2021
DOI: 10.1021/acs.cgd.1c00247
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Shortcut Method for the Prediction of the Cocrystal Solubility Line

Abstract: Knowledge of the solubility of a cocrystal in terms of solvent, temperature, and the liquid-phase concentrations of the active pharmaceutical ingredient and coformer is necessary for the pharmaceutical industry to produce pharmaceuticals with improved physicochemical properties. Here, we propose a simple and convenient shortcut calculation to predict the solubility curve of cocrystals using simple thermodynamic equations, considering the liquid-phase activity coefficient of the two species in the cocrystal, wh… Show more

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Cited by 9 publications
(8 citation statements)
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“…Even though the activities in Equation (3) are usually approximated by the corresponding molar concentration while neglecting the activity coefficients, a more valid approximation implies that the activity coefficients for the two solute species are constant along the cocrystal solubility line and equal to the activity coefficients of the pure components in the saturated solutions in the same solvent and temperature [ 96 ]. Hence, similar to the Gibbs free energy difference between the polymorphs [ 97 ], the solvent used for solubility determination has a minor impact on the resulting value of Δ form G unless the activity coefficients are strongly dependent on the solute concentration [ 44 ].…”
Section: Resultsmentioning
confidence: 99%
“…Even though the activities in Equation (3) are usually approximated by the corresponding molar concentration while neglecting the activity coefficients, a more valid approximation implies that the activity coefficients for the two solute species are constant along the cocrystal solubility line and equal to the activity coefficients of the pure components in the saturated solutions in the same solvent and temperature [ 96 ]. Hence, similar to the Gibbs free energy difference between the polymorphs [ 97 ], the solvent used for solubility determination has a minor impact on the resulting value of Δ form G unless the activity coefficients are strongly dependent on the solute concentration [ 44 ].…”
Section: Resultsmentioning
confidence: 99%
“…|Δ form G °| > |Δ form H °|, is likely to be result of the utilization of analytical concentrations of the components in saturated solutions instead of their thermodynamic activities as eq requires. Although the Δ form G ° values can be further refined by evaluating the activity coefficients of species in the liquid phase at the equilibrium state to account for nonideal behavior, , this aspect is beyond the scope of the current work. Overall, the NFT cocrystals with the structurally related coformers reported here demonstrate a wide spectrum of thermodynamic formation properties that are challenging to deduce based on structural data alone.…”
Section: Resultsmentioning
confidence: 99%
“…The discrimination between congruent and incongruent dissolution behavior requires labor-intensive and material-demanding experiments, as the characterization of the monovariant, eutectic liquid phases at process-relevant temperatures and solvent compositions is required. Models to predict ternary phase diagrams of cocrystals usually require large sets of solubility data measured at different temperatures . A method to identify solvent systems in which the cocrystal may dissolve congruently and also to enable identifying particularly unfavorable ones requiring large excesses to reach thermodynamic stability of the cocrystal leveraging on readily accessible data is welcome.…”
Section: Introductionmentioning
confidence: 99%
“…Models to predict ternary phase diagrams of cocrystals usually require large sets of solubility data measured at different temperatures. 2 A method to identify solvent systems in which the cocrystal may dissolve congruently and also to enable identifying particularly unfavorable ones requiring large excesses to reach thermodynamic stability of the cocrystal leveraging on readily accessible data is welcome.…”
Section: Introductionmentioning
confidence: 99%