Controlled Synthesis of New 5‑Fluorocytosine Cocrystals Based on the pKa Rule

5-Fluorocytosine (5-FC) was investigated for the controlled synthesis of cocrystals by applying the pKa rule. Five cocrystals were designed and developed with adipic, succinic, terephtalic, benzoic, and malic acids, all exhibiting negative ΔpKa 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 R22(8) motifs and assembled via complementary N–H···O and N–H···N hydrogen bonds, respectively. However, in the cocrystal with malic acid (ΔpKa = −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.