Experimental, Thermodynamic, and Molecular Modeling Evaluation of Amorphous Simvastatin-Poly(vinylpyrrolidone) Solid Dispersions

Abstract

A crucial step for the selection of proper amorphous solid dispersion (ASD) matrix carriers is the in-depth assessment of drug/polymer physicochemical properties. In this context, the present study extends the work of previously published attempts by evaluating the formation of simvastatin (SIM)–poly­(vinylpyrrolidone) (PVP) ASDs with the aid of thermodynamic and molecular modeling. Specifically, the implementation of both Flory–Huggins lattice theory and molecular dynamics (MD) simulations was able to predict the miscibility between the two components (a finding that was experimentally verified via differential scanning calorimetry (DSC) and hot stage polarized microscopy), while a complete temperature-concentration phase-transition profile was constructed, leading to the identification of the thermodynamically metastable and unstable ASD zones. Furthermore, as in the case of previously published reports, the analysis of the ASDs via Fourier transform infrared spectroscopy did not clarify the type and extent of observed molecular interactions. Hence, in the present study, a computer-based MD simulation model was developed for the first time in order to gain an insight into the properties of the observed interactions. MD amorphous assemblies of SIM, PVP, and their mixtures were initially developed, and the calculated glass transition temperatures were in close agreement with experimentally obtained results, indicating that the developed models could be considered as realistic representations of the actual systems. Furthermore, molecular interactions evaluation via radial distribution function and radius of gyration analysis revealed that increasing SIM content results in a significant PVP chain shrinkage, which eventually leads to SIM–SIM amorphous intermolecular interactions, leading to the formation of amorphous drug zones. Finally, MD-based results were experimentally verified via DSC.

Study on the Effect of Polymer Excipients on the Dispersibility, Interaction, Solubility, and Scavenging Reactive Oxygen Species of Myricetin Solid Dispersion: Experiment and Molecular Simulation

“…The radial distribution function (RDF and g ( r )) can be used to describe the distribution of hydrogen bonds. 52 The g ( r ) is the probability of finding another atom when the distance is r , where g ( r ) is a quantity of dimension 1. When r is near 2–2.5Å, the possibility of forming hydrogen bonds is the largest.…”

Drug crystal growth in ternary amorphous solid dispersions: Effect of surfactants and polymeric matrix-carriers

“…9 shows the constructed amorphous assemblies for the pure APT, the binary (i.e., APT-PVP and APT-TPGS) and the ternary (APT-PVP-TPGS) systems in the presence and absence of water. It should be noted that the initial molecular structure of APT was obtained from the Cambridge Structural Database (CSD Deposition Number: 117932) based on the published work of Hale et al ( Hale et al, 1998 ), while PVP's molecular chains (consisting of 40 N-vinylpyrrolidone monomers) were constructed based on a previous study of ours ( Kapourani et al, 2020a ), and TPGS's chains (consisting of 22 ethylene glycol monomers) were prepared based on the reported structure of tocophersolan (Pubchem, CID: 71406).

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Multicomponent Pharmaceutical Adducts of Azoxystrobin: Physicochemical Properties, Thermodynamic, and Molecular Modeling Study

“…In contrast, computational techniques (such as molecular dynamics simulation) can provide detailed atomic‐level structural and energetic information, which can greatly assist the in‐depth evaluation of such interactions. [ 9 ] MD simulations were used to study the effect of coformers (FDO, AA, SIM, and IMD) on the formation of AZO eutectics and to provide an understanding of the interactions among the components of the studied system. During the evaluation of hydrogen bonding, the maximum hydrogen‐acceptor distance is set to 2.5 Å, and the minimum donor–hydrogen‐acceptor angle is set to 90°.…”

“…[6,7] They are similar to popular solid dispersions and amorphous solids. [8,9] However, the disadvantages of amorphous solids and solid dispersions are their long-term instability and phase transformation issues. [10][11][12][13] Generally, the solid form system that maintains the drug as a crystalline form is the best choice.…”