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API


References


Although solubility is relatively easy to define, it can be difficult to predict using computational methods primarily due to solid


state constraints (given enthalpy and entropy considerations).


assessment of both solubility and dissolution as part of pre-formulation activities, ie, salt selection, polymorphic form selection, and the effect of particle size reduction.


Finally, methods to predict drug absorption and bioavailability have been improved significantly over the last decade. This includes approaches which go beyond allometric scaling to the well-known Biopharmaceutical Classification System (BCS).47


During the last few


years, the BCS has been refined into the Development Classification System (DCS),48


which addresses solubility, permeability, and the dose


of the drug. The DCS approach also takes into account the dissolution rate and distinguishes between solubility and dissolution-limited absorption. The use of pharmacokinetic simulation software has also become widespread49


and might allow a more detailed understanding


of the behavior of the research compound in humans and animals, including dissolution, solubility, and an understanding of how a drug might precipitate in the GI tract (due to shifts in physiological pH).


Conclusion


Solubility is one of the most important physicochemical parameters used in research and development. Historically, a large number of in silico solubility methods have been employed. These computational methods provide comparative rank order assessments of solubility across different discovery programs, and they need to be able to cope with significant numbers of compounds, with the objective of filtering out “non-drug-like” compounds. Although solubility is relatively easy to define, it can be difficult to predict using computational methods primarily due to solid state constraints (given enthalpy and entropy considerations). The results from the Solubility Challenge show how difficult accurate solubility prediction can be and suggest that simpler in silico methods may be more appropriate. In parallel, experimental methods to assess solubility have been improved and automated in recent years, and currently allow measurement of solubility for large numbers of compounds. This holds especially true for the measurement of kinetic solubility. However, to ensure a sufficient bioavailability of drugs, thermodynamic solubility becomes relevant. The use of kinetic and thermodynamic solubility should be clearly distinguished because the erroneous use of kinetic solubility for compound optimization can be misleading. For a deeper understanding of the role of solubility for drug absorption in animal and humans, methods and media to mimic in vivo behavior have become more widespread and easy to use. Finally, drug absorption can be simulated and mechanistically understood based on solubility data and simulation software. Therefore, simulation applications are widespread.


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Pharmaceutical Outsourcing | 40 | March/April 2015


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