Thermodynamic Modeling for Efficient Cocrystal Formation

Abstract

The purpose of this work is to increase the efficiency of the cocrystal formation process by thermodynamic modeling using PC-SAFT. By accounting for the thermodynamic non-ideality of the components in the cocrystal system, PC-SAFT is able to model and predict the solubility behavior of pharmaceutical cocrystals based solely on the knowledge of a single cocrystal solubility point in any solvent and at any temperature. Furthermore, the cocrystal solubility in other solvents and for other temperatures can be predicted without the need for additional measurements. The (+)-mandelic acid/(-)-mandelic acid (1:1), caffeine/glutaric acid (1:1) and carbamazepine/nicotinamide (1:1) cocrystal systems were modeled, and the results were in excellent agreement with the experimental data.

Stability of co‐crystals of caffeine with gallic acid in presence of coformers

“…The solubility product values can be used to predict the solubility of co‐crystal in different solvents and at different temperatures (Kaupp, ; Lange & Sadowski, ; Wang et al, ). A model, describing co‐crystal solubility for various co‐crystal stoichiometry, is reported in the literature, but it neglects the non‐ideality of the system (Jayasankar, Reddy, Bethune, & Rodríguez‐Hornedo, ).…”

“…The formation of co‐crystal is considered as a chemical reaction between the Caffeine and a coformer resulting in the formation of a solid co‐crystal (Alsirawan et al, ; Lange & Sadowski, ; Mukaida et al, ; Schartman, ). Consider the formation of a co‐crystal between A and B, as where x and y are the stoichiometric coefficients of the co‐crystal A x B y .…”

“…The solubility product can be estimated with respect to temperature for a given co‐crystal using Gibbs‐Helmholtz equation (Dabir et al, ; Lange et al, ; Lange & Sadowski, ); …”

Predicting the Effect of pH on Stability and Solubility of Polymorphs, Hydrates, and Cocrystals

“…For a given system of API, CF, and solvent (here water) this phase diagram depicts the concentration range in which the desired CC is formed, as already earlier illustrated for systems exhibiting dissociation and salt formation 16 and for systems including polymorphic transitions and hydrate formation 18 . However, polymorphism 19,20 , as well as formation of salts and hydrates impede in turn the reliable and accurate measurement of these phase diagrams, resulting in a high experimental effort 10,[12][13][14][15] .…”

“…‫ܭ‬ ௦ is determined applying PC-SAFT-predicted activity coefficients that constitute deviations from the pure-component reference state. PC-SAFT 35 was already used in earlier studies to model and predict the activity coefficients of the neutral and ionic components involved in binary and ternary systems [35][36][37][38][39] , including those with formation of CC 14,40,41 , salts 42 and hydrates 16,18,40 . In aqueous systems, PC-SAFT has been successfully applied for modeling pH-dependent solubilities [42][43][44][45][46][47] of amino acids 43 , as well as of APIs and their corresponding salts 42 .…”