Controlled Synthesis of New 5-Fluorocytosine Cocrystals Based on the pK(a) Rule

Author(s)

da Silva, Cecilia C. P. ^[1] ; Pepino, Rebeka de O. ^[1] ; de Melo, Cristiane C. ^[1] ; Tenorio, Juan C. ^[1] ; Ellena, Javier ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Fis Sao Carlos, BR-13560970 Sao Paulo - Brazil

• Document type: Journal article
• Source: Crystal Growth & Design; v. 14, n. 9, p. 4383-4393, SEP 2014.
• Web of Science Citations: 21

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 Delta pK(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 center dot center dot center dot O and N-H center dot center dot center dot N hydrogen bonds, respectively. However, in the cocrystal with malic acid (Delta pK(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 center dot center dot center dot 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. (AU)

• FAPESP's process: 13/07581-9 - Design, Synthesis and Characterization of New Solid Forms of Anti-HIV Drugs.
• Grantee: Juan Carlos Tenorio Clavijo
• Support Opportunities: Scholarships in Brazil - Doctorate