Energetics and structure of simvastatin

Area of Science:

• Physical Chemistry
• Pharmaceutical Sciences
• Computational Chemistry

Background:

• Understanding structure-energetics relationships is vital for active pharmaceutical ingredient production and drug safety.
• Simvastatin, a widely prescribed cholesterol-lowering drug, is the focus of this investigation.

Purpose of the Study:

• To investigate the structure-energetics of simvastatin in crystalline, liquid, and gaseous phases.
• To determine the stable crystalline form and phase enthalpies of simvastatin.
• To correlate molecular conformation with phase behavior.

Main Methods:

• Combined experimental techniques: combustion calorimetry and differential scanning calorimetry (DSC).
• Computational chemistry methods: quantum chemistry (B3LYP-D3/cc-pVTZ) and molecular dynamics simulations.
• Analysis of crystalline form I, liquid, and gaseous states of simvastatin.

Main Results:

• DSC confirmed no polymorphism in crystalline simvastatin between 293 K and fusion.
• Quantum chemistry calculations showed the gas-phase conformation matches the crystal phase.
• Molecular dynamics simulations accurately reproduced crystal structure and indicated conformational changes upon melting.
• Enthalpies of formation were determined for crystalline, liquid, and gaseous simvastatin at 298.15 K.

Conclusions:

• The stable crystalline form of simvastatin was identified and characterized.
• Conformational preferences in the solid state are lost in the liquid phase.
• Accurate thermodynamic data (enthalpies of formation) were obtained for different phases of simvastatin.