Here, Pingyun (P.Y.) Chen, PhD, director of Early Development at Catalent Pharma Solutions, details some of the important considerations required in product development and how a holistic approach can help save money and time in the long run.
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Crystalline forms predominate in solid form screening, although more recently, the traditional salt and polymorphic forms have been supplemented by co-crystals and amorphous solid dispersions. The aim is to select the solid form with optimal solubility, stability and manufacturability, and balance those factors with cost and material availability to ensure projected timelines are met.
A phase-appropriate strategy to solid form screening is now common. This iterative process involves increasingly comprehensive screening activities being applied as material becomes available and technical demands alter. In the initial stages of development, speed is most important, so limited screens are used to identify a solid form that permits progression. Later, more material is available and speed is less critical, so more comprehensive screens may be employed to identify all solid forms to enable broad patent protection, and select the best of these for commercialisation.
The growing number of poorly soluble molecules in the development pipeline highlights the importance of choosing a solid form that will improve solubility and bioavailability. A successful salt form can even remove the need for more complex and expensive formulation techniques. A carefully planned strategy, employing automated screening technologies, can save both time and money.
Screening strategies
The starting point of the screen is the collation of data on its physiochemical properties, including solubility in aqueous buffers and in bio-relevant media. The solubility, permeability and projected doses are used to evaluate if solubility and dissolution rate will limit drug absorption. These provide the basis of solid form screening and formulation strategies, including any bioavailability enhancement that might be required.
Crystallisation is the preferred method for isolating and purifying the API, as it is cheaper and more effective compared to other methods, especially on larger scales. Only small quantities of API are required for crystallisation screening, which will be done with a variety of solvents and conditions.
This can be carried out as part of a salt screening to create a more soluble form, if the API has ionisable groups. Soluble salts have further benefits, including less pharmacokinetic variability, increased exposure and simpler formulations. However, solubility is not the only consideration, dissolution and precipitation kinetics in biorelevant media will also be required.
More recently, the potential of co-crystals in drug formulation has become apparent. These multicomponent crystals combine an API or its salt form with at least one other neutral co-former molecule. They allow the crystal structure to be modified, and thus the API’s properties to be optimised.
The screening process is similar, but as the molecular interactions between the API and the co-former are not as strong as the ionic bonds in salts, specialised techniques such as solvent-drop grinding must be applied. This limits its applicability to early stage development. While some are easy to find, the process for scaling up a co-crystallisation is more challenging than for a simple salt, but as experience grows, this should change.
Some molecules are polymorphic, existing in more than one crystalline form. These will have different physical properties, including solubility, stability and bulk density. Where this is the case, it is important to ascertain which is the most suitable and stable for development. Polymorph screening is required to ensure process reliability and patient safety. This should look at those parameters that may influence the formation of different forms, and whether processes such as micronisation or wet granulation might induce a polymorph change.
If a compound is particularly insoluble, then an amorphous solid dispersion may be most appropriate. Screening can be used to find more soluble dispersions, which will typically be two–1000-fold more soluble than the crystalline form, depending on its lattice energy and the presence of hydrogen bonding capability. Polymers and surfactants can be added to give further enhancements. These dispersions can be prepared by techniques including the fast evaporation, freeze drying or spray drying of solutions, or by hot melt extrusion.
Delivery considerations
Administration route, dose, dosage form and release profile also need to be considered at the outset. A salt may be optimal for oral delivery, but the uncharged active may be better for topical application.
For an oral dose, the crucial factors include stability, solubility and dissolution rate, compatibility with excipients, bulk density and compressibility. If a drug crystallises quickly and is likely to precipitate in vivothen excipients to inhibit crystallisation should be added.
Excipient and device compatibility are critical for inhaled formulations, along with hygroscopicity and milling. For solution formulations, solubility and stability in the solvent are important, as is the pH of the solution.
From discovery to development
The transition between discovery and development is rarely as smooth and efficient as it might be. The candidate molecule created by medicinal chemists should have good selectivity and potency, but is unlikely to have been designed with development and drug delivery in mind. This disconnect is at the heart of the current issues with suboptimal physicochemical and biopharmaceutical properties.
Engagement with preformulation and formulation scientists during the lead optimisation process is a key step in designing a developable molecule. All too often, the formulation scientists are brought into the process after the molecule and salt form have been determined, which is too late.
Instead of addressing the different problems in the development process holistically, they are more likely to be considered sequentially. The predominant considerations when deciding on a salt form are ease of synthesis and cost of goods, rather than the properties that will be required for optimal downstream processing and formulation. Changes get more challenging and expensive to make as the development process proceeds, with many steps having to be repeated. This extends timelines and escalates costs.
It is therefore vital to consider how a molecule will be developed at the outset. If the best option can be identified at a very early stage, it will save costs, prevent repeated re-working of steps of the development process, and ensure that effective, safe drugs reach patients as early as possible.