Applicability of Phenolic Acids as Effective Enhancers of Cocrystal Solubility of Methylxanthines

Abstract

Applicability of phenolic acids as potential cocrystal formers for methylxanthine derivatives was analyzed both in terms of cocrystallization probabilities and solubility advantage. The cocrystal formation abilities were evaluated using mixing enthalpy estimated within the conductor like screening model for real solvents (COSMO-RS) framework. The solubility improvement of potential cocrystals was estimated by formulation of the model relating experimental values to predicted solubilities. This enabled for ranking of potential cocrystals formers according to their solubility enhancement potential. According to the calculation results, a highly linear relationship (R 2 = 0.989) was found between estimated theophylline and caffeine cocrystal solubility values. It has been found that many phenolic acids, especially ones with several hydroxyl groups attached to phenyl ring, are the most promising candidates for cocrystallization with caffeine or theophylline. Experimental verification of the proposed protocol for caffeine and theophylline resulted in eight new molecular complexes, which were synthesized via a mechanochemical approach. All new solids were characterized using powder X-ray diffractometry and Fourier transform infrared spectroscopy combined with a attenuated total reflection technique.

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. Solubility increase in the presence of hydrophilic compounds is consistent with many experimental data (Brough et al, 2015;Savjani et al, 2012;Thiry et al, 2017b).…”

“…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.…”

Application of Multivariate Adaptive Regression Splines (MARSplines) for Predicting Hansen Solubility Parameters Based on 1D and 2D Molecular Descriptors Computed from SMILES String

“…e predictions based on the HSP, presented in the Tables 4 and 5, are characterized by quite good accuracy. However, it should be taken into account that, there are also other approaches which were successfully used for solubility prediction, classification, and ranking such as linear solvation energy relationship (LSER) models including the Abraham equation [112,113] and the partial solvation parameters (PSPs) approach [114,115], conductor-like screening model for real solvents (COSMO-RS) [116][117][118], UNIFAC [119][120][121], and finally (modified separation of cohesive energy density) MOSCED methodology [122,123] which is an interesting extension of the HSP method. Nevertheless, HSP are, due to their universality, still very popular in solving many solubility and miscibility problems.…”

Predicting Value of Binding Constants of Organic Ligands to Beta-Cyclodextrin: Application of MARSplines and Descriptors Encoded in SMILES String

“…Molecular complexes, such as inclusion adducts, clathrates, cocrystals and solvates, have been widely used in many fields, including pharmacy [1][2][3][4][5][6], agriculture [7], the food industry [1,8,9] and explosives [10,11]. In the past two decades, cyclodextrins (CDs) have been one of the most extensively studied complexation agents, especially as pharmaceutical excipients [12][13][14][15].…”