**4. Conclusions**

A new itraconazole cocrystal was produced using terephthalic acid, which is the first aromatic coformer described as being able to cocrystallise with ITR. The elucidation of the crystalline structure of the ITR–TER cocrystal revealed that this new form is similar to other known ITR cocrystals with a 2:1 stoichiometry, where the ITR molecules are in an antiparallel arrangemen<sup>t</sup> and the coformer is "trapped" in the space formed between the two ITR molecules. However, this supramolecular arrangemen<sup>t</sup> had a di fferent heterosynthon in comparison to the existing cocrystals based on aliphatic dicarboxylic acids with an additional H-bond stabilizing the structure.

A comparison of the dissolution behavior of the various forms of ITR, including crystalline ITR, freeze dried ITR and ITR cocrystals with oxalic acid, succinic acid and terephthalic acid, showed that they had di fferent dissolution characteristics. FD ITR showed a remarkable improvement in terms of its dissolution, considering IDR and the powder dissolution in relation to crystalline ITR. This was due to the high energy state of the API achieved by freeze drying. For the cocrystals, their IDR values and powder dissolution profiles correlated with the aqueous solubility of the coformers. The rank order of the dissolution rates of the API from the cocrystals was ITR–OXA > ITR–SUC > ITR–TER. Furthermore, physically mixing FD ITR, ITR–OXA and ITR–SUC with the same excipients as those present in the Sporanox® formulation enhanced the stability of these forms in the dissolution media, preventing their transformation into the crystalline parent API.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/1999-4923/12/8/741/s1, Figure S1: (**a**) PXRD patterns of itraconazole (ITR) and oxalic acid (OXA) starting material powders and the ITR–OXA cocrystal produced by ball milling (BM). **\*** Indicates distinct peaks of the cocrystal. (**b**) DSC thermograms of ITR and OXA starting material powders and the ITR–OXA cocrystal, Figure S2: (**a**) PXRD patterns of the itraconazole (ITR) and succinic acid (SUC) starting material powders and the ITR–SUC cocrystal produced by ball milling (BM). **\*** Indicates distinct peaks of the cocrystal. (**b**) DSC thermograms of the ITR and SUC starting material powders and the ITR–SUC cocrystal, Figure S3: Scanning electron micrographs of (**a**) the ITR–SUC cocrystal and (**b**) ITR–OXA cocrystal produced by ball milling; (**c**) freeze dried ITR, Figure S4: (**a**) PXRD pattern of freeze dried itraconazole (ITR FD) and (**b**) DSC thermogram of freeze dried itraconazole (ITR FD), Table S1: Crystal data and structure refinement for the ITR–TER cocrystal, Table S2: Hydrogen bonds for ITR–TER cocrystal [Å and ◦]. Crystallographic data, deposition number 2015894, were deposited with the Cambridge Crystallographic Data Centre. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.

**Author Contributions:** Conceptualization, R.M.C. and L.T.; methodology, R.M.C., T.B., J.B., B.T., O.D., L.T.; formal analysis, R.M.C., T.B., B.T., L.T.; investigation, R.M.C., T.B., J.B., B.T., M.J.S.-M., O.D., L.T.; resources, J.B., O.D., L.T.; data curation, R.M.C., T.B., E.T., B.T., O.D., L.T.; writing—original draft preparation, R.M.C., L.T.; writing—review and editing, T.B., J.B., B.T., M.J.S.-M., O.D., L.T.; visualization, R.M.C., B.T., L.T.; supervision, J.B., E.T., M.J.S.-M., O.D., L.T.; project administration, L.T.; funding acquisition, R.M.C., L.T. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) under the agreemen<sup>t</sup> number 99999.001482/2015-07, the Synthesis and Solid State Pharmaceutical Centre (SSPC), financed by a research gran<sup>t</sup> from Science Foundation Ireland (SFI) and co-funded under the European Regional Development Fund (grant number 12/RC/2275) and the European Union's Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie gran<sup>t</sup> agreemen<sup>t</sup> No. 778051.

**Conflicts of Interest:** The authors declare no conflict of interest. T.B., J.B., E.T. and O.D. are employees of the Zentiva, k.s. The company had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
