Controlled Synthesis of New 5-Fluorocytosine Cocrystals Based on the pK_a Rule

Abstract

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.

Same or different – that is the question: identification of crystal forms from crystal structure data

“…A common understanding in chemistry is that molecular substances might crystallise into different forms broadly classified as polymorphs, 1, 2 solvates, 3 salts, co-crystals, tautomers [4][5][6][7][8][9] and solid solutions. 10,11 Other forms might appear in response to external stimuli (thermal, electromagnetic, mechanical etc.)…”

Azo⋯phenyl stacking: a persistent self-assembly motif guides the assembly of fluorinated cis-azobenzenes into photo-mechanical needle crystals

“…In order to evaluate the importance of azoÁ Á Áphenyl stacking in the crystal packing of cis-3, we calculated intermolecular potentials using the UNI force field, implemented in MercuryCSD (version 3.5.1.). 20,21 Results reveal that stacking of cis-3 is the single most dominant stabilization factor in the crystal structure, with an intermolecular potential of À34 kJ mol À1 (see ESI, † Fig. S5-S13).…”

Engineering Cocrystals of Poorly Water-Soluble Drugs to Enhance Dissolution in Aqueous Medium

“…According to Berry and Steed [ 98 ], when ∆pKa value remains close to that of a base, then the system forms a salt and when it exists close to the acid, then the system forms a cocrystal [ 98 ]. da Silva et al [ 71 ] designed and developed five 5-Fluorocytosine cocrystals with adipic, succinic, terephthalic, benzoic, and malic acid based on the ∆pKa values for API-coformer [ 71 ]. When the ∆pKa value ranges between 0 and 3 (partially ionized states), in such cases, these solid forms were referred to as Salt-cocrystal continuum [ 93 , 99 , 100 ].…”