跳到主要內容

臺灣博碩士論文加值系統

(18.97.14.81) 您好!臺灣時間:2025/02/19 04:26
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:陳俊達
研究生(外文):Chun-Ta Chen
論文名稱:原料藥物於超臨界二氧化碳程序中溶解度、微粒化與共晶製備之研究
論文名稱(外文):Application of Supercritical Carbon Dioxide on Solubility, Micronization and Co-crystallization of Pharmaceutical Compounds
指導教授:陳延平陳延平引用關係
口試日期:2017-07-19
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:化學工程學研究所
學門:工程學門
學類:化學工程學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:中文
論文頁數:129
中文關鍵詞:固體溶解度超臨界二氧化碳造粒程序超臨界反溶劑法藥物共晶
外文關鍵詞:solubilitysupercritical carbon dioxideparticle formationsupercritical anti-solventpharmaceutical co-crystal
相關次數:
  • 被引用被引用:0
  • 點閱點閱:266
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
本研究選擇藥物選擇3種藥物:4-Aminopyridine、Edaravone與Monobenzone進行其於超臨界二氧化碳中之固體溶解度量測。4-Aminopyridine、Edaravone與Monobenzone為具有活性成分的原料藥(Active Pharmaceutical Ingredient, API) ,利用一半流動式量測設備,進行其於超臨界二氧化碳中之溶解度實驗量測,量測溫度為308.2 K、318.2 K與328.2 K,每組固定溫度下,量測壓力介於10~22 MPa之間。並利用具有三個可調參數之半經驗模式 (Semi-Empirical Model):Mendez-Santiago and Teja Model、Chrastil Model與Bartle Model,針對溶解度實驗數據進行迴歸計算。由迴歸結果可知,在半經驗模式下,其計算平均誤差(Average Absolute Relative Deviation in Solid Solubility,AADY)大約介於5-10 %以內。並藉由半經驗模式來檢驗實驗數據之一致性,以確認延伸迴歸參數的應用性。

第二部分則針對固體於超臨界二氧化碳中溶解度進行製備新形態藥物,建立一半連續式超臨界反溶劑法微粒化設備,選用藥物添加劑Fumaric acid當作合適之材料,以超臨界反溶劑法(Supercritical Anti-Solvent, SAS)進行製備粉體製備。操作溫度與壓力的範圍分別為308.2~328.2 K與10~20 MPa,實驗點為9點。製備後的產物,以各項分析儀器諸如光譜分析(FTIR)、熱分析(DSC, TGA)、與其它儀器(XRD)進行操作條件與回收率與平均粒徑進行探討。實驗結果發現,操作溫度與壓力降低,能得到最大的回收率與最小平均粒徑的理想結果。原始藥物的平均粒徑為136.3 ± 74.99 μm,經由低溫低壓之操作條件可縮減平均粒徑最小至2.84 ± 1.58 μm,操作條件越往溫度與壓力越高的環境下操作,反而得到的平均粒徑越大,最高可達223.37 ± 109.55 μm;回收率方面,很明顯地觀察得到溫度與壓力最低的操作條件中,能得到最高的回收率為57.95 %,而溫度與壓力最高的操作條件,能得到最低的回收率為30.84 %。

第三部分則針對固體於超臨界二氧化碳中溶解度進行製備新形態藥物,建立一半連續式超臨界反溶劑法微粒化設備,選用Piracetam與Salicylic acid分別當作合適之原料藥與之形成共構物(co-former),以超臨界反溶劑法(Supercritical Anti-Solvent, SAS)進行製備藥物活性成分新型式結晶:共晶藥物 (co-crystal) 製備。製備後的產物,以各項分析儀器諸如光譜分析(UV, FTIR)、熱分析(DSC, TGA)、與其它重要儀器(NMR、XRD)進行藥物形貌、晶型與化學計量比(stoimetric ratio)鑑定與解析。本計畫結果除了能得到共晶產物之成分比例外,也能經由此裝置得到最穩定之藥物共晶形態。而藥物晶體在各儀器分析鑑定下,得到接近單晶狀態。在溶離試驗的結果雖然與piracetam差異不大,是由於piracetam在水中溶解度屬於高溶解度,以及共晶藥物形成後,降低質傳擴散阻力所造成的結果。

本研究計畫首度發現,透過超臨界反溶劑技術,能將傳統藥物篩選(screening)與選擇(selection)之步驟,以超臨界反溶劑法結合在一起,得到最穩定之共結晶藥物,且化學計量比固定不變。並且也為藥物篩選手段上,為低產率之反應提出了一個概念性的篩選流程,能藉由此流程來驗證低產率共晶藥物的特徵,來交叉驗證並可能縮短藥物篩選的時間。這是目前傳統或新穎共晶藥物研究中,唯一不需大量溶劑,並能在短時間內完成共晶藥物製備之方法。
In this study, measurement and correlation of solid solubility for active pharmaceutical ingredients (APIs) in supercritical carbon dioxide were investigated. And re-crystallization and micronization for APIs were also investigated using supercritical anti-solvent (SAS) processes. The preparation of pharmaceutical co-crystals were also investigated using supercritical anti-solvent processes.

The solid solubilities of three components of 4-Aminopyridine, Edaravone and Monobenzone in supercritical carbon dioxide were measured using a semi-flow apparatus. Total 63 data points were obtained. These experimental results were correlated by three semi-empirical models : Mendez-Santiago-Teja, Chrastil and Bartle model. The measured data satisfied the self-consistency test, and the parameters in the semi-empirical models are feasible for data extrapolation.

Fumaric acid is used as drug to treat of psoriasis, and also as food additive. In this study, it was re-crystallized and micronized using supercritical anti-solvent(SAS)process. The operating parameter of temperature and pressure were 308.2~328.2 K and 10~20 MPa respectively. Total 9 data points were obtained. The mean particle size of Fumaric acid was reduced from its original 136.3 ± 74.99 μm to 2.84 ± 1.58 μm under the lowest operation conditions. The mean size of products and the recovery of products were involved to the operating parameters: the smallest mean size and 57.95 % of largest recovery operating at lower temperature and pressure, and the largest mean size and 30.84 % of smallest recovery operating at higher temperature and pressure. For pharmaceutical process, the results of the smallest mean size and largest of recovery indicate that the feasibility and potential to alternating the traditional excipient.

Finally, the drug for Alzheimer’s disease: piracteam, and salicylic acid were choose as API and co-former re-crystallization and micronization for a thiazide diuretic chlorothiazide was investigated using semi-continuous supercritical anti-solvent (SAS) process. In this study, piracetam and salicylic acid were chosen as API and co-former respectively and synthesized by prepared various molar ratio of piracetam-salicylic acid-acetone solution operating at supercritical state. Molar ratio solution, temperature and pressure were setting as operating parameters and 1:1~1:4 molar ratio solution was prepared and operating at 35~55 °C of temperature and 10~12 MPa of pressure. After SAS process, co-crystal products was collected and analyzed by SEM, PXRD, ATR-FTIR, DSC, TGA and 1H-NMR respectively. For low recovery of co-crystal products, DSC was a judgment and was firstly introduced to conform the reaction is completed or uncompleted; Then ATR-FTIR was introduced to conform the existing of hydrogen bonding of co-crystal products. The ATR-FTIR spectra of co-crystal products show that piracetam and salicylic acid were bonded with each other; Thermal analysis results such as DSC and TGA show that the good thermal stability of co-crystal products, and the residual solvent containing in co-crystal products were not observed; Morphology of co-crystal products shown on the PXRD pattern indicates that the characteristic of co-crystal products might be near single crystal form. Finally, the 1H-NMR result was illustrated that the stoichiometric ratio of a co-crystal is invariant weather the molar ratio changed at same operating condition for low recovery of product, and it can also be double conformed by TGA curve. This result of double checking has not been reported by other publication using supercritical technique. This novel screening process will further check the ideal co-crystals for developing of pharmaceutical processing.
目錄
誌謝 I
摘要 II
Abstract IV
目錄 XII
表目錄 IX
圖目錄 XI
第一章 緒論 1
1-1 超臨界流體之簡介與發展趨勢 1
1-2 熱力學性質研究之重要性 3
1-3 藥物微粒化與結晶之重要性 4
1-4 超臨界流體微粒製備技術介紹 6
1-5 共晶藥物之介紹 9
1-6 研究規劃 10
第二章 藥物固體於超臨界二氧化碳中之溶解度實驗量測 15
2-1 研究背景與動機 15
2-2 實驗方法 21
2-3 應用熱力學模式計算固體溶解度 26
2-4 實驗用藥品 28
2-5 實驗結果與討論 28
2-6 結論 30
第三章 利用超臨界反溶劑法製備藥物Fumaric acid之研究 57
3-1 研究背景與動機 57
3-2 實驗用藥品 59
3-3 實驗方法 59
3-4 分析方法 62
3-5 藥物溶離行為分析 65
3-6 實驗結果與討論 67
3-7 結論 69
第四章 利用超臨界反溶劑法進行Piracetam-salicylic acid共晶藥物製備與研究 89
4-1 研究背景與動機 89
4-2 實驗用藥品 92
4-3 實驗方法 92
4-4 實驗參數與效應 93
4-5 實驗結果與討論 95
4-6 結論 97
第五章 結論 107
符號說明 111
參考文獻 113
附錄 121
作者簡介 128
Abraham, M. A., & Sunol, A. K., Supercritical Fluids: Extraction and Pollution Prevention: p69, ACS symposium series, 1997.
Alam, M. A., Al-Jenoobi, F. I., & Al-mohizea, A. M., Commercially bioavailable proprietary technologies and their marketed products, Drug Discov. Today, 18 (2013) 936-949.
Amidon, G. L., Lennernas, H., Shah V. P., & Crison J. R., A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability, Pharm. Res., 12 (1995) 413-420.
Babu, N. J., & Nangia, A., Solubility Advantage of Amorphous Drugs and Pharmaceutical Cocrystals, Cryst. Growth Des., 11 (2011) 2662–2679.
Bahrami, M., & Ranjbarian, S., Production of micro- and nano-composite particles by supercritical carbon dioxide. J. Supercrit. Fluid, 40 (2007) 263-283.
Balak, D. M. W., Arani, S. F., Hajdarbegovic, E., Hagemans, C. A. F., Bramer, W. M., Thio, H. B., & Neumann, H. A. M., Efficacy, effectiveness and safety of fumaric acid esters in the treatment of psoriasis: a systematic review of randomized and observational studies, Brit. J. Dermatol., 175 (2016) 250–262.
Bartle, K. D., Clifford, A. A., Jafar, S. A., & Shilstone, G. F., Solubilities of solids and liquids of low volatility in supercritical carbon dioxide, J. Phys. Chem. Ref. Data, 20 (1991) 713-756.
Bond, A. D., Pharmaceutical Salts and Co-crystals (Editors: Wouters, J., & Quéré, L.), Chapter 2, RSC Drug Discovery Series No. 16, UK, 2012.
Boonnoun, P., Nerome, H., Machmudah, S., Goto, M., & Shotipruk, A., Supercritical anti-solvent micronization of marigold-derived lutein dissolved in dichloromethane and ethanol, J. Supercrit. Fluid, 77 (2013) 103-109.
Cansell, F., Aymonier, C., & Loppinet-Serani, A., Review on materials science and supercritical fluids, Curr. Opin. Solid St. M., 7 (2003) 331-340.
Castaneda-Acosta, J., Cain, A. W., Fischer, N. H., & Knopf, F. C., Extraction of Bioactive Sesquiterpene Lactones from Magnolia grandiflora Using Supercritical Carbon Dioxide and Near-Critical Propane, J. Agric. Food Chem., 43 (1995) 63–68.
Chatterjee, M., Sato, M., Kawanami, H., Ishizaka, T., Yokoyama, T., & Suzuki, T., Hydrogenation of aniline to cyclohexylamine in supercritical carbon dioxide: Significance of phase behaviour, Appl. Catal. A-Gen., 396 (2011) 186–193.
Chen, Y. M., Lin, P. C., Tang, M., & Chen Y. P., Solid solubility of antilipemic agents and micronization of gemfibrozil in supercritical carbon dioxide, J. Supercrit. Fluid, 52 (2010a) 175-182.
Chen, Y. M., Tang, M., & Chen, Y. P., Recrystallization and micronization of sulfathiazole by applying the supercritical antisolvent technology, Chem. Eng. J., 165 (2010b) 358-364.
Chimowitz, E. H., & Pennisi, K. J., Process Synthesis Concepts for Supercritical Gas Extraction in the Crossover Region, AICHE J., 32 (1986) 1665-1676.
Chrastil, J., Solubility of solids and liquids in supercritical gases, J. Phys. Chem., 86 (1982) 3016-3021.
Christov, M., & Dohrn, R., High pressure fluid-phase equilibria: experimental methods and systems investigated (1994-1999), Fluid Phase Equilibr., 202 (2002) 153-218.
Costa, P., Manuel, J., & Lobo, S., Modeling and comparison of dissolution profiles, Eur. J. Pharm. Sci., 13 (2001) 123-133.
Cuadra, I. A., Cabañas, A., Cheda, J. A. R., Martínez-Casado, F. J., & Pando, C., Pharmaceutical co-crystals of the anti-inflammatory drug diflunisal and nicotinamide obtained using supercritical CO2 as an antisolvent, Chem. Eng. J., 303 (2016) 238–251.
Desiriaju, G. R., Supramolecular Synthons in Crystal Engineering—A New Organic Synthesis, Angew. Chem. Int. Edit., 1995, 34:2311-2327.
Dohrn, R., & Brunner, G., High pressure fluid-phase equilibria: experimental methods and systems investigated (1988-1993), Fluid Phase Equilibr., 106 (1995) 213-282.
Dohrn, R., Peper, S., & Fonseca J. M. S., High-pressure fluid-phase equilibria: experimental methods and systems investigated (2000-2004), Fluid Phase Equilibr., 288 (2010) 1-54.
Esfandiari, N., & Ghoreishi, S. M., Synthesis of 5-Fluorouracil nanoparticles via supercritical gas antisolvent process, J. Supercrit. Fluid, 84 (2013) 205–210
Esmaeilzadeh F., Goodarznia I., Supercritical extraction of phenanthrene in the crossover region, J. Chem. Eng. Data, 50 (2005) 49-51.
Fonseca, J. M. S., Dohrn, R., & Peper, S., High-pressure fluid phase equilibria: Experimental methods and systems investigated (2005–2008), Fluid Phase Equilibr., 300 (2011) 1–69.
Fornari, R., Alessi, P., & Kikic, I., High pressure fluid phase equilibria: experimental methods and systems investiaged (1978-1987), Fluid Phase Equilibr., 57 (1990) 1-33.
Galia, A., Argentino, A., Scialdone, O., & Filardo, G., A new simple static method for the determination of solubilities of condensed compounds in supercritical fluids, J. Superit. Fluid, 24 (2002) 7-17.
Gharagheizi, F., Eslamimanesh, A., Mohammadi, A. H., & Richon, D., Artificial Neural Network Modeling of Solubilities of 21 Commonly Used Industrial Solid Compounds in Supercritical Carbon Dioxide, Ind. Eng. Chem. Res., 50 (2011) 221-226.
Gurdial, G. S., & Foster, N. R., Solubility of o-hydroxybenzoic acid in supercritical carbon dioxide, Ind. Eng. Chem. Res., 30 (1991) 575-580.
Hendeles, L., Weinberger, M., Milavetz, G., Hill, M., & Vaughan, L., Food-Induced “Dose-Dumping” from a Once-a-Day Theophylline Product as a Cause of Theophylline Toxicity, Chest, 87 (1985) 758-765.
Hiendrawan, S., Veriansyah, B., Widjojokusumo, E., Soewandhi, S. N., Wikarsa, S., & Tjandrawinata, R. R., Pharmaceutical Salts of Carvedilol: Polymorphism and Physicochemical Properties, Int. J. Pharm. Pharm. Sci., 8 (2016) 89–98.
Jasco analytic instruments, Rapid peptide separation by supercritical fluid chromatography, SFC Application note, 8-9, http://www.jasco.com.br/imagem/catalogos/aplicacoes/cromatografia/sfc_01.pdf
King, J. W., & Williams, L. L., Utilization of critical fluids in processing semiconductors and their related materials, Curr. Opin. Solid St. M., 7 (2003) 413-424.
Knapp, H., Doring, R., Olellrich, L., Plocker, U., & Prausnitz, J. M., Vapor-liquid equilibria for mixture of low boiling substances, Dechema Chem. Data Series VI, 1981.
Kurnlk, R. T.; Holla, S. J., & Reid, R. C., Solubility of solids in supercritical carbon dioxide and ethylene, J. Chem. Eng. Data, 26 (1981) 47-51.
Lee, L. S.; Huand, J. F., & Zhu O. X.,Solubilities of Solid Benzoic Acid, Phenanthrene, and 2,3-Dimethylhexane in Supercritical Carbon Dioxide, J. Chem. Eng. Data, 46 (2001) 1156-1159.
Lee, L. Y., Wang, C. H., & Smith, K. A., Supercritical antisolvent production of biodegradable micro- and nanoparticles for controlled delivery of paclitaxel, J. Controlled Release, 125 (2008) 96-106.
Leon, S., & Andrew, Y., Applied Biopharmaceutics and Pharmacokinetics, 4th Edition, McGraw-Hill, 1999.
Lin, H. M., Ho, C. C., & Lee, M. J., Solubilities of disperse dyes of blue 79:1, red 82 and modified yellow 119 in supercritical carbon dioxide and nitrous oxide, J. Supercrit. fluid, 32 (2004) 105-114.
Lin, P. C., Su, C. S., Tang, M., & Chen, Y.P., Micronization of ethosuximide using the rapid expansion of supercriticalsolution (RESS) process, J. Supercrit. fluid, 72 (2012) 84– 89.
Loth, H., & Hemgesberg, E., Properties and dissolution of drugs micronized by crystallization from supercritical gases, Int. J. Pharm., 32 (1986) 265-267.
Martin, A., & Cocero, M. J., Micronization processes with supercritical fluids: fundamentals and mechanism, Adv. Drug Deliv. Rev., 60 (2008) 339-350.
Mendez-Santiago, J., & Teja, A. S., The solubility of solids in supercritical fluids, Fluid Phase Equilibr., 158-160 (1999) 501-510.
Montes, A., Bendel, A., Kürti, R., Gordillo, M. D., Pereyra, C., & Martínez, de la Ossa, E. J., Processing naproxen with supercritical CO2, J. Supercrit. Fluid, 75 (2013) 21–29.
Mosharraf, M., & Nystrom, C., The effect of particle size and shape on the surface specific dissolution rate of microsized practically insoluble drugs, Int. J. Pharm., 122 (1995) 35-47.
Nejad, S. J., Abolghasemi, H., & Moosavian, M. A., Prediction of solute solubility in supercritical carbon dioxide: A novel semi-empirical model, Chem. Eng. Res. Des., 88 (2010) 893-898.
Neurohr, C., Erriguible, A., Laugier, S., & Subra-Paternault, P., Challenge of the supercritical antisolvent technique SAS to prepare cocrystal-pure powders of naproxen-nicotinamide, Chem. Eng. J., 303 (2016) 238–251.
NIST Chemistry WebBook, http://webbook.nist.gov/chemistry/.
Noroozi, J., & Paluch, A. S., Microscopic Structure and Solubility Predictions of Multifunctional Solids in Supercritical Carbon Dioxide: A Molecular Simulation Study, J. Phys. Chem. B, 121 (2017) 1660–1674.
Padrela, L., Rodrigues, M. A., Velaga, S. P., Matos, H. A., & de Azevedo, E. G., Formation of indomethacin-saccharin cocrystals using supercritical fluid technology, Eur. J. Pharm. Sci., 38 (2009) 9-17.
Padrela, L., Rodrigues, M. A., Velaga, S. P., Fernandes, A. C., Matos, H. A., & de Azevedo E. G., Screening for pharmaceutical cocrystals using the supercritical fluid enhanced atomization process, J. Supercrit. Fluid, 53 (2010) 156-164.
Padrela, L., Rodrigues, M. A., Tiago, J., Velaga, S. P., Matos, H. A., & de Azevedo E. G., Tuning physicochemical properties of theophylline by cocrystallization using the supercritical fluid enhanced atomization technique, J. Supercrit. Fluid, 86 (2014) 129-136.
Pang T. H., & McLaughlln, E., Supercritical Extraction of Aromatic Hydrocarbon Solids and Tar and Bitumens, Ind. Eng. Chem. Proc. DD., 24 (1985) 1027–1032.
Porto, C. D., Voinovich, D., Decorti, D., & Natolino, A., Response surface optimization of hemp seed (Cannabis sativa L.) oil yield and oxidation stability by supercritical carbon dioxide extraction, J. Supercrit. Fluid, 68 (2012) 45-51.
Reverchon, E., & Adami, R., Nanomaterials and supercritical fluids, J. Supercrit. Fluid, 37 (2006) 1-22.
Reverchon, E., Adami, R., Cardea, S., & Della Porta, G., Supercritical fluids processing of polymers for pharmaceutical and medical applications, J. Supercrit. Fluid, 47 (2009) 484-492.
Reverchon, E., & Donsi, G., Salicylic acid solubilization in supercritical CO2 and its micronization by RESS, J. Supercrit. Fluid, 6 (1993) 241-248.
Ricci, S., Celani, M. G., Cantisani, A. T., & Righetti, E., Piracetam for acute ischaemic stroke. Cochrane. Db. Syst. Rev., (2006).
Rostamian, H., & Lotfollahi, M. N., A New Simple Equation of State for Calculating Solubility of Solids in Supercritical Carbon Dioxide, Period. Polytech. Chem. Eng. 59 (2015) 174-185.
Schmitt W. J., & Reid R. C., Solubitity of monofunctional organic solids in chemically diverse supercritical fluids, J. Chem. Eng. Data, 31 (1986) 204-212.
Seneff, M., Scott, J., Friedman, B., & Smith, M., Acute theophylline toxicity and the use of esmolol to reverse cardiovascular instability, Ann. Emerg. Med., 19 (1990) 671–673.
Shan, N., & Zaworotko, M. J., The role of cocrystals in pharmaceutical science, Drug Disc. Today, 13 (2008) 440-446.
Shekunov, B., & York P., Crystallization processes in pharmaceutical technology and drug delivery design, J. Cryst. Growth, 211 (2000) 122-136.
Shikhar, A., Bommana, M. M., Gupta, S. S., & Squillante, E., Formulation development of Carbamazepine–Nicotinamide co-crystals complexed with γ-cyclodextrin using supercritical fluid process, J. Supercrit. Fluid, 55 (2011) 1070-1078.
Skerget, M., Kenz, Z., & Kenz-Hrncic, M., Solubility of solids in sub- and supercritical fluids: a review, J. Chem. Eng. Data, 56 (2011) 694–719.
Stassi, A., Bettini, R., Gazzaniga, A., Giordano, F., & Schiraldi, A., Assessment of solubility of ketoprofen and vanillic acid in supercritical CO2 under dynamic conditions, J. Chem. Eng. Data, 45 (2000) 161-165.
Su, C. S., Chen, Y. M., & Chen, Y. P., Correlation of solid solubilities for phenolic compounds and steroids in supercritical carbon dioxide using the solution model, J. Taiwan Inst. Chem. E., 42 (2011) 608-615.
Su, C. S., Tang, M., & Chen, Y. P., Micronization of nabumetone using the rapid expansion of supercritical solution (RESS) process, J. Supercrit. Fluid, 50 (2009) 69-76.
Tabernero A., del Valle E. M. M. & Galán M. A., Supercritical fluisd for pharmaceutical particle engineering: methods, basic fundamentals and modeling, Chem. Eng. Process., 60 (2012) 9-25
Tai C. Y., You G. S., & Wang D. C., Modified retrograde crystallization process for separation of binary solid mixtures exploiting the crossover region of supercritical carbon dioxide, Ind. Eng. Chem. Res., 39 (2000) 4357-4364.
Tsai C. C., Lin H. M., & Lee M. J., Solubility of C. I. Disperse Violet 1 in supercritical carbon dioxide with or without cosolvent, J. Chem. Eng. Data, 53 (2008) 2163-2169.
Weyna, D. R. Shattock, T., Vishweshwar, P., Zaworotko, M. J., Synthesis and Structural Characterization of Cocrystals and Pharmaceutical Cocrystals: Mechanochemistry vs Slow Evaporation from Solution, Cryst. Growth Des., 9 (2009) 1106–1123.
William, M. H., CRC Handbook of Chemistry and Physics Online (section 16), 97th ed.,2016–2017, http://www.hbcpnetbase.com/.
Wouters, J., Rome, S., & Quéré, L., Pharmaceutical Salts and Co-crystals (Editors: Wouters, J., & Quéré, L.), Chapter 16, RSC Drug Discovery Series No. 16, UK, 2012.
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
無相關期刊