Solubility Determination from Clear Points upon Solvent Addition

Abstract

A method is described for determining the solubility of multicomponent crystalline compounds from clear points upon sample dilution at a constant temperature. Clear points are established by continuously adding a solvent mixture to a suspension of known composition until a clear solution appears. For validation, this solvent addition method is compared to the traditional equilibrium concentration method at constant temperature and the more recent temperature variation method with which clear point temperatures are determined upon increasing the sample temperature. Solubility data of binary systems (1 solute, 1 solvent) measured using the solvent addition method are obtained relatively quickly compared to the equilibrium concentration method. These solubility data are consistent with those of the temperature variation and the equilibrium concentration method. For the temperature variation method, the results are dependent on the heating rate. Likewise, for the solvent addition method, they are dependent on the addition rate. Additionally, for ternary systems involving antisolvent or cocrystals, solubilities are determined at a constant temperature using the solvent addition method. The use of the solvent addition method is especially valuable in the case of solvent mixtures and other complex multicomponent systems, in which the temperature variation method cannot be applied easily. ■ INTRODUCTIONIn production often a crystallization step is required for purification and final crystalline particulate product formation. 1,2 The solubility or phase diagram of such compounds is essential information for efficient and reliable crystallization process design and operation. 3−6 The phase diagram indicates the most stable phases at specific compositional and temperature conditions, 1,4−6 determines the achievable yield, 7 and enables the monitoring of the supersaturation during the crystallization process. 7,8 Traditionally the solubility is measured through equilibration of a suspension. 1 The solubility is then equal to the concentration in the equilibrated solution, which can be sampled and determined by, for example, a gravimetric method or HPLC (Figure 1 (left)). Although the Equilibrium Concentration (EqC) method is widely accepted and considered accurate, 1 it is laborious and time-consuming. Currently, commercial equipment from various suppliers is available that streamlines measurements through a temperature variation (TV) method in which clear points are measured. 9−11 In the TV method the solubility is changed by changing the temperature, until it matches the concentration. A clear point is then the temperature at which, upon increasing the temperature, a suspension turns into a clear solution. Figure 1 (center) shows the principle of a clear point measurement using the TV method. If the heating rate is sufficiently small, the crystal dissolution rate is fast and the clear point can be assumed to be equal to the saturation temperature. 10 This TV method is much less labor intensive, is much faster, and allows f...

Measurement and Correlation of the Solubility of 5-Fluorouracil in Pure and Binary Solvents

“…Upon reviewing the available literature, limited quantitative solubility data for 5-FU in various solvents have been reported thus far. − Therefore, a detailed study of the solubility of 5-FU enabled by comprehensive experimental data is needed. In this study, the solubility of 5-FU in 11 pure solvents, including acetone, acetonitrile, n- butanol, 1,4-dioxane, ethanol, ethyl acetate, methanol, isopropanol, 1-propanol, tetrahydrofuran, water, and binary water + ethanol solvent mixtures, was investigated at temperatures ranging from 278.15 to 333.15 K using the polythermal method − in a Crystal16 multiple reactor system. The experimental solubility data of 5-FU in these solvents were correlated using the modified Apelblat and λ h model equations, which enable both the interpolation and extrapolation of the measured solubility data.…”

Automated solubility screening platform using computer vision

“…Reus et al have used vision to determine clear points based on images taken by a ReactIR probe. While less time-consuming and hands-on than HPLC, such methods still require calibration and the addition of a probe or controlled emission of light, which may not be accurate due to limited detection (Reus et al, 2015).…”

“…In the excess solvent method, a titration-like procedure is applied: solvent is added stepwise to a solute until a fully dissolved state is observed. The composition of the solution and the dissolution point are then typically measured using light scattering or imaging-based technology (Reus et al, 2015). The excess solvent method can therefore obviate the need for pre-calibrated and expensive analytical methods like HPLC, but it comes at the cost of adding the somewhat time-consuming stepwise solvent addition actions.…”

Automated Solubility Screening Platform Using Computer Vision

“…In the excess solvent method, a titration-like procedure is in place where step addition of solvent continues until a fully dissolved state is observed. Composition of the solution and dissolution point are then typically measured using light scattering or imaging-based technology 9 . The excess solvent method is therefore advantageous in that it may remove the need for pre-calibrated and expensive analytical methods like HPLC, but it comes at the cost of adding time-consuming experimental actions (step-addition of solvent).…”

“…al. 9 have used vision to determine clear points based on images taken by a ReactIR probe. While less time consuming and hands-on than HPLC, such methods still require calibration and the addition of a probe or controlled emission of light, which may not be accurate due to limited detection 9 .…”