Thermochimica Acta 507–508 (2010) 1–8 Contents lists available at ScienceDirect Thermochimica Acta journal homepage: www.elsevier.com/locate/tca Solvent-free preparation of co-crystals of phenazine and acridine with vanillin Dario Braga ∗ , Fabrizia Grepioni, Lucia Maini, Paolo P. Mazzeo, Katia Rubini Dipartimento di Chimica “G.Ciamician”, Università degli studi di Bologna, Via Selmi 2, 40126 Bologna, Italy article info Article history: Received 1 February 2010 Received in revised form 26 April 2010 Accepted 28 April 2010 Available online 7 May 2010 Keywords: Co-crystal Polymorph screening Solvent-free reactions Thermochemistry Variable temperature X-ray diffraction Hot-stage microscopy abstract Co-crystals of phenazine and acridine with vanillin have been obtained by solvent-free reaction or ther- mal treatment of the solid reactants: their structures, thermal behaviour and eutectic formation have been investigated via single crystal X-ray diffraction, differential scanning calorimetry (DSC), variable temperature X-ray powder diffraction and hot-stage microscopy (HSM). Polymorph screening of the reagents has also been carried out. © 2010 Elsevier B.V. All rights reserved. 1. Introduction The investigation of co-crystals, namely the crystalline mate- rials obtained by the supramolecular association of two or more molecules, is at the forefront in the field of crystal engineering, because they represent a route to innovation for chemical and pharmaceutical industries [1–6]. Co-crystals often show differ- ent chemical and physical properties with respect to those of the reagents or of their mixtures; their intimate association in the solid state affects solubility, dissolution rate, chemical stability, etc. [7,8]. Undoubtedly, the most common approach exploits the hydro- gen bond as the supramolecular linker of choice to bind together the molecular components; co-crystals based on acid–base pairs are particularly favoured [9,10]. On the other hand, in co-crystals formed by molecules carrying “hydrogen bonding donor” groups, i.e. –COOH, –OH, NH, etc. and molecules carrying “hydrogen bond acceptor” groups proton transfer may occur, leading to the forma- tion of charged species, i.e. a molecular salt. There is no precise borderline between “all neutral” and “charged” hydrogen bonded systems, because the position of the hydrogen atom along the D–H···A vector depends heavily on temperature and on the time scale of the experiment used to evaluate the hydrogen position [11–13]. It is often necessary, therefore, to employ complemen- tary techniques, such as solid state NMR, to understand the nature of the hydrogen bonding interactions in co-crystals [14,15]. In this paper we report the preparation of co-crystals of acri- dine and phenazine with vanillin. Phenazine, structurally related ∗ Corresponding author. Fax: +39 051 2099456. E-mail address: dario.braga@unibo.it (D. Braga). to anthracene, is an important precursor in the synthesis of dyes such as eurhodines, toluylene red, indulines and safranines [16]. Many phenazine compounds are found in nature and are produced by bacteria [17,18]. Acridine, which possesses only one N-atom, is also used as a precursor for the production of dyes [19] and some valuable drugs [20–22]. Acridine and related derivatives bind to DNA and RNA due to their abilities to intercalate [23]. We have chosen to co-crystallize these two structurally related molecules with vanillin (see Scheme 1), a co-former carrying the relatively weak –OH hydrogen bonding donor group, able to interact with the acceptor N-sites on the rings. Vanillin is a nat- ural product extracted from the vanilla bean and, although it is mainly used as a flavouring agent in foods and beverages [24,25], recently it has been studied also for its potential anticancer effects [26,27]. This study is part of a larger investigation on the formation of co- crystals and mixed-crystals of simple substituted phenyl rings [28]. More specifically we were interested in assessing, by a combined use of single crystal and variable temperature powder diffraction and thermal techniques (DSC and HSM), whether co-crystal for- mation upon mechanical mixing of the reactants took place in the solid state or in the presence of a liquid intermediate (eutectic) phase. The mechanisms of mechanically activated processes are still a matter of much debate [29]. A polymorph screening on all reagents has also been carried out. 2. Experimentals All reagents and solvents were purchased from Aldrich and used without further purification. 0040-6031/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.tca.2010.04.021