Exploring space-energy matching via quantum-molecular mechanics modeling and breakage dynamics-energy dissipation via microhydrodynamic modeling to improve the screening efficiency of nanosuspension prepared by wet media milling

ABSTRACT

Introduction: The preparation of nanosuspensions by wet media milling is a promising technique that increases the bioavailability of insoluble drugs. The nanosuspension is thermodynamically unstable, where its stability might be influenced by the interaction energy between the stabilizers and the drugs after milling at a specific collision energy. However, it is difficult to screen the stabilizers and the parameters of milling accurately and quickly by using traditional analysis methods. Quantum-molecular mechanics and microhydrodynamic modeling can be applied to improve screening efficiency.

Areas covered: Quantum-molecular mechanics model, which includes molecular docking, molecular dynamics simulations, and data on binding energy, provides insights into screening stabilizers based on their molecular behavior at the atomic level. The microhydrodynamic model explores the mechanical processes and energy dissipation in nanomilling, and even combines information on the mechanical modulus and an energy vector diagram for the milling parameters screening of drug crystals.

Expert opinion: These modeling methods improve screening efficiency and support screening theories based on thermodynamics and physical dynamics. However, how to reasonably combine different modeling methods with their theoretical characteristics and further multidimensional and cross-scale simulations of nanosuspension formation remain challenges.

KEYWORDS:

• Crystal morphology
• energy vector diagram
• frontier molecular orbitals
• molecular docking
• nanosuspension
• wet media milling

Article highlights

• We explore the molecular behavior of stabilizers and drugs by quantum-molecular mechanical modeling, physical behavior of beads and drug particles by microhydrodynamic modeling. The effects of the stabilizers and milling parameters on nanosuspension formation are explored from the perspectives of geometrical conformation, thermodynamic energy, and process dynamics.

• Frontier molecular orbitals are used to evaluate the regions of change in the electron cloud caused by the interactions to acquire information on the adsorption sites. An adsorption module is used to calculate the adsorption energy to determine the tendencies of aggregation of different molecular forms of the target drug.

• Molecular docking and binding energy modules are used to acquire information to screen the stabilizers from the point of view of geometric conformation, property complementarity, and energy matching.

• The parameters of microhydrodynamic modeling can be used to determine the impacts of bead type/size/loading, drug loading, stirrer speed, and rheology of stabilizer solutions on nanosuspension formation based on breakage kinetics and energy dissipation. This contributes to the screening of the milling parameters.

• The slip surface and energy distribution of the crystal are determined by crystal topography and the EVD (energy vector diagram). The optimal slip surface in the form of a drug crystal that is easy to fracture is obtained by BFDH (Bravais, Friedel, Donnay and Harker) analysis and periodic bond chain theory. The optimal location and area information can help screen the milling parameters, which can be acquired and explained by combining the microhydrodynamic model with the EVD.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership, or options, expert testimony, grants, or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers in this manuscript have no relevant financial or other relationships to disclose.

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Additional information

Funding

This study was supported by the Science and Technology Program of Ningxia Province (No.NXZY201713), the Key Research Funding of Ningxia Province (No.2018BFH02001) and the College Student Innovation and Entrepreneurship Training Program (No.S202010752021).