Linking Aggregation in Solution, Solvation, and Solubility of Simvastatin: An Experimental and MD Simulation Study

Abstract

The solubility is generally thought to be higher if the solvent effectively solvates solute molecules that are wellseparated from each other. The present work suggests, however, that the formation of large solute aggregates does not necessarily imply less effective solvation and lower solubility. Measurements of the solubility of simvastatin (one of the most commonly prescribed antihyperlipidemic drugs) in three solvents with different polarities and protic characters, led to the solubility order acetone > ethyl acetate > ethanol, in the full temperature range covered by the experiments (283−308 K). An analysis of the structures of the different solutions on the basis of molecular dynamics simulation results indicated that this trend seems to be determined by a balance between the solute tendency toward aggregation and the ability of the solvent to efficiently solvate it, by integrating the cluster structures, regardless of their size, and effectively establishing solvent−solute interactions.

Real-Time In situ XRD Study of Simvastatin Crystallization in Levitated Droplets

“…Previous experiments carried out with pure organic solvents suggest, however, that both these effects may be significant in an evaporative crystallization process. − Their influence was, therefore, investigated in this work by adding thermographic analysis to the above mentioned techniques (X-ray diffraction, Raman spectroscopy, and imaging) and complementing the experimental information with MD simulation results. The crystallization of simvastatin (Figure ) in acetone, ethyl acetate, and ethanol was selected as a model system, due to the variety of crystalline and amorphous forms that may be obtained − and the complex solubility behavior in these solvents already characterized in a previous work …”

“…Simvastatin is a widely used API for treatment of hyperlipidemias and prevention of cardiovascular diseases − that can exist in three polymorphic forms. Form I is the thermodynamically stable one under ambient conditions. − The III/II and II/I pairs are both enantiotropically related by reversible solid–solid-phase transitions: form III → form II at 236.9 K and form II → form I at 275.2 K. , Furthermore, amorphous phases with very long lifetimes have been reported. − Information about the complexity of simvastatin solvation and aggregation processes has also been recently provided by a study combining solubility measurements in acetone, ethyl acetate, and ethanol with molecular dynamics (MD) simulations . These solvents seemed therefore appropriate for the present study due to their significantly different volatility, hygroscopicity, polarity, and protic character.…”

Water Solubility Trends in Ionic Liquids: The Quantitative Structure–Property Relationship Model versus Molecular Dynamics

“…It is difficult to use MD simulation methods to quantitively compute the solubility of water. Still, several studies demonstrated that this methodology may be used to rationalize solubility trends from the analysis of the molecular aggregation patterns in solution. − Thus, in this work, MD simulation data were explored as a qualitative approach for comparison with the QSPR results.…”

“…Although the computation of solubility values from molecular dynamics (MD) simulations is a nontrivial process, this theoretical approach has proved valuable in the rationalization of mixability trends. − Unlike QSPR, this method provides a molecular view of the interaction between the molecules in solution, enabling a physical explanation of the experimentally observed liquid–liquid phase diagrams. One approach to investigate solubility trends involves the search for aggregation patterns of molecules in solution and how these networks (or their absence) may suggest that liquid–liquid phase separation is likely to occur. , For example, if we consider the formation of water aggregates in an IL, a high probability of finding aggregates composed of many molecules of water may suggest that, most likely, the interaction between water and the IL is inefficient and a liquid–liquid phase separation may be eminent.…”

“…Although the computation of solubility values from molecular dynamics (MD) simulations is a nontrivial process, this theoretical approach has proved valuable in the rationalization of mixability trends. − Unlike QSPR, this method provides a molecular view of the interaction between the molecules in solution, enabling a physical explanation of the experimentally observed liquid–liquid phase diagrams. One approach to investigate solubility trends involves the search for aggregation patterns of molecules in solution and how these networks (or their absence) may suggest that liquid–liquid phase separation is likely to occur. , For example, if we consider the formation of water aggregates in an IL, a high probability of finding aggregates composed of many molecules of water may suggest that, most likely, the interaction between water and the IL is inefficient and a liquid–liquid phase separation may be eminent. In turn, a high probability of finding “isolated” water molecules may suggest a favorable interaction with the IL (most often the anion), indicating that the solubility limit may be far from the composition of the investigated system. , Thus, the comparison of molecular aggregation patterns obtained for solutions with the same composition, where, e.g., the cation or anion are systematically modified, can provide information about the relative solubility trends for the investigated ILs …”