The antifungal drug 5-fluorocytosine (4-amino-5-fluoro-1,2-dihydropyrimidin-2-one) was cocrystallized with five complementary compounds in order to better understand its drug-receptor interaction. The first two compounds, 2-aminopyrimidine (2-amino-1,3-diazine) and N-acetylcreatinine (N-acetyl-2-amino-1-methyl-5H-imidazol-4-one), exhibit donor-acceptor sites for R(2)(2)(8) heterodimer formation with 5-fluorocytosine. Such a heterodimer is observed in the cocrystal with 2-aminopyrimidine (I); in contrast, 5-fluorocytosine and N-acetylcreatinine [which forms homodimers in its crystal structure (II)] are connected only by a single hydrogen bond in (III). The other three compounds 6-aminouracil (6-amino-2,4-pyrimidinediol), 6-aminoisocytosine (2,6-diamino-3H-pyrimidin-4-one) and acyclovir [acycloguanosine or 2-amino-9-[(2-hydroxyethoxy)methyl]-1,9-dihydro-6H-purin-6-one] possess donor-donor-acceptor sites; therefore, they can interact with 5-fluorocytosine to form a heterodimer linked by three hydrogen bonds. In the cocrystals with 6-aminoisocytosine (Va)-(Vd), as well as in the cocrystal with the antiviral drug acyclovir (VII), the desired heterodimers are observed. However, they are not formed in the cocrystal with 6-aminouracil (IV), where the components are connected by two hydrogen bonds. In addition, a solvent-free structure of acyclovir (VI) was obtained. A comparison of the calculated energies released during dimer formation helped to rationalize the preference for hydrogen-bonding interactions in the various cocrystal structures.

The antibiotic nitrofurantoin {systematic name: (E)-1-[(5-nitro-2-furyl)methylideneamino]imidazolidine-2,4-dione} is not only used for the treatment of urinary tract infections, but also illegally applied as an animal food additive. Since derivatives of 2,6-diaminopyridine might serve as artificial receptors for its recognition, we crystallized one potential drug-receptor complex, nitrofurantoin-2,6-diacetamidopyridine (1/1), C(8)H(6)N(4)O(5)·C(9)H(11)N(3)O(2), (I·II). It is characterized by one N-H···N and two N-H···O hydrogen bonds and confirms a previous NMR study. During the crystallization screening, several new pseudopolymorphs of both components were obtained, namely a nitrofurantoin dimethyl sulfoxide monosolvate, C(8)H(6)N(4)O(5)·C(2)H(6)OS, (Ia), a nitrofurantoin dimethyl sulfoxide hemisolvate, C(8)H(6)N(4)O(5)·0.5C(2)H(6)OS, (Ib), two nitrofurantoin dimethylacetamide monosolvates, C(8)H(6)N(4)O(5)·C(4)H(9)NO, (Ic) and (Id), and a nitrofurantoin dimethylacetamide disolvate, C(8)H(6)N(4)O(5)·2C(4)H(9)NO, (Ie), as well as a 2,6-diacetamidopyridine dimethylformamide monosolvate, C(9)H(11)N(3)O(2)·C(3)H(7)NO, (IIa). Of these, (Ia), (Ic) and (Id) were formed during cocrystallization attempts with 1-(4-fluorophenyl)biguanide hydrochloride. Obviously nitrofurantoin prefers the higher-energy conformation in the crystal structures, which all exhibit N-H···O and C-H···O hydrogen-bond interactions. The latter are especially important for the crystal packing. 2,6-Diacetamidopyridine shows some conformational flexibility depending on the hydrogen-bond pattern.

In order to better understand the interaction between the pharmaceutically active compound 5-fluorocytosine [4-amino-5-fluoropyrimidin-2(1H)-one] and its receptor, hydrogen-bonded complexes with structurally similar bonding patterns have been investigated. During the cocrystallization screening, three new pseudopolymorphs of 5-fluorocytosine were obtained, namely 5-fluorocytosine dimethyl sulfoxide solvate, C(4)H(4)FN(3)O.C(2)H(6)OS, (I), 5-fluorocytosine dimethylacetamide hemisolvate, C(4)H(4)FN(3)O.0.5C(4)H(9)NO, (II), and 5-fluorocytosine hemihydrate, C(4)H(4)FN(3)O.0.5H(2)O, (III). Similar hydrogen-bond patterns are observed in all three crystal structures. The 5-fluorocytosine molecules form ribbons with repeated R(2)(2)(8) dimer interactions. These dimers are stabilized by N-H...N and N-H...O hydrogen bonds. The solvent molecules adopt similar positions with respect to 5-fluorocytosine. Depending on the hydrogen bonds formed by the solvent, the 5-fluorocytosine ribbons form layers or tubes. A database study was carried out to compare the hydrogen-bond pattern of compounds (I)-(III) with those of other (pseudo)polymorphs of 5-fluorocytosine.

Two flexible molecules, biuret and 6-acetamidouracil, were cocrystallized with 5-fluorocytosine to study their conformational preferences. In the cocrystal with 5-fluorocytosine (I), biuret exhibits the same conformation as in its hydrate. In contrast, 6-acetamidouracil can adopt two main conformations depending on its crystal environment: in crystal (II) the trans form characterized by an intramolecular hydrogen bond is observed, while in the cocrystal with 5-fluorocytosine (III), the complementary binding induces the cis form. Three cocrystals of 6-methylisocytosine demonstrate that complementary binding enables the crystallization of a specific tautomer. In the cocrystals with 5-fluorocytosine, (IVa) and (IVb), only the 3H tautomer of 6-methylisocytosine is present, whereas in the cocrystal with 6-aminoisocytosine, (V), the 1H tautomeric form is adopted. The complexes observed in the cocrystals are stabilized by three hydrogen bonds similar to those constituting the Watson-Crick C·G base pair.

Hydantoin-5-acetic acid [2-(2,5-dioxoimidazolidin-4-yl)acetic acid] and orotic acid (2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid) each contain one rigid acceptor-donor-acceptor hydrogen-bonding site and a flexible side chain, which can adopt different conformations. Since both compounds may be used as coformers for supramolecular complexes, they have been crystallized in order to examine their conformational preferences, giving solvent-free hydantoin-5-acetic acid, C(5)H(6)N(2)O(4), (I), and three crystals containing orotic acid, namely, orotic acid dimethyl sulfoxide monosolvate, C(5)H(4)N(2)O(4)·C(2)H(6)OS, (IIa), dimethylammonium orotate-orotic acid (1/1), C(2)H(8)N(+)·C(5)H(3)N(2)O(4)(-)·C(5)H(4)N(2)O(4), (IIb), and dimethylammonium orotate-orotic acid (3/1), 3C(2)H(8)N(+)·3C(5)H(3)N(2)O(4)(-)·C(5)H(4)N(2)O(4), (IIc). The crystal structure of (I) shows a three-dimensional network, with the acid function located perpendicular to the ring. Interestingly, the hydroxy O atom acts as an acceptor, even though the carbonyl O atom is not involved in any hydrogen bonds. However, in (IIa), (IIb) and (IIc), the acid functions are only slightly twisted out of the ring planes. All H atoms of the acidic functions are directed away from the rings and, with respect to the carbonyl O atoms, they show an antiperiplanar conformation in (I) and synperiplanar conformations in (IIa), (IIb) and (IIc). Furthermore, in (IIa), (IIb) and (IIc), different conformations of the acid O=C-C-N torsion angle are observed, leading to different hydrogen-bonding arrangements depending on their conformation and composition.