Since the Pediatrics Regulation enforcement in Europe in 2007, and in 2003 in the U.S., it is now compulsory for the pharma industry to develop pediatric dosage forms for each and every new entity, as it does for adults.
Many adult dosage forms were initiated as solid forms, most often in the form of tablets. But when it comes to treating children, a liquid oral form is frequently preferred among all age groups, according to a 2006 EMA study. That particular study was performed at a time when minitablets were not very well known, so they do not appear in that survey. However, another ongoing survey, being conducted by the European Pediatric Translational Infrastructure (EPTRI), shows a real preference for oral liquid forms over oral powders or mini-tablets by children from a number of countries.
When the formulation expert starts to design a new pediatric form intended for children below the age of seven (since young children can have swallowing difficulties), they can evaluate several dosage forms depending on the characteristics of the API (Active Pharmaceutical Ingredient). Typically, API solubility and stability in a liquid medium are leading properties.
If solubility, stability and taste of the solution work well in a liquid medium, an oral solution can be developed quickly, taking into account the constraints of the drinkable volume of liquid depending on the age group and posology. This early-stage formula allows for fast manufacturing of clinical batches and for preparation for industrial scale-up. However, if the API is not soluble or is unstable in a liquid medium, or is an irritant or tastes bad, then the formulation expert may look into developing an oral suspension.
When this occurs, the development team faces a whole new of challenges.
The Chemists’ Challenge
Quite frequently, the available API exists as a physico-chemical form which meets the formulation requirements for a tablet, but the properties of the solid-form API do not meet what is necessary to develop and industrialize an oral suspension.
As a consequence, solid-state experts must collaborate with process chemists to reconsider the fi nal stages of the API synthesis process to obtain a physical profile that meets the suspension formulation needs.
The key features to control include:
- Crystalline form: in solid drug substances, materials can be found, depending on the internal packing, in either crystalline defined order, polymorphic crystals with different repeating packing arrangements or amorphous arrangement with no long range 3-D order. Drug substances can also incorporate solvent molecules as solvates or hydrates, bringing additional complexity. Any change in internal packing of a solid will involve changes in bulk properties of the solid API and potentially changes in its bioavailability.
- External shape of a crystal: also called the Crystal Habit which is the consequence of the rate at which different crystals grow.
- The particles sizes and distribution
- Apparent surface
- The drug substance wettability
In order to modify these properties, the chemist must modify different parameters at the end of the API production process for crystalline powder, including:
- The final crystallization solvent
- Nucleation (or seeding )
- Crystalline growth
- Centrifugation and washing
In addition, for amorphous APIs without any 3D organization of the molecules the key features to control, include:
- Composition of the mother solution
- Evaporation technology (vacuum + cold or turbulent air + heat)
To develop an oral suspension, the objective is usually to achieve particle dispersion which should not be too fi ne but stays homogenous in the dispersing medium. This means the API producer must design and manufacture a powder with a relatively large, but not too large particle size which is also suffi ciently homogenous.
Indeed, very fi ne particles increase the thermodynamic instability and the particles’ size distribution play an essential role in the dispersion and sedimentation processes. In an oral pediatric suspension, the particle size can reach 200 μm but a size of 50 μm is preferred. In case reasonably large particles are needed, this constraint will usually eliminate the “destructive methods” to favor technologies allowing the formation of large crystals.
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In order to facilitate the formulation work downstream, the drug substance manufacturer can infl uence the future sedimentation of the particles in suspension by modifying the surface properties of the solid API through the parameters which control the production stages.
As described in the above diagram, the specific parameters targeted can be achieved by delicately monitoring the final processing where the drug substance’s physico-chemicals properties are fixed throughout the final API crystallization to the drying stage.
Determining the expected physical properties of the solid form API can therefore have an impact on the final production stages for the drug substance, which could become specific for the “oral pediatric suspension.”
It is rare, however, to be able to sufficiently optimize all of the physical form characteristics to achieve a homogenous and stable suspension. This is when the formulation expert takes over using a wide variety of technologies and excipients to achieve the targeted result.
The Formulation Scientists’ Challenge
The first step for the formulation scientist is to achieve a dispersion of the API particles in an appropriate liquid medium and monitor two physical events:
- Particulates floating because of lack of wettability
- Sedimentation that should be avoided or monitored by ensuring re-dispersion by mild shaking of the container
In order to achieve a suspension, the formulation expert must choose the most stable crystal form, since when put in contact with a liquid medium that is different from the liquid medium used for synthesis, crystals tend to modify their properties.
Achieving a good suspension may also require working through new physical specifications for the API, specifically developed for the suspension form.
For the very specific needs of an oral suspension, the formulation scientist should collaborate closely with the chemist engineer specializing in physical properties of the API in order to re-develop the final steps of the chemical synthesis.
Choosing the right drug substance CDMO with sharp expertise in solid properties of the API solid state, along with an experienced drug product CDMO for formulation, expert in dispersed liquid systems, is a critical step along the development pathway leading to effective medicines for children.
About the Authors
Christine Adam is in charge of Business Development for Unither Pharmaceuticals, a global Drug Product CDMO with operations in France, and the U.S. and in Brazil. She has 20 years of experience in product and business development for clinical and commercial drug products within several CDMOs such as Creapharm, IDPS and UNITHER. She has worked in Europe and North America helping pharmaceutical companies navigate the formulation development pathway.
Didier Combis is the commercial director of SEQENS CDMO, an integrated global leader in pharmaceutical synthesis. Previously for 18 years, he served as global head of business development of PCAS, an internationally recognized developer of fine chemicals, until it was acquired in 2018 by Seqens CDMO. Didier has extensive experience in API development with a deep understanding of regulatory affairs and CMC requirements to help sponsors successfully meet their chemical manufacturing needs.
Jean-François Cordoliani has more than 30 years of experience in pharmaceutical development, at UPSA, BMS, Pierre Fabre and Amatsi group. He Is currently Director of Unither Développement Bordeaux, France, a drug product and R&D platform dedicated to early-stage development through to clinical and small-scale commercial supplies.