title: Uniform and amorphous rifampicin microspheres obtained by freezing induced LLPS during lyophilization.
abstract: By lyophilization of rifampicin (RIF) solution in TBA/water with various solvent compositions, uniform and amorphous rifampicin (RIF) microspheres were produced. Using 55% TBA solution, the obtained RIF microspheres have a mono-dispersive size distribution with diameters range from 1 to 3 μm. The RIF microspheres are found to be amorphous by X-ray diffraction, and are expected to dissolve much faster than the crystalline RIF upon inhalation. Mechanistic investigation revealed that the amorphous RIF microspheres were formed due to liquid-liquid phase separation (LLPS) occurred during the freezing of the TBA/water solution. We also observed that the RIF microspheres can be readily phagocytized by activated THP-1 cells within 15 min. The suitable size distribution, high solubility, and readiness for phagocytosis by macrophages, all suggest that the lyophilized amorphous RIF microspheres could be potentially used as an anti-tuberculosis inhalation therapy. In addition, similar process was used to lyophilize TBA/water solutions of several other drugs, including rifaximin, rifapentine, paclitaxel, and isoniazid. We found that for drugs with appropriate physiochemical properties, such as paclitaxel and rifaximin, mono-dispersive microspheres could be obtained as well, which demonstrated that freezing induced LLPS could be utilized as a novel particle engineering methodology to produce drug microspheres by lyophilization.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, Beijing 100084, PR China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Tsinghua University, Beijing 100084, PR China.
authors.forename: Chun
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, Beijing 100084, PR China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Tsinghua University, Beijing 100084, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: Kong
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, Beijing 100084, PR China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Tsinghua University, Beijing 100084, PR China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Basic Medical Sciences, Beijing 100084, PR China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Tsinghua University, Beijing 100084, PR China.
authors.forename: Junhao
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Basic Medical Sciences, Beijing 100084, PR China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Tsinghua University, Beijing 100084, PR China.
authors.forename: Babak
authors.initials: B
authors.lastname: Javid
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, Beijing 100084, PR China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Tsinghua University, Beijing 100084, PR China. Electronic address: qianfeng@biomed.tsinghua.edu.cn.
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
mesh_terms: D000280:Administration, Inhalation; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004337:Drug Carriers / Q000737:chemistry*; D000067493:Dynamic Light Scattering; D005612:Freeze Drying / Q000379:methods*; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage; D008264:Macrophages / Q000187:drug effects; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D017239:Paclitaxel / Q000008:administration & dosage; D010316:Particle Size; D010587:Phagocytosis / Q000187:drug effects; D012293:Rifampin / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000494:pharmacology; D012995:Solubility; D014867:Water / Q000737:chemistry; D014961:X-Ray Diffraction; D020002:tert-Butyl Alcohol / Q000737:chemistry
chemical_list: D004337:Drug Carriers; D014867:Water; D020002:tert-Butyl Alcohol; D017239:Paclitaxel; D007538:Isoniazid; D012293:Rifampin; C018421:rifapentine
keywords: Inhalation; Liquid–liquid phase separation (LLPS); Lyophilization; Rifampicin; Tuberculosis