5-Fluorocytosine (5-FC) was crystallized with complementary dicarboxylic acids, aiming to achieve a controlled synthesis of structures based on the ΔpK a rule proposed in the salt−cocrystal continuum study and to provide structural information helpful in the comprehension of its supramolecularity. Although 5-FC tends to be basic, pK a = 3.26, only three salts are reported. In this way, new 5-FC salts were obtained, the fumaric, maleic and oxalic ones, all crystallizing in the monoclinic space group P2 1 /c. In the 5-FC oxalate and fumarate cases, the acid molecules are placed on an inversion center in a fashion that each half molecule exhibits one terminal donor−acceptor site, leading to the constitution of a 5-FC− acid−5-FC heterodimer. Such a heterodimer is observed in only one donor−acceptor site of the maleate of 5-FC, whose acid molecule exhibits a closed chain architecture. Infrared and Raman spectra recorded for the three compounds complement the salt characterization on the basis of the extent of proton transfer. Thermal analysis evidence that the salt formation decreases the melting point of the new compounds, ranking this molecule as a coformer candidate to improve the physical properties of other drugs.

5-Fluorocytosine (5-FC) was investigated for the controlled synthesis of cocrystals by applying the pK a rule. Five cocrystals were designed and developed with adipic, succinic, terephtalic, benzoic, and malic acids, all exhibiting negative ΔpK a values ranging from close to zero up to roughly −1. The synthesized cocrystals were analyzed by single crystal X-ray diffraction, and the observed supramolecular synthons were compared to the reported structures containing 5-FC. In the first four cocrystals, the intermolecular interactions between adjacent 5-FC molecules form two different homodimers showing R 2 2 (8) motifs and assembled via complementary N−H···O and N−H···N hydrogen bonds, respectively. However, in the cocrystal with malic acid (ΔpK a = −0.1), an intermediate supramolecular synthon pattern between salts and cocrystals is observed. In this crystal packing, the homodimer of 5-FC molecules held by the N−H···O interactions is preserved, but a new heterodimer is formed between 5-FC and the acid molecule, such as the ones observed for 5-FC salts. These differences were analyzed using UNI Force Field Calculations to establish the intermolecular potentials of the synthons. As an application, we synthesized a cocrystal of 5-FC with 5-fluorouracil. This can be considered the first step toward the application of 5-FC for the design of new tailor-made drugs.

In this paper, the main features of Raman spectroscopy, one of the first choice methods in the study of polymorphism in pharmaceuticals, are presented taking chlorpropamide as a case of study. The antidiabetic drug chlorpropamide (1-[4-chlorobenzenesulphonyl]-3-propyl urea), which belongs to the sulfonylurea class, is known to exhibit, at least, six polymorphic phases. These forms are characterized not only by variations in their molecular packing but also in their molecular conformation. In this study, the polymorphism of chlorpropamide is discussed on the basis of Raman scattering measurements and quantum mechanical calculations. The main spectroscopic features that fingerprint the crystalline forms are correlated with the corresponding crystalline structures. Using a theoretical approach on the energy dependence of the conformers, simulated molecular torsion angles are plotted versus the formation energy, which provides a satisfactory agreement between the torsion angles at the energy minima and the experimental values observed in the different solid forms of chlorpropamide. Copyright