Abstract
In this work, we describe the successful preparation of a series of cocrystals of the modified nucleobase 1-ethyluracil with different coformers in a 1:1 or 2:1 (nucleobase:coformer) ratio including urea (URE) or some compounds containing carboxylic and hydroxyl groups such as l-malic acid (MAL), l-tartaric acid (TAR), 2-hydroxybenzoic acid (SAL), 4-hydroxybenzoic acid (4HB), and 2,4-dihydroxybenzoic acid (DHB). The influence of the hydroxyl substituent on the alkyl chain for 1·TAR and 1·SAL cocrystals or the phenyl ring for 1·SAL, 1·4HB, and 1·DHB multicomponent solids was studied. All of the compounds were characterized by powder X-ray diffraction, FT-IR, and thermal methods. Moreover, for those whose single-crystal structures could be determined, computational studies were also performed to investigate the factors that may affect the cocrystal formation, the recurrent motifs, and the energies associated with the H-bonding interactions using DFT calculations and a combination of the quantum theory of atoms in molecules (QTAIM) and the noncovalent interaction index (NCIplot) computational tools.
Highlights
Not just active pharmaceutical ingredients and energetic materials have been studied from a crystal engineering point of view
This is the case for the modified uracils: 6chlorouracil and 6-chloro-3-methyluracil,22 6-methyl-2-thiouracil,[23] orotic and isoorotic acids,[24] and the well-known antineoplastic agent 5-fluorouracil[5,25−31] and its analogue, tegafur.[32]
We explore the ability of 1-ethyluracil (1), a modified uracil with a N−H group blocked as observed in many other known APIs, as a new scaffold for cocrystallization by liquid-assisted grinding (LAG) and solvent crystallization
Summary
Crystal engineering has emerged as a predictive tool for studying and understanding the arrangement of molecules, giving birth to different solid materials with modified physicochemical properties and performances.[1,2] Especially in the pharmaceutical industry and in other areas such as energetic materials, the objective has been to overcome undesirable properties (chemical instability, low solubility, hygroscopicity, untableting, ...) before the commercialization of drugs or to ameliorate the viability of the available explosives.[3,4] traditionally polymorphic and salt screenings have been the selected methods for exploring these versatile solid materials, more recently cocrystals have reemerged as useful alternatives.[5,6] Cocrystals are defined as multicomponent solids in which individual molecules are held together by noncovalent interactions, often hydrogen bonds as well as halogen bonding,[7−10] and π−π stacking interactions. Uracil and its derivatives contain N− H and C O groups, which are suitable hydrogen-bonding donors and acceptors, respectively, and could result in strong hydrogen-bonded synthons.[6] Up to now, several uracil derivatives have been described for cocrystallization with other nucleobases[18−21] or with several small molecules used as coformers This is the case for the modified uracils: 6chlorouracil and 6-chloro-3-methyluracil,22 6-methyl-2-thiouracil,[23] orotic and isoorotic acids,[24] and the well-known antineoplastic agent 5-fluorouracil[5,25−31] and its analogue, tegafur.[32]. The presence of malic and tartaric acids is very common in some fruits (pears, bananas, apples, and grapes). 2-Hydroxybenzoic acid, known as salicylic acid, is a recognized drug used for aches and pain treatment, and its structural isomer, 4-hydroxybenzoic acid, is used as a flavoring or adjuvant agent and has antioxidant properties.[34]
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