Quantitative Analysis the Weak Non-Covalent Interactions of the Polymorphs of Donepezil

Abstract

Donepezil has polymorphism. Different crystalline forms can exhibit different physicochemical properties and biological activities. Exploration of intermolecular interactions is essential to reveal the formation mechanism and differences in properties of polymorphs. This study explores the weak non-covalent intermolecular interactions of donepezil polymorphs through fully ab initio quantum mechanical methods, semi-empirical methods, and Hirshfeld surface analysis. The results show that the Hirshfeld surface analysis method can clearly and intuitively reveal the intermolecular interactions. Theoretical calculations using the atom–atom Coulomb–London–Pauli (AA-CLP) method were also performed to understand the interaction energies toward the total lattice energy. The value of the lattice energy was in accordance with the melting points of the donepezil polymorphs and brought to light the nature of thermal stability. In the specific energy distribution, the contribution of the dispersion force is the most prominent. Further interaction energy analysis found that within a distance of 3.8 Å from the center of the donepezil molecule, different crystalline forms of donepezil molecules have different interaction energies with surrounding molecules. The different interaction energies between polymorphs may lead to polymorphs with different physical–chemical properties.

Toltrazuril Polymorphs and the Effect on Hygroscopicity and Dissolution Rate

“…To deeply understand and anatomize the packing modes and interaction force of Forms I and II, interaction energies were calculated based on monomer wave functions and a 3.8 Å radius around the intermediate molecule at the B3LYP/6-31G (p, d) level by CrystalExplorer17 software. − Meanwhile, Hirshfeld surface (HS) analyses were performed using CrystalExplorer17 software to quantify and visualize intermolecular interactions.…”

Microelectron Diffraction Reveals Contamination of Polymorphs by Structure Analysis of Microscale Crystals in a Novel Pharmaceutical Cocrystal

“…Polymorphs are crystal forms composed of the same molecules with different molecular states due to changes in intermolecular interactions, resulting in changes in their physicochemical properties. − Different molecular states among polymorphs can alter the physicochemical properties, which critically impact the in vivo performance of drugs, such as oral bioavailability. − In addition, stability differences are particularly focused on in polymorphs, and metastable forms are often thermodynamically and kinetically transformed to a stable form with convergence to low free energy according to Ostwald’s rule of stages. − Hence, revealing polymorphic forms and investigating their relationships are required for novel drug discovery. In the case of ritonavir, following its removal from the market, it was observed that the generation of a stable form during the manufacturing process reduced the dissolution rate and bioavailability of the drug. , Recent studies have found new polymorphic forms of traditional drugs, including ritonavir. − From this viewpoint, polymorphs are considered regulatory…”