Multiple possibilities, one decision
Pediatric formulation development usually starts with understanding the exact drug product (DP) requirements followed by subsequent benchmarking against the available formulation options as there is no such thing as one technology fits all. Before starting, the above evaluation sets the taste masking, the stability profile, the final presentation, and the age range requirements. Two further requirements are easy to leave implicit and expensive to retrofit, and belong in the same evaluation: the dose range in mg/kg across the youngest and the oldest age subset in scope, together with the smallest dose increment the product has to deliver; and the maximum permitted daily excipient exposure for the smallest patient at the highest dose over the longest intended treatment duration. Considering these criteria, the best suited oral DP strategy can thereafter be selected for development.
Five oral dosage forms carry most pediatric programs, namely: oral liquids, orally disintegrating tablets, granules, multiparticulates and minitablets. Granules and multiparticulates overlap, so it is worth being explicit about the distinction used here: granules means granulated material dosed by weight, volume or sachet, while multiparticulates means engineered discrete particles – pellets, beads, spheroids and coated microparticles, typically below about 1 mm. Powders for oral suspension and dispersible tablets sit outside this set but remain the dominant flexible solid oral forms in global health programs, and are worth naming for completeness. No single option can be regarded as universally preferable. Each dosage form offers distinct benefits, but these are accompanied by corresponding limitations.
This post compares these five options and then sets out what Ardena runs for pediatric oral solid dosage development at its Somerset, New Jersey site. For the regulatory framing, age group definitions, excipient safety and palatability testing that sit underneath these choices, see our earlier post on age-appropriate pediatric formulations.
Pediatric dosage forms compared
| Dosage form | Advantages | Disadvantages |
|---|---|---|
| Oral liquids | Dose flexibility by volume, down to sub-milligram doses; ease of administration; well established acceptance for pediatric medicine; the default form for newborns and infants, and frequently the only workable option in preterm neonates and for administration | Taste masking challenges; because dissolved drug is in direct contact with taste receptors; stability issues; susceptible to microbial growth; requires preservatives; that are themselves restricted in neonates and infants; co-solvent, sweetener and polyol burden set against tight pediatric exposure limits; risk of dosing error during administration which is device- and concentration-dependent, with additional redispersion error in suspensions; high shipping mass and short or refrigerated in-use periods. |
| Orally disintegrating tablets (ODT) | Precise dosing; improved stability; ease of ingestion; no water needed for administration | Sensitive to moisture; friable, so specialized blister or sachet packaging is needed; limited drug load; taste masking has to survive rapid disintegration in the mouth; part of the dose may be absorbed pre-gastrically, which needs characterizing rather than assuming away; generally not used below 2 years. |
| Granules | Dose flexibility; by weight, volume or number of sachets ; precise dosing; improved stability; multiple taste masking options; dispersed in liquid or sprinkled on food; unit dose presentation as capsules, sachets or stick-packs; dry state removes the need for a preservative system | Irregular particle shape creates mouthfeel challenges; total administered volume is a limiting factor and the maximum volume acceptable by age is still poorly defined in the literature; risk of incomplete administration when mixed with food; and every food or vehicle named in the product information needs compatibility and in-use stability data; not preferred for newborns and children under 1 year |
| Multiparticulates | Dose flexibility by weight, volume or sachet count; precise dosing; improved stability; taste masking options; immediate and controlled release; sprinkled on food; unit dose presentation as capsules, sachets or stick-packs; smooth, narrowly distributed spheroids below roughly 500 microns minimize grittiness | Risk of incomplete administration when mixed with food; vehicle compatibility data required for each claimed food; chewing can rupture taste-masking or modified-release coats; residue left in the sachet, spoon or dosing device is an underestimated dose loss; not preferred for newborns and children under 1 year |
| Minitablets | Dose flexibility by counting units; precise dosing; improved stability; taste masking options; immediate and controlled release; sprinkled on food; unit dose presentation as capsules, sachets or stick-packs; the only form in this table with randomized acceptability data extending down to term neonates | Mouthfeel challenges depending on minitablet size; risk of incomplete administration when mixed with food; the only form in this table with randomized acceptability data extending down to term neonates |
Three patterns are worth pulling out of that table.
The first is the trade between liquids and everything else. Liquids are the most accepted form in the youngest patients and the easiest to administer, but they carry the whole burden of aqueous formulation: microbial growth, preservative systems, physical and chemical stability, and dosing accuracy that depends on whoever is holding the syringe. Every solid form on the list improves stability and dosing precision; and the older assumption that none of them suits the youngest patients no longer holds. Randomized cross-over trials have shown 2 mm uncoated minitablets to be accepted at least as well as sweet syrup in children from six months to five years; in 151 term neonates, both a 2 mm minitablet and 0.5 mL of syrup were accepted by every infant, swallowability of the minitablet was superior to syrup, and no coughing or aspiration was recorded. Multiple-unit designs are a different matter: acceptability of sixteen to thirty-two 3 mm film-coated minitablets has been demonstrated from two years upwards, not below. The binding constraint in neonates and preterm infants is therefore dose accuracy at the microgram to low milligram level, and excipient exposure per kilogram, rather than the physical act of swallowing a small unit.
The second is that risks shift, rather than disappear. Granules, multiparticulates and minitablets can provide accurate dosing at the point of manufacture, but administration may still introduce variability if the dose is mixed with food and children do not consume it completely. Liquid formulations face a different challenge: even when the dose is accurately measured, poor taste or palatability may lead to partial or refused administration. . Each mechanism for achieving dose flexibility also carries its own characteristic error: volumetric metering carries measurement error, counted units carry miscounts, weighed or sachet-dosed multiparticulates carry transfer losses, and a fixed-strength portfolio carries the tablet splitting and crushing that accounts for a large share of pediatric administrations wherever no age-appropriate form exists. The design objective is to pick the mechanism whose error mode is smallest at the doses that will actually be given, and then to engineer that error down through the device and the instructions for use.
The third is mouthfeel. Granules carry irregular particle shape and the mouthfeel challenge that comes with it. Minitablets have controlled geometry, but mouthfeel becomes a challenge again depending on the size of the minitablet. Multiparticulates sit between the two: smooth, narrowly distributed spheroids are the least gritty of the three. Grittiness is only half the problem, though, because the total volume a child will accept at one dose is the harder constraint, and the evidence defining that volume by age remains incomplete.
Taste masking sets the formulation approach
Taste masking is where the dosage form decision becomes a formulation decision. A bitter API in a liquid has few places to hide, which is one reason some of the solid forms carry the taste masking advantage in the comparison above. In granules, multiparticulates and minitablets, if coated, the drug can be enclosed before it ever comes into contact with the tongue. That protection is conditional on the unit being swallowed intact. In the largest published minitablet acceptability study, acceptability exceeded 80 per cent while swallowability fell as low as 42 per cent in some groups, meaning a substantial share of children chewed the units. A coat that carries the taste masking or the release control has to be specified against that behavior, not against an assumption of intact swallowing.
Five approaches are available for pediatric formulation development at Somerset: viscosity modified formulations, particle coating, complexation with ion exchange resin, inclusion complexation with cyclodextrin, and microencapsulation. Having a range that wide matters, because the taste masking route has to fit both the molecule and the dosage form the program has already chosen, and a site that only runs one approach will steer every project towards it.
Note one limitation worth planning around. Testing of taste masking using an e-tongue could be outsourced if needed rather than run in house.
In practice this weighs less than it first appears, because the e-tongue is a screening tool. It ranks candidate formulations early and cheaply, but assessors look for adult sensory panel data and, ultimately, in-use acceptability data in the target age groups. It is the design of that pediatric study – comparator, age stratification, and pre-specified acceptability and swallowability endpoints – that determines whether a taste-masking claim survives review.
Twin screw extrusion across the process toolbox
The process set at Somerset is built around twin screw platforms. Twin screw extrusion, twin screw dry granulation, twin screw wet granulation and twin screw melt granulation cover a wide span of pediatric feedstocks from a common equipment base, which matters when a program changes direction between granules and multiparticulates partway through development.
Alongside those sit extrusion spheronization, fluid bed coating, tablet compression and encapsulation, plus hot melt extrusion where a solvent-free amorphous route is the right answer for the molecule.
The practical value of that range is that the process does not dictate the dosage form. Spheronization and coating produce the multiparticulates. Compression produces the minitablets. Granulation produces the granules. The decision can stay a patient-driven one rather than a capability-driven one.
Sprinkle capsules and the presentation question
A pediatric formulation is not finished at the particle. It still has to reach the patient in a unit the caregiver can handle. Presentation is also where avoidable arithmetic is designed out. A unit-dose presentation replaces a measurement with a count, and the unit strength or concentration chosen decides whether a typical dose is a round, readable number or an invitation to a tenfold error.
Sprinkle capsules are the presentation Ardena manufactures for pediatric programs at Somerset. They give a defined unit dose that opens onto soft food, which is what makes granules, multiparticulates and minitablets usable in children who cannot swallow an intact capsule. Sachets and stick-packs are also available as presentations, currently through subcontracting rather than in-house.
Pediatric dosage forms at a US site
Somerset develops and manufactures granules, multiparticulates and minitablets for pediatric programs, with liquid formulation supported at preclinical stage. One commercial pediatric formulation is manufactured at the site for a large pharmaceutical company.
That last point is the one that is hard to match. Describing pediatric capability is common. Having taken a pediatric formulation through to commercial manufacture is not, and it is the difference between a site that can run the work and a site that has already run it at full scale. It also matters for timing. In the US a new dosage form is itself a trigger for a pediatric assessment under PREA, and in the EU the pharmaceutical development section of an agreed Paediatric Investigation Plan commits a sponsor to a named formulation and a defined set of age subsets. Both push the dosage form decision earlier than teams expect, which is precisely when a comparison like the one above is worth making properly. More on the facility itself is in our post on the Ardena Somerset site.
Subject Matter Experts
Hibreniguss (Hibre) Terefe
Product Development Director & Site R&D Head
Hibreniguss (Hibre) Terefe, PhD, is Director of Product Development and Site Head of R&D at Ardena Somerset. He leads integrated preformulation, formulation R&D, and analytical R&D teams supporting drug product development programs from early-stage enabling technologies through Phase III and commercial launch. Hibre brings more than 20 years of pharmaceutical industry experience in oral drug delivery systems and drug product development. His expertise includes hot melt extrusion, solubility enhancement, amorphous solid dispersions, modified release technologies, pediatric formulations, and abuse deterrent platforms. Throughout his career, he has combined scientific expertise with strategic and organizational leadership to support efficient and milestone-driven development programs. He is also recognized as an industry thought leader in oral drug product development and CMC strategy, with more than 15 publications across industry and scientific journals, contributions to the Handbook of Pharmaceutical Granulation Technology, and involvement as co-inventor on 10 patents and patent applications related to drug delivery technologies. Hibre obtained his pharmacy degree and earned his PhD in Pharmaceutical Chemistry, with an emphasis in Analytical Chemistry, from Westfälische Wilhelms-Universität Münster, Germany. He also served as a Fulbright Visiting Scholar at the University of California, Berkeley.
Iñaki Bueno
Formulation-Production & Maintenance Director
Iñaki Bueno is Formulation-Production and Maintenance Director at Ardena Pamplona. He is a pharmacist with more than 30 years of experience in pharmaceutical development, specializing in formulation design, process scale-up, and GMP manufacturing of innovative drug products. At Ardena, Iñaki leads formulation and production activities, supporting drug product development from pre-formulation through clinical supply and commercial readiness. His expertise includes oral solid dosage forms, pharmaceutical process transfer, Quality by Design (QbD), experimental design (DoE), and solubility enhancement technologies, including spray drying. Iñaki brings extensive technical and operational experience across pharmaceutical development and manufacturing environments, supporting efficient and compliant drug product development programs.
Timothy Pas
AD, Formulation & Production
Dr. Timothy Pas is Associate Director, Formulation Development and Production at Ardena. He leads a team supporting formulation development and GMP manufacturing activities for early clinical programs. Since joining Ardena, Timothy has progressed from Formulation Scientist to Group Leader and currently Associate Director. Throughout his career at Ardena, he has developed extensive expertise in oral and parenteral formulations, formulation development strategies, and GMP manufacturing operations supporting early-stage pharmaceutical development programs. Timothy obtained a Master’s degree in Drug Development and earned his PhD in Pharmaceutical Technology from KU Leuven, specializing in enabling technologies and galenic principles.