Pharmaceutics, Drug Delivery and Pharmaceutical Technology Solid and Solution State Thermodynamics of Polymorphs of Butamben (Butyl 4-Aminobenzoate) in Pure Organic Solvents Michael Sv € ard 1 , 2, * , Lai Zeng 2 , Masood Valavi 1 , Gamid Rama Krishna 1 , Åke C. Rasmuson 1 , 2 1 Department of Chemical and Environmental Science, Synthesis and Solid State Pharmaceutical Centre (SSPC), Bernal Institute, University of Limerick, Castletroy, Ireland 2 Department of Chemical Engineering, KTH Royal Institute of Technology, Teknikringen 42, SE-10044 Stockholm, Sweden article info Article history: Received 14 December 2018 Revised 7 February 2019 Accepted 19 February 2019 Keywords: solubility activity coefficient polymorphism crystallization differential scanning calorimetry (DSC) X-ray powder diffraction (XRD) thermal analysis abstract The solubility of butamben has been measured gravimetrically in pure methanol, 1-propanol, 2-propanol, 1-butanol, and toluene over the temperature range 268-298 K. Polymorph transition and melting temperatures, associated enthalpy changes, and the heat capacity of the solid forms and the supercooled melt have been measured by differential scanning calorimetry. Based on extrapolated calorimetric data, the Gibbs energy, enthalpy and entropy of fusion, and the activity of solid butamben (the ideal solubility) have been calculated from below ambient temperature up to the melting point. Activity coefficients of butamben at equilibrium in the different solvents have been estimated from solubility data and the activity of the solid, revealing that all investigated systems exhibit positive deviation from Raoult's law. Solubility data are well correlated by a semiempirical regression model. On a mass basis, the solubility is clearly higher in methanol than in the other solvents, but mole fraction solubilities are very similar across all 5 solvents. The 2 known polymorphs are enantiotropically related, and the transition point is located at 283 K. Polymorph interconversions occur within 0.3 K of the transition point even in the solid state, and the 2 forms exhibit strong similarities in investigated properties. © 2019 American Pharmacists Association ® . Published by Elsevier Inc. All rights reserved. Introduction Crystallization is a common unit operation used for separation and purification in many branches of chemical industry. It is of particular importance in the pharmaceutical industry, where regu- lations mandate strict control of crystallization processes in terms of resulting crystal size, shape, and polymorph. 1 The possibility of obtaining such control depends strongly on obtaining knowledge of the solid-liquid solubility as a function of temperature in relevant solvents and on mapping the phase diagram of all potential solid phases. 2 The temperature dependence of the solubility is key to controlling the driving force for nucleation and crystal growth. Moreover, it governs the potential yield, and the in vivo solubility of an active pharmaceutical ingredient directly affects its bioavailability within the human body. A large number of models for the prediction of solubility have been developed, including PC-SAFT, 3 Pharma UNIFAC, 4 and NRTL-SAC. 5 So far, however, no predictive model has been shown to offer sufficient accuracy to replace the often tedious experimental determination of solubility curves, and there remains a need for robust models for correlation and extrapolation of data. Butamben (butyl 4-aminobenzoate) is a local anesthetic used in topical preparations, belonging to the same family of pharmaceu- tical compounds as, for example, benzocaine, procaine, and iso- butamben. There is 1 crystal structure published in the Cambridge Structural Database, determined at 298 K in the monoclinic space group P2 1 /c (CSD refcode EZAVIK) by Caira et al. 6 Schmidt 7 char- acterized the compound by differential scanning calorimetry (DSC) and reports a reversible transformation between this room tem- perature stable polymorph (henceforth FI) and a low temperature stable polymorph (FII), with a transition temperature proposed to be located in the temperature range of 281-285 K. The aqueous solubility is very low; Rytting et al. 8 report the room temperature solubility to be 8.9  10 4 M, which translates to 0.17 g per kg of water. The molecular geometry of butamben is shown in Figure 1 , optimized in the gas phase at the HF/6-311þG(d) level using Gaussian 03W, with the molecular electrostatic potential mapped onto an electron density isosurface. To the best of our knowledge, the solubility of the butamben polymorphs in common organic solvents has not previously been This article contains supplementary material available from the authors by request or via the Internet at https://doi.org/10.1016/j.xphs.2019.02.013. * Correspondence to: Michael Sv€ ard (Telephone: þ46 87908228). E-mail address: micsva@kth.se (M. Sv€ ard). Contents lists available at ScienceDirect Journal of Pharmaceutical Sciences journal homepage: www.jpharmsci.org https://doi.org/10.1016/j.xphs.2019.02.013 0022-3549/© 2019 American Pharmacists Association ® . Published by Elsevier Inc. All rights reserved. Journal of Pharmaceutical Sciences xxx (2019) 1-6