Organic Process Research & Development最新文献_第7页

Polymorph and Salt/Cocrystal Screening to Identify a Suitable Physical Form for an LPAR1 Antagonist, GS-2278 LPAR1拮抗剂GS-2278的多晶和盐/共晶筛选

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-06-25 DOI: 10.1021/acs.oprd.5c00065

Henry Morrison*, Kathy Dao, Dane Holte, Nathaniel Kadunce and Anna M. Wagner,

{"title":"Polymorph and Salt/Cocrystal Screening to Identify a Suitable Physical Form for an LPAR1 Antagonist, GS-2278","authors":"Henry Morrison*, Kathy Dao, Dane Holte, Nathaniel Kadunce and Anna M. Wagner, ","doi":"10.1021/acs.oprd.5c00065","DOIUrl":"10.1021/acs.oprd.5c00065","url":null,"abstract":"GS-2278 (1), a novel freebase lysophosphatidic acid receptor 1 (LPAR1) antagonist, was selected as a development candidate for the treatment of idiopathic pulmonary fibrosis (IPF). Investigations on this active pharmaceutical ingredient (API) resulted in the discovery of 15 crystalline forms, of which the unsolvated form 1-A was initially selected as the development form over the hemihydrate 1-1/2H2O due to superior physical properties, including its unsolvated nature, simple thermal profile, and hygroscopicity profile. However, due to low solubility in simulated physiological fluids (∼10 μg/mL) and poor pharmacokinetics (30× lower than a nonprecipitating solution), investigations into acidic salts and cocrystals (∼50 coformers) were conducted to identify an acceptable physical form for long-term development. While no crystalline cocrystals were identified, several crystalline salts were identified, including an HCl salt, of which the dihydrate (1-HCl 2H2O) was extensively characterized to mitigate potential challenges of its hydrated status. Ultimately, it was found to be nonhygroscopic, to have an acceptable pharmacokinetics profile (comparable to the nonprecipitating solution), robustness toward milling, compression, and drying, as well as physical/chemical stability in the drug product tablet. Because of this, a process was designed whereby 1-A and 1-HCl 2H2O were selected as the penultimate and drug substance forms, respectively.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 7","pages":"1727–1739"},"PeriodicalIF":3.5,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144479359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Insights into the Oxidation Mechanism and Kinetics of Dimethyl Sulfoxide by Peroxymonosulfate 过氧单硫酸盐氧化二甲亚砜的机理及动力学研究

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-06-24 DOI: 10.1021/acs.oprd.5c00115

Xingyu Shao, Wei Feng, Wenqian Wu, Zichao Guo*, Liping Chen and Wanghua Chen,

{"title":"Insights into the Oxidation Mechanism and Kinetics of Dimethyl Sulfoxide by Peroxymonosulfate","authors":"Xingyu Shao, Wei Feng, Wenqian Wu, Zichao Guo*, Liping Chen and Wanghua Chen, ","doi":"10.1021/acs.oprd.5c00115","DOIUrl":"10.1021/acs.oprd.5c00115","url":null,"abstract":"Dimethyl sulfone (DMSO2) plays a crucial role in human health, particularly in collagen synthesis, owing to its significant biochemical functions. Although traditional oxidation methods are effective, they present significant environmental and operational challenges that hinder their widespread application. This study systematically investigated the reaction kinetics and mechanistic pathway of dimethyl sulfoxide (DMSO) oxidation catalyzed by peroxymonosulfate (PMS) under low-temperature (0–20 °C) and nonactivated catalytic conditions. A comprehensive oxidation kinetic model was developed, and all kinetic parameters were meticulously determined. Density functional theory (DFT) calculations confirmed that the nucleophilic attack by the O–O bond in PMS on the sulfur atom of DMSO facilitates the oxidation process. Experimental and DFT-derived activation energies for the oxidation reaction were measured at 64.33 and 65.54 kJ/mol, respectively. These findings elucidate the potential mechanism of PMS-mediated oxidation of DMSO and offer a reliable reference for the safe production of DMSO2.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 7","pages":"1766–1774"},"PeriodicalIF":3.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144371257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Accurate and Scalable Prediction of a Fast and Highly Exothermic Nonlinear Reaction System: Reaction Development Using Coupled Simulation of a Mechanism-Oriented Kinetic Model and a Customized Heat Removal Model 一个快速和高度放热的非线性反应系统的准确和可扩展的预测：反应发展使用耦合模拟面向机理的动力学模型和定制的热量去除模型

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-06-24 DOI: 10.1021/acs.oprd.5c00107

Yuya Orito*,

{"title":"Accurate and Scalable Prediction of a Fast and Highly Exothermic Nonlinear Reaction System: Reaction Development Using Coupled Simulation of a Mechanism-Oriented Kinetic Model and a Customized Heat Removal Model","authors":"Yuya Orito*, ","doi":"10.1021/acs.oprd.5c00107","DOIUrl":"10.1021/acs.oprd.5c00107","url":null,"abstract":"A precise reaction prediction method by coupled simulations of a reaction kinetic model and a heat removal model is demonstrated, incorporating the development of the selective monobenzylation of unprotected aniline as a model reaction. To enhance the accuracy of the technique, the extrapolatable kinetic model is built based on a detailed understanding of the reaction mechanism of a nonlinear reaction system including equilibria before the rate-determining step (rds), and the heat removal model is carefully adjusted for small reaction vessels by combining the heat transfer coefficient and the heat inertia caused by the reactor system setup. The simulation showed high accuracy prediction in temperature trend within ± 2 K to experimentally measured values as well as for chemical yield of the reaction. This systematic approach will lead to useful methodology to evaluate the accuracy of coupled process simulations involving reaction models and also runaway risk prior to scale-up, especially for fast and highly exothermic reactions that raise safety concerns in industrial chemistry.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 7","pages":"1757–1765"},"PeriodicalIF":3.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

GreenScore: A User-Friendly Tool for Assessing the Sustainability of Chemical Processes 绿色评分：一个评估化学过程可持续性的用户友好工具

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-06-22 DOI: 10.1021/acs.oprd.5c00047

Frédéric Pin*, Julien Picard* and Sylvie Dhulut*,

引用次数: 0

IF 3.1 3区化学