CrystEngComm PAPER Cite this: DOI: 10.1039/d0ce00514b Received 4th April 2020, Accepted 13th May 2020 DOI: 10.1039/d0ce00514b rsc.li/crystengcomm Ciprofloxacin salts with benzoic acid derivatives: structural aspects, solid-state properties and solubility performance† Artem O. Surov, a Nikita A. Vasilev, a Alexander P. Voronin, a Andrei V. Churakov, b Franziska Emmerling c and German L. Perlovich * a In this work, three new pharmaceutical hydrated salts of ciprofloxacin with selected derivatives of benzoic acid, namely 4-hydroxybenzoic acid, 4-aminobenzoic acid and gallic acid, were obtained and systematically investigated by several solid-state analytical techniques. In situ Raman spectroscopy was applied to elucidate the alternative pathways of the solid forms' formation under mechanochemical conditions. Crystal structure analysis and a CSD survey allowed us to establish a distinct supramolecular motif formed by infinite columnar stacks of ciprofloxacin dimers arranged in the “head-to-tail” manner. An alternative “head-to-head” packing arrangement was only observed in the crystal of the hydrated ciprofloxacin salt with 4-aminobenzoic acid. In addition, the pH-solubility behavior of the solid forms was thoroughly investigated. Furthermore, a distinct structure–property relationship between the specific features of the supramolecular organization of the hydrated salts and their solubility was observed and discussed. 1. Introduction Ciprofloxacin (CIP) (Fig. 1) is a potent fluoroquinolone antibacterial compound, which is widely used in the treatment of various bacterial infections caused by both Gram-positive and Gram-negative bacteria. 1,2 The aqueous solubility of CIP is strongly pH-dependent and exhibits a “U-shaped” profile with an isoelectric point near the physiological pH 7.4. 3 It has been recently demonstrated that the solubility of anhydrous ciprofloxacin is also determined by solid-state issues due to strong dipole–dipole interactions between the zwitterionic molecules in the crystal. 4,5 Typically, salt formation with a suitable counterion is the most preferred solution to the problem of enhancing the aqueous solubility of such drugs in the pharmaceutical industry. In the case of CIP , salt formation makes the drug molecules in the crystal change their zwitterionic state to the cationic one, effectively reducing the lattice energy and improving the aqueous solubility. Organic counterions have gained increased attention in pharmaceutical salt formulation 6 since they are less likely to disproportionate in aqueous solutions due to a lower pK a difference 7,8 and may also show better solubility performance in gastric media compared to hydrochloride due to the common ion effect of the latter. In this context, a significant number of CIP multicomponent crystals with various organic acids have been obtained, including salts with aliphatic and aromatic carboxylic acids, 9–13 artificial sugars, 14,15 and drug–drug solid forms, 16,17 with several of them found to be polymorphic. 18–20 Recently, a few cocrystals of ciprofloxacin have been also discovered. 21,22 However, the relationship between the structural aspects of fluoroquinolone CrystEngComm This journal is © The Royal Society of Chemistry 2020 a G.A. Krestov Institute of Solution Chemistry RAS, 153045, Ivanovo, Russia. E-mail: glp@isc-ras.ru b Institute of General and Inorganic Chemistry RAS, Leninsky Prosp. 31, 119991, Moscow, Russia c Federal Institute for Materials Research and Testing (BAM), Richard-Willstaetter- Str. 11, 12489 Berlin, Germany † Electronic supplementary information (ESI) available: Details of the experiments and computations, and PXRD, Raman, DSC and TG experiments. Crystallographic data for the obtained hydrated salts (CCDC 1993397–1993399). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d0ce00514b Fig. 1 Molecular structures of ciprofloxacin and the salt formers (4-hydroxybenzoic acid, 4-aminobenzoic acid and gallic acid). Published on 14 May 2020. Downloaded on 6/15/2020 10:03:19 AM. View Article Online View Journal