Experimental and Computational Hydrate Screening: Cytosine, 5-Flucytosine, and Their Solid Solution

Abstract

The structural, temperature- and moisture dependent stability features of cytosine and 5-flucytosine monohydrates, two pharmaceutically important compounds, were rationalized using complementary experimental and computational approaches. Moisture sorption/desorption, water activity, thermal analysis and calorimetry were applied to determine the stability ranges of hydrate ↔ anhydrate systems, while X-ray diffraction, IR spectroscopy and crystal structure prediction provided the molecular level understanding. At 25 °C, the critical water activity for the cytosine hydrate ↔ anhydrate system is ~0.43 and for 5-flucytosine ~0.41. In 5-flucytosine the water molecules are arranged in open channels, therefore the kinetic desorption data, dehydration < 40% relative humidity (RH), conform with the thermodynamic data, whereas for the cytosine isolated site hydrate dehydration was observed at RH < 15%. Peritectic dissociation temperatures of the hydrates were measured to be 97 °C and 84.2 °C for cytosine and 5-flucytosine, respectively, and the monohydrate to anhydrate transition enthalpies to be around 10 kJ mol–1. Computed crystal energy landscapes not only revealed that the substitution of C5 (H or F) controls the packing and properties of cytosine/5-flucytosine solid forms, but also have enabled the finding of a monohydrate solid solution of the two substances which shows increased thermal- and moisture-dependent stability compared to 5-flucytosine monohydrate.

Prediction and experimental validation of solid solutions and isopolymorphs of cytosine/5-flucytosine

“…1), we reported a monohydrate solid solution of these two substances. Preliminary dehydration studies of this monohydrate indicated the formation of two distinct solid forms with powder X-ray diffraction and IR spectroscopy data showing structural resemblance with the data of the two known 5-flucytosine anhydrates 30. This observation motivated us to take a closer look at the existence of isomorphic phases and isopolymorphs in this binary system.…”

“…Also, 5-flucytosine shows anhydrate polymorphism ( F-I : MEBQEQ01 (ref. 41) and F-II : MEBQEQ41) and a rich solvate/hydrate crystal form landscape: hemihydrate,42 two monohydrates,41 hemipentahydrate41 and six solvates (methanol,41 ethanol,30 2,2,2-trifluoroethanol,41 dimethyl acetamide,42 dimethyl sulfoxide42 and dimethyl formamide30).…”

“…The insolubility in most organic solvents as well as hydrate formation and decomposition at higher temperatures drastically limits the experimental space for polymorphism screens of each of the two compounds and also for co-crystals or solid solutions thereof. Our experimental screens30 (sections 2.3–2.5 of the ESI†) were limited to sublimation, slurry and dehydration studies and were therefore complemented with computational searches, CSP, for anhydrate (cytosine and 5-flucytosine) and 1 : 1 co-crystals. The crystal energy landscapes ( Z ′ = 1 & 2) for cytosine and 5-flucytosine, as well as the 1 : 1 cytosine/5-flucytosine crystal energy landscape ( Z ′ = 1) were generated by searches for the low energy minima of the keto tautomer on the lattice energy surface,43–46 and the final lattice energies were evaluated using DFT-D calculations 47–51.…”

Transformation of terahertz vibrational modes of cytosine under hydration

“…The lengths of the hydrogen bonds between the C ketone groups and the hydrogen atoms of water molecules were 1.781 Å for O1⋯H21-O5 and 1.735 Å for O1⋯H27-O7. The C-MH hydrogen bonds were stronger and more abundant than those of C, which leads to different intermolecular interactions of C molecules and a more stable crystal structure with new cell parameters, i.e., the co-crystallization process 12,44 . Also, a change in the molecule's environment and conformation leads to a characteristic change in the THz spectra.…”

Accurate and efficient representation of intramolecular energy in ab initio generation of crystal structures. II. Smoothed intramolecular potentials

“…The above strategy has been deployed successfully in the blind tests and in the prediction of the crystal structures of pharmaceutically relevant molecules (Braun et al, 2016(Braun et al, , 2017Price et al, 2016). However, in view of the need to tackle ever larger and more flexible molecules of pharmaceutical interest, further improvements to the efficiency of the algorithms are required.…”