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<p>2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine, known as olanzapine, is a second-generation antipsychotic drug that exhibits extensive polymorphism in the solid state, which can influence its physicochemical and pharmacokinetic behavior. In this study, we investigated six anhydrous polymorphic forms of olanzapine through a combined theoretical and experimental approach, including DFT calculations, PXRD, UV–Vis spectroscopy, DSC, and molecular docking. Geometry optimizations using the GGA + TS functional yielded lattice parameters with deviations below 2% from experimental values. Three polymorphs—αOLZ I (Bhardwaj), αOLZ II (Gorczyca), and αOLZ I (Reutzel)—showed identical indirect band gaps (2.26&#xa0;eV), while others ranged from 2.28 to 2.47&#xa0;eV. Simulated optical spectra revealed absorption onset between 2.2 and 2.4&#xa0;eV, with βOLZ IV displaying the highest initial absorption intensity (~ 1.2&#xa0;Å). Experimental UV–Vis spectra indicated an earlier onset (~ 1.5&#xa0;eV), likely due to polymorph coexistence. PXRD confirmed a mixture of αOLZ I, αOLZ II, and βOLZ IV, and DSC revealed a melting point at 179.4&#xa0;°C, below the value expected for pure αOLZ I. Dielectric functions indicated strong optical anisotropy, and Hirshfeld charges proved more chemically consistent than Mulliken charges. Molecular docking simulations showed stable binding to the D<sub>2</sub> dopamine receptor, involving key residues such as TRP100 and ASP114. These findings highlight how polymorphism can modulate olanzapine’s structural and pharmacological behavior, offering useful insights for solid-state drug design.</p>

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Structural, electronic, and optical properties of olanzapine polymorphs: experimental characterization, DFT studies and molecular docking with the D2 dopamine receptor

  • 期刊论文

  • 发表日期：

    2025年12月3日

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  • José Barbosa Silva,
  • Matheus Nunes da Rocha,
  • Valder Nogueira Freire,
  • Alejandro Pedro Ayala,
  • Ewerton Wagner Santos Caetano,
  • Regina Claudia Rodrigues dos Santos,
  • Bruno Poti e Silva,
  • Francisco Ferdinando Mesquita Cajazeiras,
  • Jaíza Maria Lima Dias,
  • Jésyka Macedo Guedes,
  • Márcia Machado Marinho,
  • Emmanuel Silva Marinho,
  • Alexandre Magno Rodrigues Teixeira,
  • Hélcio Silva dos Santos

摘要

2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine, known as olanzapine, is a second-generation antipsychotic drug that exhibits extensive polymorphism in the solid state, which can influence its physicochemical and pharmacokinetic behavior. In this study, we investigated six anhydrous polymorphic forms of olanzapine through a combined theoretical and experimental approach, including DFT calculations, PXRD, UV–Vis spectroscopy, DSC, and molecular docking. Geometry optimizations using the GGA + TS functional yielded lattice parameters with deviations below 2% from experimental values. Three polymorphs—αOLZ I (Bhardwaj), αOLZ II (Gorczyca), and αOLZ I (Reutzel)—showed identical indirect band gaps (2.26 eV), while others ranged from 2.28 to 2.47 eV. Simulated optical spectra revealed absorption onset between 2.2 and 2.4 eV, with βOLZ IV displaying the highest initial absorption intensity (~ 1.2 Å). Experimental UV–Vis spectra indicated an earlier onset (~ 1.5 eV), likely due to polymorph coexistence. PXRD confirmed a mixture of αOLZ I, αOLZ II, and βOLZ IV, and DSC revealed a melting point at 179.4 °C, below the value expected for pure αOLZ I. Dielectric functions indicated strong optical anisotropy, and Hirshfeld charges proved more chemically consistent than Mulliken charges. Molecular docking simulations showed stable binding to the D2 dopamine receptor, involving key residues such as TRP100 and ASP114. These findings highlight how polymorphism can modulate olanzapine’s structural and pharmacological behavior, offering useful insights for solid-state drug design.