The solvation-free energy calculation compared the solubility of vitamin D2 and D3 in water relative to other organic solvents. It was observed that even though both vitamin D2 and D3 strongly interact with water, the overall solubility is low due to higher correction contribution which is highly attributed by unfavorable higher cavity formation in water. Even when compared with other solvents water scores low solubility, these findings verify that vitamin D2 and D3 prefer to interact with SIRT1 than in a bulk aqueous environment strongly.