STABILITY OF UREA IN SOLUTION AND PHARMACEUTICAL PREPARATIONS 193 glycol, hexylene glycol, and polyethylene glycol) was intended to evaluate the effect com- paring to aqueous solution on urea degradation rate constant. However, urea did not dis- solve after sonication for 30 min or afterward precipitation in N-methylpyrrolidone, dimethylisosorbide, and hexylene glycol. The urea solutions of concentration 2.5% with residual non-aqueous solvents were prepared and incubated at 25° and 40°C. The linear regression of the decomposition data shows that urea degradation reaction in non-aqueous solvents obeys fi rst-order kinetics at all measured temperature values of the experiments. Table IV demonstrates the values of the rate constant, k, in h-1 calculated from the experimental data of the residual urea concentration as a function of solvent and temperature. Both isopropanol and ethanol show lower degradation rate constants (2.70 × 10−6 h−1 at 25°C, 3.92 × 10−5 h−1 at 40°C 2.73 × 10−6 h−1 at 25°C, 4.02 × 10−5 h−1 at 40°C, respectively) than that of water (3.03 × 10−6 h−1 at 25°C, 4.29 × 10-5 h−1 at 40°C). The calculated values of the decomposition free energies as a function of temperature are also shown in Table IV and can be used for stability analysis of urea in non-aqueous sol- vents. The maximum value of ∆Gi or the maximum stability of urea in non-aqueous solvent was performed by isopropanol used as a solvent for the temperature ranges under study. A work by Alexandrova and Jorgensen (4) also demonstrated that NH3 elimination as- sisted by a water molecule was found to have the lowest activation energy, and the pre- ferred reaction route was initiated via hydrogen transfer between the two amino groups mediated by one water molecule. The forming zwitterionic intermediate, H3NCONH, received substantial stabilization via extended hydrogen bonding to the solvent, and its subsequent decomposition was found to be rate-determining. A computational study of the solution phase decomposition of urea by Estiu and Merz (3) showed that elimination was favored for the solution phase reaction, which proceeded by H-bond coordination of a water molecule to the amine nitrogen atoms. The coordination of one water molecule greatly facilitates the reaction by allowing it to proceed through a cyclic six-member transition state. According to both previous studies, we therefore postulate that water molecule acts as a hydrogen shuffl e for the fi rst step of the elimination reaction. In the elimination step, the hydrogen atom can easily undergo nucleophilic attack by nitrogen atom of one NH2 group followed by concerted H-transfer. Alcohols with various dipole moments in O–H Table IV The values of rate constants, k, in h−1 and the free energies of decomposition, ∆Gi, in kJ/gmol calculated from the experimental data of rate constant as a function of temperature Non-aqueous solvents 25°C 40°C k Value ∆Gi k Value ∆Gi Isopropanol 2.70 × 10−6 104.81 3.92 × 10−5 103.24 Ethanol 2.73 × 10−6 104.78 4.02 × 10−5 103.18 Water 3.03 × 10−6 104.52 4.29 × 10−5 103.01 Pentylene glycol 5.00 × 10−6 103.28 6.85 × 10−5 101.79 Propylene glycol 5.07 × 10−6 103.25 6.85 × 10−5 101.79 Glycerol 5.43 × 10−6 103.08 6.93 × 10−5 101.76 Polyethylene glycol 5.72 × 10−6 102.95 6.97 × 10−5 101.75

JOURNAL OF COSMETIC SCIENCE 194 bond can act in the same way to water molecule as hydrogen shuffl e. This can imply that increase in dipole moment in O–H bonds of different solvents increased the electron at- tracting ability of oxygen atom, as a result, facilitating the elimination step and thus the urea degradation. The effect of isopropanol in retarding the decomposition of urea in so- lution is explained by our hypothesis described above, with which it is in perfect agree- ment with the lowest dipole moment. THE KINETICS OF UREA DEGRADATION IN PHARMACEUTICAL PREPARATIONS According to the optimum result in retarding urea decomposition in aqueous solution, preparations adjusting with lactate buffer pH 6.0 were subjected to study in this experi- ment. Pharmaceutical preparations composed of urea at varying concentrations of 2.5%, 5%, 10%, 15%, and 20% (w/w) with pH 4.50 (no further pH adjusting) and pH 6.00 (adjusting with lactate buffer) were examined. Table V demonstrates the values of the rate constant, k, in h−1 calculated from the experimental data of the residual urea concentra- tion as a function of temperature. Within the experimental range of temperature and initial urea concentration values, the lowest urea degradation was found with lactate buf- fer pH 6.0. Degradation rate constant slightly decreases as the initial urea concentration is increased. Since more ammonium cyanate was produced (in the same time interval) at the higher urea concentration than at the lower ones, this was tentatively attributed to the reverse reaction as also observed in solution, thus lowering the urea degradation. CONCLUSION The proposed model for prediction of the combined effect of pH and temperature on decomposition of urea was used to investigate the decomposition rate constants and the stability of urea for pH values between 3.11 and 9.67 and a temperature range of 25°– 60°C. The rate constant values obtained from the experiment are in good agreement with those of the literature values. The urea decomposition rate in aqueous solution, repre- sented by the fi rst-order reaction kinetics, shows the dependence of the initial urea con- centrations. At higher initial urea concentrations, the rate of degradation is a decreasing function with time. This suggests that the reverse reaction is a factor in the degradation of concentrated urea solution. The obtained results also show that urea is more unstable Table V The values of the rate constants, k, in h−1 calculated from the experimental data of the residual urea concentrations with various initial concentrations as a function of temperature Concentration (%) k Value at 25°C k Value at 40°C Normal cream Cream pH 6 (lactate) Normal cream Cream pH 6 (lactate) 2.50 8.59 × 10−7 8.37 × 10−7 7.13 × 10−6 6.86 × 10−6 5 8.44 × 10−7 8.05 × 10−7 7.05 × 10−6 6.81 × 10−6 10 8.39 × 10−7 7.96 × 10−7 7.03 × 10−6 6.80 × 10−6 15 8.38 × 10−7 7.93 × 10−7 7.01 × 10−6 6.70 × 10−6 20 8.23 × 10−7 7.08 × 10−7 6.87 × 10−6 6.58 × 10−6