A considerable library of structurally diverse 21 hydrophobic drugs was tested with four POx/POzi based triblock copolymer which differ from each other by one methylene unit (shuffling either in the side chain or backbone) rendering them the structural isomers of each other (i.e. pBuOx/pPrOzi and pPentOx/pBuOzi, respectively). The results obtained by compatibility estimation (by group contribution method i.e. HnV and YMB) were not in accordance with the obtained formulation results with only a few exceptions, which can be considered as more coincidental rather than systematic. The practical weakness of this approach is the limited number of functional groups available in the literature and most importantly the impact of secondary factors like thermodynamics, hydrophilic lipophilic balance, drug structure, drug rigidity, interfacial tension, polymer and drug concentration, the solvent and the method for formulation development, which are not taken into consideration in such approaches. In particular, also the block copolymer nature is not at all taken into account. Thus, the theoretical prediction based on the assumption that majority of the drug is located in the core of polymeric micelles is not comprehensive and should be practised with caution. Therefore, it is extremely essential to build a theoretical method, capable to bring most of the factor discussed above into consideration, for drug-polymer compatibility evaluation to guide the formulation design of polymeric micelles.