阿那非共晶的开发和优化：提高水溶性和溶解速率的硅分子对接方法

IF 4.7 2区化学 Q2 CHEMISTRY, PHYSICAL

Journal of Molecular Structure Pub Date : 2025-10-06 DOI:10.1016/j.molstruc.2025.144281

Suhas Shivaji Siddheshwar, Mr. Ankur Machhindra Jadhav, Someshwar Dattatraya Mankar, Arti Changdev Ghorpade, Pratibha Bhalerao

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引用次数: 0

摘要

davanafil是第二代磷酸二酯酶5型抑制剂，其水溶性较差（0.058 mg/mL），导致生物利用度变化，治疗勃起功能障碍的效果不理想。溶出率有限，严重影响药物吸收和临床疗效。目的利用系统的分子对接方法开发和优化阿瓦那非-烟酰胺共晶，以提高其水溶性和溶解性能，解决生物制药的关键限制。方法利用已验证的分子对接方案，通过结合能分析计算筛选潜在的共构象。采用溶剂蒸发法制备共晶，并采用三因素析因设计优化。综合表征采用差示扫描量热法、傅里叶变换红外光谱、粉末x射线衍射和溶解研究。优化后的制剂制成了速释片剂，并在动物实验中进行了药代动力学性能评价。结果分子对接成功鉴定出烟酰胺为结合能最强、相互作用网络广泛的最佳共成体。与纯药物和市售制剂相比，优化后的共晶具有明显的溶解度增强和更好的溶解谱。片剂配方表现出加速药物吸收，增强生物利用度，改善药代动力学参数，包括缩短达到最大浓度的时间和增加曲线下面积。结论系统共晶工程方法通过合理的分子设计，成功地增强了阿那非的生物制药性能，为药物开发提供了有效的方法。未来的范围人体生物等效性试验、GMP生产验证、IV区稳定性研究和患者可接受性评估对临床转化至关重要。

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Development and optimization of avanafil cocrystals: in silico molecular docking approach for enhanced aqueous solubility and dissolution rate

Background

Avanafil, a second-generation phosphodiesterase type-5 inhibitor, demonstrates poor aqueous solubility (0.058 mg/mL) resulting in variable bioavailability and suboptimal therapeutic outcomes in erectile dysfunction treatment. The limited dissolution rate significantly impacts drug absorption and clinical efficacy.

Objective

To develop and optimize avanafil-nicotinamide cocrystals using systematic molecular docking approach for enhanced aqueous solubility and dissolution performance, addressing critical biopharmaceutical limitations.

Methods

Computational screening evaluated potential coformers through binding energy analysis using validated molecular docking protocols. Cocrystals were prepared via solvent evaporation method and optimized using three-factor factorial design. Comprehensive characterization employed differential scanning calorimetry, Fourier-transform infrared spectroscopy, powder X-ray diffraction, and dissolution studies. Optimized formulations were developed into immediate-release tablets and evaluated for pharmacokinetic performance in animal studies.

Results

Molecular docking successfully identified nicotinamide as optimal coformer with strongest binding energy and extensive interaction network. The optimized cocrystal demonstrated significant solubility enhancement with superior dissolution profiles compared to pure drug and marketed formulations. Tablet formulation exhibited accelerated drug absorption, enhanced bioavailability, and improved pharmacokinetic parameters including reduced time to maximum concentration and increased area under curve.

Conclusion

Systematic cocrystal engineering approach successfully enhanced avanafil's biopharmaceutical properties through rational molecular design, providing validated methodology for pharmaceutical development.

Future Scope

Human bioequivalence trials, GMP manufacturing validation, Zone IV stability studies, and patient acceptability assessments are essential for clinical translation.

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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.