Various techniques have been used for improving the solubility of poorly soluble drugs. pH control and cosolvents are important examples of such techniques. Common to both approaches is the likelihood of drug precipitation upon administration to human body. Dilution of such formulations in biological fluids may create a supersaturated system with the potential for drug precipitation. This may not only affect the efficacy and pharmacokinetics of the drug, but may also cause thromobophlebitis. Thus, development of an estimation scheme to predict the possibility and the extent of drug precipitation is important. A mathematical equation to estimate drug precipitation upon dilution of a pH controlled formulation has been developed. This equation also accounts for the pKa induced by the change in the ionic strength following dilution. This equation was used to check the effect of pH, as well as the type and the concentration of buffer spices used in the formulation. According to the proposed equation, the type and the strength of the buffer species significantly affects the pH and the drug solubility during dilution. The initial pH is a less critical factor. To demonstrate the utility and accuracy of the proposed equation, experimental measurements were performed using a phenytoin solution in carbonate and phosphate buffers as the model formulation. Sorensen's phosphate buffer was used as a diluent and blood surrogate. The good agreement between the estimated and the experimental data suggests that the proposed equation can be used to estimate the possibility and degree of precipitation that would occur upon injection. This provides a useful tool for checking the feasibility of a successful pH-controlled formulation. The model will be expanded to study drug precipitation upon dilution of pH-controlled cosolvent formulation.