Pharmaceutics, Drug Delivery and Pharmaceutical Technology Nuances in the Calculation of Amorphous Solubility Enhancement Ratio Arushi Manchanda 1 , Mary S. Kleppe 1 , Robin H. Bogner 1 , 2, * 1 Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269 2 Institute of Material Science, University of Connecticut, Storrs, Connecticut 06269 article info Article history: Received 30 April 2019 Revised 17 June 2019 Accepted 26 June 2019 Available online 2 July 2019 Keywords: amorphous crystal thermodynamics solubility solubility enhancement differential scanning calorimetry abstract The theoretical amorphous solubility enhancement ratio (R s ) can be calculated based on the free energy difference between amorphous and crystalline forms (DG x/a ), using several experimentally determined input parameters. This work compares the various approaches for the calculation of R s and explores the nuances associated with its calculation. The uncertainty of R s values owing to experimental conditions (differential scanning calorimetry heating rates) used to measure the input parameters was determined for 3 drugs (indomethacin, itraconazole, and spironolactone). The calculated value of R s was most influenced by the measurement of heat of fusion. The range in values of R s using the various equations in the literature was within the calculated uncertainty of the theoretical R s value. Still, all equations appear to overpredict the experimental value of R s , sometimes by more than a factor of 5, when an experimental value is attainable. Methods for the calculation of DG x/a for molecules undergoing additional phase transitions (other than glass transition and melting) were developed, employing itraconazole as a model drug. In addition, the influences of enthalpy relaxation and entropy of mixing for racemic compounds on R s were also considered. These additional corrections improved agreement between theoretical and experimental R s . © 2019 American Pharmacists Association ® . Published by Elsevier Inc. All rights reserved. Introduction As high as 90% of the drug candidates are poorly soluble, that is, they belong to BCS class II or class IV. 1 This estimate is significantly higher than the approximately 30% of marketed drugs that fall into these 2 categories. Poor solubility can result in poor and variable bioavailability, which often leads to increased timeline and cost for drug development. 2-4 The increase in the proportion of poorly soluble drugs in the pharmaceutical industry is leading to signifi- cant growth in enabling technologies to increase solubility and thus oral bioavailability. Amorphization is one of the most commonly used technologies in this area. 5 The neat amorphous form of any drug exists in a higher free energy state than its crystalline counterpart and therefore provides enhanced solubility, that is, supersaturated solutions. 6-19 The enhanced solubility is often expressed as a “solubility advantage”, which is the ratio of the theoretical solubility of the amorphous form, C a T , to the measured solubility of the crystalline form, C X T , and is often designated as R s . 10 However, the solubility advantage of the amorphous form is not realized when it crystallizes upon contact with water during dissolution. Crystallization of amorphous ma- terial during dissolution poses a challenge not only for bioavail- ability but also for the accurate experimental determination of amorphous solubility. 10,11,13-15,18,20 Various groups have reported theoretical frameworks to calculate the amorphous solubility advantage of pharmaceuticals, using 2 general approaches. One is based on the Gibbs free energy difference between the amorphous and crystalline states. 10-13,16-18,21 The other is based on modeling the drug-solvent phase diagrams using the perturbed-chain sta- tistical associating fluid theory. 19 This article focuses on theories based on the former. The equations derived using the Gibbs free energy difference include up to 3 terms (Eq. 1). All equations have Term I that describes the enhancement in solubility owing to the free energy difference between neat amorphous and crystalline forms, DG x/a (T), that can be calculated from experimentally determined thermal properties. 10-18,21 Some of the equations include Term II, a s 2;a1¼1 , that accounts for the reduction in activity of the amorphous solute owing to moisture sorption that presumably occurs faster than dissolution of the poorly soluble forms. 13-18 One of the equations includes Conflicts of interest: None. Current address for Dr. Kleppe Regeneron Pharmaceuticals Inc., Tarrytown, New York, 10591. * Correspondence to: Robin H. Bogner (Telephone: 860-486-2136). E-mail address: robin.bogner@uconn.edu (R.H. Bogner). Contents lists available at ScienceDirect Journal of Pharmaceutical Sciences journal homepage: www.jpharmsci.org https://doi.org/10.1016/j.xphs.2019.06.020 0022-3549/© 2019 American Pharmacists Association ® . Published by Elsevier Inc. All rights reserved. Journal of Pharmaceutical Sciences 108 (2019) 3560-3574