Spherical Crystallization for Lean Solid-Dose Manufacturing by Initial Solvent Screening: The Study of Phenylbutazone 苯丁唑酮的初始溶劑篩選應用在球形結晶技術來做固體藥劑的精益製造

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题名:	Spherical Crystallization for Lean Solid-Dose Manufacturing by Initial Solvent Screening: The Study of Phenylbutazone 苯丁唑酮的初始溶劑篩選應用在球形結晶技術來做固體藥劑的精益製造
作者:	謝翔宇;Hsiang-yu Hsieh
贡献者:	材料科學與工程研究所
关键词:	結晶度;晶貌;溶解度;苯丁唑酮;球形結晶;初始溶劑篩選;同質異相;同質異相表;Form Space;crystal habit;crystallnity;polymorphism;initial solvent screening;solubility;spherical crystallization;phenylbutazone
日期:	2008-06-16
上传时间:	2009-09-21 11:29:10 (UTC+8)
出版者:	國立中央大學圖書館
摘要:	藥物的研究與發展是一個很費時與昂貴的過程。平均來說，一個新藥物從在實驗室研發到真正上市大約需要500到880百萬美元，而且整個過程需要約15年。在本論文中，最終的目標是要在藥物發展階段建立一套快速、便利和有系統的方法來改善效率以及節省時間和金錢。首先，我們建立了一個有關苯丁唑酮(phenylbutazone)結晶的資料庫。利用23種有機溶劑篩選的方式，有關苯丁唑酮溶解度(solubility)、同質異相(polymorphism)、結晶度(crystallinity)、晶貌(crystal habit)以及同質異相表的資料被完整收集。一種粗糙但簡單方便且只需要少量樣品的篩選方法也將在本論文中介紹給大家。同時，有關於苯丁唑酮新的同質異相，構形F，其結晶體是利用降溫的路徑個別在正丁醇(n-butyl alcohol)和苯甲醇(benzyl alcohol)的溶液裡所產生的。第二，苯丁唑酮的精益製造是利用球形結晶的方法在由同質異相表所推算出來的136組有機溶劑組合裡實行的。並且成功地提供了一組由乙腈(acetonitrile)、水(water)和正庚醇(n-heptane)的有機溶劑組合是具有最佳的產率、球形度和脆碎度來提供製藥業做為量產的依據。除此之外，利用球形結晶的方法，構形E是以一種跟文獻相較之下，更快速、簡單且省能源的方法製造出來。苯丁唑酮本身具有豐富的有關特性研究文獻以及不同的同質異構體，這就是我們選擇它當作我們的活性藥物成分（active pharmaceutical ingredient, API）的原因。但是本論文中的研究方法，可以用在其他的活性藥物成分、候選藥物或是簡單的有機分子上。 Drug discovery and development process was a long and expensive process. The average cost for a drug from laboratory to market was about USD 500 to USD 880 million and it takes ten to fifteen years to complete the whole process. In this thesis, the final target was to establish fast, convenient and systematic method to improve the efficiency, and money-saving for scale up in drug development stage. Firstly, a useful engineering data bank of solubility, polymorphism, crystallinity, crystal habit and Form Space by solvent screening for phenylbutazone would be established and a robust, miniature solvent screening method would be introduced. In the meantime, the new polymorph, Form F, was discovered in the crystals precipitated in n-butyl alcohol and benzyl alcohol by temperature cooling respectively. Secondly, the study of phenylbutazone in spherical crystallization for lean solid manufacturing was carried out through 136 solvent combinations derived from the Form Space. A successful solvent combination giving the best yield, sphericity, and friability for scale-up in the pharmaceutical industry was acetonitrile-water-n-heptane. Besides, with spherical crystallization, Form E was produced in a fast, energy saving and easy way compared with literatures. Phenylbutazone was chosen as the active pharmaceutical ingredient (API) because of the abundance in literatures about the characterization of phenylbutazone and its polymorphs. By the initial solvent screening methods in this thesis could also be applied to some other APIs or drug candidates or simple organic materials.
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