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Exploring the Cocrystallization Potential of Urea and Benzamide

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Exploring the Cocrystallization Potential of Urea and Benzamide JMolModel (2016) 22:103 DOI 10.1007/s00894-016-2964-6 ORIGINAL PAPER Exploring the cocrystallization potential of urea and benzamide Piotr Cysewski1 & Maciej Przybyłek1 & Dorota Ziółkowska 2 & Karina Mroczyńska2 Received: 14 November 2015 /Accepted: 14 March 2016 # The Author(s) 2016. This article is published with open access at Springerlink.com Abstract The cocrystallization landscape of benzamide and defined by excess thermodynamic functions, and all known urea interacting with aliphatic and aromatic carboxylic acids cocrystals are outside of this range belonging to the third or was studied both experimentally and theoretically. Ten new fourth quartile. On the contrary, such a simple separation of cocrystals of benzamide were synthesized using an oriented positive and negative cases of benzamide miscibility in the samples approach via a fast dropped evaporation technique. solid state is not observed. The difference in properties be- Information about types of known bi-component cocrystals tween urea and benzamide R2,2(8) heterosynthons is also augmented with knowledge of simple binary eutectic mixtures documented by alterations of substituent effects. was used for the analysis of virtual screening efficiency Intermolecular interactions of urea with para substituted among 514 potential pairs involving aromatic carboxylic acids benzoic acid analogues are stronger compared to those of interacting with urea or benzamide. Quantification of intermo- benzamide. Also, the amount of charge transfer from amide lecular interaction was achieved by estimating the excess ther- to aromatic carboxylic acid and vice versa is more pronounced modynamic functions of binary liquid mixtures under for urea. However, in both cases, the greater the electron with- supercooled conditions within a COSMO-RS framework. drawing character of the substituent, the higher the binding The smoothed histograms suggest that slightly more potential energy, and the stronger the supermolecule polarization via the pairs of benzamide are characterized in the attractive region charge transfer mechanism. compared to urea. Finally, it is emphasized that prediction of cocrystals of urea is fairly direct, while it remains ambiguous Keywords Cocrystals . Eutectic . Binary mixtures . for benzamide paired with carboxylic acids. The two known Screening . Heat of mixing . COSMO-RS . Molecular simple eutectics of urea are found within the first two quartiles descriptors This paper belongs to Topical Collection MIB 2015 (Modeling Interaction in Biomolecules VII) Introduction Electronic supplementary material The online version of this article (doi:10.1007/s00894-016-2964-6) contains supplementary material, Cocrystals represent an interesting and practically important which is available to authorized users. subgroup of multicomponent solids. By definition, they are homogenous crystalline systems containing stoichiometric * Piotr Cysewski amounts of one or more neutral molecular species, which are [email protected] in the solid state under ambient temperature and pressure con- ditions [1]. Consequently, species such as clathrates, solvates and salts are not usually classified as cocrystals. It is worth 1 Department of Physical Chemistry, Faculty of Pharmacy, Collegium Medicum of Bydgoszcz, Nicolaus Copernicus University in Toruń, mentioning that cocrystallization has been used widely in Kurpińskiego 5, 85-950 Bydgoszcz, Poland many fields, including the agrochemistry, electronics, textile 2 Research Laboratory, Faculty of Chemical Technology and and pharmaceutical industries. The latter probably accounts Engineering, University of Technology and Life Sciences in for their the most valuable applications [2]. Supramolecular Bydgoszcz, Seminaryjna 3, 85-326 Bydgoszcz, Poland synthesis has been applied mainly to overcome the poor 103 Page 2 of 10 J Mol Model (2016) 22:103 2 solubility of active pharmaceutical ingredients (API) [3], and RCOOH⋯H2NCOR’ R 2(8) heterosynthon stabilities consequently improve their bioavailability, mechanical prop- and charge transfer were explained. erties [4], stability [5] and other physicochemical properties. There are several efficient methods of cocrystal prepara- tion, such as solvent-assisted grinding [6–8], anti-solvent crys- Methods tallization [9–11], slurry cocrystallization [12–14] and solvent evaporation [15, 16] approaches. Generally speaking, Chemicals cocrystal preparation methods can be divided into two cate- gories, namely kinetic (fast crystal growth) and thermodynam- All chemicals in this study were of analytical grade and were ic (slow crystallization) [17–19]. Notably, grinding is the used as received without further purification. Urea (U, CAS: oldest method of cocrystal preparation, and was used for syn- 57-13-6), benzamide (B, CAS: 55-21-0), oxalic acid (OA, thesis of the very first molecular complex formed by hydro- CAS: 144-62-7), benzoic acid (BA, CAS: 65-85-0), salicylic quinone and quinone [20]. Particularly interesting are methods acid (SA, CAS: 69-72-7), 3-hydroxybenzoic acid (3HBA, like spray drying [21–23] and droplet evaporative crystalliza- CAS: 99-06-9), 2,5-dihydroxybenzoic acid (2,5DHBA, tion (DEC) [24] that involve evaporation of small amounts of gentisic acid, CAS: 490-79-9), 2,6-dihydroxybenzoic acid solution. They are efficient, fast, environmentally friendly and (2,6DHBA, γ-resorcylic acid, CAS:303-07-1), acetylsalicylic cost preserving, as documented in our previous studies acid (ASA, CAS: 50-78-2) and methanol (CAS: 67-56-1) [24–26]. The formation of oriented crystallite samples on were purchased from POCH (Gliwice, Poland). Malonic acid glass surfaces can be analyzed successfully with the aid of (MOA, CAS: 141-82-2), maleic acid (MEA, CAS: 110-16-7), instrumental methods such as powder X-ray diffraction fumaric acid (FA, CAS: 110-17-8), succinic acid (SUA, CAS: (PXRD) and attenuated total reflectance Fourier transform 110-15-6), glutaric acid (GA CAS: 110-94-1), 4- infrared spectroscopy (ATR-FTIR). The main advantage of hydroxybenzoic acid (4HBA, CAS: 99-96-7), 3,5- PXRD measurements of oriented samples is the enhancement dihydroxybenzoic acid (3,5DHBA, CAS: 99-10-5) and 2,4- of the intensity of diffraction signals coming from the dihydroxybenzoic acid (2,4DHBA, β-resorcylic acid, cocrystal and the decrease in most of the other signals corre- CAS:89-86-1) were obtained from Sigma-Aldrich (St. Louis, sponding to the coformers [26]. MO). Amides such as nicotinamide, isonicotinamide and hydroxybenzamides are often used as coformers of pharma- Experimental procedure ceutical multicomponent crystals [18, 27, 28]. However, it has been proved that, in the case of substituted analogues of The samples used for cocrystal screening were prepared via benzamide-benzoic acid pairs, cocrystals are formed only if the DEC approach, as described in detail in our previous stud- substitution of the benzoic acid moiety is done with electron- ies [24–26]. This simple procedure, validated and successfully withdrawing functional groups [29]. This indicates that the applied for cocrystal screening, consists of the three following ability of benzamide to form cocrystals is limited. Urea, on steps. Firstly, the methanolic solutions of the solid mixtures the other hand, can easily form molecular complexes in the components were prepared and mixed together in equimolar solid state, as evidenced by the large number of cocrystal proportions. Then, 20 μl of the mixtures and pure components structures deposited in the Cambridge Structural Database solutions were placed on glass microscope slides and left to (CSD) [30]. This high potential of cocrystal formation of urea evaporate under conditions of 43 °C and atmospheric pres- can be explained by the fact that it possess both good hydro- sure. Finally, the crystallite layers thus formed were analyzed gen bond (HB) donor and acceptor capabilities. However, directly on the slide using PXRD and ATR-FTIR. These mea- only a few cocrystal structures of urea with aromatic carbox- surements were performed with the help of a Goniometer ylic acids can be found in CSD, for example with salicylic PW3050/60 equipped with an Empyrean XRD tube Cu LFF acid (SLCADC), 3,5-dinitrosalicylic acid (NUHYAQ), 1,1- DK303072 and Bruker Alpha-PFT-IR spectrometer (Bruker, binaphthyl-2,2′-dicarboxylic acid (ROGKOO), trimesic acid Karlsruhe, Germany) combined with an attenuated total re- (CEKSIU), o-phthalic acid (NUHYIY) and 5-nitrosalicylic flection (ATR) diamond device. acid (NUHXUJ). The aim of this paper was threefold. Firstly, a simple Computations cocrystallization method developed by our group was ap- plied to extend the cocrystallization landscape of urea and The computations performed relied on the assumption that benzamide with carboxylic acids. Secondly, the applica- intermolecular interactions responsible for formation of inter- bility of post-quantum chemistry approach within molecular molecular complexes in the solid state can be esti- COSMO-RS framework for theoretical cocrystal screen- mated reliably based on mixing thermodynamic functions ing was considered. Finally, substituents effects on characterizing the super cooled liquid solution obtained after JMolModel (2016) 22:103 Page 3 of 10 103 mixing of components at a specific stoichiometric ratio under alternative one assuming that the entropy of mixing is also ambient conditions. Thus, negative values of mixing enthalpy negligible. Thus, for further characterization of cocrystals or Gibbs free energy are thought to indicate that the mixture
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