Are we selecting the right model compounds for advanced formulation research?

Numerous advanced-formulation papers begin with the same problem statement: "30-40% of marketed drugs, 70-75% of clinical candidates and 90% of new chemical entities are poorly soluble in water". However, these figures are not fully supported by data and citations. We traced these numbers back to their original sources and reassessed them against the current API landscape. The 30-40% value was derived from a 2006 analysis of top selling drugs. Reassessing the top selling drugs in 2025 reveals a marked increase: about 55% of the orally administered small molecules now fall into the practically insoluble category. The 70-75% and 90% claims could only be traced to conference presentations and a review abstract with no underlying data. We further argue that the Biopharmaceutics Classification System categorization is not an intrinsic property of an API since it shifts depending on dose, particle size and formulation, i.e., no compound can be classified without considering the formulation and dose. A Scopus analysis showed that the APIs most frequently used as poorly soluble model compounds are the NSAIDs, antifungals and compounds, such as carbamazepine, carvedilol and simvastatin. The majority of these "poorly solubles" are in fact completely absorbed in vivo with no solubility issues at all. As more relevant alternatives to the above-mentioned compounds, we propose and briefly review ten marketed non-oncology APIs with unresolved dissolution and solubility limitations that would make better model compounds for advanced formulation research.