In silico screening of dicarboxylic acids for cocrystallization with phenylpiperazine derivatives based on both cocrystallization propensity and solubility advantage

Abstract

In silico screening was performed to search for binary solids in which a phenylpiperazine-derivative drug was cocrystallized with a dicarboxylic acid. The phenylpiperazine derivative could be any of 61 such drugs, while the dicarboxylic acid could be any of nine such acids. The uniqueness of this approach was that two criteria had to be fulfilled simultaneously, namely a high propensity for cocrystallization and a sufficient solubility advantage. Using the mixing enthalpies of selected pairs of crystal formers with high affinities for one another permitted the classification of candidates with a high probability of cocrystallization. Further modeling of the solubility advantage allowed the identification of many binary solids that potentially exhibit significantly enhanced solubility in water. Based on the computed values for the mixing enthalpies and solubility advantage factors, it was concluded that dicarboxylic acids are both excellent coformers for cocrystallization with phenylpiperazines and very good solubility enhancers; indeed, the use of dicarboxylic acids as coformers would allow the degree of dissolution to be tuned for many of the studied drugs. The observed similarities of the cocrystallization landscapes of the studied drugs and excipients were also explored.Electronic supplementary materialThe online version of this article (doi:10.1007/s00894-017-3287-y) contains supplementary material, which is available to authorized users.

Selection of effective cocrystals former for dissolution rate improvement of active pharmaceutical ingredients based on lipoaffinity index

“…As it was reported in our previous works Cysewski, 2017;Przybyłek et al, 2017), in silico methods can be quite successful in cocrystal screening and predicting cocrystal solubility advantage. Particularly, it was shown Przybyłek et al, 2017) that compounds containing polar OH and COOH groups are excellent methylxanthines solubility enhancers.…”

“…Recently there has been a growing interest in in-silico pharmaceutical excipients screening methods including bioavailability and solubility improvement agents such as soluble polymers, surfactants and nutraceutical cocrystals formers (Bergström et al, 2016;Christensen et al, 2017;Cysewski, 2017;Przybyłek et al, 2017). The major advantage of efficient theoretical approaches, important from the economic viewpoint, is reducing the time and reagents costs.…”

“…This indispensable additional criterion is a well-accepted measure of cocrystallization propensity. This kind of quantification of coformers affinity was successfully used for experimentally verified cocrystals screening (Cysewski, 2017(Cysewski, , 2016aCysewski et al, 2016;Klamt, 2012Klamt, , 2011Klamt et al, 2002;Klamt and Schüürmann, 1993;Loschen and Klamt, 2015; Przybyłek et al., 2016b). In order to demonstrate the usefulness of the screening procedure proposed here, the search for DSR enhancers was extended over a quite comprehensive set of coformers defined in the methodology part.…”

Engineering Cocrystals of Poorly Water-Soluble Drugs to Enhance Dissolution in Aqueous Medium

“…These include calculation of interaction energies [ 116 , 117 ], electrostatic potentials [ 118 ], molecular complementarity between API and coformers [ 119 , 120 ], solubility behavior [ 121 , 122 , 123 ], crystal energy landscapes of API-coformer pairs [ 124 ] and hydrogen bond propensities [ 125 ]. Table 6 presents the summary of various computational coformer screening methods [ 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 ] reported so far in the literature. Despite being less labor intensive, computational screening methods suffer from the requirement of large simulation times to perform molecular dynamic simulations.…”

Analysis of Solid-State Interactions of Ketoprofen-Coformer Binary Mixtures by DSC and Hot Stage Microscopy

“…This phenomenon can be used to design the new solid forms of an active pharmaceutical ingredient in order to improve physicochemical properties (Bartsch & Griesser, 2004). Therefore, data relating to interactions between solid compounds are essential in the formation of multicomponent solid forms of active pharmaceutical ingredient (Cysewski, 2017;Yamashita, Hirakura, Yuda, & Terada, 2014).…”