Amoxicillin Solubility and Supercritical Carbon Dioxide Mehdi Ahmadi Sabegh, † Hamid Rajaei, ‡ Ali Zeinolabedini Hezave, ‡ and Feridun Esmaeilzadeh* ,‡ † Department of Chemistry, Ahar Branch, Islamic Azad University-Ahar, Iran ‡ Chemical and Petroleum Engineering Department, School of Engineering, Shiraz University, Iran ABSTRACT: During the past 20 years, an increase through measuring, correlating, and calculating solid solubilities especially pharmaceuticals in supercritical fluids for processes such as purification, extraction, and size reduction processes have been observed. In this direction, the solubility of amoxicillin with the International Union of Pure and Applied Chemistry (IUPAC) name of (2S,5R,6R)-6-{[(2R)-2-amino-2-(4- hydroxyphenyl)-acetyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0] heptane- 2-carboxylic acid in the pressure and temperature ranges of 16 MPa to 40 MPa and 308.15 K to 338.15 K, respectively, has been measured. For this purpose, a simple gravimetric-based method was utilized to obtain the amoxicillin solubility in supercritical carbon dioxide. During the measurements it was found that the amoxicillin solubility was in the range of 1.08·10 -5 and 7.23·10 -3 based on the mole fraction. Besides, due to a vast number of efforts have been performed on the solubility correlation by several researchers, four semiempirical density-based correlations including Mendez-Santiago and Teja (MST), Bartle et al., Chrastil, and Kumar and Johnston (K-J) models were used to correlate the measured solubility data. The obtained results revealed the capability of the used correlation through the solubility correlation with an acceptable level of accuracy. ■ INTRODUCTION Supercritical-based technologies have widely used in the past 20 years in particular for particle engineering, treatment, and purification of pharmaceuticals. 1-5 The greatest benefits of using supercritical fluids instead of traditional processes are a few environmental related problems and a low level of product contamination and that easy recovery of the solvent leads to a small amount of solvent losses. Among the different candidates for supercritical solvents, carbon dioxide is the most favorable one due its mild critical conditions and other beneficial features especially being environmentally friendly. 1,2,6 Among the many possible applications of the supercritical fluid-based technologies, the particle size reduction of active pharmaceutical ingredients (APIs) is the most interesting one. 7-9 The supercritical fluid method involving the recrystal- lization process was adopted by pharmaceutical industry since the mid-1980s. 10 The point is crucial to develop the suitable processes for the pharmaceuticals, especially APIs, is their solubilities in super- critical fluids, in particular in supercritical carbon dioxide. In this direction, numbers of researchers and scientific groups around the world have examined the solubility of several pharmaceuticals in supercritical fluids especially in carbon dioxide. 11-13 But, unfortunately, it is crucially necessary to measure more experimental data for APIs for the proper selection of the suitable supercritical-based processes. 14 It should be mentioned that, due to the large number of pharmaceutics, it is not always possible to measure the solubility experimentally. In this direction, besides the experimentally measuring the solid solubility in supercritical carbon dioxide, correlating, predicting, and estimating using different approaches such as equation of state (EoS), semiempirical correlation, and solution models have been examined during the past few decades. 15-19 Generally, EoS's are the first option to predict the solubility of compounds in supercritical fluids. Unfortunately, the application of the EoS's is not commonly proposed since the availability of necessary parameters through them is limited especially for pharmaceuticals. In other words, if the EoS approach is applied, the sublimation pressure and the critical properties of the solute, which are not experimentally available in many cases especially for a complex solid which must be estimated through different prediction tools such as group contribution methods, are required. 20 So, for most of the pharmaceutical compounds, EoS-based modeling is usually limited due to these uncertain data. With respect to this, more recently density-based semiempirical correlations such as Mendez-Santiago and Teja (MST), 16 Bartle et al., 17 Chrastil, 18 and Kumar and Johnston (K-J) 19 models have been considered as candidates for a replacement of EoS-based solubility modeling. The obtained results through the different published works have been reported rather successful for these correlations to well-correlate the solubilities. What makes these correlations interesting is that the supercritical density and the system temperature and pressure are the only necessary parameters to find a fitting parameter of those correlations. In other words, they do not require physical properties such as critical properties, acentric factors, and so forth. Received: June 6, 2012 Accepted: August 30, 2012 Article pubs.acs.org/jced © XXXX American Chemical Society A dx.doi.org/10.1021/je3006826 | J. Chem. Eng. Data XXXX, XXX, XXX-XXX