Poor solubility library design

Even though we have seen that the solubility predictions are poor for individual compounds, there is still a question over whether such predictions could nevertheless be useful in library design. We believe that they can. Figure 15.5 shows that QMPRPIus gets the general trend correct it shows that the proportion of soluble compounds increases with an increase in the solubility predicted by QMPRPIus (where a soluble compound is defined to have intrinsic solubility greater than 10 M). 

In summary, poor aqueous solubility is the single physicochemical property that is most likely to be problematical in a combinatorial library. It can be avoided in part by intelligent use of batch-mode solubility calculations. The solubility problem is not simply a technical issue in library design. It is exacerbated by chemistry synthesis considerations and by the timing of the availabihty of combinatorial exemplars. Formulation fixes are available unless the solubility is extremely poor, but these should be avoided as much as possible. Poor permeability is seldom a problem in combinatorial libraries, but is disastrous if present since effectively formulation fixes do not currently exist. 

Effectiveness of designing for adequate aqueous solubility depends on whether chemistry protocol development or chemistry production is rate determining. If chemistry production is rate determining, there will be excess validated protocols relative to library production. This means that protocols can be prioritized as to the attractiveness of the compound solubility profile and the least attractive protocols from a solubility perspective may never be translated into actual library production. However, often protocol development and not library production is the rate-determining step. This eventuality is unfortunate because there is an understandable reluctance to discontinue chemistry synthetic efforts due to poor experimental solubility profile if considerable chemistry effort has already been expended. Consider the following situation. The effort toward library production is 70% complete. The experimental solubility profile is poor. Would you discontinue completion of library synthesis because of poor solubility if 70% of the chemistry effort had already been completed So a key issue becomes how much chemistry experimental effort takes place before exemplars are experimentally profiled in solubility screens ... 

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