Kinetic Insights into the Role of the Solvent in the Polymorphism of 5-Fluorouracil from Molecular Dynamics Simulations

Abstract

We investigate the fundamental factors controlling polymorphism in 5-fluorouracil by performing molecular dynamics simulations of solutions of the compound in water, nitromethane, and wet nitromethane. Analysis of the effect of solvent on the initial aggregation of 5-fluorouracil molecules shows that the strong binding of water to the 5-fluorouracil molecule hinders the formation of the doubly hydrogen-bonded dimer and, by default, promotes close hydrophobic F...F interactions that are a feature of the unusual (Z' = 4) structure of form I. In contrast, doubly hydrogen-bonded dimers are observed to form readily in solution in dry nitromethane, consistent with the crystallization of the doubly hydrogen-bonded ribbon structure of form II from this solvent. When nitromethane is doped with water, the water forms hydrogen bonds to the solute, interfering with the formation of the doubly hydrogen-bonded dimers, which is consistent with the crystallization of form I from this hygroscopic solvent when it is not dried. Overall, the molecular dynamics simulations provide an atomistic picture of how solvent-solute interactions can significantly affect the initial association of 5-fluorouracil molecules to the extent that they determine the polymorphic outcome of the crystallization.

Solvent Effect on the Singlet Excited-state Dynamics of 5-Fluorouracil in Acetonitrile as Compared with Water

“…10 Our model is confirmed by the results of a recent MD study of 5-fluorouracil, where no indication of hydrogen bonding between the fluorine atom and water hydrogens was found. 23 Here we only treat the diketo form of 5FU. This is the most stable form in the electronic ground state, 24,25 and the only tautomer identified in solution and in the gas phase.…”

Structures and Hydrogen Bonding Recognition of Mefenamic Acid Form I Crystals in Mefenamic Acid/ Ethanol Solution

“…Molecular dynamics simulation method is a computational experiment conducted on a Manuscript received March 10, 2013 targeted molecular model with the aim to simulate the behavior of molecules [9]- [11]. From pharmaceutical point of view, molecular dynamics simulation plays an important role to increase an understanding of crystallization process and mechanism leads to production of different polymorphs [12].Fourier transform infrared (FTIR) spectroscopy, on the other hand, is a recognized method used to obtain an infrared spectrum of absorption, emission, photoconductivity or Raman scattering of a solid, liquid or gas [13]. Based on the extensive literature review, a new approach is adopted in this study, which is based on molecular dynamics simulation and FTIR spectroscopy analyses for a mixture of mefenamic acid and ethanol.…”

Capturing the Role of Temperature and Entropy in Crystal Polymorphs Through Molecular Simulations

“…Each participant in the challenge can use any computational methods necessary to predict the correct structure and are allowed to submit 3 proposed structures for Ultimately, the recent blind crystal prediction studies demonstrate that current computational methods are capable of identifying the true experimentally preferred structure. Furthermore, the insight from computer models can occasionally guide the experimental synthesis procedure to crystallize the new stable solid forms [54,89,106]. These computational successes reveal the potential for computer-aided crystal structure prediction in screening for all solid forms of a given material.…”

“…Properties than can change between polymorphs include density [11,20,31], compressibility [32], hardness [33,34], gel strength [35], flexibility [36], conductivity [26][27][28][29][30][37][38][39], explosivity [20,[22][23][24], catalytic activity [40,41], transparency [42,43], weather resistance [25,44], heat capacity [20], melting point [32,45,46], vapor pressure [46], stability [25,29], solubility [14,[47][48][49], bioavailability [14,33,48,[50][51][52][53][54], and dissolution rate [47,55,56].…”

“…The scientifically alluring aspect of polymorphic solids is that a material's properties can be greatly influenced by the specific crystal structure that it is currently adopting. In the example [14,33,48,[50][51][52][53][54], and dissolution rate [47,55,56].…”