The A Priori Design and Selection of Ionic Liquids as Solvents for Active Pharmaceutical Ingredients

Abstract

Abstract:In this paper we derive a straightforward computational approach to predict the optimal ionic liquid (IL) solvent for a given compound, based on COSMO-RS calculations. These calculations were performed on 18 different active pharmaceutical ingredients (APIs) using a matrix of 240 hypothetical ILs. These results indicated that the 18 APIs could be classified into 3 distinct categories based on their relative hydrogen bond donating or accepting ability, with similar optimal IL solvent predictions within each class. Informed by these results, a family of strongly hydrogen bond donating ILs based on the Nalkylguanidinium cation were prepared and characterized. The solubility of the APIs in each of these classes was found to be qualitatively consistent with the predictions of the COSMO-RS model. The suitability of these novel guanidinium salts as crystallization solvents was demonstrated by the use of Nbutylguanidinium bis(trifluoromethanesulfonyl)imide for the purification of crude fenofibrate using dimethylsulfoxide as an antisolvent, which resulted in good yields and excellent purities. Finally, a simple descriptor based model is proposed to suggest the best IL solvent for arbitrary APIs.Introduction:

How imidazolium‐based ionic liquids solubilize the poorly soluble ibuprofen? A theoretical study

“…As shown in Figure , all the first peaks for anion‐ibuprofen RDFs are greatly sharper and higher compared with those of cation‐ibuprofen RDFs regardless of cation–anion combinations, which suggests that the anions primarily offer interaction sites to attract ibuprofen. This behavior is expected because ibuprofen is a Lewis acid and thus the interactions of ibuprofen with anions are much stronger than those with cations . Moreover, Figure a,d presents that the peak with the highest intensity of RDFs occurs at 1.8 Å for the [AcO] − and [TfO] − anions, while that for [BF 4 ] − and [PF 6 ] − anions locates at about 2.8 Å and 3.2 Å, respectively.…”

“…In another study, they found that the favorable solvation of lidocaine in imidazolium‐based ILs did not only result from the HB interactions between lidocaine and anions but also from the electrostatic interactions between lidocaine and cations, which was different from conventional experimental results that the cations played a negligible role . Furthermore, Myerson et al used COSMO‐RS calculations to demonstrate that both anions and cations form the HB interactions with the drugs, which were considered as one of the main contributing factors for the favorable solubility. In addition, Coutinho et al illustrated that the solvation mechanism of vanillin was observed to be most likely the formation of π–π interactions between vanillin and cations.…”

“…The initial configurations were constructed by applying Packmol in a cubic box, where the number of ibuprofen was fixed at 30 while that of ion pairs was 512 according to the experimental solubility of ibuprofen in the corresponding ILs . To avoid the possible atomic coordinate overlap at the initial state, each system first was energy minimized prior to a short NVT MD simulation of 500 ps.…”

“…To avoid the possible atomic coordinate overlap at the initial state, each system first was energy minimized prior to a short NVT MD simulation of 500 ps. Next, an NPT MD simulation of 5 ns was performed to maintain the temperature at 338.15 K and the pressure at 1.0 atm, which was consistent with the experimental dissolution conditions . Subsequently, an NPT MD simulation of 10 ns was performed for equilibration, and then another NVT MD simulation of 5 ns following the above final configuration from the NPT MD simulation was performed for further equilibration.…”

“…Recently, various computational methods have been used to investigate the solute‐solvent interaction at the molecular level in order to understand the major factors contributing to the favorable solvation of drugs in various ILs . For example, Paluch et al used molecular dynamics (MD) simulations to study the solvation mechanism of acetaminophen in 21 imidazolium‐based ILs.…”