Importance of Solvent Selection for Stoichiometrically Diverse Cocrystal Systems: Caffeine/Maleic Acid 1:1 and 2:1 Cocrystals

Abstract

Phase diagrams of cocrystals often show a highly unsymmetrical nature. The solvent has an important impact on the overall aspect of these diagrams. In this paper, we show how the solvent affects the composition of the stoichiometric solid phase nucleated. Suitable conditions for nucleation and growth of a single 2:1 caffeine/maleic acid cocrystal are obtained in ethyl acetate, showing comparable solubility toward both caffeine and maleic acid. Through a full kinetic screen, we were able to identify, for the first time, reproducible conditions for the spontaneous crystallization of the 2:1 phase in solution. Furthermore, during the screening experiments, a hithertho unknown form of the 1:1 cocrystal phase was encountered. Structural X-ray diffraction analyses of both the 2:1, as well as the 1:1 polymorphic phases, show an out of plane maleic acid compound. The carboxylic acid groups are oriented in such a manner to promote intermolecular formation of hydrogen bonded synthons

Synthesis of Caffeine/Maleic Acid Co-crystal by Ultrasound-assisted Slurry Co-crystallization

“…5,6,7 Similarly, the caffeine/maleic acid 2:1 co-crystal observed in the current study can be assumed to be formed due to high levels of supersaturation achieved mainly because of slurry co-crystallization.…”

“…Caffeine -dicarboxylic acid is the most studied co-crystal pair showing non-congruency. [3][4][5][6][7][8] Several approaches have been used to overcome the non-congruent solubility of co-crystal components. Friščić et al 4 carried out ultrasound assisted slurry cocrystallization experiments using different organic solvents for caffeine with l-malic acid or l-tartaric acid.…”

Hydrogen Bond Synthons in the Interplay of Solubility and Membrane Permeability/Diffusion in Variable Stoichiometry Drug Cocrystals

“…14 The effects of crystallization solvent on the composition of urea•succinic acid (1:1 & 2:1) cocrystals has been demonstrated. 20,21 The solid stoichiometric interconversion, solvent-mediated conversion for pyrazinamide•pnitrobenzoic acid with two stoichiometric cocrystals in 1:1 and 2:1 ratio are also reported. 15 -III IC CC-VI Dioxane 1:1 IC IC IC 1:2 IC IC IC 2:1 IC IC IC Diethyl ether 1:1 IC IC IC 1:2 IC IC IC 2:1 IC IC IC Dichloromethane 1:1 IC CC-V VI 1:2 IC CC-V* CC-VI* 2:1 IC CC-V* CC-VI* Chloroform 1:1 IC CC-V* IC 1:2 IC CC-V* IC 2:1 IC CC-V* IC Acetone 1:1 IC IC IC 1:2 IC IC IC 2:1 IC IC IC Acetic acid 1:1 IC IC IC 1:2 IC IC IC 2:1 IC IC IC Tetrahydrofuran 1:1 IC IC IC 1:2 IC IC IC 2:1 IC IC IC 1-Propanol 1:1 CC-I CC-V CC-VI …”

Solution mediated phase transformations between co-crystals

“…Construction of the TPD for malic acid/caffeine/ethyl acetate allowed for the controlled growth of the 1:2 co-crystal. 22 For polymorphic systems, solution mediated transformations are an important process for the conversion of metastable phases 85 into stable crystalline phases. 23,24 While the general mechanism is the dissolution of the metastable phase and regrowth of the stable one, these conversions may also occur through heterogeneous nucleation driven by an epitaxial interaction between the two phases due to similarities in selected surfaces of the two forms.…”