The intriguing properties of graphene have led to wide explorations into scalable, reproducible methods of its bulk-scale production. This work expands upon the Hansen Solubility Parameters (HSP) theory to predict the lowest Ra distance in a particular solvent-water system for optimum exfoliation process. This simple, one-step facile synthesis is able to exfoliate graphene sheets from Highly Oriented Pyrolytic Graphite (HOPG), producing homogeneous dispersions of graphene sheets with average lateral dimensions of more than 2 μm and average thickness of <2 nm. This has provided a viable avenue for a single-step direct exfoliation of graphene in various solvent-water system. A range of solvents ranging from alcohol-water systems to mild acid-water systems were studied in order to prove the suitability of the HSP theory in predicting the efficiency of exfoliation in these solvent systems. Further studies on the effect of the Ra distance upon the degree of exfoliation were also demonstrated by studying the biosensing potential of the as-produced graphene sheets. Improvements in sensitivity by 10 to 80 times, depending on the lowest Ra value of a particular solvent system in comparison to the bare electrode, reinforced the hypothesis that the Ra value has impact on the exfoliation efficiency. These results show that by choosing solvent combinations with the lowest minimum Ra values, it is possible to further increase the efficiency of exfoliation, as reflected in higher sensitivities and faster amperometric responses. The proposed method is not only easy, low cost and low toxic, the ability to employ an unlimited number of solvent combinations opens up vast opportunities for future applications.