Rational Coformer or Solvent Selection for Pharmaceutical Cocrystallization or Desolvation

Abstract

It is demonstrated that the fluid-phase thermodynamics theory conductor-like screening model for real solvents (COSMO-RS) as implemented in the COSMOtherm software can be used for accurate and efficient screening of coformers for active pharmaceutical ingredient (API) cocrystallization. The excess enthalpy, H(ex) , between an API-coformer mixture relative to the pure components reflects the tendency of those two compounds to cocrystallize. Thus, predictive calculations may be performed with decent effort on a large set of molecular data in order to identify potentially new cocrystal systems. In addition, it is demonstrated that COSMO-RS theory allows reasonable ranking of coformers for API solubility improvement. As a result, experiments may be focused on those coformers, which have an increased probability of cocrystallization, leading to the largest improvement of the API solubility. In a similar way as potential coformers are identified for cocrystallization, solvents that do not tend to form solvates may be determined based on the highest H(ex) s with the API. The approach was successfully tested on tyrosine kinase inhibitor axitinib, which has a propensity to form relatively stable solvated structures with the majority of common solvents, as well as on thiophanate-methyl and thiophanate-ethyl benzimidazole fungicides, which form channel solvates.

Transferability of cocrystallization propensities between aromatic and heteroaromatic amides

“…This approach was successfully applied to a variety of systems including cocrystals [44][45][46]. It assumes that the miscibility of supercooled liquids is also associated with miscibility in the solid state.…”

“…A virtual cocrystal screening method [43] was successfully validated against experimental cocrystals. Besides, the mixing enthalpy of supercooled liquid coformers with a given stoichiometry can be used for screening of cocrystallization potential [44][45][46]. Besides, the supramolecular phenomena expressed in terms of homo-or heterosynthons proved to be valuable guidance for practical applications [47][48][49].…”

Stability Order of Caffeine Co-crystals Determined by Co-crystal Former Exchange Reaction and Its Application for the Validation of in Silico Models

“…16) Similarly, some in silico physicochemical parameters for CCF selection were proposed by several research groups. [17][18][19][20] For example, the difference in hydrogen bond energy between a co-crystal and each of the sole components (ΔE) was proposed by Musumeci et al, based on the hypothesis that the formation of a co-crystal becomes more probable as ΔE becomes larger. [21][22][23] However, ΔE has not been rigorously validated due to the lack of information about the stability order of co-crystals.…”

“…[17][18][19][20] For example, the difference in hydrogen bond energy between a co-crystal and each of the sole components (ΔE) was proposed by Musumeci et al, based on the hypothesis that the formation of a co-crystal becomes more probable as ΔE becomes larger.…”

Pharmaceutical Cocrystals: An Overview

“…In a similar way as potential coformers were identified for cocrystallization, solvents with highest value of H ex with an API, were selected which had the least probability to form solid solvates. Different coformers for itraconazole and solvents for Axitinib (tyrosine kinase inhibitor) were selected by this method to avoid formation of hydrates and solvents [66] .…”