Solubility enhancement and solid-state characterisation

The concept of “molecular inflation”¹, where the molecular weight of patented and marketed drugs is increasing (as is their molecular complexity), is now demonstrated to be a reality. At the same time advances in synthetic chemistry allow molecules to be made, at small and large scale, which previously could only be envisaged in silico. We are now seeing “isotopically controlled” drugs², where deuterated molecules can provide specific clinical advantages, but analytical challenges!

At this exciting time in drug discovery, new challenges emerge for those who are trying to turn these marvellous molecules into dosage forms. The Lipinski Rule of 5, and associated “druggability” systems for molecules require ongoing updated with improved knowledge and understanding, so that new, potent, molecules can have a framework for feasible development to help patients.

In parallel, there is a need for an increased understanding of all elements of a formulation, so that the role of each is clearly appreciated and delineated, and a design space defined for any deemed “functional”. Thus those dosage forms with complex, multicomponent, mixtures of materials may be physically transparent, but now their regulatory package cannot be opaque either. Transparency in reaching scientific conclusions is a necessity. This may be a challenge for “old school” formulators, who rely on their knowledge and judgement, but is an opportunity for those who rely on mechanistic understanding to produce robust dosage forms, and for those developing the analytical techniques to further understand them.

We now have the data technology, and associated regulatory framework and guidance, to take large amounts of data and reduce it to improve our understanding. Thus the complexity of these systems can be comprehended.³

Liquid and solid dosage forms (traditional and novel) are acceptable to patients and can be commercialised at any scale.

The fascinating netherworld of the metastable material form (with properties shared between solids and liquids), is the amorphous system, saved from disaster only by kinetics. Although the amorphous system is now better understood and has been in commercial dosage forms for some decades, high profile technical disasters, and unrelated clinical failures, held the technology back. However we now have unprecedented knowledge on these systems, so that future failures are less likely. With this knowledge comes the ability to think of new ways, and new materials to assemble amorphous forms and develop new medicines with improved safety and efficacy.

Currently we have at our disposal some very advanced techniques for understanding all of the above, and more are being developed. The next stage will be to take these offline techniques into the online arena, so that the knowledge generated from these techniques can be applied in real time to the manufacturing process.

This Special Edition of Pharmaceutical Development and Technology is a timely addition to the literature on how we address the challenges of new, “more difficult”, compounds for unmet medical needs, and how we can better understand the resultant dosage forms. We have innovation in coming up with new, effective, dosage forms, along with an understanding of how these dosage forms “work”. We appear ready to meet the challenges of “molecular inflation”.