通過阻抗和溶解度曲線確定鹽酸伊立替康三水合物注射液過飽和度的穩定性，以最大程度地減少碳足跡

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莫仁云(Jen-Yun Mo) 查詢紙本館藏

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論文名稱

通過阻抗和溶解度曲線確定鹽酸伊立替康三水合物注射液過飽和度的穩定性，以最大程度地減少碳足跡
(Stability of Supersaturation in Irinotecan Hydrochloride Trihydrate Injection Concentrate by Frustration and Solubility Curve for Maximum Carbon Footprint Reduction)

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摘要(中)

鹽酸伊立替康三水合物作為濃縮注射液在 25 ºC 下表現出奇特的穩定性，過飽和度為 20 mg/mL。這種晶體生長前的現象是由鹽酸伊立替康三水合物分子自組裝成大小約為 1 nm 的二聚體引起的阻抗並隨後聚集形成大小約為 100 nm 的液體狀團簇。非線性范特霍夫圖驗證了鹽酸伊立替康三水合物溶液中結構組織的存在，而動態光散射分析證實了濃度高於 10 μM 時二聚體聚集體的形成。鹽酸伊立替康三水合物的晶型 b 已通過粉末 X 射線衍射確定為鹽酸伊立替康三水合物的穩定形式，使用單晶和高溫 X 射線衍射技術的進一步研究揭示了其作為通道水合物的特性。熱重分析表明脫水發生在大約 90 ºC。將鹽酸伊立替康三水合物保持在 25 ºC 或以下以及 30 至 60 % 的相對濕度範圍內以保持其化學計量至關重要，如動態蒸汽吸附實驗所證明的那樣。以新發現的 30 mg/mL 作為目標是有望用於更濃縮的注射劑配方，經計算後發現當以 30 mg/mL 作為運輸以及儲存的濃縮注射液時，在空運、卡車、鐵路和海運相關的碳足跡分別為 62.27、 11.26、1.16 和 2.21 公斤 CO2/公里已經比原來濃度 20 mg/mL 的少了約 33.4 %。另外如遵循且應用溶解度曲線在加熱過程上，年銷售濃縮注射液可以有效減少 CO2 排放量 1603.86 公斤。

摘要(英)

Irinotecan HCl･3H2O demonstrates surprising stability as a concentrated injection at 25 ºC, with a supersaturation level of 20 mg/mL. This pre-nucleation phenomenon is a frustration caused by the self-assembly of irinotecan HCl･3H2O molecules into dimers with a size of about 1 nm and subsequent aggregation to form liquid-like clusters with a size of about 100 nm. Nonlinear Van′t Hoff plots verified the presence of the structural organization in irinotecan HCl ･3H2O solutions, while dynamic light scattering analysis was employed to confirm the formation of dimer aggregates at concentrations above 10 μM. Irinotecan HCl･3H2O Form b has been identified as the stable form by powder X-ray diffraction, and further studies using single crystal and high temperature X-ray diffraction techniques revealed its properties as a channel hydrate. Thermogravimetric analysis showed that dehydration occurred at approximately 90 ºC. It is critical to maintain irinotecan HCl･3H2O at or below 25 ºC and within a relative humidity range of 30 to 60% to maintain its stoichiometry, as demonstrated by the dynamic vapor sorption experiments. The newly discovered concentration of 30 mg/mL holds promising potential for use in more concentrated formulations of injectable drugs, then when combined with the solubility curve as an operational condition during the heating process, it enables effective energy conservation and carbon reduction. Calculations indicate that when transported as a commercial product at a concentration of 30 mg/mL, the carbon footprints associated with air, truck, rail, and sea transport are 62.27, 11.26, 1.16, and 2.21 kg CO2/km, III respectively, representing a reduction of approximately 33.4 % compared to the initial 20 mg/mL concentration. Furthermore, by following the dissolution curve as a guide during the heating process, the annual sales of concentrated injection solution can effectively reduce CO2 emissions by 1603.86 kg.

關鍵字(中)

★ 鹽酸伊立替康三水合物
★ 碳足跡

關鍵字(英)

★ Irinotecan Hydrochloride Trihydrate
★ Carbon Footprint

論文目次

摘要 I
Abstract II
Acknowledgment IV
Table of Contents VI
List of Figures IX
List of Tables XIV
Chapter 1 Introduction 1
1.1 Brief Introduction of Pharmaceutical Industry 1
1.2 Injection drug of Irinotecan HCl･3H2O 3
Chapter 2 Experimental Sections 11
2.1 Materials 11
2.1.1 Chemicals 11
2.1.2 Solvents 12
2.2 Experimental Methods 13
2.2.1 Initial Solvent Screening and Solubility Measurement 13
2.2.2 Recrystallization of Irinotecan HCl･3H2O 14
2.2.3 Stability of Irinotecan HCl･3H2O 15
2.3 Analytical Instruments 19
2.3.1 Optical Microscopy (OM) 19
2.3.2 Hot-Stage & Polarizing Optical Microscopy (HSOM) 19
2.3.3 Powder X-ray Diffraction (PXRD) 20
2.3.4 High Temperature X-ray Diffractometer (HT-PXRD) 20
2.3.5 Fourier Transform Infrared (FT-IR) Spectroscopy 20
2.3.6 Thermal Gravimetric Analysis (TGA) 21
2.3.7 Differential Scanning Calorimetry (DSC) 21
2.3.8 Nuclear Magnetic Resonance (NMR) 22
2.3.9 High Performance Liquid Chromatographic analyzer (HPLC) 22
2.3.10 Dynamic vapor sorption (DVS) 23
2.3.11 Dynamic Light Scattering (DLS) 24
Chapter 3 Results and Discussion 25
3.1 Use Test of Irinotecan HCl･3H2O 25
3.2 Initial Solvent Screening 31
3.3 Solubility Measurements 33
3.4 Stability Test for Irinotecan HCl･3H2O 34
3.4.1 Determination on Temperature 38
3.4.2 Storage Time without Crystallization 44
3.4.3 Determination on Humidity 56
3.4.4 Determination on NaCl wt % 62
3.5 Recrystallization of Irinotecan HCl･3H2O 64
3.5.1 Recrystallization by Cooling and Cooling-Antisolvent 64
3.5.2 Processing Operation of Recrystallization 65
Chapter 4 Conclusions and Future Works 67
4.1 Conclusions 67
4.2 Future Works 68
Appendices 69
References 78

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指導教授

李度(Tu Lee)

審核日期

2023-7-20

推文