Polymorphism in Simvastatin: Twinning, Disorder, and Enantiotropic Phase Transitions

Abstract

Simvastatin is one of the most widely used active pharmaceutical ingredients for the treatment of hyperlipidemias. Because the compound is employed as a solid in drug formulations, particular attention should be given to the characterization of different polymorphs, their stability domains, and the nature of the phase transitions that relate them. In this work, the phase transitions delimiting the stability domains of three previously reported simvastatin forms were investigated from structural, energetics, and dynamical points of view based on single crystal X-ray diffraction (SCXRD), hot stage microscopy (HSM), and differential scanning calorimetry (DSC) experiments (conventional scans and heat capacity measurements), complemented with molecular dynamics (MD) simulations. Previous assignments of the crystal forms were confirmed by SCXRD: forms I and II were found to be orthorhombic ( P222, Z'/ Z = 1/4) and form III was monoclinic ( P2, Z'/ Z = 2/4). The obtained results further indicated that (i) the transitions between different forms are observed at 235.9 ± 0.1 K (form III → form II) and at 275.2 ± 0.2 K (form II → form I) in DSC runs carried out at 10 K min and close to these values when other types of techniques are used (e.g., HSM). (ii) They are enantiotropic (i.e., there is a transition temperature relating the two phases before fusion at which the stability order is reversed), fast, reversible, with very little hysteresis between heating and cooling modes, and occur under single crystal to single crystal conditions. (iii) A nucleation and growth mechanism seems to be followed since HSM experiments on single crystals evidenced the propagation of an interface, accompanied by a change of birefringence and crystal contraction or expansion (more subtle in the case of form III → form II), when the phase transitions are triggered. (iv) Consistent with the reversible and small hysteresis nature of the phase transitions, the SCXRD results indicated that the molecular packing is very similar in all forms and the main structural differences are associated with conformational changes of the "ester tail". (v) The MD simulations further suggested that the tail is essentially "frozen" in two conformations below the III → II transition temperature, becomes progressively less hindered throughout the stability domain of form II, and acquires a large conformational freedom above the II → I transition. Finally, the fact that these transitions were found to be fast and reversible suggests that polymorphism is unlikely to be a problem for pharmaceutical formulations employing crystalline simvastatin because, if present, the III and II forms will readily convert to form I at ambient temperature.

Enantiotropy of Simvastatin as a Result of Weakened Interactions in the Crystal Lattice: Entropy-Driven Double Transitions and the Transient Modulated Phase as Seen by Solid-State NMR Spectroscopy

“…On the other hand, the weak thermal dependence of the relaxation rate R 1ρ observed for these units (C22 and C23) in high-temperature Form I indicates that all the energy barriers had already been overcome, thus allowing free unhindered rotation motions for the whole ester group. In this regard it is worth noting that the obtained experimental ss-NMR relaxation data are in good agreement with the previously published molecular dynamics simulations [ 5 , 25 ].…”

“…Two-dimensional (2D) 1 H- 13 C HETCOR experiments [ 39 ] were performed using the FSLG (Frequency Switched Lee–Goldburg) decoupling during the t 1 evolution period consisting of 128 increments each made of 64–128 scans with a dwell time of 42.6 μs. Further experimental details can be found in our previous work [ 5 ]. All the variable temperature experiments were conducted between temperatures of 330 and 220 K. Frictional heating [ 19 , 40 ] of the spinning samples was compensated for by active cooling.…”

“…Although active pharmaceutical ingredients (APIs) have long been used to control hypercholesterolemia, new low-temperature polymorphic APIs were serendipitously discovered in 2010 [ 4 ]. Later in 2018, Simões et al [ 5 ] investigated the three-fold polymorphism of simvastatin, exploiting X-ray, calorimetry and molecular-simulation methods to investigate the related structural, conformational and thermodynamic aspects. In the present study, we report a detailed analysis of simvastatin polymorphisms and focus on unravelling the dynamical nature of the disorder in its high-temperature polymorph.…”

Effects of Solvent Stabilization on Pharmaceutical Crystallization: Investigating Conformational Polymorphism of Probucol Using Combined Solid-State Density Functional Theory, Molecular Dynamics, and Terahertz Spectroscopy

“…For MD simulations, the GROMACS v5.0.4 software package − was used with an optimized potentials for liquid simulations (OPLS)-AA force field parameter set . Developing a suitable molecular mechanical description of organic molecules in the crystal phase remains a challenge, and commonly used force fields have been employed for studies of such systems. − The OPLS-AA force field was chosen for this study because of its initial parameterization to reproduce small organic molecule properties and for the availability of the existing models for developing small-molecule topologies . The molecular topologies for probucol, methanol, and ethanol were initially generated using the LigParGen server .…”

Same or different – that is the question: identification of crystal forms from crystal structure data

“…Form II (EJEQAL02) is known to be the room temperature phase, which transforms to form I upon cooling at 275 K. The phase change is confirmed by a variation in the heat capacity. 73 A further analysis reveals that the major structural change involves the conformation around the peripheral group of the compound (see Fig. 13 left).…”