Review Pembuatan Kokristal Farmasi dengan Metode Mekanokimia
Abstrak
Pengembangan bahan aktif farmasi saat ini cukup pesat, salah satunya adalah pengembangan kokristal. Kokristal dibuat dengan menggabungkan antara bahan aktif farmasi dan koformernya dengan berbagai metode misalnya pelarutan dan penggilingan. Mekanokimia adalah metode yang efektif untuk persiapan sistem kristal multikomponen. Mekanokimia dianggap sebagai alternatif pendekatan ramah lingkungan karena dilakukan dalam kondisi bebas pelarut atau dengan adanya pelarut dalam jumlah minimal. Artikel review ini dibuat dengan metode instrumen pencarian online terbitan internasional yang akan membahas definisi dan sejarah kokristal farmasi, teknik pembuatan kokristal, sejarah dan definisi mekanokimia, metode mekanokimia pada pembuatan kokristal farmasi, mekanisme metode mekanokimia, serta keuntungan dan kerugian metode mekanokimia. Oleh karena itu pada ulasan ini dijelaskan dan dibahas relevansi prosedur mekanokimia dalam pembentukan kristal multikomponen yang fokus pada kokristal farmasi. Selain itu pada akhir tinjauan ini juga dilaporkan ringkasan makalah ilmiah tentang sintesis mekanokimia kokristal farmasi.
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K. Yuvaraja and J. Khanam, “Enhancement of carvedilol solubility by solid dispersion technique using cyclodextrins, water soluble polymers and hydroxyl acid,” J. Pharm. Biomed. Anal., vol. 96, pp. 10–20, 2014, doi: 10.1016/j.jpba.2014.03.019.
S. L. Childs, G. P. Stahly, and A. Park, “The salt-cocrystal continuum: The influence of crystal structure on ionization state,” Mol. Pharm., vol. 4, no. 3, pp. 323–338, 2007, doi: 10.1021/mp0601345.
J. B. Zawilska, J. Wojcieszak, and A. B. Olejniczak, “Prodrugs: A challenge for the drug development,” Pharmacol. Reports, vol. 65, no. 1, pp. 1–14, 2013, doi: 10.1016/S1734-1140(13)70959-9.
S. J. Kim et al., “A novel composition of ticagrelor by solid dispersion technique for increasing solubility and intestinal permeability,” Int. J. Pharm., vol. 555, no. October 2018, pp. 11–18, 2019, doi: 10.1016/j.ijpharm.2018.11.038.
J. Varshosaz, R. Talari, S. A. Mostafavi, and A. Nokhodchi, “Dissolution enhancement of gliclazide using in situ micronization by solvent change method,” Powder Technol., vol. 187, no. 3, pp. 222–230, 2008, doi: 10.1016/j.powtec.2008.02.018.
N. Ikeda et al., “Improvement of the Solubility and Evaluation of the Physical Properties of an Inclusion Complex Formed by a New Ferulic Acid Derivative and γ-Cyclodextrin,” ACS Omega, vol. 5, no. 21, pp. 12073–12080, 2020, doi: 10.1021/acsomega.0c00277.
D. P. Elder, R. Holm, and H. L. De Diego, “Use of pharmaceutical salts and cocrystals to address the issue of poor solubility,” Int. J. Pharm., vol. 453, no. 1, pp. 88–100, 2013, doi: 10.1016/j.ijpharm.2012.11.028.
K. Stoyanova, Z. Vinarov, and S. Tcholakova, “Improving Ibuprofen solubility by surfactant-facilitated self-assembly into mixed micelles,” J. Drug Deliv. Sci. Technol., vol. 36, pp. 208–215, 2016, doi: 10.1016/j.jddst.2016.10.011.
A. Firmansya, F. Setiawan, L. Nurdianti, and A. Yuliana, “Formulation And Characterization Of Buccal Film Nanoemulsion Apigenin As Antidiabetic,” Indones. J. Pharm. Sci. Technol., vol. 1, no. 1, p. 22, 2022, doi: 10.24198/ijpst.v1i1.42829.
E. Zaini, L. Fitriani, R. Y. Sari, H. Rosaini, A. Horikawa, and H. Uekusa, “Multicomponent Crystal of Mefenamic Acid and N-Methyl-D-Glucamine: Crystal Structures and Dissolution Study,” J. Pharm. Sci., vol. 108, no. 7, pp. 2341–2348, 2019, doi: 10.1016/j.xphs.2019.02.003.
M. A. E. Yousef and V. R. Vangala, “Pharmaceutical cocrystals: molecules, crystals, formulations, medicines,” Cryst. Growth Des., vol. 19, no. 12, pp. 7420–7438, 2019, doi: 10.1021/acs.cgd.8b01898.
R. Thakuria, A. Delori, W. Jones, M. P. Lipert, L. Roy, and N. Rodríguez-Hornedo, “Pharmaceutical cocrystals and poorly soluble drugs,” Int. J. Pharm., vol. 453, no. 1, pp. 101–125, 2013, doi: 10.1016/j.ijpharm.2012.10.043.
I. Sathisaran and S. V. Dalvi, “Engineering cocrystals of poorlywater-soluble drugs to enhance dissolution in aqueous medium,” Pharmaceutics, vol. 10, no. 3, 2018, doi: 10.3390/pharmaceutics10030108.
E. Grothe, H. Meekes, E. Vlieg, J. H. Ter Horst, and R. De Gelder, “Solvates, Salts, and Cocrystals: A Proposal for a Feasible Classification System,” Cryst. Growth Des., vol. 16, no. 6, pp. 3237–3243, 2016, doi: 10.1021/acs.cgd.6b00200.
S. J. Kim et al., “A novel composition of ticagrelor by solid dispersion technique for increasing solubility and intestinal permeability,” Int. J. Pharm., vol. 555, no. October 2018, pp. 11–18, 2019, doi: 10.1016/j.ijpharm.2018.11.038.
J. Varshosaz, R. Talari, S. A. Mostafavi, and A. Nokhodchi, “Dissolution enhancement of gliclazide using in situ micronization by solvent change method,” Powder Technol., vol. 187, no. 3, pp. 222–230, 2008, doi: 10.1016/j.powtec.2008.02.018.
N. Ikeda et al., “Improvement of the Solubility and Evaluation of the Physical Properties of an Inclusion Complex Formed by a New Ferulic Acid Derivative and γ-Cyclodextrin,” ACS Omega, vol. 5, no. 21, pp. 12073–12080, 2020, doi: 10.1021/acsomega.0c00277.
D. P. Elder, R. Holm, and H. L. De Diego, “Use of pharmaceutical salts and cocrystals to address the issue of poor solubility,” Int. J. Pharm., vol. 453, no. 1, pp. 88–100, 2013, doi: 10.1016/j.ijpharm.2012.11.028.
K. Stoyanova, Z. Vinarov, and S. Tcholakova, “Improving Ibuprofen solubility by surfactant-facilitated self-assembly into mixed micelles,” J. Drug Deliv. Sci. Technol., vol. 36, pp. 208–215, 2016, doi: 10.1016/j.jddst.2016.10.011.
A. Firmansya, F. Setiawan, L. Nurdianti, and A. Yuliana, “Formulation And Characterization Of Buccal Film Nanoemulsion Apigenin As Antidiabetic,” Indones. J. Pharm. Sci. Technol., vol. 1, no. 1, p. 22, 2022, doi: 10.24198/ijpst.v1i1.42829.
E. Zaini, L. Fitriani, R. Y. Sari, H. Rosaini, A. Horikawa, and H. Uekusa, “Multicomponent Crystal of Mefenamic Acid and N-Methyl-D-Glucamine: Crystal Structures and Dissolution Study,” J. Pharm. Sci., vol. 108, no. 7, pp. 2341–2348, 2019, doi: 10.1016/j.xphs.2019.02.003.
M. A. E. Yousef and V. R. Vangala, “Pharmaceutical cocrystals: molecules, crystals, formulations, medicines,” Cryst. Growth Des., vol. 19, no. 12, pp. 7420–7438, 2019, doi: 10.1021/acs.cgd.8b01898.
R. Thakuria, A. Delori, W. Jones, M. P. Lipert, L. Roy, and N. Rodríguez-Hornedo, “Pharmaceutical cocrystals and poorly soluble drugs,” Int. J. Pharm., vol. 453, no. 1, pp. 101–125, 2013, doi: 10.1016/j.ijpharm.2012.10.043.
I. Sathisaran and S. V. Dalvi, “Engineering cocrystals of poorlywater-soluble drugs to enhance dissolution in aqueous medium,” Pharmaceutics, vol. 10, no. 3, 2018, doi: 10.3390/pharmaceutics10030108.
E. Grothe, H. Meekes, E. Vlieg, J. H. Ter Horst, and R. De Gelder, “Solvates, Salts, and Cocrystals: A Proposal for a Feasible Classification System,” Cryst. Growth Des., vol. 16, no. 6, pp. 3237–3243, 2016, doi: 10.1021/acs.cgd.6b00200.
N. K. Duggirala, M. L. Perry, Ö. Almarsson, and M. J. Zaworotko, “Pharmaceutical cocrystals: Along the path to improved medicines,” Chem. Commun., vol. 52, no. 4, pp. 640–655, 2016, doi: 10.1039/c5cc08216a.
S. Mohamed, D. A. Tocher, M. Vickers, P. G. Karamertzanis, and S. L. Price, “Salt or cocrystal? A new series of crystal structures formed from simple pyridines and carboxylic acids,” Cryst. Growth Des., vol. 9, no. 6, pp. 2881–2889, 2009, doi: 10.1021/cg9001994.
G. C. Bazzo, B. R. Pezzini, and H. K. Stulzer, “Eutectic mixtures as an approach to enhance solubility, dissolution rate and oral bioavailability of poorly water-soluble drugs,” Int. J. Pharm., vol. 588, no. May, p. 119741, 2020, doi: 10.1016/j.ijpharm.2020.119741.
S. J. Dengale, H. Grohganz, T. Rades, and K. Löbmann, “Recent advances in co-amorphous drug formulations,” Adv. Drug Deliv. Rev., vol. 100, no. 2016, pp. 116–125, 2016, doi: 10.1016/j.addr.2015.12.009.
F. Fischer, G. Scholz, S. Benemann, K. Rademann, and F. Emmerling, “Evaluation of the formation pathways of cocrystal polymorphs in liquid-assisted syntheses,” CrystEngComm, vol. 16, no. 35, pp. 8272–8278, 2014, doi: 10.1039/c4ce00472h.
M. Guo, X. Sun, J. Chen, and T. Cai, “Pharmaceutical cocrystals: A review of preparations, physicochemical properties and applications,” Acta Pharm. Sin. B, vol. 11, no. 8, pp. 2537–2564, 2021, doi: 10.1016/j.apsb.2021.03.030.
M. Solares-Briones et al., “Mechanochemistry: A green approach in the preparation of pharmaceutical cocrystals,” Pharmaceutics, vol. 13, no. 6, pp. 1–49, 2021, doi: 10.3390/pharmaceutics13060790.
S. Huang, J. Xu, Y. Peng, M. Guo, and T. Cai, “Facile Tuning of the Photoluminescence and Dissolution Properties of Phloretin through Cocrystallization,” Cryst. Growth Des., vol. 19, no. 12, pp. 6837–6844, 2019, doi: 10.1021/acs.cgd.9b01111.
A. Karagianni, M. Malamatari, and K. Kachrimanis, “Pharmaceutical cocrystals: New solid phase modification approaches for the formulation of APIs,” Pharmaceutics, vol. 10, no. 1, pp. 1–30, 2018, doi: 10.3390/pharmaceutics10010018.
V. S. Mandala, S. J. Loewus, and M. A. Mehta, “Monitoring cocrystal formation via in situ solid-state NMR,” J. Phys. Chem. Lett., vol. 5, no. 19, pp. 3340–3344, 2014, doi: 10.1021/jz501699h.
L. Takacs, “The historical development of mechanochemistry,” Chem. Soc. Rev., vol. 42, no. 18, pp. 7649–7659, 2013, doi: 10.1039/c2cs35442j.
S. Rehder et al., “Investigation of the formation process of two piracetam cocrystals during grinding,” Pharmaceutics, vol. 3, no. 4, pp. 706–722, 2011, doi: 10.3390/pharmaceutics3040706.
R. L. Carneiro, C. C. de Melo, B. R. de Alvarenga, B. C. Dayo Owoyemi, J. Ellena, and C. C. P. da Silva, “Mechanochemical synthesis and characterization of a novel AAs–Flucytosine drug–drug cocrystal: A versatile model system for green approaches,” J. Mol. Struct., vol. 1251, p. 132052, 2022, doi: 10.1016/j.molstruc.2021.132052.
N. Madusanka, M. D. Eddleston, M. Arhangelskis, and W. Jones, “Polymorphs, hydrates and solvates of a co-crystal of caffeine with anthranilic acid,” Acta Crystallogr. Sect. B Struct. Sci. Cryst. Eng. Mater., vol. 70, no. 1, pp. 72–80, 2014, doi: 10.1107/S2052520613033167.
M. Rodrigues, B. Baptista, J. A. Lopes, and M. C. Sarraguça, “Pharmaceutical cocrystallization techniques. Advances and challenges,” Int. J. Pharm., vol. 547, no. 1–2, pp. 404–420, 2018, doi: 10.1016/j.ijpharm.2018.06.024.
D. Hasa, G. Schneider, D. Voinovich, and W. Jones, “Cocrystal Formation through Mechanochemistry: From Neat and Liquid-Assisted Grinding to Polymer-Assisted Grinding,” Angew. Chemie - Int. Ed., vol. 54, no. 25, pp. 7371–7375, 2015, doi: 10.1002/anie.201501638.
S. Du et al., “Two novel cocrystals of lamotrigine with isomeric bipyridines and in situ monitoring of the cocrystallization,” Eur. J. Pharm. Sci., vol. 110, no. February, pp. 19–25, 2017, doi: 10.1016/j.ejps.2017.06.001.
A. C. de Almeida et al., “Cocrystals of ciprofloxacin with nicotinic and isonicotinic acids: Mechanochemical synthesis, characterization, thermal and solubility study,” Thermochim. Acta, vol. 685, no. May 2019, p. 178346, 2020, doi: 10.1016/j.tca.2019.178346.
E. Zaini, Y. C. Sumirtapura, A. Halim, L. Fitriani, and S. N. Soewandhi, “Formation and characterization of sulfamethoxazole-trimethoprim cocrystal by milling process,” J. Appl. Pharm. Sci., vol. 7, no. 12, pp. 169–173, 2017, doi: 10.7324/JAPS.2017.71224.
A. O. Surov, T. V. Volkova, A. V. Churakov, A. N. Proshin, I. V. Terekhova, and G. L. Perlovich, “Cocrystal formation, crystal structure, solubility and permeability studies for novel 1,2,4-thiadiazole derivative as a potent neuroprotector,” Eur. J. Pharm. Sci., vol. 109, no. June, pp. 31–39, 2017, doi: 10.1016/j.ejps.2017.07.025.
G. Row, “Do carboximide-carboxylic acid combinations form co-crystals? The role of hydroxyl substitution on the formation of co-crystals and eutectics,” pp. 341–351, 2015, doi: 10.1107/S2052252515002651.
M. Guerain, Y. Guinet, N. T. Correia, L. Paccou, F. Danède, and A. Hédoux, “Polymorphism and stability of ibuprofen/nicotinamide cocrystal: The effect of the crystalline synthesis method,” Int. J. Pharm., vol. 584, no. May, 2020, doi: 10.1016/j.ijpharm.2020.119454.
T. Friščič and W. Jones, “Recent advances in understanding the mechanism of cocrystal formation via grinding,” Cryst. Growth Des., vol. 9, no. 3, pp. 1621–1637, 2009, doi: 10.1021/cg800764n.
Rastogi RP, “Acid I ?; Solid Mechanism of the Reaction Between Hydrocarroks Ani ) Picric,” J Phys Chem, vol. 67, no. 3, p. 2569, 1963.
R. Kuroda, K. Higashiguchi, S. Hasebe, and Y. Imai, “Crystal to crystal transformation in the solid state,” CrystEngComm, vol. 6, no. 76, pp. 463–468, 2004, doi: 10.1039/b408971e.
M. Karimi-Jafari, L. Padrela, G. M. Walker, and D. M. Croker, “Creating cocrystals: A review of pharmaceutical cocrystal preparation routes and applications,” Cryst. Growth Des., vol. 18, no. 10, pp. 6370–6387, 2018, doi: 10.1021/acs.cgd.8b00933.
D. Hasa, E. Miniussi, and W. Jones, “Mechanochemical Synthesis of Multicomponent Crystals: One Liquid for One Polymorph? A Myth to Dispel,” Cryst. Growth Des., vol. 16, no. 8, pp. 4582–4588, 2016, doi: 10.1021/acs.cgd.6b00682.
K. Užarević et al., “Exploring the Effect of Temperature on a Mechanochemical Reaction by in Situ Synchrotron Powder X-ray Diffraction,” Cryst. Growth Des., vol. 16, no. 4, pp. 2342–2347, 2016, doi: 10.1021/acs.cgd.6b00137.
A. Kozak and E. Pindelska, “Spectroscopic analysis of the influence of various external factors on ethenzamide-glutaric acid (1:1) cocrystal formation,” Eur. J. Pharm. Sci., vol. 133, no. March, pp. 59–68, 2019, doi: 10.1016/j.ejps.2019.03.017.
U. Iqbal, M. I. Choudhary, and S. Yousuf, “Synthesis of co-crystals of anti-cancer nandrolone as a potential leads towards treatment of cancer,” J. Mol. Struct., vol. 1224, no. February 2018, p. 128981, 2021, doi: 10.1016/j.molstruc.2020.128981.
P. K. Goswami, V. Kumar, and A. Ramanan, “Multicomponent solids of diclofenac with pyridine based coformers,” J. Mol. Struct., vol. 1210, p. 128066, 2020, doi: 10.1016/j.molstruc.2020.128066.
I. Nugrahani, D. Utami, B. Permana, and S. Ibrahim, “Development of the NSAID-L-proline amino acid zwitterionic cocrystals,” J. Appl. Pharm. Sci., vol. 8, no. 4, pp. 57–63, 2018, doi: 10.7324/JAPS.2018.8408.
D. Utami, I. Nugrahani, and S. Ibrahim, “Formation and characterization of mefenamic acid-nicotinamide cocrystal during co-milling based on X-ray powder diffraction analysis,” J. Appl. Pharm. Sci., vol. 6, no. 10, pp. 075–081, 2016, doi: 10.7324/JAPS.2016.601010.
M. K. C. Mannava, A. Gunnam, A. Lodagekar, N. R. Shastri, A. K. Nangia, and K. A. Solomon, “Enhanced solubility, permeability, and tabletability of nicorandil by salt and cocrystal formation,” CrystEngComm, vol. 23, no. 1, pp. 227–237, 2021, doi: 10.1039/d0ce01316a.
J. H. An et al., “Structural characterization of febuxostat/L-pyroglutamic acid cocrystal using solid-state 13C-NMR and investigational study of its water solubility,” Crystals, vol. 7, no. 12, 2017, doi: 10.3390/cryst7120365.
F. M. Khan, M. Ahmad, and F. Batool, “Enhancement of solubility and release profile of simvastatin by co-crystallization with citric acid,” Trop. J. Pharm. Res., vol. 18, no. 12, pp. 2465–2472, 2019, doi: 10.4314/tjpr.v18i12.1.
B. Wisudyaningsih, D. Setyawan, and S. Siswodihardjo, “Co-crystallization of quercetin and isonicotinamide using,” Trop. J. Pharm. Res., vol. 18, no. 4, pp. 697–702, 2019.
Y. Luo et al., “Luteolin cocrystals: Characterization, evaluation of solubility, oral bioavailability and theoretical calculation,” J. Drug Deliv. Sci. Technol., vol. 50, no. January, pp. 248–254, 2019, doi: 10.1016/j.jddst.2019.02.004.
M. S. Hossain Mithu, S. A. Ross, A. P. Hurt, and D. Douroumis, “Effect of mechanochemical grinding conditions on the formation of pharmaceutical cocrystals and co-amorphous solid forms of ketoconazole – Dicarboxylic acid,” J. Drug Deliv. Sci. Technol., vol. 63, no. March, p. 102508, 2021, doi: 10.1016/j.jddst.2021.102508.
G. L. Huang et al., “Simultaneously improving the physicochemical and pharmacokinetic properties of vemurafenib through cocrystallization strategy,” J. Drug Deliv. Sci. Technol., vol. 70, no. January, p. 103230, 2022, doi: 10.1016/j.jddst.2022.103230.
L. Wang et al., “Drug-drug cocrystals of theophylline with quercetin,” J. Drug Deliv. Sci. Technol., vol. 70, no. January, p. 103228, 2022, doi: 10.1016/j.jddst.2022.103228.
H. Liu, H. Lin, Z. Zhou, and L. Li, “Bergenin-isonicotinamide (1:1) cocrystal with enhanced solubility and investigation of its solubility behavior,” J. Drug Deliv. Sci. Technol., vol. 64, no. March, p. 102556, 2021, doi: 10.1016/j.jddst.2021.102556.
S. Latif et al., “Improvement of Physico-mechanical and pharmacokinetic attributes of naproxen by cocrystallization with L-alanine,” J. Drug Deliv. Sci. Technol., vol. 61, no. August 2020, 2021, doi: 10.1016/j.jddst.2020.102236.
E. Hriňová et al., “Explaining dissolution properties of rivaroxaban cocrystals,” Int. J. Pharm., vol. 622, no. May, 2022, doi: 10.1016/j.ijpharm.2022.121854.
M. Xia et al., “Rucaparib cocrystal: Improved solubility and bioavailability over camsylate,” Int. J. Pharm., vol. 631, no. October 2022, p. 122461, 2023, doi: 10.1016/j.ijpharm.2022.122461.
L. Wang, Y. Yan, X. Zhang, and X. Zhou, “Novel pharmaceutical cocrystal of lenalidomide with nicotinamide: Structural design, evaluation, and thermal phase transition study,” Int. J. Pharm., vol. 613, no. August 2021, p. 121394, 2022, doi: 10.1016/j.ijpharm.2021.121394.
K. Wang, Y. Hao, C. Wang, X. Zhao, X. He, and C. C. Sun, “Simultaneous improvement of physical stability, dissolution, bioavailability, and antithrombus efficacy of Aspirin and Ligustrazine through cocrystallization,” Int. J. Pharm., vol. 616, no. January, p. 121541, 2022, doi: 10.1016/j.ijpharm.2022.121541.
R. M. Cruz et al., “Identification and pharmaceutical characterization of a new itraconazole terephthalic acid cocrystal,” Pharmaceutics, vol. 12, no. 8, pp. 1–18, 2020, doi: 10.3390/pharmaceutics12080741.
L. S. Germann, M. Arhangelskis, R. S. Stein, M. Etter, R. E. Dinnebier, and T. Friščić, “Profound effect of the milling assembly on polymorphism in mechanochemical cocrystallization,” ChemRxiv, pp. 32–36, 2020.
H. L. Lin, T. K. Wu, and S. Y. Lin, “Screening and characterization of cocrystal formation of metaxalone with short-chain dicarboxylic acids induced by solvent-assisted grinding approach,” Thermochim. Acta, vol. 575, pp. 313–321, 2014, doi: 10.1016/j.tca.2013.10.029.
O. Shemchuk et al., “Natural Antimicrobials Meet a Synthetic Antibiotic: Carvacrol/Thymol and Ciprofloxacin Cocrystals as a Promising Solid-State Route to Activity Enhancement,” Cryst. Growth Des., vol. 20, no. 10, pp. 6796–6803, 2020, doi: 10.1021/acs.cgd.0c00900.
A. Wróblewska et al., “Application of 1-hydroxy-4,5-dimethyl-imidazole 3-oxide as coformer in formation of pharmaceutical cocrystals,” Pharmaceutics, vol. 12, no. 4, 2020, doi: 10.3390/pharmaceutics12040359.
J. L. Jia et al., “Cocrystals of regorafenib with dicarboxylic acids: Synthesis, characterization and property evaluation,” CrystEngComm, vol. 23, no. 3, pp. 653–662, 2021, doi: 10.1039/d0ce01341b.
A. O. Surov, N. A. Vasilev, A. P. Voronin, A. V. Churakov, F. Emmerling, and G. L. Perlovich, “Ciprofloxacin salts with benzoic acid derivatives: Structural aspects, solid-state properties and solubility performance,” CrystEngComm, vol. 22, no. 25, pp. 4238–4249, 2020, doi: 10.1039/d0ce00514b.
N. Tumanova et al., “Exploring polymorphism and stoichiometric diversity in naproxen/proline cocrystals,” CrystEngComm, vol. 20, no. 45, pp. 7308–7321, 2018, doi: 10.1039/C8CE01338A.
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