Integration of Chemical Synthesis with Co-crystallization: The Study of 1:1 Sulfathiazole-Theophylline and 1:1 Sulfathiazole-Sulfanilamide Co-crystal Systems

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Title:	Integration of Chemical Synthesis with Co-crystallization: The Study of 1:1 Sulfathiazole-Theophylline and 1:1 Sulfathiazole-Sulfanilamide Co-crystal Systems
Authors:	葉冠麟;Yeh,Kuan-Lin
Contributors:	化學工程與材料工程學系
Keywords:	共晶;磺胺噻唑;氨苯磺胺;一鍋式製程;co-crystal;sulfathiazole;sulfanilamide;one-pot process
Date:	2016-06-16
Issue Date:	2016-10-13 12:38:50 (UTC+8)
Publisher:	國立中央大學
Abstract:	共晶是改善藥物溶解度的方法之一，近幾年來發展尤為迅速，但大部分的研究仍著重於共晶本身的探討而並未考慮化學合成，因此本篇研究主要目的在於結合化學反應與共結晶的製程，對於磺胺噻唑(sulfathiazole)－茶鹼(theophylline)共晶與磺胺噻唑(sulfathiazole)－氨苯磺胺(sulfanilamide)共晶的製程進行討論，組成此兩種共晶的成分其莫爾比均為一比一。首先，依據文獻所提供的反應，我們可以製造出Form III磺胺噻唑與β-form、γ-form混合的氨苯磺胺。為了將化學反應與共晶製程串連在一起，我們在磺胺噻唑的合成過程中加入茶鹼，並進行酸鹼中和使磺胺噻唑－茶鹼共晶析出沉澱，而磺胺噻唑－氨苯磺胺共晶則是於氨苯磺胺的合成過程中，加入磺胺噻唑並酸鹼中和令共晶形成，獲得的晶體經粉末X射線繞射儀(PXRD)、示差掃描量熱儀(DSC)及傅立葉轉換紅外線光譜儀(FT－IR)等儀器檢測後證實的確為共晶，由此製程所獲得的磺胺噻唑－茶鹼與磺胺噻唑－氨苯磺胺的產率分別為81.02wt%與88.48wt%。此外，我們也探討了磺胺噻唑與茶鹼以及磺胺噻唑與氨苯磺胺的添加比例對產物的影響，在磺胺噻唑－茶鹼共晶的部分，除了添加比例為接近一的情況外，磺胺噻唑或茶鹼皆會作為不純物出現在產物中，在磺胺噻唑－氨苯磺胺共晶的部分，當添加比例為1:1.5與1:1時，我們觀察到產物為磺胺噻唑－氨苯磺胺與磺胺噻唑的混合物，而當添加比例為1:0.5時，產物則為磺胺噻唑－氨苯磺胺與氨苯磺胺的混合物。我們還嘗試將磺胺噻唑和氨苯磺胺的合成步驟合併，也成功製造出磺胺噻唑－氨苯磺胺的共晶，這項研究不僅能夠減少製程所需的步驟，也同時符合「綠色製程」的概念，此外也具有發展成連續式製程的可能性。在溶解度測試的部分，兩種共晶的溶解度均介於各自形成體的溶解度之間，磺胺噻唑－茶鹼在15°C、25°C、40°C及6°C純水中的溶解度大約為每毫升0.28、0.81、0.91及3.61毫克，而磺胺噻唑－氨苯磺胺在15°C、25°C、40°C及60°C純水中的溶解度則分別為每毫升0.59、1.10、2.18與4.30毫克。最後，將磺胺噻唑－茶鹼共晶與磺胺噻唑－氨苯磺胺置於相對濕度75%、40°C的環境裡一個月，測試這兩種共晶對於濕度的穩定性。;Co-crystals has been regarded as an approach to promote the solubility of drugs and developed rapidly in recent years. However, most of the studies mainly focus on the co-crystallization step rather than concerning about the synthesis and co-crystallization together. The aim of this thesis was integrating the co-crystallization with chemical synthesis to produce the 1:1 co-crystals of sulfathiazole-theophylline (STZ-THE) and 1:1 co-crystals of sulfathiazole-sulfanilamide (STZ-SNM). According to the original regular synthetic method, the sulfathiazole Form III and a mixture of sulfanilamide β-form and γ-from were obtained. The 1:1 co-crystals of STZ-THE was produced by adding theophylline into the synthetic process of sulfathiazole, and the 1:1 co-crystals of STZ-SNM was obtained by introducing sulfanilamide into the synthetic process of sulfanilamide. Based on the concept of direct co-crystal assembly, we successfully produces the 1:1 co-crystals of STZ-THE and 1:1 co-crystals of STZ-SNM by integrating the chemical synthesis and co-crystallization. The yield of 1:1 co-crystals of STZ-THE and 1:1 co-crystals of STZ-SNM obtained by integration method were 81.02 wt% and 88.48 wt%, respectively. In the study of the loading ratio (LR) of API to co-former, the impurity would be formed except LR was close to 1 for 1:1 co-crystals of STZ-THE based on the characterization of PXRD, DSC and FT-IR. In addition, either sulfanilamide or sulfathiazole was formed in the product of 1:1 co-crystals of STZ-SNM regardless of the value of LR. The experiment of combining the synthesis of sulfathiazole and sulfanilamide for preparing the 1:1 co-crystals of STZ-SNM was successful even though traces of impurity were presented. This study might correspond with the new concept of “green process”. It not only reduced the processing steps, but also had the potential to be developed for continuous co-crystallization. The solubility of two co-crystals was between their individual components. The solubility of 1:1 co-crystals of STZ-THE in water at 15°C, 25°C, 40°C and 60°C was 0.28, 0.81 ,0.91 and 3.6 mg/mL, respectively. On the other hand, the solubility of 1:1 co-crystals of STZ-SNM in water at 15°C, 25°C, 40°C and 60°C was 0.59, 1.10, 2.18 and 4.30 mg/mL. Finally, both 1:1 co-crystals of STZ-THE and 1:1 co-crystals of STZ-SNM were stored in a condition of 75% relative humidity and 40°C to test the moisture stability of co-crystals.
Appears in Collections:	[National Central University Department of Chemical & Materials Engineering] Electronic Thesis & Dissertation

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