| 摘要: | 在製藥工業中，藥物發現與發展所遇到的瓶頸之一是鹽類的製程與選擇。為了克服瓶頸所用的高速鹽類篩選法，研磨法和溶劑點滴研磨法，往往只能提供鹽類的類型數量與物理化學性質而已，至於如何生產某特定鹽類卻一無所知。通常花在某特定鹽類的製程研發所需的時間是12~18 個月。結果瓶頸卻從藥物發現與發展的階段轉移到臨床實驗的量產階段。有很多文獻探討高速鹽類篩選的方法、鹽類合成的原理、合成鹽類方法的不同個案，鹽類的驗證、選擇鹽類的規範、pH 值、超飽和、結晶溫度對於鹽類的物理化學性質的影響。但是，卻沒有任何文獻提到可以直接用來量產的鹽類篩選法。所以本計畫的目標是要發展一種初步鹽類篩選的平台技術，在20 毫升的玻璃瓶實驗中所獲得的數據，可用做為後續大量生產中10~100 公升結晶槽的依據。辦法是在小瓶子裡合成鹽類的過程中，避開溶劑蒸發的模式和減少有機溶劑的使用。初步鹽類篩選的步驟中所選擇的結晶路徑為降溫、添加反溶劑和水的大量使用。水是最理想的溶劑，因為鹽類在水中特別容易形成弱酸或弱鹼，但往往卻在其他有機溶劑中無法形成。而在酸鹼中的解離常數差(ΔpKa< 2)，在有機溶劑中會發生偏移而導致非常小甚至負的差異。我們將會對製造出來的鹽類(和共晶、同質異構物和奈米鹽晶粒)進行全面的分析和鑑定，這包括熱行為、結晶架構、pH-溶解度的探討、溼度吸收、溶解測試。對於分子間的作用力如何影響鹽類合成、共晶合成及對掌性分子的分離，會根據潛熱和熔點來一一的解釋與探討。所有新發現的穩定鹽類類型將會申請專利。我們會謹慎的學習所有的篩選邏輯，做為日後國科會自動化平台和連續結晶槽設計的構想書的概念。更重要的是，我們所發展出的初步鹽類和共晶篩選的平台技術，不但可以造福製藥業，甚至光電、陶瓷、食品、炸藥和染料工業都可從中得到裨益。The high-throughput salt screening methods, the grinding method and the solvent-drop grinding method meant to remove the bottleneck in the formation and selection of salts in late discovery and early development in the pharmaceutical industry only reveal the maximum available numbers and the physicochemical properties of salt forms. Little information is obtained for the possible manufacturing route of the salt formation. In practice, it usually takes another 12 to 18 months to identify a viable synthetic route after the right salt form of the most promising drug candidate is chosen. As a consequence, the bottleneck of the formation and selection of salts has shifted from discovery to preclinical and clinical drug development. Although there is a large number of publications covering methods for high-throughput salt screening, principles for salt formation, case-by-case methods for salt formation, approved salt forms, criteria for salt selection, and the effects of pH, supersaturation, and temperature of crystallization on the physicochemical properties of salts, there is almost no publication dealing with a method for salt screening readily to be scaled-up as a manufacturing route. Therefore, the aim of this proposal is to develop the initial salt screening technology enabling platform in a 20 mL scintillation vial for future manufacturing applicable in a 10- to 100-L batch crystallizer at the stage of late drug discovery and early drug development. To avoid the mode of evaporation and the use of organic solvents in the formation of salts, initial salt screening procedures intentionally involve crystallization pathways such as temperature cooling, the addition of an anti-solvent and the extensive use of water. Water is preferred because salts, particularly of weak acids or bases, that form readily in water can be missed completely in nonaqueous solvents due to the small or negative difference between the acid and base dissociation constants (ΔpKa < 2 ) caused by the shift of pKa values in organic solvents. Comprehensive analyses in thermal behaviors, crystal lattice structures, pH-solubility studies, moisture sorption studies and dissolution tests of all salts (along with co-crystals, polymorphs and nano-salt crystals) would be carried out. The underlying intermolecular forces responsible for the formation of salts and co-crystals and chiral discrimination as reflected by the heats of fusion and the melting points will be unveiled and compared. All newly discovered stable solid forms would be patented. The screening logics are carefully learned for paving the way of the designs of an automation platform and a continuous crystallizer for the next NSC proposal. More importantly, the initial salt and co-crystal screening technology enabling platform that we develop here not only will benefit the pharmaceutical industry but also optoelectronic industry, ceramics industry, food industry, explosive industry and dye industry. 研究期間 : 9808 ~ 9907 |
