Diah Lia Aulifa, Adnan Aly Al Shofwan, Sandra Megantara, Taufik Muhammad Fakih, Arif Budiman
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The inter-molecular interactions between drug and polymer plays a role in the improvement of the dissolution rate, solubility, and physical stability of drug.</p><p><strong>Aim: </strong>This study aims to investigate the formation and interactions of ritonavir (RTV)/poloxamer (PLX) amorphous formulation using a computational approach via molecular dynamics (MD) simulations, which mimicked solvent evaporation and melt-quenching method.</p><p><strong>Methods: </strong>TheRoot Mean Square Deviation (RMSD) value, Root Mean Square Fluctuation (RMSF), Radial Distribution Function (RDF), Radius of Gyration (Rg), Solvent Accessible Surface Area (SASA), and hydrogen bond interactions were analyzed to determine interaction mechanisms between RTV and PLX in amorphous solid dispersion.</p><p><strong>Results: </strong>The pi-alkyl bonds between RTV and PLX were formed after simulations of solvent evaporation, while the hydrogen bond interactions of RTV-PLX was observed during melt method simulations. These results indicate the successful formulation of amorphous solid dispersion (ASD) from RTV and PLX. The RMSD values obtained from the solvent evaporation, melt-cooling-A, melt-cooling-B, and melt-cooling-C methods were 3.33 Å, 1.97 Å, 1.30 Å, and 1.29 Å, respectively, while the average RMSF values were 2.65 Å, 1.04 Å, 1.05 Å, and 1.07 Å, respectively. This indicates that the suppression of translational motion of RTV from the melt method can be stronger than solvent evaporation caused by the intermolecular interactions of RTV-PLX.</p><p><strong>Conclusion: </strong>MD simulations helped in understanding the formation and interaction mechanisms of ASD formulations that were difficult to detect by experimental approaches.</p>","PeriodicalId":53584,"journal":{"name":"Advances and Applications in Bioinformatics and Chemistry","volume":"17 ","pages":"1-19"},"PeriodicalIF":0.0000,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10821732/pdf/","citationCount":"0","resultStr":"{\"title\":\"Elucidation of Molecular Interactions Between Drug-Polymer in Amorphous Solid Dispersion by a Computational Approach Using Molecular Dynamics Simulations.\",\"authors\":\"Diah Lia Aulifa, Adnan Aly Al Shofwan, Sandra Megantara, Taufik Muhammad Fakih, Arif Budiman\",\"doi\":\"10.2147/AABC.S441628\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>Amorphous drug dispersion is frequently used to enhance the solubility and dissolution of poorly water-soluble drugs, thereby improving their oral bioavailability. The dispersion of these drugs into polymer matrix can inhibit their recrystallization. The inter-molecular interactions between drug and polymer plays a role in the improvement of the dissolution rate, solubility, and physical stability of drug.</p><p><strong>Aim: </strong>This study aims to investigate the formation and interactions of ritonavir (RTV)/poloxamer (PLX) amorphous formulation using a computational approach via molecular dynamics (MD) simulations, which mimicked solvent evaporation and melt-quenching method.</p><p><strong>Methods: </strong>TheRoot Mean Square Deviation (RMSD) value, Root Mean Square Fluctuation (RMSF), Radial Distribution Function (RDF), Radius of Gyration (Rg), Solvent Accessible Surface Area (SASA), and hydrogen bond interactions were analyzed to determine interaction mechanisms between RTV and PLX in amorphous solid dispersion.</p><p><strong>Results: </strong>The pi-alkyl bonds between RTV and PLX were formed after simulations of solvent evaporation, while the hydrogen bond interactions of RTV-PLX was observed during melt method simulations. These results indicate the successful formulation of amorphous solid dispersion (ASD) from RTV and PLX. The RMSD values obtained from the solvent evaporation, melt-cooling-A, melt-cooling-B, and melt-cooling-C methods were 3.33 Å, 1.97 Å, 1.30 Å, and 1.29 Å, respectively, while the average RMSF values were 2.65 Å, 1.04 Å, 1.05 Å, and 1.07 Å, respectively. 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引用次数: 0
摘要
导言：无定形药物分散体常用于提高水溶性差的药物的溶解度和溶出度，从而改善其口服生物利用度。将这些药物分散到聚合物基质中可抑制其再结晶。目的：本研究旨在通过分子动力学（MD）模拟，模拟溶剂蒸发和熔淬法，采用计算方法研究利托那韦（RTV）/聚羟酰胺（PLX）无定形制剂的形成和相互作用：方法：分析了 RTV 和 PLX 在无定形固体分散体中的均方根偏差（RMSD）值、均方根波动（RMSF）、径向分布函数（RDF）、半径（Rg）、溶剂可及表面积（SASA）和氢键相互作用，以确定它们之间的相互作用机制：结果：在模拟溶剂蒸发后，RTV 和 PLX 之间形成了对烷基键，而在熔融法模拟中观察到了 RTV-PLX 的氢键相互作用。这些结果表明 RTV 和 PLX 成功配制出了无定形固体分散体（ASD）。溶剂蒸发法、熔融冷却-A 法、熔融冷却-B 法和熔融冷却-C 法得到的 RMSD 值分别为 3.33 Å、1.97 Å、1.30 Å 和 1.29 Å，而平均 RMSF 值分别为 2.65 Å、1.04 Å、1.05 Å 和 1.07 Å。这表明熔融法对 RTV 平移运动的抑制作用可能强于 RTV-PLX 分子间相互作用引起的溶剂蒸发：MD 模拟有助于理解 ASD 配方的形成和相互作用机制，而这些机制是实验方法难以检测到的。
Elucidation of Molecular Interactions Between Drug-Polymer in Amorphous Solid Dispersion by a Computational Approach Using Molecular Dynamics Simulations.
Introduction: Amorphous drug dispersion is frequently used to enhance the solubility and dissolution of poorly water-soluble drugs, thereby improving their oral bioavailability. The dispersion of these drugs into polymer matrix can inhibit their recrystallization. The inter-molecular interactions between drug and polymer plays a role in the improvement of the dissolution rate, solubility, and physical stability of drug.
Aim: This study aims to investigate the formation and interactions of ritonavir (RTV)/poloxamer (PLX) amorphous formulation using a computational approach via molecular dynamics (MD) simulations, which mimicked solvent evaporation and melt-quenching method.
Methods: TheRoot Mean Square Deviation (RMSD) value, Root Mean Square Fluctuation (RMSF), Radial Distribution Function (RDF), Radius of Gyration (Rg), Solvent Accessible Surface Area (SASA), and hydrogen bond interactions were analyzed to determine interaction mechanisms between RTV and PLX in amorphous solid dispersion.
Results: The pi-alkyl bonds between RTV and PLX were formed after simulations of solvent evaporation, while the hydrogen bond interactions of RTV-PLX was observed during melt method simulations. These results indicate the successful formulation of amorphous solid dispersion (ASD) from RTV and PLX. The RMSD values obtained from the solvent evaporation, melt-cooling-A, melt-cooling-B, and melt-cooling-C methods were 3.33 Å, 1.97 Å, 1.30 Å, and 1.29 Å, respectively, while the average RMSF values were 2.65 Å, 1.04 Å, 1.05 Å, and 1.07 Å, respectively. This indicates that the suppression of translational motion of RTV from the melt method can be stronger than solvent evaporation caused by the intermolecular interactions of RTV-PLX.
Conclusion: MD simulations helped in understanding the formation and interaction mechanisms of ASD formulations that were difficult to detect by experimental approaches.
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