The stability of penicillin G was analyzed as a function of temperature, pH, and the combined effects of pH and temperature were investigated by proposing a second-order polynomial model for penicillin G decomposition reaction rate constant. The modeling results obtained for the first-order decomposition reaction of penicillin G are in good agreement with the experimental data obtained at the pH range of 1.8-10.0 and temperature range of 0-52 degrees C. The stability analysis shows that penicillin G is more stable at the pH range of 5.0-8.0 than out of it and lower temperatures for subsequent isolation. The maximum stability of penicillin G is at about pH 6.0 and its instability its much higher at acidic than basic pH values. The stability of penicillin G decreases by increase in temperature for all pH values. The stability results as well as the proposed second-order model for penicillin G decomposition reaction rate constant can be used for investigating penicillin G losses during its isolation process.