J. Soc. Co,•met. Chem., 25, 495-506 (September 1974) Kinetics of Degradation of the Parabens SEYMOUR M. BLAUG, Ph.D.,* and DONALD E. GRANT, Ph.D.t Synopsis-The effect of pH and TEMPERATURE on the HYDROLYSIS of methyl, ethyl, propyl, and n-butyl PARABEN was studied at 70øC in 0.1M phosphate buffer so]u- tions at ionic strength 0.3 from pH 2.75 to 9.16 and at 40 ø and 50øC at pH 9.16. The REACTION xvas first order with respect to paraben. ENERGIES OF ACTIVATION were determined from Arrhenius plots. RATE CONSTANTS and HALF-LIVES of each paraben at 25øC were obtained by extrapolation of the Arrhenius plots. The half-life of each paraben at 70øC and pH 8.24 was essentially independent of the initial concentration of paraben. Increasing ionic strength resulted in a slight increase in the rate of hydrolysis of each paraben. Increasing the phosphate concentration in buffer solutions at pH 8.24 at 70øC produced an increase in the rate of hydrolysis of each paraben. This indicated that the parabens undergo general base catalysis and that hydroxyl ion is not the only species that can catalyze their hydrolysis. INTRODUCTION The parabens have been reported to be stable, and to show no hydrolysis under conditions of heat steril/zat'on (2 hours at 100øC or 0.5 hour at 120øC) at a pH range of 3-8 (1). Pekkarinen and Tommila (2) studied the alkaline hydrolysis of ethyl esters of para and meta hydroxybenzoates in potassium hydroxide solution, and in various organic solvents. They con- c]uded that the hydrolysis takes place solely as a reaction between the ester ion and the hydroxide ion. Other authors found that the methyl ester of p- hydroxybenzoic acid is hydrolyzed at high temperature and in strongly acid solution (3). Ravel and Parrott (4) studied the hydrolysis of methyl paraben in aqueous solutions at temperatures of 70-85øC in a pH range of 6-9. * University of North Carolina, School of Pharmacy. Chapel Hill, N.C. Investigation was conducted at University of Iowa, Iowa City, Iowa 52242. '• Beecham-Massengill Pharmaceuticals, Bristol, Tenn. 495

496 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Methyl, ethyl, propyl, and butyl paraben are widely used in many types of pharmaceutical preparations such as ophthalmic, oral, and topical dosage forms and in cosmetic creams and lotions. They are used singly or in combina- tion with one another. Mixtures of the parabens have been shown to be more effective as preservatives than the individual parabens (5, 6). Their hydrolysis yields p-hydroxybenzoic acid, which possesses little preservative activity. It was the purpose of this investigation to study the stability of the esters of p-hydroxybenzoic acid over pH range of 3-9 and various temperatures. EXPERIMENTAL Reagents and Apparatus Reagents used were p-hydroxybenzoic acid (mp 213-214øC), methyl paraben (top 126-128øC), ethyl paraben (mp 116-117øC), propyl para- ben (mp 95-97øC), and n-butyl paraben (mp 73øC), all recrystallized from hydroalcoholic solution also, sodium hydroxide, monobasic potassium phosphate, potassium chloride, phosphoric acid, and chloroform, all AR grade. All pH's were measured using a Beckman model H-2 pH meter* and spectra were obtained with a Beckman DU spectrophotometer* with 1-cm quartz cells. A constant temperature bath with a Haake thermoregulator, series ED,t with a thermometer calibrated to 0.1øC was used for all the studies. Procedure Preparation o[ Buffers The buffers used in this investigation were prepared from monobasic po- tassium phosphate solutions of desired molarity which were adjusted to the desired pH with sodium hydroxide pellets and phosphoric acid. Buffers were adjusted to constant ionic strength of either 0.3, 0.6, 0.9, or 1.2 by the addition of potassium chloride. All buffers were prepared at 25øC. Since the studies were conducted at elevated temperatures, the pH of the buffers at those temperatures would be different from the pH determined at 25øC. The pH values of the buffers were calculated using the ion product of water at the various temperatures of the study, 40 ø, 50 ø, and 70øC. For example, a buffer of pH 9 at 25øC would have a calculated pH of 8.24 at 70øC. The pKw of water at 70 ø C is 12.82 (7, 8 ). Calibration Curves for the Paraber• For each of the parabens studied, calibration curves were prepared using chloroform as the solvent. The optical density of each paraben dilution was -- *Beckman Instruments, Fullerton, Calif. ?Gebriider Haake, Berlin, Germany.