Insight into the Manipulation Mechanism of Polymorphic Transformation by Polymers: A Case of Cimetidine.

IF 3.5 3区医学 Q2 CHEMISTRY, MULTIDISCIPLINARY

Pharmaceutical Research Pub Date : 2024-07-01 Epub Date: 2024-07-02 DOI:10.1007/s11095-024-03734-x

Beiqian Tian, Na Wang, Jinyue Yang, Zhicheng Jiang, Yaoguang Feng, Ting Wang, Lina Zhou, Xin Huang, Hongxun Hao

{"title":"Insight into the Manipulation Mechanism of Polymorphic Transformation by Polymers: A Case of Cimetidine.","authors":"Beiqian Tian, Na Wang, Jinyue Yang, Zhicheng Jiang, Yaoguang Feng, Ting Wang, Lina Zhou, Xin Huang, Hongxun Hao","doi":"10.1007/s11095-024-03734-x","DOIUrl":null,"url":null,"abstract":"Purpose: Employing polymer additives is an effective strategy to realize the manipulation of polymorphic transformation. However, the manipulation mechanism is still not clear, which limit the precise selection of polymeric excipients and the development of pharmaceutical formulations.Methods: The solubility of cimetidine (CIM) in acetonitrile/water mixtures were measured. And the polymorphic transformation from CIM form A to form B with the addition of different polymers was monitored by Raman spectroscopy. Furthermore, the manipulation effect of polymers was determined based on the results of experiments and molecular simulations.Results: The solubility of form A is consistently higher than that of form B, which indicate that form B is the thermodynamically stable form within the examined temperature range. The presence of polyvinylpyrrolidone (PVP) of a shorter chain length could have a stronger inhibitory effect on the phase transformation process of metastable form, whereas polyethylene glycol (PEG) had almost no impact. The nucleation kinetics experiments and molecular dynamic simulation results showed that only PVP molecules could significantly decrease the nucleation rate of CIM, due to the ability of reducing solute molecular diffusion and solute-solute molecular interaction. A combination of crystal growth rate measurements and calculations of the interaction energies between PVP and the crystal faces of CIM indicate that smaller molecular weight PVP can suppress crystal growth more effectively.Conclusion: PVP K16-18 has more impact on the stabilization of CIM form A and inhibition of the phase transformation process. The manipulation mechanism of polymer additives in the polymorphic transformation of CIM was proposed.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.5000,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmaceutical Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s11095-024-03734-x","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/2 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}

引用次数: 0

Abstract

Purpose: Employing polymer additives is an effective strategy to realize the manipulation of polymorphic transformation. However, the manipulation mechanism is still not clear, which limit the precise selection of polymeric excipients and the development of pharmaceutical formulations.

Methods: The solubility of cimetidine (CIM) in acetonitrile/water mixtures were measured. And the polymorphic transformation from CIM form A to form B with the addition of different polymers was monitored by Raman spectroscopy. Furthermore, the manipulation effect of polymers was determined based on the results of experiments and molecular simulations.

Results: The solubility of form A is consistently higher than that of form B, which indicate that form B is the thermodynamically stable form within the examined temperature range. The presence of polyvinylpyrrolidone (PVP) of a shorter chain length could have a stronger inhibitory effect on the phase transformation process of metastable form, whereas polyethylene glycol (PEG) had almost no impact. The nucleation kinetics experiments and molecular dynamic simulation results showed that only PVP molecules could significantly decrease the nucleation rate of CIM, due to the ability of reducing solute molecular diffusion and solute-solute molecular interaction. A combination of crystal growth rate measurements and calculations of the interaction energies between PVP and the crystal faces of CIM indicate that smaller molecular weight PVP can suppress crystal growth more effectively.

Conclusion: PVP K16-18 has more impact on the stabilization of CIM form A and inhibition of the phase transformation process. The manipulation mechanism of polymer additives in the polymorphic transformation of CIM was proposed.

Abstract Image

查看原文本刊更多论文

聚合物操纵多晶型转化机制的启示：以西咪替丁为例。

目的：使用聚合物添加剂是实现多晶型转化操纵的有效策略。然而，其操纵机理尚不明确，限制了高分子辅料的精确选择和药物制剂的开发：方法：测定了西咪替丁 (CIM) 在乙腈/水混合物中的溶解度。方法：测量了西咪替丁在乙腈/水混合物中的溶解度，并通过拉曼光谱监测了添加不同聚合物后西咪替丁从 A 型向 B 型的多态转变。此外，还根据实验结果和分子模拟确定了聚合物的操纵效应：结果：形态 A 的溶解度始终高于形态 B，这表明在研究的温度范围内，形态 B 是热力学上稳定的形态。链长较短的聚乙烯吡咯烷酮（PVP）对蜕变形式的相变过程有较强的抑制作用，而聚乙二醇（PEG）几乎没有影响。成核动力学实验和分子动力学模拟结果表明，只有 PVP 分子能显著降低 CIM 的成核率，这是因为 PVP 分子具有降低溶质分子扩散和溶质-溶质分子相互作用的能力。结合晶体生长速率测量和 PVP 与 CIM 晶面之间相互作用能的计算，可以看出分子量较小的 PVP 能更有效地抑制晶体生长：结论：PVP K16-18 对稳定 A 型 CIM 和抑制相变过程的影响更大。结论：PVP K16-18 对 CIM 形态 A 的稳定和相变过程的抑制作用更大，提出了聚合物添加剂在 CIM 多晶型转化过程中的作用机理。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Pharmaceutical Research 医学-化学综合

CiteScore

6.60

自引率

5.40%

发文量

276

审稿时长

3.4 months

期刊介绍： Pharmaceutical Research, an official journal of the American Association of Pharmaceutical Scientists, is committed to publishing novel research that is mechanism-based, hypothesis-driven and addresses significant issues in drug discovery, development and regulation. Current areas of interest include, but are not limited to: -(pre)formulation engineering and processing- computational biopharmaceutics- drug delivery and targeting- molecular biopharmaceutics and drug disposition (including cellular and molecular pharmacology)- pharmacokinetics, pharmacodynamics and pharmacogenetics. Research may involve nonclinical and clinical studies, and utilize both in vitro and in vivo approaches. Studies on small drug molecules, pharmaceutical solid materials (including biomaterials, polymers and nanoparticles) biotechnology products (including genes, peptides, proteins and vaccines), and genetically engineered cells are welcome.