Molecular dynamics and interactions in amorphous solid dispersion of Erlotinib HCl for improved cancer therapy

IF 4 2区化学 Q2 CHEMISTRY, PHYSICAL Journal of Molecular Structure Pub Date : 2025-03-10 DOI:10.1016/j.molstruc.2025.142014

K.P. Safna Hussan , G. Govindaraj , Natália T. Correia , Naoki Shinyashiki , M. Shahin Thayyil , Thekkekara D Babu

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Abstract

Background

Cancer remains a leading cause of mortality worldwide despite advancements in oncology. Chemotherapy is essential for treating aggressive cancers, but its efficacy is limited by systemic toxicity, off-target effects, and drug resistance. Poor aqueous solubility and low oral bioavailability of many anticancer drugs necessitate high doses or intravenous administration, increasing adverse effects. Erlotinib-HCl (ERL), a tyrosine kinase inhibitor, has poor aqueous solubility and low oral bioavailability, limiting its clinical use. Strategies like salt formation, prodrugs, nano-formulations, and cyclodextrin complexation improve solubility. Among them, amorphous solid dispersion (ASD) is a highly effective approach.

Aim

The study aimed to characterise the ASD formulations of ERL using polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), and their combinations.

Experimental section

Physical characterization of ASD was analyzed by optical microscopy, powder X-ray diffraction (PXRD), thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), molecular dynamics (MD) simulations, broadband dielectric spectroscopy (BDS), and temperature-modulated differential scanning calorimetry (TMDSC).

Results and discussion

Microscopic images and PXRD pattern revealed the amorphization of ERL. DSC and TMDSC indicated no residual crystallinity, with glass transitions at 252 K, 373 K, and 272 K for ERL+PEG, ERL+PVP, and ERL+PEG+PVP, respectively. MD simulations showed PEG and PVP influenced the spatial distribution and dynamics of ERL, enhancing miscibility. ASDs modify intermolecular forces and cohesive energy density. ERL+PEG exhibits α (portions within the semi-crystalline phase of PEG, 331 K) and β (glassy state) relaxations, while ERL+PVP shows a single α relaxation linked to segmental motions in the entire amorphous phase of PVP (373 K). ERL+PEG+PVP displays two α relaxations (PVP and PEG) and one β relaxation. Fragility indices are 148 (ERL+PEG), 62.1 (ERL+PVP), and 45.5 (ERL+PEG+PVP), indicating improved stability.

Conclusion

The study characterized amorphous solid dispersions of ERL with enhanced amorphization, miscibility and molecular interactions. The reduced fragility index in ERL+PEG+PVP suggests improved stability, making it a promising formulation for enhanced drug solubility.

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背景尽管肿瘤学取得了进步，但癌症仍然是导致全球死亡的主要原因。化疗对治疗侵袭性癌症至关重要，但其疗效受到全身毒性、脱靶效应和耐药性的限制。许多抗癌药物的水溶性差，口服生物利用度低，因此需要大剂量或静脉给药，从而增加了不良反应。厄洛替尼-HCl（ERL）是一种酪氨酸激酶抑制剂，水溶性差，口服生物利用度低，限制了其临床应用。盐形成、原药、纳米制剂和环糊精复合物等策略可提高溶解度。本研究旨在对使用聚乙烯吡咯烷酮（PVP）、聚乙二醇（PEG）及其组合的艾瑞洛无定形固体分散体（ASD）制剂进行表征。实验部分通过光学显微镜、粉末 X 射线衍射（PXRD）、热重分析（TGA）、差示扫描量热法（DSC）、分子动力学（MD）模拟、宽带介电光谱（BDS）和温度调制差示扫描量热法（TMDSC）分析了 ASD 的物理特性。DSC 和 TMDSC 显示没有残余结晶，ERL+PEG、ERL+PVP 和 ERL+PEG+PVP 的玻璃态转变温度分别为 252 K、373 K 和 272 K。MD 模拟显示，PEG 和 PVP 会影响 ERL 的空间分布和动力学，从而提高混溶性。ASD 可改变分子间作用力和内聚能密度。ERL+PEG表现出α（PEG半结晶相中的部分，331 K）和β（玻璃态）弛豫，而ERL+PVP则表现出与PVP整个无定形相（373 K）中的分段运动有关的单一α弛豫。ERL+PEG+PVP 显示两个 α 弛豫（PVP 和 PEG）和一个 β 弛豫。脆性指数分别为 148（ERL+PEG）、62.1（ERL+PVP）和 45.5（ERL+PEG+PVP），表明其稳定性有所提高。ERL+PEG+PVP的脆性指数降低，表明其稳定性有所提高，是一种很有前途的提高药物溶解度的制剂。

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来源期刊

Journal of Molecular Structure 化学-物理化学

CiteScore

7.10

自引率

15.80%

发文量

2384

审稿时长

45 days

期刊介绍： The Journal of Molecular Structure is dedicated to the publication of full-length articles and review papers, providing important new structural information on all types of chemical species including: • Stable and unstable molecules in all types of environments (vapour, molecular beam, liquid, solution, liquid crystal, solid state, matrix-isolated, surface-absorbed etc.) • Chemical intermediates • Molecules in excited states • Biological molecules • Polymers. The methods used may include any combination of spectroscopic and non-spectroscopic techniques, for example: • Infrared spectroscopy (mid, far, near) • Raman spectroscopy and non-linear Raman methods (CARS, etc.) • Electronic absorption spectroscopy • Optical rotatory dispersion and circular dichroism • Fluorescence and phosphorescence techniques • Electron spectroscopies (PES, XPS), EXAFS, etc. • Microwave spectroscopy • Electron diffraction • NMR and ESR spectroscopies • Mössbauer spectroscopy • X-ray crystallography • Charge Density Analyses • Computational Studies (supplementing experimental methods) We encourage publications combining theoretical and experimental approaches. The structural insights gained by the studies should be correlated with the properties, activity and/ or reactivity of the molecule under investigation and the relevance of this molecule and its implications should be discussed.