Hiroshi Ueda, Jun Yee Tse, Tetsuya Miyano, Yuzuki Nakayama, Peiwen Mo, Yuta Hatanaka, Hiromasa Uchiyama, Yuichi Tozuka and Kazunori Kadota
{"title":"药物-药物盐晶体的形成和左氧氟沙星和4-氨基水杨酸的共无定形肺应用†","authors":"Hiroshi Ueda, Jun Yee Tse, Tetsuya Miyano, Yuzuki Nakayama, Peiwen Mo, Yuta Hatanaka, Hiromasa Uchiyama, Yuichi Tozuka and Kazunori Kadota","doi":"10.1039/D4PM00250D","DOIUrl":null,"url":null,"abstract":"<p >A dry powder inhaler is a viable formulation for pulmonary delivery; however, the co-delivery of multiple drugs requires a specially designed device. This study aimed to design multi-component crystal and amorphous forms for the co-delivery of levofloxacin (LVF) and 4-aminosalicylic acid (ASA). New multi-component crystals of LVF and ASA, crystal-I and crystal-II, were formed by solvent evaporation and slurry conversion. Thermal analysis revealed that crystal-I and crystal-II were the hydrate and anhydrate forms, respectively. Upon heating, each crystal was converted to different crystals. All polymorphs reverted to crystal-I during storage. The co-amorphous (CA) form was obtained by spray drying, which exhibited a relatively high glass transition temperature above 100 °C. Multi-component crystals and CA were estimated as salts by single crystal X-ray diffraction and infrared spectroscopy. An <em>in vitro</em> aerodynamic performance test was performed for LVF, ASA, physical mixture (PM), crystal-I, and CA. The fine particle fraction (FPF, %) of LVF/ASA was 0.9/13.3 for pure drugs and 0.4/14.1 for PM. However, the FPF (%) for crystal-I and CA significantly improved to 25.4/29.9 and 20.0/20.6, respectively, with the co-delivery of LVF and ASA. We conclude that the design of multi-component crystals and co-amorphous forms is an effective strategy for the simultaneous delivery of inhalation drugs.</p>","PeriodicalId":101141,"journal":{"name":"RSC Pharmaceutics","volume":" 2","pages":" 264-278"},"PeriodicalIF":0.0000,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2025/pm/d4pm00250d?page=search","citationCount":"0","resultStr":"{\"title\":\"Formation of drug–drug salt crystals and co-amorphous forms of levofloxacin and 4-aminosalicylic acid for pulmonary applications†\",\"authors\":\"Hiroshi Ueda, Jun Yee Tse, Tetsuya Miyano, Yuzuki Nakayama, Peiwen Mo, Yuta Hatanaka, Hiromasa Uchiyama, Yuichi Tozuka and Kazunori Kadota\",\"doi\":\"10.1039/D4PM00250D\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >A dry powder inhaler is a viable formulation for pulmonary delivery; however, the co-delivery of multiple drugs requires a specially designed device. This study aimed to design multi-component crystal and amorphous forms for the co-delivery of levofloxacin (LVF) and 4-aminosalicylic acid (ASA). New multi-component crystals of LVF and ASA, crystal-I and crystal-II, were formed by solvent evaporation and slurry conversion. Thermal analysis revealed that crystal-I and crystal-II were the hydrate and anhydrate forms, respectively. Upon heating, each crystal was converted to different crystals. All polymorphs reverted to crystal-I during storage. The co-amorphous (CA) form was obtained by spray drying, which exhibited a relatively high glass transition temperature above 100 °C. Multi-component crystals and CA were estimated as salts by single crystal X-ray diffraction and infrared spectroscopy. An <em>in vitro</em> aerodynamic performance test was performed for LVF, ASA, physical mixture (PM), crystal-I, and CA. The fine particle fraction (FPF, %) of LVF/ASA was 0.9/13.3 for pure drugs and 0.4/14.1 for PM. However, the FPF (%) for crystal-I and CA significantly improved to 25.4/29.9 and 20.0/20.6, respectively, with the co-delivery of LVF and ASA. We conclude that the design of multi-component crystals and co-amorphous forms is an effective strategy for the simultaneous delivery of inhalation drugs.</p>\",\"PeriodicalId\":101141,\"journal\":{\"name\":\"RSC Pharmaceutics\",\"volume\":\" 2\",\"pages\":\" 264-278\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2025-02-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://pubs.rsc.org/en/content/articlepdf/2025/pm/d4pm00250d?page=search\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"RSC Pharmaceutics\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://pubs.rsc.org/en/content/articlelanding/2025/pm/d4pm00250d\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"RSC Pharmaceutics","FirstCategoryId":"1085","ListUrlMain":"https://pubs.rsc.org/en/content/articlelanding/2025/pm/d4pm00250d","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Formation of drug–drug salt crystals and co-amorphous forms of levofloxacin and 4-aminosalicylic acid for pulmonary applications†
A dry powder inhaler is a viable formulation for pulmonary delivery; however, the co-delivery of multiple drugs requires a specially designed device. This study aimed to design multi-component crystal and amorphous forms for the co-delivery of levofloxacin (LVF) and 4-aminosalicylic acid (ASA). New multi-component crystals of LVF and ASA, crystal-I and crystal-II, were formed by solvent evaporation and slurry conversion. Thermal analysis revealed that crystal-I and crystal-II were the hydrate and anhydrate forms, respectively. Upon heating, each crystal was converted to different crystals. All polymorphs reverted to crystal-I during storage. The co-amorphous (CA) form was obtained by spray drying, which exhibited a relatively high glass transition temperature above 100 °C. Multi-component crystals and CA were estimated as salts by single crystal X-ray diffraction and infrared spectroscopy. An in vitro aerodynamic performance test was performed for LVF, ASA, physical mixture (PM), crystal-I, and CA. The fine particle fraction (FPF, %) of LVF/ASA was 0.9/13.3 for pure drugs and 0.4/14.1 for PM. However, the FPF (%) for crystal-I and CA significantly improved to 25.4/29.9 and 20.0/20.6, respectively, with the co-delivery of LVF and ASA. We conclude that the design of multi-component crystals and co-amorphous forms is an effective strategy for the simultaneous delivery of inhalation drugs.