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  • 标题:Development of Universal Formulation with Superior Re-dispersion Using Nanocrystal Approach with Simultaneous Identification of API Physicochemical Properties
  • 本地全文:下载
  • 作者:Hiroyuki Fujii ; Satoru Watano
  • 期刊名称:Chemical and Pharmaceutical Bulletin
  • 印刷版ISSN:0009-2363
  • 电子版ISSN:1347-5223
  • 出版年度:2019
  • 卷号:67
  • 期号:10
  • 页码:1050-1060
  • DOI:10.1248/cpb.c19-00092
  • 出版社:The Pharmaceutical Society of Japan
  • 摘要:

    Universal nanocrystal formulation which can be applied to water-insoluble compounds was proposed and the criteria of its physicochemical properties as an active pharmaceutical ingredients (API) were investigated. Nanocrystal suspension was prepared by a wet-beads milling method. An acceptable Critical Quality Attributes (CQA) of nanocrystal suspension was defined by Z-average less than 500 nm and Polydispersity index (PDI) less than 0.3. Screening studies of dispersing and wetting agents were conducted using three model compounds in different p K a, melting points, etc. , to find universal nanocrystal formulation. The effect of four structurally different polymer species (hydroxypropyl cellulose (HPC), hydoroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP) and polyvinyl alcohol (PVA)) and their different grades or five different surfactants (docusate sodium (DOSS), sodium lauryl sulfate (SLS), cetyl trimethyl ammonium bromide (CTAB), polysolbate80 (PS80), and polyoxyethylene castor oil (CO-35)) were studied on the re-dispersion stability. It was found that the combination of 4% (w/v) HPC-SSL and 0.2% (w/v) DOSS was the most robust nanocrystal formulation owing to Z-average less than 200 nm and good re-dispersion stability without aggregates at pH 1.2 and pH 6.8. API physicochemical properties were also identified using ten water-insoluble compounds. Consequently, it was found that solubility (water, pH 1.2 and pH 6.8), molecular weight, hydrogen bonding acceptor and the ratio of log D 7.4 to C Log P were critical factors.

  • 关键词:nanocrystal;wet beads milling;re-dispersion stability;dispersing agent;wetting agent
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