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Karl BoxKarl Box is head of research and development, Sirius Analytical Instruments, where his responsibilities include leading instrumentation and assay development for physicochemical property evaluation.


The pipelines of pharmaceutical companies involved in the development of new drugs are filled with clinical development candidates with very poor water solubility. There are several opinions about why this is. Some lay the blame on combinatorial chemistry, which directs research towards finding large, active molecules that are highly lipophilic. This has a corresponding negative impact on solubility. Others suggest that the target (receptor) space has changed necessitating more complex and challenging chemistries. Still others believe that the easy “me-too” compounds have already been developed and finding first-in-class for a new chemical type, even against an existing target, requires different structures. The drive towards achieving higher potency (greater efficacy for a lower dose) has also resulted in increased lipophilicity and poor solubility.

Whatever the reasons, poor solubility of molecules provides a huge challenge for delivery techniques in order to ensure sufficient bioavailability. This has led to the rise of many enabling formulation methodologies which typically work by providing increased dissolution performance or enhanced solubilization, or a combination of both. Examples include amorphous solid dispersions, lipid based formulations, nano-particle technology, and complexation (e.g., cyclodextrins). Many of these induce a state of supersaturation but this situation is metastable with respect to the equilibrium conditions. If supersaturation can be maintained, this provides a driving force for absorption. However, the natural tendency may be for the active pharmaceutical ingredient (API) to precipitate leading to solubility limited oral absorption. How can we develop a better understanding of these effects and characterize this behavior earlier in the drug development process?

Clearly there is a need to develop newer and better tools for studying supersaturation and precipitation behaviour of APIs. To date, these have ranged from plate-based screening methods for looking at precipitation inhibition of different polymers and surfactants, all the way through to modified 900 mL United States Pharmacopeia dissolution chambers for trying to assess dissolution performance and generate in-vitro in-vivo correlations.

We will review some of these techniques and describe some additional methodology in the upcoming AAPS webinar session Small Scale Solubility and Dissolution Assays: Providing Insights into Solubilization, Supersaturation, and Precipitation Behavior of APIs on April 11.