An integrated approach combining experimental, informatics and energetic methods for solid form derisking of PF-06282999.

IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Journal of pharmaceutical sciences Pub Date : 2024-10-16 DOI:10.1016/j.xphs.2024.10.013
Ghazala Sadiq, Shubham Sharma, Joanna S Stevens, Pablo Martinez-Bulit, Lily M Hunnisett, Christopher Cameron, Brian Samas, Emma Hawking, Nicholas Francia, Jeff Lengyel, Elna Pidcock, Sadia Rahman, Matthew Nisbet, Kevin Back, Cheryl Doherty, Patricia Basford, Timothy G Cooper, Garry O'Connor, Rajni M Bhardwaj
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Abstract

The landscapes of observed and predicted three-dimensional crystal packing arrangements of small-molecule drug candidates can be complex. The possible appearance of a more thermodynamically stable solid form during drug development has led to the digital workflow of informatics-based risk assessments, named a Solid Form Health Check. Herein, we describe the use of a combined approach consisting of experiments, informatics together with energetic calculations in analysis of four competing polymorphs of PF-06282999, a myeloperoxidase (MPO) inhibitor with conformational flexibility and multiple plausible hydrogen bond networks. This combined approach offered a comprehensive understanding of the solid form structure, properties, and performance, ensuring robust solid form derisking and selection.

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结合实验、信息学和能量学方法的综合方法用于 PF-06282999 的固态脱脂。
小分子候选药物观察到的和预测的三维晶体堆积排列情况可能非常复杂。在药物开发过程中,可能会出现热力学上更稳定的固体形式,这就促成了基于信息学的风险评估数字化工作流程,并将其命名为 "固体形式健康检查"。在本文中,我们介绍了在分析 PF-06282999 的四种竞争多晶型时使用的实验、信息学和能量计算相结合的方法,PF-06282999 是一种髓过氧化物酶 (MPO) 抑制剂,具有构象灵活性和多种可信的氢键网络。这种综合方法提供了对固态结构、特性和性能的全面了解,确保了稳健的固态去风险和选择。
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来源期刊
CiteScore
7.30
自引率
13.20%
发文量
367
审稿时长
33 days
期刊介绍: The Journal of Pharmaceutical Sciences will publish original research papers, original research notes, invited topical reviews (including Minireviews), and editorial commentary and news. The area of focus shall be concepts in basic pharmaceutical science and such topics as chemical processing of pharmaceuticals, including crystallization, lyophilization, chemical stability of drugs, pharmacokinetics, biopharmaceutics, pharmacodynamics, pro-drug developments, metabolic disposition of bioactive agents, dosage form design, protein-peptide chemistry and biotechnology specifically as these relate to pharmaceutical technology, and targeted drug delivery.
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