Effects of Templating Molecules of Sodium Benzoate, 1:1 Co-crystal of Benzoic Acid - Sodium Benzoate, and 2:1 Co-crystal of Benzoic Acid - Sodium Benzoate on the Crystallization Kinetics of 2:1 Co-crystal of Benzoic Acid – Sodium Benzoate

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Title:	Effects of Templating Molecules of Sodium Benzoate, 1:1 Co-crystal of Benzoic Acid - Sodium Benzoate, and 2:1 Co-crystal of Benzoic Acid - Sodium Benzoate on the Crystallization Kinetics of 2:1 Co-crystal of Benzoic Acid – Sodium Benzoate
Authors:	菲斯雅;LINI, FRESHSYA ZATA
Contributors:	化學工程與材料工程學系
Keywords:	共晶;Co-crystal
Date:	2017-07-28
Issue Date:	2017-10-27 12:57:17 (UTC+8)
Publisher:	國立中央大學
Abstract:	製藥工業中，製藥工業中， 65% 以上的新候選藥物其水溶性極低，可通過將一活性藥物成分（活性藥物成分（ API）與一共形成體結合共晶（形成體結合共晶（形成體結合共晶（形成體結合共晶（ Co-crystal），藉此提升），藉此提升），藉此提升高端產物高端產物的純化效果以及藥物的效果以及藥物的效果以及藥物的生物相容性來克服此問題。問題。在我的研究當中，苯甲酸作為活性藥物成分與鈉共在我的研究當中，苯甲酸作為活性藥物成分與鈉共在我的研究當中，苯甲酸作為活性藥物成分與鈉共形成體通過反應結晶的方式在積比 4：1的乙醇－水溶液中產生共晶：將含有溶液中產生共晶：將含有溶液中產生共晶：將含有 17.22克（0.141 莫耳）的苯甲酸溶液Ａ在 50毫升的乙醇水溶液加入含有 1.89克（0.047莫耳）的氫氧化鈉溶液Ｂ在 6毫升的乙醇水溶液。接著，接著，將溶液Ａ與Ｂ混合後所形成的一澄清飽和溶液從室溫冷卻至 16度，直到晶體開始形成，即溶液變得渾濁，表明該系統的成核引發時間（τ）結束，進而可用於推算出一些重要結晶成核與長的動力學和熱學參數，例如：界面能（γ）、 Gibbs能障（ΔGcr）、成核速率（J）、成核的臨界尺寸（rc）及相對生長速率（RG），針對此系統不同初始過飽和比（），針對此系統不同初始過飽和比（），針對此系統不同初始過飽和比（），針對此系統不同初始過飽和比（ S0）： 1.66、1.54、1.48與 1.43來計算上述所提之參數，並進行分析。為更一步探討子模板對於共晶的影響苯甲酸計算上述所提之參數，並進行分析。為更一步探討子模板對於共晶的影響苯甲酸計算上述所提之參數，並進行分析。為更一步探討子模板對於共晶的影響苯甲酸計算上述所提之參數，並進行分析。為更一步探討子模板對於共晶的影響苯甲酸計算上述所提之參數，並進行分析。為更一步探討子模板對於共晶的影響苯甲酸計算上述所提之參數，並進行分析。為更一步探討子模板對於共晶的影響苯甲酸計算上述所提之參數，並進行分析。為更一步探討子模板對於共晶的影響苯甲酸計算上述所提之參數，並進行分析。為更一步探討子模板對於共晶的影響苯甲酸納、苯甲酸其 2:1以及 1:1的共結晶分別以 1.5的重量百分比添加至上述所提之溶液 A，重複量測其結晶的，重複量測其結晶的動力學和熱參數。此系統的成核引發時間為 3到 40分鐘，分鐘，隨著較高的初始過飽和比，可得到著較高的初始過飽和比，可得到著較高的初始過飽和比，可得到較短的成核引發短的成核引發時間。時間。此外，在分子模板的影響下可此外，在分子模板的影響下可此外，在分子模板的影響下可此外，在分子模板的影響下可此外，在分子模板的影響下可此外，在分子模板的影響下可在更短的時間內來引發共晶系統成核過程，提供較低在更短的時間內來引發共晶系統成核過程，提供較低在更短的時間內來引發共晶系統成核過程，提供較低Gibbs能障和成障和成核的臨界尺寸，以及較高的成核速率和相對生長速率。相對生長速率。不同條件下所形成的產物經由不同條件下所形成的產物經由 PXRD、FTIR、DSC和 TGA的鑑定，證實的鑑定，證實的鑑定，證實為苯甲酸－苯甲酸鈉的 2:1共晶。最後，這些。最後，這些。最後，這些。最後，這些研究結果說明不論是從動力學或是熱的角度，苯甲酸－苯甲酸鈉的 2:1共晶的形成是可行;More than 65% of new drug candidates in pharmaceutical industry are poorly aqueous soluble drug. Co-crystallization technique can be used to overcome this problem through enhancing the high-end product purification and bioavailability of the drug by combining the API (Active Pharmaceutical Ingredient) with the co-former agent. In this work, co-crystallization of benzoic acid as the API with sodium benzoate as the co-former in co-solvent of 4:1 v/v of ethanol-water was generated by reaction crystallization method. A clear saturated solution was prepared by diluting Solution A containing 17.22 g (0.141 mol) of benzoic acid (HBz) in 50 mL of 4:1 v/v ethanol – water co-solvent and Solution B containing 1.89 g (0.047 mol) of sodium hydroxide (NaOH) in 6 mL of 2:1 v/v ethanol – water co-solvent. The solution then was cooled from room temperature to 16oC until the crystals were generated and the solution became turbid, indicating that the system had reached the end of the induction time, τ, of crystallization which can be used to determine some fundamental kinetic and thermodynamic parameters of nucleation and crystal growth, such as: the interfacial energy, γ, the Gibbs energetic barrier, ΔGcr, the nucleation rate, J, the critical size of stable nuclei, rc, and the relative growth rate, RG. All of these parameters were evaluated with different initial supersaturation ratio of the system, S0, which were: 1.66, 1.54, 1.48, and 1.43. To study the effect of templating in co-crystal system, about 1.5 wt % template of: sodium benzoate, 2:1 co-crystal of benzoic acid-sodium benzoate, and 1:1 co-crystal of benzoic acid-sodium benzoate were iii introduced for each system with different S0. In general, the induction times for all systems ranged from 3 to 40 minutes, where the higher S0 value gave the faster τ value. Moreover, introducing a template in the system gave a faster induction time, τ. ΔGcr and rc decreased, while J and RG increased on a faster induction time, indicating that co-crystallization thermodynamic and kinetic were directly related to the initial concentration of the drug. The final product of the solid crystals for each system was verified as 2:1 co-crystal of benzoic acid – sodium benzoate by PXRD, FTIR, DSC, and TGA. Finally, these results showed that co-crystallization of API, benzoic acid, with its co-former, sodium benzoate, was feasible, both kinetically and thermodynamically.
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