol is used if the
caused by pH of the solution, type of solvent, light, temperature and drug is poorly soluble in water. However, it is difficult to prepare
excipients. pH-solubility and pH-stability profile are evaluated methyl cellulose suspensions which have caused a surge in the use
during formulation development to obtain optimum pH62,63. Drugs of ready to use suspensions in USA. Ora-Plus and Ora-Sweet have
undergoing hydrolysis in a liquid dosage form can be stabilized by been used as suspending and sweetening agents, respectively, for
formulating them with buffers at pH of maximum stability. many extemporaneously prepared formulations. The possible
However, sometimes the components of buffer system can adverse effects of excipients should be considered while preparing
themselves lead to hydrolytic degradation. Codeine buffered at these formulations. Sucrose is known to promote dental caries on
pH 7 using 0.05 M phosphate buffer hydrolyzed 20 times faster chronic use and parabens can cause hypersensitivity reactions64.
than un-buffered solution at the same pH62. Due to its effect on These preparations should remain within their physical,
oxidation reduction potential of the drug, pH may also influence chemical and microbiological specifications during storage for a
the oxidative degradation of drugs. Drugs undergoing oxidative specified time62. The shelf lives of extemporaneous preparations
degradation may be stabilized by antioxidants and/or stored in are empirically assigned or may be based on published
containers containing nitrogen or carbon dioxide. Temperature can information65.
enhance the hydrolysis rate of drugs. Photolabile drugs are stored The drug is readily available for a chemical reaction in liquid
in amber glass containers and protected from light exposure. dosage forms which is one of the primary reasons for using the
Elastomeric and plastic containers and closures may leach conservative expiration date for extemporaneously prepared liquid
nitrosamines, monomers, plasticizers, antioxidants and vulcaniz- dosage forms. The stability of excipients such as preservatives,
ing agents into the liquid dosage form. Therefore, the stability of organoleptic additives, solubilizers and viscosity enhancers used
product is determined in the final container closure system62,63. in liquid dosage forms is equally important.
Extemporaneously prepared liquid dosage forms of lisinopril
prepared in 1% methylcellulose, simple syrup NF (1:13) and Ora
Extemporaneously prepared formulations
Plus-Ora sweet (1:1) was found stable for at least 13 weeks under
In spite of many initiatives that have been undertaken in refrigerated conditions and 8 weeks at room temperature66.
improving the availability of drug products to children, the Folic acid was found to retain its potency at pH 5.0–5.5 in liquid
demand for pediatric medicines still remains huge. The medical dosage formulations. Degradation rate was higher in water as
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Table 3. Commonly used excipients for solid dosage formulations with their associated toxicities and acceptable daily intake (ADI)*.

ADI
Function Excipient Toxicities Marketed formulations containing these excipients (mg/kg/day)
Diluent Lactose Induces diarrhea Thiabendazole suspension and chewable tablets, Cetirizine HCl chewable tablets, *
Lansoprazole ODT, Ondansetron ODT, Busulfan tablets, Dextroamphetamine Sulfate,
Dextrostat tablets, Cefpodoxime Proxetil for oral suspension, Deferasirox tablets for oral
suspension, Mefloquine HCl/Lariam tablets for suspension
Mannitol Allergic reactions Thiabendazole suspension, Amoxicillin chewable tablets, Cetirizine chewable tablets, *
Thiabendazole chewable tablets, Desloaratadine ODT, Ondansetron ODT, Amoxicillin and
DOI: 10.3109/03639045.2013.850713

Clavulanate powder for suspension, Linezolid powder for suspension


Microcrystalline cellulose – Mefloquine HCl tablets for suspension; Acyclovir suspension, Cetirizine chewable tablets, *
Desloratadine ODT
Sorbitol Laxative effect Oseltamivir phosphate powder for suspension, Granisetron HCl oral solution *
Binder Povidone – Lamotrigine chewable tablets, Atovaquone and Proguanil tablets, Cefuroxime Axetil powder 25
for suspension, Clarithromycin for suspension
Starch Celiac disease – *
Disintegrant Croscarmellose sodium – Montelukast sodium chewable tablets, Loratadine ODT, Fexofenadine HCl tablets, *
Cefpodoxime Proxetil for oral suspension
Crospovidone – Granisetron HCl chewable tablets, desloratadine ODT, Nelfinavir Mesylate oral powder, *
Mefloquine HCl tablets for suspension
Lubricant Magnesium strearate – Mefloquine HCl tablets for suspension, Thiabendazole suspension, Amoxicillin chewable *
tablets, Carbamazepine chewable tablets, Cetirizine chewable tablets, Lamotrigine chew-
able tablets, Desloratadine ODT, Loratadine ODT
Stearic acid – Cefuroxime axetil powder for oral suspension, Carbamazepine chewable tablets *
Glidant Silicon dioxide Amoxicillin and Clavulanate Potassium powder for suspension, Cefdinir powder for *
suspension, Cefixime powder for suspension, Ceftibuten powder for suspension, Linezolid
powder for suspension
Preservative Benzyl alcohol –Neurotoxicity, metabolic – 5
acidosis
–Contraindicated in neo-
nates and should be
avoided in children 53
years
Benzoic acid Allergic reactions, increase Efavirenz oral solution, Fluoxetine oral solution 5
risk of jaundice
Sodium benzoate Urticaria, dermatitis Granisetron HCl oral solution, Ondansetron HCl orla solution, Ribavirin oral solution, 5
Desloratadine syrup, Zidovudine syrup, Ranitidine effervescent tablets, Cefadroxil powder
for suspension, Amoxicilline for oral suspension, Cefdinir for oral suspension, Cefixime for
oral suspension
Methyl paraben – Famotidine powder for suspension, Mycophenolate Mofetil powder for suspension, Abacavir 10
Sulfate solution, Emtricitabine oral solution, Galantamine oral solution, Lamivudine oral
solution
Propyl paraben – Abacavir Sulfate solution, Emtricitabine oral solution, Galantamine oral solution, Lamivudine 10
oral solution
Sorbic acid – Oxcarbazepine oral suspension 25
Benzalkonium chloride Induces bronchospasm – *
Sulphite Wheezing – *
Pediatric drug development

Thiomersal Toxicity, banned for use in – *


pediatric medicines
7

(continued )
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8

Table 3. Continued

ADI
Function Excipient Toxicities Marketed formulations containing these excipients (mg/kg/day)

Sweetener Sucrose Should be avoided in pedi- Lamivudine oral solution, Nizatidine oral solution, Ribavirin oral solution, Hydrocodone *
atric patients suffering Bitartrate syrup, valproic acid syrup, Zidovudine syrup, Carbamazepine suspension,
A. A. Ali et al.

from fructose intoler- Nevirapine suspension, Carbamazepine chewable tablets, Dextroamphetamine Sulfate
ance, high amounts tablets, Stavudine powder for suspension
should be avoided in
patients with diabetes,
chronic use may promote
dental caries
Fructose Contraindicated in patients Lopinavir solution, Dextromethorphan Polistirex suspension *
with hypoglycaemia or
fructose intolerance
Sorbitol/xylitol May cause osmotic diar- Lamivudine oral solution, Granisetron HCl oral solution, Ondansetron HCl oral solution, *
rhea, contraindicated in Ribavirin oral solution, Amantadine HCl syrup
hypoglycaemic patients
and diabetics, IV use
should be avoided
Aspartame Induces headaches, cross Amoxicilline chewable tablets, Methylphenidate HCL chewable tablets, Desloratadine ODT, 40
reactivity with sul- Ondansetron free base ODT, Ranitidine effervescent tablets, Amoxicillin and Clavulanate
phonamides, contraindi- Potassium powder for oral suspension, Cefprozil powder for suspension, Cefuroxime axetil
cated in homozygous powder for suspension, Linezolid powder for suspension
autosomal recessive
patients, may be harmful
to patients with
phenylketonuria
Saccharine Cross sensitivity reactions Oseltamivir phosphate powder for suspension, Abacavir Sulfate oral solution, Amprenavir oral 2.5
with sulphonamides, solution, Galantamine HBr oral solution, Lopinavir and Ritonavir oral solution, Nizatidine
poor after taste, allergic oral solution
reaction (urticaria,
pruritis)
Solvent Water – Methylphenidate HCL oral solution, Nizatidine oral solution, Ondansetron HCl oral solution, *
Ribavirin oral solution, Ritonavir oral solution, Cetirizine HCl syrup, Desloratadine syrup,
Ranitidine HCl syrup
Ethanol Neurotoxicity, drug inter- Dextromethorphan Polistirex suspension, Oxcarbazepine suspension, Ritonavir oral solution *
actions CNS adverse
effects
Propylene glycol Seizures, neurotoxicity, Carbamazepine suspension, Dextromethorphan Polistirex suspension, Oxcarbamazepine 25
contact dermatitis, laxa- suspension, Cefpodoxime Proxetil for oral suspension, Benazepril HCl tablets for
tive effect, CNS depres- suspension, Imatinib Mesylate tablets for suspension
sion, should not be
administered in children
54 years
Coloring agent Azo dyes (tartrazine, sunset Should be avoided in chil- –
yellow and new coccine) dren. Negative effect on
children behavior, urti-
caria, bronchoconstric-
tion, angioedema
Drug Dev Ind Pharm, Early Online: 1–17
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– *
Quinoline dyes (quinoline – – *
yellow)
Triphenylmethane dyes – *
(e.g. FD&C blue)
Erythrosine dyes – *
Flavoring agent Banana – Abacavir sulfate oral solution, Lamivudine oral solution, Cetirizine syrup, Acyclovir *
suspension, Amoxicilline chewable tablets, Azithromycin for oral suspension
Blackcurrent – Lamotrigine chewable tablets *
DOI: 10.3109/03639045.2013.850713

Cherry – Azithromycin for oral suspension, Cefprozil powder for suspension, Amoxicilline chewable *
tablets
Mint – Efavirenz oral solution, Fluoxetine HCl oral solution, Loratadine ODT *
Tutti fruiti – – *
Peppermint – Amprenavir oral solution, Lopinavir and Ritonavir oral solution, Amoxicilline chewable tablets *
Vanilla – Azithromycin for oral suspension *
Buble gum – Nizatidine oral solution, Desloratadine syrup, Amoxicillin drops for suspension *
Strawberry – Ondansetron HCl oral solution, Lansoprazole ODT, Cefdinir powder for suspension, Cefixime *
powder for suspension, Ciprofloxacin microcapsules for suspension, Nitazoxanide powder
for suspension
Coating material Methacrylic acid and ethy- Fibrosing colonopathy – *
lacrylate copolymer
Butylated methacrylate – Desloratadine ODT *
copolymer
Methacrylic acid – Lansoprazole ODT delayed release, Ciprofloxacin microcapsules for suspension *
Ammonium methacrylate – Dexmethyl-phenidate sprinkle powder in capsules *
copolymer
Cellulose acetate – Topiramate sprinkle capsules *
carbomer – Clarithromycin powder for suspension, Nevirapine suspension *
Ethyl cellulsoe – – *
pH modifier Sodium phosphate – Didanosine powder for suspension, Azithromycin for suspension, Emtricitabine oral solution, *
Ranitidine HCl syrup
Ascorbic acid – Oxcarbazepine oral suspension *
Acetic acid – Cetirizine HCl syrup *
Citric acid – Amantadine HCl syrup, Desloratadine syrup, ranitidine HCl syrup, Zidovudine syrup, *
Carbamazepine suspension, Desloratadien ODT, Cefdinir powder for suspension
Sodium hydroxide – Galantamine HBr/oral solution, Nevirapine suspension *
Hydrochloric acid – – *
Magnesium phosphate – – *
Magnesium carbonate – Lansoprazole ODT delayed release *
Suspending agent Xanthan gum – Carbamazepine suspension, Dextromethorphan Polistirex suspension, Phenylephrine Tannate 10.0
suspension, Thiabendazole chewable tablets, Amoxicillin and Clavulanate Potassium
powder for suspension, Azithromycin for oral suspension
Acacia gum – Nitazoxanide powder for suspension, Thiabendazole suspension, Thiabendazole chewable *
tablets, Dextroamphetamine Sulfate tablets
Guar gum – Cefdinir powder for suspension, Methylphenidate HCL chewable tablets
Hydroxypropyl cellulose – Azithromycin for oral suspension, Cefpodoxime Proxetil for oral suspension, Atovaquone and 1500
Proguanil HCl tablets
Hydroxypropyl methyl – Nelfinavir Mesylate oral powder for suspension *
Pediatric drug development

cellulose
(continued )
9
10 A. A. Ali et al. Drug Dev Ind Pharm, Early Online: 1–17

compared to sorbitol, glycerine and propylene glycol67. Similarly,

(mg/kg/day)
Enalpril maleate liquid formulations prepared from tablets were

25.0
found to retain 98% of the initial enalpril maleate concentration in
ADI

*
*

*
*

*
*

*
sugar containing and sugar free vehicles at 4  C and 25  C for 30
days68. Many extemporaneously prepared suspensions have
demonstrated therapeutically effective concentration and were
Famotidine powder for suspension, Linezolid powder for suspension, Nitazoxanide powder for found stable69.

Solid dosage forms

Ciprofloxacin microcapsules for suspension, Mycophenolate Mofetil powder for suspension


Dextromethorphan Polistirex suspension, Nevirapine suspension, Cefadroxil powder for
Tablets and capsules are portable, show better stability profile and
dose accuracy as compared to the liquid dosage formulations.
suspension, Cefprozil powder for suspension, Ceftibuten powder for suspension

Taste can be easily masked by film or sugar coating. Usually


Drug Development and Industrial Pharmacy Downloaded from informahealthcare.com by University of Texas at Austin on 06/15/14

children 56 years of age do not accept them easily whereas


children 46 years may experience swallowing difficulty which
Marketed formulations containing these excipients

necessitates control over tablet size. Scoring/breakline on tablets


facilitate in breaking/splitting them into smaller fractions for dose

*The ADI levels are either not specified or the levels necessary to achieve a desired effect were not considered to represent a hazard to health by WHO.
adjustment and ease in swallowing. Each fraction should deliver
Topiramate sprinkle capsules, Deferasirox tablets for suspension

the minimum therapeutic dose as indicated on the approved drug


product labeling. This is ensured by compliance of each portion to
the ‘‘Uniformity of Dosage Units’’ test70. Food and Drug
Administration (FDA) recently issued a draft guidance document
Lansoprazole delayed release for oral suspension

on tablet scoring to address the need for consistent scoring


between generic and Reference Listed drug (RLD) product71.
Thomson et al. observed that pre-school children were able to
Dextromethorphan Polistirex suspension

swallow mini-tablets of 53 mm diameter with some water72.


Lopinavir and Ritonavir oral solution
suspension, Acyclovir suspension

Similarly, mini-tablets and multiparticulate formulations permit


flexible dosing, drug release modification and taste masking
opportunities. They can be consumed with or without water and
may be mixed with some food. However, sophisticated technology
For personal use only.

Table 3. Continued

Nizatidine oral solution

needed for their manufacturing increases their cost significantly.


Ritonavir oral solution

Different types of tablet dosage forms are available each with


specific characteristics as depicted in Figure 2.
Orally disintegrating tablets (ODTs) disperse or melt within
seconds on coming in contact with saliva and thus overcome
swallowing problems73. No water is needed for their administra-
tion74. A post marketing surveillance carried from 2008 to 2010 in
Japan indicated improved efficacy, safety and palatability of
amlodipine ODT75. Ondansetron ODT was found useful for the
treatment of gastroenteritis and dehydration in 6 months old
children76. Approximately 90% of the patients aged 5–11 years
undergoing adenotonsillectomy dosed preoperatively ondanse-
Liver/kidney failure

traon ODT found its taste good with significant reduction in


Toxicities

incidence of vomiting77. These dosage forms consist of either soft


porous matrix or low hardness tablets with high amount of super-
disintegrants. They are highly moisture sensitive and require
specialized peel off packaging to ensure physical integrity and
stability. Such specialized packaging needs are met by using



sophisticated packaging equipment such as robotic hand in Cima’s


PakSolv technology78. Blister and bottle packaging is the most
commonly used. However, the regular push through blister
Polyoxyl 40 hydrogenated
castor oil (Cremophor
Carboxymethyl cellulose

packaging may not work in most of the ODTs and hence peelable
Sodium lauryl sulphate
Polyoxyl 35 castor oil

closures are used. Rigid multilayer foil based materials are


(Cremophor EL)
Excipient

Polysorbate 20/80

commonly used to protect dosage form integrity79.


Docusate sodium
Sodium alginate

The challenges in developing ODT are palatability79, mech-


anical strength80,81, fast disintegration, hygroscopicity82, drug
Tragacanth

sodium

solubility83, drug loading84, size of tablets85 and packaging.


Lecithin

Mannitol is an excipient of choice in ODT and chewable


tablets for its good compressibility, sweetness, low hygroscopicity
*References: [124–130].

and slower dissolution kinetics. It is also available as directly


compressible material. Mannitol based ready to use excipients
LudiflashÕ (BASF SE, Ludwigshafen, Germany), Parteck ODTÕ
(Merck Millipore, Darmstadt, Germany), Pearlitol FlashÕ
Surfactant

(Roquette Pharma, France), Pharmaburst 500Õ (SPI Pharma,


Function

Les Vallons, France) and Prosolv ODTÕ (JRS Pharma,


Rosenberg, Germany), were used to prepare directly compressed
DOI: 10.3109/03639045.2013.850713 Pediatric drug development 11

mini-tablets for pediatric use. ODT could be produced with all the Effervescent tablets like dispersible tablets are dissolved or
excipients studied. Ludiflash showed better crushing strength and dispersed in water before administration95,96. They contain acid
wetting results86. In another study pellets prepared from Ludiflash and carbonates or bicarbonates which react in the presence of
improved the swallowing and palatability of ibuprofen and water to release carbon dioxide96. Effervescence creates a
paracetamol ODTs87. Solid dispersions of water soluble highly palatable sparkling solution which may enhance the drug
bitter drug pryidostigmine bromide were prepared using eudragit permeability due to carbon dioxide bubbling effect on the
EPO and incorporated into the ODTs. The bitter taste was masked intestinal epithelium97. Ekenved et al.98 found that the absorption
below the threshold value and tablets disintegrated rapidly in of acetylsalicylic acid form effervescent tablets was rapid. These
the oral cavity88. tablets should be stored in tightly closed containers and desiccants
The USP apparatus 2 with a paddle speed of 50 rpm is may be needed in some cases. Excipients used should have low
considered most suitable apparatus for dissolution testing of moisture, good solubility and wetting properties. These tablets
ODT89. The pH sensitivity of polymer coatings should be have to be manufactured at low humidity (530% RH) and
considered in dissolution method development. The effect of temperature (525  C)99.
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taste masking approaches such as complexation and coating on Chewable tablets are also used to administer drugs to children
dissolution and pharmacokinetic profile of ODT’s should be of 2 years or older under elderly supervision to ensure tablets are
evaluated89. chewed not ingested100. They are safe, well tolerated, palatable,
Orally disintegrating tablets of various drugs are available stable, portable, can be precisely dosed and do not need water for
commercially, e.g. ZydisÔ (R. P. Scherer Inc., Somerset, NV), administration100. Didanosine chewable tablets allowed higher
OraSolvÔ (Cima Labs Inc., Brooklyn Park, MN), WOWTABÔ dosing precision in children as compared to zidovudine cap-
(Yamanouchi Pharma Technologies Inc., Palo Alto, CA) and sules101. Safety of chewable tablets in children of 42 years old is
Films (LTS Lohmann, West Caldwell, NJ). The technologies for documented100. The critical quality attributes of chewable tablets
preparing ODT include Freeze-Drying/Lyophilization (ZydisÔ among other attributes include taste and mouth feel. Different
(Catalent, Somerset, NJ), QuicksolvÔ (Janssen Pharmaceutica, grades of microcrystalline cellulose such as Avicel CE-15 are
Titusville, NJ)), Molding (Fast meltÔ (Athena Pharmaceutiques available as directly compressible material102. Microcrystalline
SAS, Saint Cloud, France), ZipletsÔ (Eurand-Aptalis cellulose along with mannitol enhance smooth feel, eliminate
Pharmaceutical Technologies Inc, Bridgewater, NJ)), grittiness and reduce tooth packing. More than 60 chewable tablet
Compaction (OrasolvÔ (Cima Labs Inc., Brooklyn Park, MN), formulations are approved for use in USA. Aspiration injury
DurasolvÔ (Cima Labs Inc., Brooklyn Park, MN)), disintegrant due to chewable tablets is rare100. These tablets may be swallowed
addition, Sublimation, Spray Drying, Mass Extrusion, Cotton- by the patient without chewing and hence they should be
candy process (FlashDoseÔ, Fuisz Technologies, Chantilly, VA) formulated such that on chewing or swallowing they meet the
For personal use only.

and NanoCrystalÔ (Elan Pharmaceutical Technologies, PA) quality control test requirements for conventional tablets includ-
technology. These technologies are complex and proprietary ing dissolution test103. Chewing gums have been developed for
which increase the cost of their production in comparison to dimenhydrate and fluoride104. The minimum chewing time
conventional tablets. Advantages and disadvantages of these required to ensure complete drug release should be determined
technologies were listed comprehensively by Hirani et al.90. and mentioned in the label. Since they are not meant to be
Fast dissolving films also known as oral wafers have quickly swallowed they can be recommended for children 46 years.
emerged as an alternative to the OTC medicines. They are also Children tend to confuse them with candies and carry a risk of
placed directly on the tongue where they disintegrate in seconds. consuming a large number of these dosage forms. Parents or
They stick to the oral mucosa and hence are unlikely to be spat caregivers should be adequately warned about the danger of
out. Usually they range from 2 to 8 cm2 area with a thickness of excessive consumption of these tablets. Marked increase in retinol
20–500 mm76. Their size confers many advantages including dose and retinyl palmitate concentration was noted after overdose of
accuracy, portability, less choking risk, improved bioavailability vitamin A chewable tablets105.
and can be consumed without water. These attributes make them Buccal and sublingual tablets are usually not recommended for
suitable for pediatric population. These films should be robust children because their contact time with saliva is long.
enough to handle wear and tear during transportation. Polymers Powders (or granules) for oral suspensions are dispersed in the
and plasticizers form the backbone of these films. Ondansetron 4 prescribed amount of water prior to oral administration. Powder
and 8 mg (ZuplenzÕ , Monosol Rx, LLC, Warren, NJ), fast (granules) can also be sprinkled on food or sauce before
dissolving films are available commercially for use in children of administering it. The excipients usually present in these formu-
44 years of age. Other products available in fast dissolving films lations include sweeteners, colorants, stabilizing agents, suspend-
are Orajel Kids (Menthol/pectin, product for dental pain), Sudafed ing agents and preservatives. Single dose sachets are meant to be
(phenylephrine or pseudoephedrine product for nasal congestion), consumed immediately whereas multiple dose bottle packs are
Suppress (Menthol), TheraFlu (combination product of pain usually stored at 5–8  C till the complete consumption of
reliever, anti-pyretic and decongestant), Triaminic (children’s medicine. Multiple dose formulations may need antimicrobial
anti-tussive product)76,91,92. preservatives and should be evaluated for in-use stability1,10.
Dispersible tablets are manufactured with commonly available
technology and packaging. These tablets must disintegrate within
Excipients
3 min in water into a uniform dispersion. Dispersible tablets of
anti-retroviral therapy were preferred by caregivers and children Taste of medication is an important CQA for pediatric formula-
and preference increased with the passage of therapy93. tions. The organoleptic appeal of a pediatric formulation is
Dispersible tablets for WHO recommended zinc treatment for usually enhanced by the addition of flavorants, colorants and
childhood diarrhea were received well94. Taste of these tablets sweeteners. Risk of non-compliance to the dosage regimen due to
should be adequate for acceptability. They have relatively less unacceptable taste increases significantly in therapies for chronic
physical strength and are more sensitive to moisture. Hence ailments. The flavor should be compatible with the color and taste
tablets should be packed in stronger packaging such as in conveying the correct message such as lemon tasting formu-
polyvinylidene chloride, polychlorotrifluoroethylene and alumin- lation should be colored yellow and lemon flavored106. Colorants
ium foil. are added to make medication attractive. Like other excipients,
12 A. A. Ali et al. Drug Dev Ind Pharm, Early Online: 1–17

they should be thoroughly evaluated for their compatibility with long time. Intermediate represent the structural modification of
other formulation components as incompatibility of certain dyes the existing approved excipients whereas newer compounds have
with calcium, magnesium and aluminium containing substances is never been used before.
known107. The shade and stability of dyes is affected by pH, Pharmacokinetic variations between pediatric and adult popu-
microbial activity and exposure to light107. The use of colorants is lation should be considered in the selection of excipients for
regulated by the amendments effected in 1960 in Federal pediatric formulations.
Food, Drug and Cosmetic Act of 1938108. The preference for a The acceptable daily intake (ADI) expressed as mg/kg/day is
flavor varies with individual and age. Children seem to like sweet determined by dividing NOEL (no observed effect level) by safety
candy fruit flavors whereas adults like sweet tart flavored factors taking into consideration inter individual variation within
preparations. the same species and difference between tested animals and
A bulk portion of liquid dosage forms consists of sweeten- humans115–129. PDE (permitted daily exposure) determined by
ing agents. Most commonly used sweetener, sucrose, when similar approach for solvents, is used together with ADI for risk
used 465% w/w inhibits the microbial growth. It is stable at assessment of excipients in drugs.
Drug Development and Industrial Pharmacy Downloaded from informahealthcare.com by University of Texas at Austin on 06/15/14

pH 4.0–8.0, however it tends to crystallize around the neck of The high permeability of BBB in neonates and infants resulted
bottles leading to ‘‘Cap Lock’’109. Sorbitol and glycerine in higher concentration of propylene glycol causing several
reduce its tendency to crystallize. Long term use of sucrose is fatalities in pediatric population116,117. The higher blood level of
discouraged as it may cause dental caries and may complicate benzoic acid (oxidation product of benzyl alcohol) due to its poor
the management of diabetes. Liquid glucose is another conjugation with glycine caused Gasping Syndrome complica-
commonly used sweetener consisting of dextrose, dextrins, tions like metabolic acidosis, seizures, encephalopathy, thrombo-
maltose and water. It is obtained by incomplete hydrolysis of cytopenia, renal dysfunction and deaths in pediatric
starch and has a characteristic odor and flavor. Its method of patients118,119. Oral liquid with ethanol should not be given to
manufacture is easily controllable and hence batch to batch neonates. The ICH limit for residual solvents like ethanol may not
variability is insignificant. A new generation of sweeteners such be acceptable to children. Allergic reactions such as asthmatic
as sucralose, acesulfame and stevia overcome the issues of reactions, rashes and abdominal upset due to sulfites are not un-
metabolism and toxicity associated with traditional sweeteners common120. Aluminium containing salts or substances accumu-
saccharine, aspartame and cyclamates (Table 3). Sucralose, late in patients with reduced kidney function121. The toxicological
acesulfame and stevia are 600, 130 and 30 times sweeter than risk associated with excipients used in liquid formulations is
sucrose, respectively. These sweeteners are heat stable and higher than the excipients used in solid formulations. Like drug
exhibit stability over wide pH range110. substances excipients may also degrade and contain trace amounts
Besides enhancing organoleptic properties, excipients are of their degradation products which may be carried over to the
For personal use only.

incorporated to ensure physical/chemical stability, precision and drug product. The stability of the formulations may be impacted
accuracy of dosing, improve bioavailability, control release and due to these degradants and hence should be considered during
aid in manufacturing. Antimicrobial preservatives are usually product development. Povidone and lactose are known to contain
required in aqueous liquid preparation such as syrups, emulsions, trace amount of peroxides and aldehydes, respectively. N-oxide
suspensions and some semisolid preparations. Preparations con- degradation product of raloxefen was increased in presence of
taining high alcoholic or hydro-alcoholic content may not require povidone122. Maillard’s reaction leading to browning color of the
preservatives. The preservatives selected should be safe, stable, product is well known interaction of lactose with drugs containing
compatible with other formulation ingredients including container primary and secondary amine123.
closure system and have enough water solubility to achieve
required concentration in the aqueous phase in a multiphase
Taste masking
system. The un-dissociated form responsible for preservative
action depends on the pH of the formulation. Benzoic acid and Each taste bud contains 50–100 taste cells130,131. Taste sensation
other acidic preservatives are un-dissociated in acidic pH whereas is elicited when drugs dissolve in saliva and interact with taste
alkaline preservative remain un-dissociated in alkaline pH111. receptors (surface proteins) or ion channels (pore like proteins)132.
Some excipients may physically hold preservatives and make Salt and sour tastes interact with ion channels and sweet and bitter
them unavailable for action112. trigger surface protein responses. The concentration of positive
Pediatric formulations are often more complex due to taste ions increases due to the taste receptor stimulation. The varying
masking, dose volume, delivery and aesthetic requirements which ion concentration initiates electrical changes in the negatively
demand incorporation of a broad range of excipients. For instance, charged taste cells causing generation of chemical signals.
a typical liquid dosage forms may contain solvent/vehicle, co- Neurotransmitters are released due to this process and are
solvent, preservatives, viscosity enhancers, wetting agents, perceived by brain as taste130,131,133,134.
bulking agents, taste masking agents and other excipients as Several observations have been made to correlate taste of the
dictated by the drug characteristics. Higher number of excipients drug to its functional group. (Table 4)
results in increased potential for drug-excipient and excipient- The adults and children perceive taste differently134,135.
excipient incompatibility. Preferably, formulation should contain Therefore, the taste of a pediatric formulation should ideally be
as minimum excipients as possible. One opportunity to achieve evaluated in children. The cultural, regional and age differences in
this is by sprinkling the medication on juice, sauce or cocktail of taste perception are not uncommon. For example in USA, bubble
children’s choice thereby obviating the need for adding taste gum and grape flavors are preferred whereas the majority of
masking agents. Dose volume in such instances may be population in Europe likes citrus and red berry flavors. These
minimized by increasing the solid fraction of the formulation113 differences should be considered while selecting flavoring and
for achieving suitable dilution. The stability of drug in recom- sweetening agents.
mended diluents must be proven and such diluents must have been According to EU adhoc committee, the taste masking studies
shown to improve the taste of formulations. should be performed in adults wherever possible. Though phase I
Excipients are classified into GRAS (Generally regarded as clinical studies performed in adults provide useful information but
safe) approved, intermediate and newer compounds114. GRAS the data cannot be directly extended to children136–138. However,
excipients have been used in the pharmaceutical industry for a healthy children can participate in palatability testing for a new
DOI: 10.3109/03639045.2013.850713 Pediatric drug development 13

Table 4. Relationship of drug functional group to the taste and preferred taste masking flavors used.

Active pharmaceutical
ingredient with
functional group Taste observed General observation Taste masking flavors
–Cl Salty taste Low molecular weight salts – salty Cinnamon, orange, raspberry, apple,
High molecular weight salts – bitter vanilla, apricot
–Br Bitter and salty Cocoa-flavored vehicles, cherry,
walnut
–OH Sweetness Increase in –OH groups increases Berry, vanilla, grapefruit
the sweetness
–RCOOR’ (alcohols, and Pleasant taste and odor – –
aldehydes)
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–N Bitter and sweet Alkaloids (quinine) – bitterAspartame – sweet Cocoa-flavored vehicles


–COOH Acid Citrus, orange, cherry
Iron containing preparations Metallic mint, barries, gurana

flavored medicine when the study is ‘‘swill and spit’’ type taste Poor mouth feel (grittiness) can make otherwise excellent
testing for drugs with known safety profile139. There are many preparation unacceptable. The texture can be improved by using
practical and technical challenges in performing taste testing in correct viscosity modifiers.
children including designing questionnaire, reliability of pediatric The coating prevents physical contact of the drug with the
response and interpretation of results140. taste receptors. Due to the inherent complexity of the process, it
Different approaches used in masking the unpleasant taste should be resorted to only when other simpler taste masking
are; adding sweeteners, flavorants, complexation141, particle approaches do not work. Microencapsulation is the process of
coating142, ion exchange143, multiple unit coated system and coating drug with polymeric film using coacervation and spray
encapsulation of drug144,145. Fluid bed coating is usually used to drying techniques. Coating materials used for this purpose are
prepare multi-particulate granules or pellets146. starch; eudragits, povidone, hydroxypropyl cellulose, gelatin,
Taste perception can be suppressed either at mouth or at brain methylcellulose, ethyl cellulose and hydroxyl propyl methyl
For personal use only.

level147. Alternatively, source of undesirable taste can be cellulose156–161,144. The polymers which are insoluble at salivary
eliminated by techniques like encapsulation. Two different pH 6.8 but dissolve at gastric pH 1.2 or at higher pH 47.5 are
substances may compete for the same taste receptors or interfere ideal candidates.
with taste transduction mechanism and enhance or suppress each Eudragit E100 coated indinavir microparticles prepared by
other’s taste. Sodium and zinc salts when used at certain double emulsion solvent diffusion considerably improved the taste
concentrations, suppress bitter tasting substances148–150. Strong of a bitter drug162. The polymer coated microparticles dissolved in
tastant such as angelica oil aroma can completely mask weaker the gastric medium while remaining unchanged above pH 7.
sweet tasting substances by suppressing their taste perception in Besides their use in sustained release and drug stabilization,
brain149. Cooling sensation of some flavoring agents may numb ion exchange resins have found application also in taste masking.
taste buds which can mask bitterness of certain drugs151. Flavors The taste of ranitidine and paroxetine was masked using this
with different mechanisms of action may be combined to achieve technique163,164. These are synthetic inert organic polymers to
the synergetic taste masking effect. Taste receptor desensitizer, which insoluble groups are attached. They exchange their labile
sodium phenolate, was used with chocolate flavor to mask aspirin ions with the drug ions present in solution and form insoluble
taste152. Flavoring and sweetening agents are effective taste drug resonates with virtually no taste. Copolymer of styrene and
masking excipients for less to moderately bitter drugs. For highly divinylbenzene are most commonly used polymers165.
bitter drugs these must be used along with other taste masking Cyclodextrins provide host cavities for the guest drug
approaches. molecules in inclusion complexation process166. In addition to
The nature of the ODT dosage form demands use of minimal decrease in drug solubility, the drug–cyclodextrin complex
quantity of excipients which makes taste masking a major minimizes its contact with the saliva. The strength of drug–
challenge in these dosage forms. Flavoring and sweetening cyclodextrin complex determines the effectiveness of taste
agents alone may be of little value in these dosage forms hence masking. An association constant value of 101–104 mol is ideal.
other taste masking strategies such as, complexation, particle Sucrose potentiated the effect of hydroxypropyl-beta-cyclodextrin
coating, microencapsulation and use of insoluble salt may be (HP-b-CD) by increasing the stability constant of the complex167.
considered for preventing exposure of the drug to the tongue151. Bitter taste of bromoisovaleryl urea was successfully masked by
Taste masking strategies used in ODT have been reviewed153. this approach168. Complexation of atorvastatin with hydroxypro-
Children are fond of sweetness. Sweetened formulations can pyl-beta cyclodextrin improved its stability, bioavailability and
increase the compliance to dosage regimen. Due to the risk of mouth feel169.
developing dental caries, sucrose should be replaced in chronic Insoluble drugs are generally tasteless unless they are
therapies with sugar free formulations. Neohesperidine dihydro- extremely bitter so much so that they elicit taste sensation in
chalone extracted from Citrus aurantium is effective bitterness parts per million (PPM) levels. In case of prodrugs, chemical
suppressor154. modification of drug molecule alters its interaction with taste
Children are attracted to bright colors and when used with receptors besides affecting solubility.
right flavors and sweeteners will further enhance compliance. Taste evaluation techniques include panel testing in humans,
However, many colors are known to elicit hypersensitivity frog taste nerve response measurement, taste sensor (artificial
reactions and these should not be used unless necessary and tongue) and spectrophotometric evaluation. An electronic tongue
product label should clearly list them125,155. provides information on bitterness levels and global taste
14 A. A. Ali et al. Drug Dev Ind Pharm, Early Online: 1–17

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10. Commission of the European Communities Regulation (EC) No
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1901/2006 on medicinal products for paediatric use and amending
dihydrochalcone171. Regulation (EC) No 1768/92, Directive 2001/20/EC, Directive 2001/
83/EC and Regulation (EC) No 726/2004.(2006). Official Journal of
the European Communities, L378 27/12/2006. 1–19.19.
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Declaration of interest 19. Weiss CF, Glazko AJ, Weston JK. Chloramphenicol in the newborn
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The authors report no declarations of interest for this article content. This excessive doses. N Engl J Med 1960;62:787–94.
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