US009096743B2

(12) United States Patent (10) Patent No.: US 9,096,743 B2 Qin et al. (45) Date of Patent: Aug. 4, 2015

(54) PROCESS FOR FORMING FILMS, FIBERS, 4,522,934 A 6, 1985 Shum et al. AND BEADS FROM CHITNOUS BOMASS 4,970,156 A 1 1/1990 Avrameas et al. 5,077.414 A 12/1991 Arduengo, III 5,679,146 A 10, 1997 Kalt et al. (75) Inventors: Ying Qin, Tuscaloosa, AL (US); Robin 5,683,832 A 1 1/1997 Bonhote et al. D. Rogers, Tuscaloosa, AL (US); Daniel 5,714,536 A 2f1998 Ziolo et al. T. Daly, Tuscaloosa, AL (US) 5,747,125 A 5/1998 Markulin 5,792,399 A 8, 1998 Meister et al. (73) Assignee: The Board of Trustees of the 3.53% A 3. t al. University of Alabama, Tuscaloosa, AL 5,856,513w - w A 1/1999 UeetaC al. (US) 6,376,712 B2 4/2002 Narizuka et al. 6,451,220 B1 9, 2002 Ziolo et al. (*) Notice: Subject to any disclaimer, the term of this 6,613,310 B1 9/2003 Campbell et al. patent is extended or adjusted under 35 3. R: 1939 E. al U.S.C. 154(b) by 558 days. 7,198,695wa. I B2 4/2007 KettenbachWaCSK ea. et al. 7,253,289 B2 8, 2007 Ren et al. (21) Appl. No.: 13/375,245 7.550,520 B2 6/2009 Daly et al. 8,030,030 B2 10/2011 Varansi et al. (22) PCT Filed: Jun. 1, 2010 8,038,840 B2 10/2011 Li 8,044,120 B2 10/2011 D'Andola et al. (86). PCT No.: PCT/US2O10/036904 8, 110,667 B2 2/2012 Zhang et al. S371 (c)(1), (Continued) (2), (4) Date: Jan. 26, 2012 FOREIGN PATENT DOCUMENTS (87) PCT Pub. No.: WO2O10/141470 CA 2479941 10, 2003 PCT Pub. Date: Dec. 9, 2010 CH 153446 6, 1932 (Continued) (65) Prior Publication Data OTHER PUBLICATIONS US 2012/O115729 A1 May 10, 2012 Hasegawa et al., New Pretreatment Methods Combining a HotWater Related U.S. Application Data Treatment and Water/Acetone Extraction for Thermo-Chemical .S. App Conversion of Biomass, Energy and Fuels, 18:755-760 (2004). (60) Provisional application No. 61/182,833, filed on Jun. Kenealy et al., Pretreatments for Converting Wood into Paper and 1, 2009. Chemicals, Materials, Chemicals and Energy from Forest Biomass; Argyropoulos, D.; ACS Symposium Series; American Chemical (51) Int. Cl. Society, Washington, DC, chapter 25, pp. 392-408 (2007). A6 IK3I/4164 (2006.01) Office Action for U.S. Appl. No. 13/129,060 dated Apr. 8, 2013. A6 IK3I/722 (2006.01) International Search Report and Written Opinion for Application No. COSL 5/08 (2006.01) (Continued) DOIF 9/00 (2006.01) A6 IK 8/49 (2006.01) A6 IK 8/73 (2006.01) Primary Examiner — Abigail Fisher DOIF I/O (2006.01) (74) Attorney, Agent, or Firm — Meunier Carlin & Curfman (52) U.S. Cl. LLC CPC ...... C08L 5/08 (2013.01); A61K 8/4946 (2013.01); A61K 8/736 (2013.01); A61 K (57) ABSTRACT 31/4164 (2013.01); A61 K3I/722 (2013.01): C08K 5/3445 (2013.01): D0IF I/10 (2013.01); Disclosed is a process for forming films, fibers, and beads D0IF I/103 (2013.01): D0IF 9/00 (2013.01) comprising a chitinous mass, for example, chitin, chitosan (58) Field of Classification Search obtained from one or more biomasses. The disclosed process CPC ...... C08K 5/3445; C08L 5/08: D01F 1/10; can be used to prepare films, fibers, and beads comprising D01F 1/103: D01F 9/00; A61K 8/736: A61 K only polymers, i.e., chitin, obtained from a suitable biomass, 3 1/722: A61K 8/4946; A61K 31/4164 or the films, fibers, and beads can comprise a mixture of See application file for complete search history. polymers obtained from a suitable biomass and a naturally occurring and/or synthetic polymer. Disclosed herein are the (56) References Cited films, fibers, and beads obtained from the disclosed process. This Abstract is presented solely to aid in searching the sub U.S. PATENT DOCUMENTS ject matter disclosed herein and is not intended to define, 1943,176 A 1/1934 Graenacher limit, or otherwise provide the full scope of the disclosed 4,063,017 A 12/1977 Tsao et al. Subject matter. 4,097.666 A 6, 1978 Johnson et al. 4,188,263. A 2, 1980 Hulsmann et al. 4,520,105 A 5, 1985 Sinner et al. 25 Claims, 10 Drawing Sheets US 9,096,743 B2 Page 2

(56) References Cited WO 2006116126 A2 11/2006 WO WO2007OO5388 1, 2007 U.S. PATENT DOCUMENTS WO WO2007O63327 6, 2007 WO WO2007 111605 A1 10/2007 8,182.557 B2 5/2012 Argyropoulos WO WO2009 105236 8, 2009 2001/002471.6 A1 9, 2001 Chen et al. WO WO2O10056790 5, 2010 2002/0010291 A1 1/2002 Murphy 2003/0059604 A1 3, 2003 Hattori et al. OTHER PUBLICATIONS 2003. O157351 A1 8, 2003 Swatloski et al. Deng et al., Phase Diagram of AmimCI + Salt Aqueous Biphasic 2003. O165445 A1 9, 2003 Malnou et al. Systems and Its Application for AmimCI Recovery, J. Chem. Eng. 2003/0233742 A1 12/2003 Jones et al. Data, 54:2470-2473 (2009). 2004/OO38031 A1 2, 2004 Holbrey et al. Fukuyama et al., A Copper-Free Sonogashira Coupling Reaction in 2004/OO77519 A1 4/2004 Price et al. Ionic Liquids and Its Application to a Microflow System for Efficient 2005, OO58694 A1 3/2005 Nielsen 2005/0061457 A1 3/2005 Skuratowicz Catalyst Recycling, Org. Lett.4(10): 1691-1694 (2002). 2005, 0123851 A1 6, 2005 Shinbori et al. Gutowski et al., Controlling the Aqueous Miscibility of Ionic Liq 2005, 0194561 A1 9, 2005 Davis uids: Aqueous Biphasic Systems of Water-Miscible Ionic Liquids 2005/O196671 A1 9/2005 Paonessa et al. and Water-Structuring Salts for Recycle, Metathesis, and Separa 2005/0285073 A1 12/2005 Singh et al. tions, J. Am. Chem. Soc., 125:6632-6633 (2003). 2005/0288484 Al 12/2005 Holbrey et al. Mathews et al., Palladium catalysed Suzuki cross-coupling reactions 38: 5. A. 39. t;R al in ambient temperature ionic liquids, Chem. Commun., 1249-1250 2006/0194197 A1 8/2006 Spangler et al. (2000). 2006/0241287 A1* 10, 2006 Hecht et al...... 530,356 Qin et al., Dissolution or extraction of crustacean shells using ionic 2007/OOO6774 A1 1/2007 Rogers et al. liquids to obtain high molecular weight purified chitin and direct 2007/0093462 A1 4, 2007 Rogers et al. production of chitin films and fibers, Green Chem., 12:968-971 2007/0112185 A1 5/2007 Myllymaki (2010). 2007/0215300 A1 9, 2007 Upfal et al. 2007/0225191 A1 9, 2007 Scheibel et al. Remsing et al., Mechanism of cellulose dissolution in the ionic liquid 2008, 0023162 A1 1, 2008 Myllymaki et al. 1-n-butyl-3-methylimidazolium chloride: a 13C and 35137CINMR 2008/0097001 A1 4, 2008 Miraftab et al. relaxation study on model systems, Chem. Commun., 1271-1273 2008. O190013 A1 8, 2008 Argyropoulos (2006). 2008/0227162 A1 9, 2008 Varanasi et al. Scurto et al., Carbon dioxide induced separation of ionic liquids and 2008/0241536 A1 10, 2008 Luo et al. water, Chem. Commun., 572-573 (2003). 2009/0010983 A1 1/2009 Melvik et al. Stepnowski, Solid-phase extraction of room-temperature 2009 OO88564 A1 4, 2009 Luo et al. imidazolium ionic liquids from aqueous environmental samples, 2009.0099353 A1 4, 2009 Miraftab et al. Anal. Bioanal. Chem., 381: 189-193 (2005). 2009/0215720 A1 8, 2009 Thibodeau et al. Sun et al., Complete dissolution and partial delignification of wood in 2010.0081798 A1 4, 2010 Balensiefer et al. 2010, 0087369 A1 4, 2010 Cutsem et al. the ionic liquid 1-ethyl-3-methylimidazolium acetate, Green Chem. 2010, 0112646 A1 5, 2010 Balensiefer et al. 11:646-655 (2009). 2010/017.0504 A1 T/2010 Zhang Vijayaraghavan et al... An Assessment on the Interaction of a 2010, 0196967 A1 8, 2010 Edye et al. Hydrophilic Ionic Liquid with Different Sorbents, Ind. Eng. Chem. 2010/0249432 A1 9, 2010 Siemer et al. Res., 48:7283-7288 (2009). 2010/0287826 A1 11, 2010 Hoffman et al. Wu et al., Do we understand the recyclability of ionic liquids?, Chem. 2010/03 19862 A1 12, 2010 Rahman Eur, J., 15:1804-1810 (2009). 2012fO24.533.6 A1 9, 2012 Daly et al. Huddleston et al., Room Temperature Ionic Liquids as Novel Media 2014/OO27.938 A1* 1/2014 Swatloski et al...... 264/10 for 'Clean' Liquid-Liquid Extraction, Chem. Commun., 1765-1766 (1998). FOREIGN PATENT DOCUMENTS Husemann et al., Homogeneous Acetylation of Cellulose, Buletinul Institutului Politehnic Din Lasi, 1(1-2):47-51 (1970) (abstract). CN 138O110 11, 2002 Illanes et al., Immobilization of Lactase and Invertase on Crosslinked DE 27O37O3 1, 1977 Chitin, in Bioreactor Immobilized Enzymes and Cells, Moo-Young, EP O780391 6, 1997 Ed., Elsevier Applied Science: London, 233-249 (1998). EP 1222918 T 2002 Illanes, Stability of Biocatalysts, Elec. J. Biotechnol. 2(1): 1-9 EP 1854.786 11, 2007 (1999). JP 581836O1 10, 1983 International Search Report and Written Opinion for PCT/US2009/ JP 630565O1 3, 1988 JP 64017649 1, 1989 64 105 issued Jan. 13, 2010. JP 80O89796 4f1996 International Search Report and Written Opinion for PCT/US2009/ JP 10265674 10, 1998 01.066 issued Jun. 22, 2009. JP 200229.0011 10, 2002 International Search Report and Written Opinion for PCT/US2006/ JP 2003171144 6, 2003 24863 issued Jan. 3, 2007. JP 2003335887 11, 2003 International Search Report and Written Opinion for PCT/US2006/ WO WO942O521 9, 1994 020941 issued Feb. 27, 2008. WO WO9521871 8, 1995 International Search Report and Written Opinion for PCT/US2005/ WO WO9606593 3, 1996 01.0235 issued Jan. 3, 2007. WO WOOO32658 6, 2000 Kilpeläinen et al., Dissolution of wood in ionic liquids, J. Agric. Food WO WOO181436 11, 2001 Chem, 55:9142-91.48 (2007). WO WOO2O79269 10, 2002 Kirk-Othmer, Encyclopedia of Chemical Technology, 4 Ed., 5:476 WO WOO2100360 12/2002 WO WOO2102586 12/2002 563 (1993). WO WOO3O29329 4/2003 Krajewska, Application of Chitin- and Chitosan-based Materials for WO WOO3O41692 5, 2003 Enzyme Immobilizations: A Review, Enz. Microb. Techno. 35:126 WO WOO3074.031 9, 2003 139 (2004). WO WO2004O27897 4/2004 Lau et al., Dissolution of Candida Antarctica Lipase B in Ionic WO WO2005O17252 2, 2005 Liquids: Effects on Structure and Activity, Green Chem, 6:483-487 WO 2006097571 A1 9, 2006 (2004). US 9,096,743 B2 Page 3

(56) References Cited Swatloski et al., Ionic Liquids for the Dissolution and Regeneration of Cellulose, in Molten Salts XIII: Proceedings of the International OTHER PUBLICATIONS Symposium, Trullove, P.C., DeLong, H.C., Mantz, R.A., Stafford, G.R., Matsunaga, M., Eds. The Electrochemical Society: Pen Lee et al., Ionic Liquid-Mediated Selective Extraction of Lignin from nington, NJ. 19:155-164 (2002). wood leading to enhanced enzymatic cellulose hydrolysis, Biotech. Tiller et al., A Novel Efficient Enzyme-Immobilization Reaction on and Bioeng, 102(5):1368-1376 (2009). NH2 Polymers by Means of L-Ascorbic Acid, Biotechnol. Appl. Leipner et al., Structural Changes of Cellulose Dissolved in Molten Biochem., 30:155-162 (1999). Salt Hydrates, Macromol Chem Phys, 201 (15): 2041-2049 (2000). Turner et al., Production of Bioactive Cellulose Films Reconstituted Liebert et al., Tailored Cellulose Esters: Synthesis and Structure from Ionic Liquids, Biomacromolecules, 5:1379-1384 (2004). Determination, Biomacromolecules, 6:333-340 (2005). Linko et al., Cellulose Bead Entrapped Microbial Cells Biotechnical Turner, Immobilization of Biocatalysts. Using Novel IL-Reconsti Applications, Enzyme Microb. Technol. 1:26-30 (1979). tuted Cellulosic Support Materials, presentation on Apr. 19, 2005. Ma et al., Reverse Atom Transfer Radical Polymerization of Methyl Visser et al., Task Specific Ionic Liquids for the Extraction of Metal Methacrylate in Room-Temperature Ionic Liquids, J. Polymer Sci. Ions from Aqueous Solutions, Chem. Commun., 135-136 (2001). Pt. A-Polymer Chem., 41: 143-151 (2003). Weckstrometal. Entrapment of Whole Cell Yeast B-Galactosidase in Maia et al., Cellulose Organic Solvents. 1. The Structure of Anhy Precipated Cellulose Derivatives, Food Process Eng., vol. 2, Applied drous N-Methylmorpholine N-Oxide and N-Methylmorphline Science Publishers Ltd., pp. 148-151 (1979). N-Oxide Monohydrate, Acta Cryst., B37: 1858-1862 (1981). Wilkes et al., Air and Water Stable 1-Ethyl-3-methylimidazolium Mais et al., Modification of Cellulose Using Cellulose p-Toluene Based Ionic Liquids, J. Chem. Soc. Chem. Commun., 13:965-967 Sulfonates as Intermediates, Zeszyty Naukowe Politechniki Slaskie (1992). Chemm., 140: 121-125 (1999). Willauer et al., Investigation of aqueous biphasic systems for the Manangeeswaran et al., Degradation of indulin, a kraft pine lignin, by separation of lignins from cellulose in paper pulping process, J. Serratia marcescens, J. Environ. Sci. Health, Part B: Pesticides, Food Chromatogr. B: Biomed. Sci. Applic. 743(1-2): 127-135 (2000). Contaminants, and Agricultural Wastes, 42(3):321-327 (2007). Wu et al., Homogeneous Acetylation of Cellulose in a New Ionic Marson et al., A Novel, Efficient Procedure for Acylation of Cellulose Liquid, Biomacromol. 5:266-268 (2004). Under Homogeneous Solution Conditions, J. Appl. Polymer Sci., Office Action for U.S. Appl. No. 12/735,827 dated Feb. 6, 2013. 74: 1355-1360 (1999). Armstrong et al., Structure and properties of high stability geminal Mazurkiewicz et al., Conducting Polymer Electrochemistry in Ionic dicationic ionic liquids, J. Amer. Chem. Soc., 127(2):593-604 Liquids, Synthetic Metals, 135:31-32 (2003). (2005). Nara et al., Lipase-Catalysed Polyester Synthesis in 1-Butyl-3- Black et al., The estimation of chitin and chitin nitrogen in crawfish Methylimidazolium Hexafluorophosphate Ionic Liquid, Tetrahedron waste and derived products, Analyst, 75:185-189 (1950). Lett., 44:1371-1373 (2003). Brugnerotto et al. An infrared investigation in relation with chitin Ngo et al., Thermal Properties of Imidazolium Ionic Liquids, and chitosan characerization, Polymer, 42:3569-3580 (2001). Thermochimica Acta, 357-358:97-102 (2000). Holbrey et al., Mercury(II) partitioning from acqueous Solutions with Ohno et al., A New Type of Polymer Gel Electrolyte: Zwitterionic a new, hydrophobic ethylene-glycol functionalized bis-imidazolium Liquid/Polar Polymer Mixture, Electrochimica Acta, 48:2079-2083 ionic liquid, Green Chem. 5:129-135 (2003). (2003). International Search Report and Written Opinion for PCT/US2010/ Okamato et al., Synthesis, Spectra, and Reactions of 036904 dated Jan. 3, 2011. N-Triphenylmethylpyridinium Salts. Reactions of Triphenylmethyl Kadokawa et al. A facile preparation of gel materials from a solution Chlordie with Pyridine Under High Pressure, J. Org. Chem. of cellulose in ionic liquid, Carbohydrate Research, 343:769-772 35(11):3752-3756 (1970). (2008). Padhye et al., Cellulose Degradation in Xanthate Process, J. App. Min et al., Chitin and chitosan nanofibers: electrospinning of chitin Polymer Sci., 36:1475-1478 (1988). and deacetylation of chitin nanofibers, Polymer, 45:7137-7142 Perrier et al., Reversible Addition—Fragmentation Chain Transfer (2004). Polymerization of Methacrylate, Acrylate and Styrene Monomers in Official Methods of Analysis of the Association of Official Analytical 1-Alkyl-3-Methylimidazolium Hexfluorophosphate, European Poly Chemists, 13a ed.: Horwitz, W. Ed.; AOAC International, Washing mer J. 39(3):417-422 (2003). ton, DC, pp. 14-15 (1980). Pu et al., Ionic liquid as a green solvent for lignin, J. Wood Chem. Rodde et al., A Seasonal Study of the Chemical Composition and Technol, 27:23–33 (2007). Chitin Quality of Shrimp Shells obtained from Northern Shrimp Ren et al., Synthesis of 1-Allyl-3-Methylimidazolium-Based Room (Pandalus borealis), Carbohydrate Polymers, 71:388-393 (2008). Temperature Ionic Liquid and Preliminary Study of its Dissolving Sukhanova et al., Vysokomol. Soedin. Ser. B31 (1989) 381; Chem. Cellulose, Acta Polymerica Sinica, 3:448-451 (2003) (abstract). Abstr. 111 (20): 175985n. Rogers et al., Ionic Liquids—Solvents of the Future?, Science, Sun et al., Magnetite-embedded cellulose fibers from ionic liquid, J. 302:792-793 (2003). Mater. Chem. 18:283-290 (2008). Sakai, Determination of Pore Size and Pore Size Distribution, J. Xie et al., Chitin and chitosan dissolved in ionic liquids as reversible Membr. Sci., 96:91-130 (1994). sorbents of CO2, Green Chem., 8:630-633 (2006). Shriver et al., Inorganic Chemistry, W. H. Freeman & Co., New York, Wu et al. A novel biomass-ionic liquid platform for the utilization of pp. 405-407 (1990). native chitin, Polymer, 49:2321-2327 (2008). Snedden et al., Cross-Linked Polymer-Ionic Liquid Composite Al-Adhami et al., Immobilization of Wood-Rotting Fungi Laccases Materials, Macromolecules, 36(12):4549-4556 (2003). on Modified Cellulose and Acrylic Carriers, J. Process Biochemistry, Stöllner et al., Activation of Cellulose Membranes with 1, 1'- 37: 1387-1394 (2002). Carbonyldiimidazole or 1-Cyano-4-Dimethylaminopyridinium Ast et al., Efficient Assembly of Peptomers on Continous Surfaces, Tetrafluoroborate as a Basis for the Development of Immunosensors, Tetrahedron Lett., 40:4317-4318 (1999). Anal. Biochem., 304: 157-165 (2002). Axegård, The Future Pulp Mill-A Biorefinery? Presentation at 1st Suarez et al., Synthesis and Physical-Chemical Properties of Ionic International Biorefinery Workshop, Washington, DC., Jul. 20-21. Liquids Based on 1-n-Butyl-3-Methylimidazolium Cation, J. Chim. 2005. Phys. 95:1626-1639 (1998). Benton et al., Effect of Room-Temperature Ionic Liquids as Replace Sun et al., Magnetite-Embedded Cellulose Fibers Prepared From ments for Volatile Organic Solvents in Free-Radical Polymerization, Ionic Liquid, J. Mat. Chem., 18:283-290 (2008). Ionic Liquids, 818:125-133 (2002). Supplemental Search Report for EP4757863 issued May 12, 2009. Biedron et al., Ionic Liquids as reaction Media for Polymeriazation Swatloski et al., Dissolution of Cellulose with Ionic Liquids, J. Am. Processes: Atom Transfer Radical Polymerization (ATRP) of Chem. Soc., 124:4974-4975 (2002). Acrylates in Ionic Liquids, Polymer Intl., 52(10): 1584-1588 (2003). US 9,096,743 B2 Page 4

(56) References Cited Fukaya et al., Cellulose dissolution with polar ionic liquids under mild conditions: required factors for anions, Green Chem., 10:44-46 OTHER PUBLICATIONS (2008). Gallezot, Process options for converting renewable feedstocks to Blankemeyer-Menge et al., Simultaneous Multiple Synthesis of Pro tected Peptide Fragments on Ally’ Functionalized Cellulose Disc bioproducts, Green Chem., 9:295-302 (2007). Supports, Tetrahedron Lett., 29:5871-5874 (1988). Gelbrich, Colloidal Structures Based on Topochemically Modified Bonhote et al., Hydrophobic, Highly Conductive Ambient-Tempera Cellulose, Papier (Heidelberg), 52:755-758 (1998). ture Molten Salts, Inorg. Chem., 35:1 168-1178 (1996). Gemeiner, Immobilized Enzymes, Organelles and Cells, in Enzyme Bora et al., A Simple Method for Functionalization of Cellulose Engineering, Gemeiner, Ed., Ellis Horwood Series in Biochemistry Membrane for Covalent Immobilization of Biomolecules, J. Membr. and Biotechnology, Ellis Horwood Limited: West Sussex, England, Sci., 250:215-222 (2005). pp. 158-179 (1992). Cateto et al., Monitoring of lignin-based polyurethane synthesis by Gordon et al., Fused Organic Salts. 8. Properties of Molten Straight FTIR-ATR, Ind. Crops Prod., 27(2):168-174 (2008). Chain Isomers of Tetra-n-Pentylammonium Salts, J. Amer. Chem. Chesney et al., Amino-Derivatised Beaded Cellulose Gels, Novel Soc., 100(24):7445-7454 (1978). Accessible and Biodegradable Scavenger Resins for Solution Phase Harkin et al., Lignification in Trees: Indication of Exclusive Cominatorial Synthesis, Green Chem, 2:57-62 (2000). Peroxidase Participation, Science, 180:296-98 (1973). Earle et al., Ionic liquids. Green Solvents for the future, Pure Appl. Heinze et al., Unconventional Methods in Cellulose Functionaliza Chem., 72(7): 1391-1398 (2000). tion, Prog. Polym. Sci., 26:1689-1762 (2001). El Seoud et al., Applications of ionic liquids in carbohydrate chem Hirayama, Rapid Confirmation and Revision of the Primary Struc istry: A window of opportunities, Biomacromol. 8 (9):2629-2647 ture of Bovine Serum Albumin by ESIMS and Frit-FAB LC/MS, (2007). Biochem. Biophys. Comm., 173:639-646 (1990). Endres, Ionic Liquids: Solvents for the Electrodeposition of Metals Holbrey et al. The Phase Behaviour of 1-Alkyl-3-Methlimidazolium and Semiconductors, Chem. Phys. Chem. 3 (2): 144-154 (2002). Tetrafluoroborates; Ionic Liquids and Ionic Liquid Crystals, J. Chem. Fanninet al., Properties of 1,3-Dialkylimidazolium Chloride-Alumi Soc. Dalton Trans., 2133-2139 (1999). num Choride Ionic Liquids. 2. Phase Transitions, Densities, Electri Huddleston et al., Characterization and Comparison of Hydrophilic cal Conductivities, and Viscosities, J. Phys. Chem. 88:2614-2621 and Hydrophobic Room Temperature Ionic Liquids Incorporating (1984). the Imidazolium Cation, Green Chem, 3:156-164 (2001). Fischer et al., Structural Changes of Cellulose Dissolved in Molten Yamazaki et al. An acidic cellulose-chitin hybridgel as novel elec Salt Hydrates, 219th ACS National Meeting, San Francisco, CA trolyte for an electric double layer capacitor, Electrochem. Commun., (2000) (abstract). 11:68-70, 2009. Fort et al., Can ionic liquids dissolve wood? Processing and analysis International Search Report and Written Opinion, dated Aug. 27. of lignocellulosic materials with 1-n-butyl-3-methylimidazolium 2014, received in connection with International Application No. chloride, Green Chem. 9:63-69 (2007). PCT/US 2014/O34793. Froehner et al., Properties of the Glycoprotein Laccase Imobilised by Two Methods, Acta Chem Scand B, 29:691-694 (1975). * cited by examiner U.S. Patent Aug. 4, 2015 Sheet 1 of 10 US 9,096,743 B2

4000 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 650 co FG. U.S. Patent Aug. 4, 2015 Sheet 2 of 10 US 9,096,743 B2

1620.7863 1259,696 v

620. 865 125s bes

% ------" "- W . --- - lessess-WVVV,1259,2696 A A? N. 1620.7865 W

4000 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 650 cro FG.2 U.S. Patent Aug. 4, 2015 Sheet 3 of 10 US 9,096,743 B2

4000 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 650 Cir FG.3 U.S. Patent Aug. 4, 2015 Sheet 4 of 10 US 9,096,743 B2

8 8 2 OO 8 8 i O ppm U.S. Patent Aug. 4, 2015 Sheet 5 of 10 US 9,096,743 B2

O 200 400 600 800 1000 1200 1400 line, in FG.5 U.S. Patent Aug. 4, 2015 Sheet 6 of 10 US 9,096,743 B2

5 10 5 2 25 TT 5 40 2 Theta, degrees FIG.6 U.S. Patent Aug. 4, 2015 Sheet 7 of 10 US 9,096,743 B2

O OO 40 6. 80 emperature, oc FG.7 U.S. Patent Aug. 4, 2015 Sheet 8 of 10 US 9,096,743 B2

88:

U.S. Patent Aug. 4, 2015 Sheet 9 of 10 US 9,096,743 B2

O O) CD 1 s

S S.

S.S s

SSS.Š

S

SSŠ S

S S S S

S Š S.

SSS

5. U.S. Patent Aug. 4, 2015 Sheet 10 of 10 US 9,096,743 B2

Acc. V Spot Mag Det WD 20.0 kV 5.0 58X

Acc. W xxxxxxSpot Magn 285 US 9,096,743 B2 1. 2 PROCESS FOR FORMING FILMS, FIBERS, million tons, respectively. Producing chitin in industry is AND BEADS FROM CHTINOUS BOMASS primarily from the exoskeletons of marine crustacean shell waste by a chemical method that involves acid demineraliza CROSS REFERENCE TO RELATED tion, alkali deproteinization, and followed by decolorization. APPLICATIONS Even though the current industrialized chemical process iso lates chitin from crustacean shells efficiently, disadvantages This application claims the benefit of priority to U.S. Pro exist in these procedures, including, inter alia, the use of visional Application No. 61/182,833, filed Jun. 1, 2009, corrosive acids, bases, and strong oxidants which are not which is incorporated by reference herein in its entirety. environmentally friendly. In addition, these processes can 10 modify or nullify the desired physiochemical properties of FIELD OF THE DISCLOSURE chitin, for example, by acid demineralization, shorting the Disclosed herein is a process for forming films, fibers, and chitin chain length, as well as, degrading the chitin during beads comprising a chitinous mass, for example, chitin and deproteinization in hot alkali solutions. These undesired chitosan obtained from one or more biomasses. The disclosed 15 changes in the properties of chitin can have a profound affect process can be used to prepare films, fibers, and beads com when the chitin obtained therefrom must have specific prising only polymers, e.g., chitin, obtained from a Suitable molecular weight distributions and degrees of acetylation biomass, or the films, fibers, and beads can comprise a mix (DA). ture of polymers obtained from a suitable biomass and a As such, there is a long felt need for films, fibers, and beads naturally occurring and/or synthetic polymer. Also, disclosed formed from chitin wherein the chitin has both consistent, as herein are the films, fibers, and beads obtained from the well as, desirable properties. There is also a need for chitin disclosed process. compositions that can be efficiently and reproducibly manu factured under environmentally friendly and mild conditions. BACKGROUND Disclosed herein are processes and compositions that address 25 these and other needs. Each year humans place an increasingly greater demandon the biosphere. The world’s increasing level of industrializa SUMMARY OF THE DISCLOSURE tion has come to produce a Surge in the consumption of natural resources, while at the same time producing an The present disclosure relates to processes for forming equally large amount of waste material that is either non 30 films, fibers, and beads from a chitinous biomass. In one recyclable or simply not recycled. The replacement of metals aspect, chitin can be directly extracted from a chitinous bio by plastics in the last century somewhatabated the growth in mass, for example, from shrimp or crab shells and directly the demand for this resource commodity. But with the rise in used to form fibers, films, and beads which comprise chitin synthetic polymer technology, came an explosion in the use having a higher molecular weight than chitin derived from of synthetic polymers with the result that today plastics and 35 practical grade or pure grade sources. In another aspect, an other synthetic polymers are the most utilized category of ionic liquid can be used to dissolve a source of chitin in the non-naturally occurring materials. first step of the process. In a further aspect, a combination of Polymers, however, are ubiquitous in nature. These natural an ionic liquid and a co-solvent, for example, DMSO, can be building blocks have been used by mankind since antiquity, used to dissolve a source of chitin in the first step of the for example, fibers made of hemp, cotton, wool, and silk are 40 process. In a yet further aspect, an organic solvent, for all a part of human development. Processes directed to the example, DMSO, can be used to dissolve a source of chitin in manufacture of articles comprising recyclable plant polymers the first step of the process. In a still further aspect, the such as cellulose, are well known and have been under devel purified chitinous biomass can be combined with a naturally opment for many centuries. Less well studied are processes occurring or synthetic polymer, interalia, cellulose, poly(2- that utilize natural polymers derived from non-plant sources, 45 hydroxyethyl methacrylate (PHEMA), to form composite i.e., the hard outer shells of marine animals. films, fibers, and beads. Chitin is the most abundant polymer in the marine envi Additional advantages of the disclosed process will be set ronment. Chitin is the main component of the exoskeletons of forth in part in the description which follows, and in part will arthropods, such as crustaceans and in the cell walls of fungi. be obvious from the description, or can be learned by practice It has been a major source of Surface pollution in coastal 50 of the disclosed process. The advantages of the disclosed areas. Both chitin and its major derivative chitosan (obtained process will be realized and attained by means of the elements by deacetylation of chitin) have numerous applications. The and combinations particularly pointed out in the appended bioactivity, biocompatibility, and low toxicity of native or claims. It is to be understood that both the foregoing general chemically-modified chitin and chitosan make them Suitable description and the following detailed description are exem for controlled drug release, cosmetics, food preservation, fer 55 plary and explanatory only and are not restrictive of the dis tilizer, or biodegradable packaging materials, or waste water closed process, as claimed. processing and other industrial applications. Chitin, however, is highly hydrophobic and is insoluble in water and most BRIEF DESCRIPTION OF THE FIGURES organic solvents due to the high density of hydrogen bonds of the adjacent chains in solid state. The difficulty in the disso 60 FIG. 1 is the IR spectra of polymer films prepared by the lution restricts the use of chitin as a replacement for synthetic disclosed process. Spectrum 1 A depicts the IR spectrum of a polymers. polymer film comprising chitin derived from shrimp shells Crustacean shells are currently the major source of chitin according to Example 1. Spectrum 1B depicts the IR spec available for industrial processing. The best characterized trum of a polymer film comprising practical grade chitin Sources of chitin are shellfish (including shrimp, crab, lobster, 65 according to Example 2. Spectrum 1C depicts the IR spec and krill), oyster, and squids. Annual synthesis of chitin in trum of a polymer film comprising practical grade chitin freshwater and marine ecosystem is about 600 and 1600 according to Example 3. US 9,096,743 B2 3 4 FIG. 2 is the IR spectra of composite polymer fibers with that the Subsequently described event or circumstance can or fibers made from a single polymer. Spectrum 2A depicts a cannot occur, and that the description includes instances polymer comprising chitin/cellulose (3:4 wit/wt). Spectrum where the event or circumstance occurs and instances where 2B depicts a polymer comprising chitin derived from shrimp it does not. shell/cellulose (1:15.8 wit/wt). Spectrum 2C. depicts a poly Ranges can be expressed herein as from “about one par mer comprising chitin. Spectrum 2D depicts a polymer com ticular value, and/or to “about another particular value. prising cellulose. When Such a range is expressed, another aspect includes from FIG. 3 is the IR spectra obtained from fibers comprising a the one particular value and/or to the other particular value. blended polymer comprising 2:1 Poly-HEMA/chitin (Spec Similarly, when values are expressed as approximations, by trum 3A), pure Poly-HEMA (Spectrum 3B), and pure chitin 10 use of the antecedent “about it will be understood that the (Spectrum 3C). particular value forms another aspect. It will be further under FIG. 4 is the CNMR spectra of reconstituted pure chitin stood that the endpoints of each of the ranges are significant dissolved in CamimOAc. FIG. 5 is a graph of TGA of CamimOAc by heating at both in relation to the other endpoint, and independently of target temperature and environment for 24 h: (a) 100° C. in 15 the other endpoint. It is also understood that there are a N; (b) 100° C. in air; (c) 110°C. in N; (d) 110°C. in air; and number of values disclosed herein, and that each value is also (e) 130° C. in air. herein disclosed as “about that particular value in addition to FIG. 6 is a plot of X-ray diffractograms of (a) pure chitin: the value itself. For example, if the value “10 is disclosed, (b) reconstituted pure chitin; (c) practical grade chitin; (d) then “about 10' is also disclosed. It is also understood that reconstituted practical grade chitin; and (e) reconstituted when a value is disclosed, then “less than or equal to the chitin from shrimp shells. value, “greater than or equal to the value and possible ranges FIG. 7 is a TGA of (a) practical grade chitin; (b) reconsti between values are also disclosed, as appropriately under tuted pure chitin; (c) pure chitin; (d) reconstituted practical stood by the skilled artisan. For example, if the value “10' is grade chitin; and (e) reconstituted chitin from shrimp shells. disclosed, then “less than or equal to 10” as well as “greater FIG. 8 is a pair of SEM micrographs of the chitin fibers: (a) 25 than or equal to 10” is also disclosed. It is also understood that from shrimp shells and (b) from PG-chitin. throughout the application data are provided in a number of FIG. 9 is a group of SEM micrographs obtained for (a) different formats and that this data represent endpoints and shrimp shells; (b) undissolved shrimp shell residue; and (c) starting points and ranges for any combination of the data reconstituted chitin from shrimp shells. points. For example, if a particular data point “10 and a 30 particular data point “15” are disclosed, it is understood that DETAILED DISCLOSURE greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as The materials, compounds, compositions, articles, and well as between 10 and 15. It is also understood that each unit methods described herein may be understood more readily by between two particular units are also disclosed. For example, reference to the following detailed description of specific 35 if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also aspects of the disclosed subject matter and the Examples disclosed. included therein and to the Figures. As used herein, the term "dissolving or dispersing means Before the present materials, compounds, compositions, contacting a source of a chitinous biomass with an ionic articles, and methods are disclosed and described, it is to be liquid, an organic solvent, or mixture thereof to solublize the understood that the aspects described below are not limited to 40 chitan, chitosan, or other polysaccharide materials present in specific synthetic methods or specific reagents, as such may, the biomass. Depending upon the relative purity of the bio of course, vary. It is also to be understood that the terminology mass, some of the material present, especially impurities, will used herein is for the purpose of describing particular aspects not dissolve and it is this undissolved material that is removed only and, unless a particular term is specifically defined from the Solublized biomass. As such, relatively pure grades herein, is not intended to be limiting. 45 of the biomass, for example, pure or practical grade chitin, Also, throughout this specification, various publications are will be completely “dissolved, whereas dried, ground biom referenced. The disclosures of these publications in their ass, for example, shrimp or crab shells will be “dispersed” entireties are hereby incorporated by reference into this appli with the effect that the chitin will be solublized and the cation in order to more fully describe the state of the art to impurities will not be. which the disclosed matter pertains. The references disclosed 50 As used herein, the term "chitinous biomass” means any are also individually and specifically incorporated by refer Source of chitin, chitosan, or other polysaccharide derived ence herein for the material contained in them that is dis from a marine exoskeleton (e.g., the shells of crustaceans like cussed in the sentence in which the reference is relied upon. shrimp, crab, lobster, crawfish, prawns, etc.). Chitosan is Definitions typically deacetylated chitin. Throughout the description and claims of this specification 55 As used herein, the term “chitosan' means deacetylated the word “comprise' and other forms of the word, such as chitin or any other form of chemically modified chitin. “comprising and "comprises.” means including but not lim A weight percent (wt.%) of a component, unless specifi ited to, and is not intended to exclude, for example, other cally stated to the contrary, is based on the total weight of the additives, components, integers, or steps. formulation or composition in which the component is As used in the description and the appended claims, the 60 included. singular forms “a” “an.” and “the include plural referents The term “ion, as used herein, refers to any molecule, unless the context clearly dictates otherwise. Thus, for portion of a molecule, cluster of molecules, molecular com example, reference to “a composition' includes mixtures of plex, moiety, or atom that contains a charge (positive, nega two or more such compositions, reference to “an ionic liquid tive, or both (e.g., Zwitterions) or that can be made to contain includes mixtures of two or more Suchionic liquids, reference 65 a charge. Methods for producing a charge in a molecule, to “the compound includes mixtures of two or more such portion of a molecule, cluster of molecules, molecular com compounds, and the like. “Optional or “optionally’ means plex, moiety, or atom are disclosed herein and can be accom US 9,096,743 B2 5 6 plished by methods known in the art, e.g., protonation, depro iodine. The term “alkoxyalkyl specifically refers to an alkyl tonation, oxidation, reduction, alkylation, etc. group that is Substituted with one or more alkoxy groups, as The term “anion' is a type of ion and is included within the described below. The term “alkylamino” specifically refers to meaning of the term “ion'. An "anion' is any molecule, an alkyl group that is Substituted with one or more amino portion of a molecule (e.g., Zwitterion), cluster of molecules, groups, as described below, and the like. When “alkyl is used molecular complex, moiety, or atom that contains a net nega in one instance and a specific term Such as “alkylalcohol is tive charge or that can be made to contain a net negative used in another, it is not meant to imply that the term “alkyl charge. The term "anion precursor is used herein to specifi does not also refer to specific terms such as “alkylalcohol cally refer to a molecule that can be converted to an anion via and the like. a chemical reaction (e.g., deprotonation). 10 This practice is also used for other groups described herein. The term “cation' is a type of ion and is included within the That is, while a term such as “cycloalkyl refers to both meaning of the term “ion'. A "cation' is any molecule, por unsubstituted and substituted cycloalkyl moieties, the substi tion of a molecule (e.g., Zwitterion), cluster of molecules, tuted moieties can, in addition, be specifically identified molecular complex, moiety, or atom, that contains a net posi herein; for example, a particular Substituted cycloalkyl can be tive charge or that can be made to contain a net positive 15 referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substi charge. The term “cation precursor is used herein to specifi tuted alkoxy can be specifically referred to as, e.g., a "halo cally refer to a molecule that can be converted to a cation via genated alkoxy, a particular Substituted alkenyl can be, e.g., a chemical reaction (e.g., protonation or alkylation). an “alkenylalcohol and the like. Again, the practice of using As used herein, the term “substituted is contemplated to a general term, Such as “cycloalkyl and a specific term, Such include all permissible Substituents of organic compounds. In as “alkylcycloalkyl is not meant to imply that the general a broad aspect, the permissible Substituents include acyclic term does not also include the specific term. and cyclic, branched and unbranched, carbocyclic and het The term “alkoxy” as used herein is an alkyl group bound erocyclic, and aromatic and nonaromatic Substituents of through a single, terminal ether linkage; that is, an “alkoxy” organic compounds. Illustrative Substituents include, for group can be defined as -OD' where D'' is alkyl as defined example, those described below. The permissible substituents 25 above. can be one or more and the same or different for appropriate The term “alkenyl' as used herein is a hydrocarbon group organic compounds. For purposes of this disclosure, the het of from 2 to 24 carbon atoms with a structural formula con eroatoms, such as nitrogen, can have hydrogen Substituents taining at least one carbon-carbon double bond. Asymmetric and/or any permissible Substituents of organic compounds structures such as (D"D)C=C(DD) are intended to described herein which satisfy the valencies of the heteroat 30 include both the E and Z isomers. This may be presumed in oms. This disclosure is not intended to be limited in any structural formulae herein wherein an asymmetric alkene is manner by the permissible substituents of organic com present, or it may be explicitly indicated by the bond symbol pounds. Also, the terms “substitution” or “substituted with C=C. The alkenyl group can be substituted with one or more include the implicit proviso that such substitution is in accor groups including, but not limited to, alkyl, halogenated alkyl, dance with permitted valence of the substituted atom and the 35 alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, substituent, and that the substitution results in a stable com carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, pound, e.g., a compound that does not spontaneously undergo silyl, Sulfo-oxo, Sulfonyl, Sulfone, Sulfoxide, or thiol, as transformation Such as by rearrangement, cyclization, elimi described below. nation, etc. The term “alkynyl as used herein is a hydrocarbon group “D’.” “D’.” “D” and “D are used herein as generic 40 of 2 to 24 carbon atoms with a structural formula containing symbols to represent various specific Substituents. These at least one carbon-carbon triple bond. The alkynyl group can symbols can be any Substituent, not limited to those disclosed be substituted with one or more groups including, but not herein, and when they are defined to be certain substituents in limited to, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, one instance, they can, in another instance, be defined as some aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, other substituents. 45 ether, halide, hydroxy, ketone, nitro, silyl, Sulfo-oxo, Sulfo The term “aliphatic' as used herein refers to a non-aro nyl, sulfone, sulfoxide, or thiol, as described below. matic hydrocarbon group and includes branched and The term “aryl as used herein is a group that contains any unbranched, alkyl, alkenyl, or alkynyl groups. carbon-based aromatic group including, but not limited to, The term “alkyl as used herein is a branched or benzene, naphthalene, phenyl, biphenyl, phenoxybenzene, unbranched saturated hydrocarbon group of 1 to 24 carbon 50 and the like. The term “aryl also includes "heteroaryl.” atoms, such as methyl, ethyl, n-propyl, isopropyl. n-butyl, which is defined as a group that contains an aromatic group isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl. that has at least one heteroatom incorporated within the ring dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the of the aromatic group. Examples of heteroatoms include, but like. The alkyl group can also be substituted or unsubstituted. are not limited to, nitrogen, oxygen, Sulfur, and phosphorus. The alkyl group can be substituted with one or more groups 55 Likewise, the term “non-heteroaryl, which is also included including, but not limited to, alkyl, halogenated alkyl, alkoxy, in the term “aryl. defines a group that contains an aromatic alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxy group that does not contain a heteroatom. The aryl group can lic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, be substituted or unsubstituted. The aryl group can be substi sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described tuted with one or more groups including, but not limited to, below. 60 alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, het Throughout the specification “alkyl is generally used to eroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, refer to both unsubstituted alkyl groups and substituted alkyl hydroxy, ketone, nitro, silyl, Sulfo-oxo, Sulfonyl, Sulfone, groups; however, Substituted alkyl groups are also specifi sulfoxide, or thiol as described herein. The term “biary1' is a cally referred to herein by identifying the specific substituent specific type of aryl group and is included in the definition of (s) on the alkyl group. For example, the term "halogenated 65 aryl. Biaryl refers to two aryl groups that are bound together alkyl specifically refers to an alkyl group that is substituted via a fused ring structure, as in naphthalene, or are attached with one or more halide, e.g., fluorine, chlorine, bromine, or via one or more carbon-carbon bonds, as in biphenyl. US 9,096,743 B2 7 8 The term “cycloalkyl as used herein is a non-aromatic The term “halide' as used herein refers to the halogens carbon-based ring composed of at least three carbon atoms. fluorine, chlorine, bromine, and iodine. Examples of cycloalkyl groups include, but are not limited to, The term “hydroxyl as used herein is represented by the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The formula—OH. term "heterocycloalkyl is a cycloalkyl group as defined 5 The term “nitro” as used herein is represented by the for above where at least one of the carbon atoms of the ring is mula—NO. substituted with a heteroatom such as, but not limited to, The term “silyl as used herein is represented by the for nitrogen, oxygen, Sulfur, or phosphorus. The cycloalkyl mula –SiD' DD, where D', D, and D can be, indepen group and heterocycloalkyl group can be substituted or dently, hydrogen, alkyl, halogenated alkyl, alkoxy, alkenyl, unsubstituted. The cycloalkyl group and heterocycloalkyl 10 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocy group can be substituted with one or more groups including, cloalkyl, or heterocycloalkenyl group described above. but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, het The term “sulfo-oxo' as used herein is represented by the eroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, formulas-S(O)D', -S(O),D', OS(O).D", or—OS(O) hydroxy, ketone, nitro, silyl, Sulfo-oxo, Sulfonyl, Sulfone, OD', where D' can be hydrogen, an alkyl, halogenated alkyl, sulfoxide, or thiol as described herein. 15 alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, The term “cycloalkenyl' as used herein is a non-aromatic heterocycloalkyl, or heterocycloalkenyl group described carbon-based ring composed of at least three carbon atoms above. Throughout this specification “S(O) is a short hand and containing at least one double bound, i.e., C=C. notation for S=O. Examples of cycloalkenyl groups include, but are not limited The term "sulfonyl is used herein to refer to the sulfo-oxo to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopenta group represented by the formula—S(O),D', where D' can dienyl, cyclohexenyl, cyclohexadienyl, and the like. The term be hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl, "heterocycloalkenyl is a type of cycloalkenyl group as aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, defined above, and is included within the meaning of the term or heterocycloalkenyl group described above. “cycloalkenyl, where at least one of the carbon atoms of the The term "sulfonylamino” or “sulfonamide' as used herein ring is substituted with a heteroatom Such as, but not limited 25 is represented by the formula—S(O)NH-. to, nitrogen, oxygen, Sulfur, or phosphorus. The cycloalkenyl The term “sulfone' as used herein is represented by the group and heterocycloalkenyl group can be substituted or formula D'S(O),D', where D'and D can be, independently, unsubstituted. The cycloalkenyl group and heterocycloalk an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, enyl group can be substituted with one or more groups includ cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocy ing, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, 30 cloalkenyl group described above. heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, The term "sulfoxide’ as used herein is represented by the halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sul formula D'S(O)D, where D'' and D can be, independently, fone, sulfoxide, or thiol as described herein. an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, The term “cyclic group' is used hereinto refer to eitheraryl cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocy groups, non-aryl groups (i.e., cycloalkyl, heterocycloalkyl, 35 cloalkenyl group described above. cycloalkenyl, and heterocycloalkenyl groups), or both. The term “thiol as used herein is represented by the for Cyclic groups have one or more ring systems that can be mula—SH. Substituted or unsubstituted. A cyclic group can contain one “R',” “R” “R” “R”,” etc., where n is some integer, as used or more aryl groups, one or more non-aryl groups, or one or hereincan, independently, possess one or more of the groups more aryl groups and one or more non-aryl groups. 40 listed above. For example, if R is a straight chain alkyl group, The term "aldehyde' as used herein is represented by the one of the hydrogen atoms of the alkyl group can optionally formula—C(O)H. Throughout this specification “C(O) is a be substituted with a hydroxyl group, an alkoxy group, an short hand notation for C=O. amine group, an alkyl group, a halide, and the like. Depending The terms “amine' or "amino” as used herein are repre upon the groups that are selected, a first group can be incor sented by the formula NDDD, where D, D, and D can 45 porated within second group or, alternatively, the first group be, independently, hydrogen, an alkyl, halogenated alkyl, can be pendant (i.e., attached) to the second group. For alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, example, with the phrase “an alkyl group comprising an heterocycloalkyl, or heterocycloalkenyl group described amino group, the amino group can be incorporated within above. the backbone of the alkyl group. Alternatively, the amino The term “carboxylic acid as used herein is represented by 50 group can be attached to the backbone of the alkyl group. The the formula —C(O)OH. A “carboxylate” as used herein is nature of the group(s) that is (are) selected will determine if represented by the formula—C(O)O. the first group is embedded or attached to the second group. The term “ester” as used herein is represented by the for The world market for chitin-based materials exceeded S2 mula–OC(O)ID' or - C(O)OD', where D' can be an alkyl, billion annually in the year 2005. Analysts also predict that halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, 55 markets for these materials are likely to grow rapidly over the cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocy next ten years. Chitin has been known to form microfibrillar cloalkenyl group described above. arrangements in living organisms. The presence of The term “ether as used herein is represented by the for microfibrils suggests that chitin has characteristics which mula D'OD, where D'' and D can be, independently, an make it a good candidate for fiber spinning. To spin chitin alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, 60 fibers, the raw polymer must be suitably redissolved after cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocy removal of extraneous material Such as calcium carbonate cloalkenyl group described above. and proteins, which encase the microfibrils, indicating the The term “ketone' as used herein is represented by the purification and complete dissolution of chitinare key steps in formula D'C(O)ID, where D'' and D' can be, independently, chitin fiber making. As such, the following is a disclosure of an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, 65 a process for forming chitin-based films, fibers, and beads. cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocy The following are non-limiting examples of aspects, itera cloalkenyl group described above. tions, and examples of the disclosed process. The following US 9,096,743 B2 9 10 are not meant to be limiting in Scope, but to provide an c) adding a coagulant to the second solution to form regen overview of the process and the combinations of steps that can erated chitin; comprise the disclosed process. d) isolating the regenerated chitin; Chitin derived from crustaceans is available from suppliers e) dissolving the regenerated chitin in an ionic liquid; and as “pure chitin' and as “practical grade chitin.” These forms f) adding a coagulant and casting the regenerated chitin of chitin undergo a process similar to the Kraft Process for from step (e) into a film, a fiber, or a bead. obtaining cellulose from wood or other sources of cellulose. One iteration of this aspect of the disclosed process relates During the process of preparing pure chitin and practical to a process for preparing chitin films, fibers, or beads and grade chitin, there is a break down of the polysaccharide comprises: chains such that the resulting chitin has a shorter chain length 10 a) dissolving or dispersing a source of chitin in an ionic and therefore a lower average molecular weight than it had liquid at a temperature of from about 70° C. to about before it was processed. The disclosed processes provide a 130° C. to form a first solution; method of directly extracting chitin from a chitinous biomass b) separating the undissolved material to form a second without Substantially shortening the polysaccharide chains. 15 Solution; As such, the films, fibers, and beads formed from the dis c) adding a coagulant to the second solution to form regen closed process wherein the chitin is directly extracted from erated chitin; the chitinous biomass provides the first method for obtaining d) isolating the regenerated chitin; polymeric materials comprising chitin that has the original e) dissolving the regenerated chitin in an ionic liquid; and full polysaccharide chain length (and molecular weight). f) adding a coagulant and casting the regenerated chitin Moreover the disclosed chitin can be substantially free of from step (e) into a film, a fiber, or a bead. agents that are typically found in pure and practical grade One example of this iteration relates to a process for pre chitin, Such as methanesulfonic acid, trichloroacetic acid, paring chitin films, fibers, or beads, and comprises: dichloroacetic acid, formic acid, and dimethylacetamide. a) dissolving or dispersing a source of chitin in an ionic Direct Extraction of Chitin from a Biomass 25 liquid at a temperature of from about 90° C. to about In one embodiment, the disclosed process, wherein chitin 110° C. to form a first solution; is extracted directly from a chitinous biomass, can comprise: b) separating the undissolved material to form a second a) contacting an ionic liquid with a chitinous biomass to Solution; form a residue and a chitin comprising solution; and c) adding a coagulant to the second solution to form regen b) adding a coagulant to the Solution formed in step (a) and 30 erated chitin; casting the chitin comprising Solution into a film, a fiber, d) isolating the regenerated chitin; or a bead. e) dissolving the regenerated chitin in an ionic liquid; and In a further embodiment, the process wherein chitin is f) adding a coagulant and casting the regenerated chitin extracted directly from a chitinous biomass, can comprise: from step (e) into a film, a fiber, or a bead. a) contacting an ionic liquid with a chitinous biomass to 35 Another example of this iteration relates to a process for form a residue and a chitin comprising solution; preparing chitin films, fibers, or beads, and comprises: b) adding an adjunct ingredient to the chitin comprising a) dissolving or dispersing a source of chitin in an ionic Solution; and liquid at a temperature of about 100° C. to form a first c) adding a coagulant to the Solution formed in step (a) and Solution; casting the chitin comprising Solution into a film, a fiber, 40 b) separating the undissolved material to form a second or a bead. Solution; However, this process can be used to prepare high molecu c) adding a coagulant to the second solution to form regen lar weight chitin, by: erated chitin; a) contacting an ionic liquid with a chitinous biomass to d) isolating the regenerated chitin; form a residue and a chitin comprising solution; 45 e) dissolving the regenerated chitin in an ionic liquid; and b) separating the chitin comprising solution from the resi f) adding a coagulant and casting the regenerated chitin due; and from step (e) into a film, a fiber, or a bead. c) adding a coagulant to the Solution that is separated in Another iteration of this aspect of the disclosed process step (b) to form a high molecular weight regenerated relates to a process for preparing chitin films, fibers, or beads, chitin. 50 and comprises: These processes can also be performed using pure chitin a) dissolving or dispersing a source of chitin in an ionic and practical grade chitin. However, because of the commer liquid to form a first Solution; cial processing used to provide pure chitin and practical grade b) separating the undissolved material to form a second chitin, the chitin in these sources has a lower molecular Solution; weight than it had prior to processing (i.e., in the unprocessed 55 c) adding a coagulant to the second solution to form regen chitinous biomass). Consequently, the regenerated chitin erated chitin; obtained when using the disclosed processes with these d) isolating the regenerated chitin; sources of chitin will likewise be of lower molecular weight e) dissolving the regenerated chitin in an ionic liquid at a than had the disclosed processes been followed with unproc temperature of from about 70° C. to about 130° C.; and essed chitinous biomass. 60 f) adding a coagulant and casting the regenerated chitin Ionic Liquids Used for the Dissolution of the Source of Chitin from step (e) into a film, a fiber, or a bead. One aspect of the present disclosure relates to a process for One example of this iteration relates to a process for pre preparing chitin films, fibers, or beads comprising: paring chitin films, fibers, or beads, and comprises: a) dissolving or dispersing a source of chitin in an ionic a) dissolving or dispersing a source of chitin in an ionic liquid to form a first Solution; 65 liquid to form a first Solution; b) separating the undissolved material to form a second b) separating the undissolved material to form a second Solution; Solution; US 9,096,743 B2 11 12 c) adding a coagulant to the second solution to form regen a) dissolving or dispersing a source of chitin in 3-ethyl-1- erated chitin; methyl-1H-imidazol-3-ium acetate, CamimOAc, hav d) isolating the regenerated chitin; ing the formulae: e) dissolving the regenerated chitin in an ionic liquid at a temperature of from about 90° C. to about 110°C.; and f) adding a coagulant and casting the regenerated chitin from step (e) into a film, a fiber, or a bead. OAc Another example of this iteration relates to a process for preparing chitin films, fibers, or beads, and comprises: a) dissolving or dispersing a source of chitin in an ionic 10 at a temperature of from about 70° C. to about 130° C. to liquid to form a first Solution; form a first solution; b) separating the undissolved material to form a second b) separating the undissolved material to form a second Solution; Solution; c) adding a coagulant to the second solution to form regen 15 c) adding a coagulant to the second solution to form regen erated chitin; erated chitin; d) isolating the regenerated chitin; d) isolating the regenerated chitin; e) dissolving the regenerated chitin in an ionic liquid at a e) dissolving the regenerated chitin in 3-ethyl-1-methyl temperature of about 100° C.; and 1H-imidazol-3-ium acetate, CamimOAc, having the f) adding a coagulant and casting the regenerated chitin formulae: from step (e) into a film, a fiber, or a bead. Another iteration of this aspect of the disclosed process relates to a process for preparing chitin films, fibers, or beads HC NYS-Gb CHs G and comprises: OAc a) dissolving or dispersing a source of chitin in an ionic 25 liquid at a temperature of from about 70° C. to about 130° C. to form a first solution; at a temperature of from about 70° C. to about 130° C.; b) separating the undissolved material to form a second and Solution; f) adding a coagulant and casting the regenerated chitin c) adding a coagulant to the second solution to form regen 30 from step (e) into a film, a fiber, or a bead. erated chitin; One example of this iteration relates to a process for pre d) isolating the regenerated chitin: paring chitin films, fibers, or beads and comprises: e) dissolving the regenerated chitin in an ionic liquid at a a) dissolving or dispersing a source of chitin in 3-ethyl-1- temperature of from about 70° C. to about 130° C.; and methyl-1H-imidazol-3-ium acetate, CamimOAc, hav f) adding a coagulant and casting the regenerated chitin 35 ing the formulae: from step (e) into a film, a fiber, or a bead. One example of this iteration relates to a process for pre paring chitin films, fibers, or beads and comprises: HC G CHs a) dissolving or dispersing a source of chitin in an ionic n 1n- O OAc liquid at a temperature of from about 90° C. to about 40 110° C. to form a first solution; b) separating the undissolved material to form a second Solution; at a temperature of from about 90° C. to about 110°C. to c) adding a coagulant to the second solution to form regen form a first solution; erated chitin; 45 b) separating the undissolved material to form a second d) isolating the regenerated chitin; Solution; e) dissolving the regenerated chitin in an ionic liquid at a c) adding a coagulant to the second solution to form regen erated chitin; temperature of from about 90° C. to about 110°C.; and d) isolating the regenerated chitin; f) adding a coagulant and casting the regenerated chitin e) dissolving the regenerated chitin in 3-ethyl-1-methyl from step (e) into a film, a fiber, or a bead. 50 Another example of this iteration relates to a process for 1H-imidazol-3-ium acetate, CamimOAc, having the preparing chitin films, fibers, or beads and comprises: formulae: a) dissolving or dispersing a source of chitin in an ionic liquid at a temperature of about 100° C. to form a first HC 6 CHs Solution; 55 N/SS- G b) separating the undissolved material to form a second OAc Solution; c) adding a coagulant to the second solution to form regen erated chitin; at a temperature of from about 90° C. to about 110° C.; d) isolating the regenerated chitin; 60 and e) dissolving the regenerated chitin in an ionic liquid at a f) adding a coagulant and casting the regenerated chitin temperature of about 100° C.; and from step (e) into a film, a fiber, or a bead. f) adding a coagulant and casting the regenerated chitin Another example of this iteration relates to a process for from step (e) into a film, a fiber, or a bead. preparing chitin films, fibers, or beads and comprises: A further iteration of this aspect of the disclosed process 65 a) dissolving or dispersing a source of chitin in 3-ethyl-1- relates to a process for preparing chitin films, fibers, or beads methyl-1H-imidazol-3-ium acetate, CamimOAc, hav and comprises: ing the formulae: US 9,096,743 B2 13 14 c) adding a coagulant to the second solution to form regen H3C G CHs erated chitin; N1s- G OAc d) isolating the regenerated chitin; e) dissolving the regenerated chitin in an ionic liquid; and f) adding a coagulant and casting the regenerated chitin from step (e) into a film, a fiber, or a bead. at a temperature of about 100° C. to form a first solution; One example of this iteration relates to a process for pre b) separating the undissolved material to form a second paring chitin films, fibers, or beads and comprises: Solution; a) dissolving or dispersing a source of chitin in an ionic c) adding a coagulant to the second solution to form regen 10 liquid and a co-solvent at a temperature of from about erated chitin; d) isolating the regenerated chitin; 90° C. to about 110° C. to form a first solution; e) dissolving the regenerated chitin in 3-ethyl-1-methyl b) separating the undissolved material to form a second 1H-imidazol-3-ium acetate, CamimOAc, having the Solution; formulae: c) adding a coagulant to the second solution to form regen 15 erated chitin; d) isolating the regenerated chitin; e) dissolving the regenerated chitin in an ionic liquid; and HC NYS-6 CHs O f) adding a coagulant and casting the regenerated chitin OAc from step (e) into a film, a fiber, or a bead. Another example of this iteration relates to a process for preparing chitin films, fibers, or beads and comprises: at a temperature of about 100° C.; and a) dissolving or dispersing a source of chitin in an ionic f) adding a coagulant and casting the regenerated chitin liquid and a co-solvent at a temperature of about 100°C. from step (e) into a film, a fiber, or a bead. to form a first solution; A further aspect of the present disclosure relates to a pro 25 b) separating the undissolved material to form a second cess for preparing chitin films, fibers, or beads and comprises: Solution; a) dissolving or dispersing a source of chitin in an ionic c) adding a coagulant to the second solution to form regen liquid to form a first Solution; erated chitin; b) separating the undissolved material to form a second d) isolating the regenerated chitin; Solution; 30 e) dissolving the regenerated chitin in an ionic liquid; and c) adding a coagulant to the second solution to form regen f) adding a coagulant and casting the regenerated chitin erated chitin: from step (e) into a film, a fiber, or a bead. d) isolating the regenerated chitin; Another iteration of this aspect of the disclosed process e) dissolving the regenerated chitin in an ionic liquid to relates to a process for preparing chitin films, fibers, or beads form a solution; 35 and comprises: f) adding an adjunct ingredient to the solution formed in a) dissolving or dispersing a source of chitin in an ionic step (e) to form a chitin/adjunct ingredient admixture liquid and a co-solvent to form a first Solution; Solution; and b) separating the undissolved material to form a second g) adding a coagulant to the Solution of step (f) and casting Solution; the regenerated chitin/adjunct ingredient admixture into 40 c) adding a coagulant to the second solution to form regen a film, a fiber, or a bead. erated chitin; It is noted that while the above examples disclose the ionic d) isolating the regenerated chitin; liquid CamimOAc, the disclosed processes can use other e) dissolving the regenerated chitin in an ionic liquid at a ionic liquids, for example, C.mimRCO, where n is an temperature of from about 70° C. to about 130° C.; and integer of from 1 to 8 and R is H or substituted or unsubsti 45 f) adding a coagulant and casting the regenerated chitin tuted Cls alkyl. from step (e) into a film, a fiber, or a bead. Co-solvent Used for Dissolution of the Source of Chitin One example of this iteration relates to a process for pre Another aspect of the present disclosure relates to a process paring chitin films, fibers, or beads and comprises: for preparing chitin films, fibers, or beads and comprises: a) dissolving or dispersing a source of chitin in an ionic a) dissolving or dispersing a source of chitin in an ionic 50 liquid and a co-solvent to form a first Solution; liquid and a co-solvent to form a first Solution; b) separating the undissolved material to form a second b) separating the undissolved material to form a second Solution; Solution; c) adding a coagulant to the second solution to form regen c) adding a coagulant to the second solution to form regen erated chitin; erated chitin; 55 d) isolating the regenerated chitin; d) isolating the regenerated chitin; e) dissolving the regenerated chitin in an ionic liquid at a e) dissolving the regenerated chitin in an ionic liquid; and temperature of from about 90° C. to about 110°C.; and f) adding a coagulant and casting the regenerated chitin f) adding a coagulant and casting the regenerated chitin from step (e) into a film, a fiber, or a bead. from step (e) into a film, a fiber, or a bead. One iteration of this aspect of the disclosed process relates 60 Another example of this iteration relates to a process for to a process for preparing chitin films, fibers, or beads and preparing chitin films, fibers, or beads and comprises: comprises: a) dissolving or dispersing a source of chitin in an ionic a) dissolving or dispersing a source of chitin in an ionic liquid and a co-solvent to form a first Solution; liquid and a co-solvent at a temperature of from about b) separating the undissolved material to form a second 70° C. to about 130° C. to form a first solution: 65 Solution; b) separating the undissolved material to form a second c) adding a coagulant to the second solution to form regen Solution; erated chitin; US 9,096,743 B2 15 16 d) isolating the regenerated chitin; c) adding a coagulant to the second solution to form regen e) dissolving the regenerated chitin in an ionic liquid at a erated chitin; temperature of about 100° C.; and d) isolating the regenerated chitin; f) adding a coagulant and casting the regenerated chitin e) dissolving the regenerated chitin in 3-ethyl-1-methyl from step (e) into a film, a fiber, or a bead. 5 1H-imidazol-3-ium acetate, CamimOAc, having the Another iteration of this aspect of the disclosed process formulae: relates to a process for preparing chitin films, fibers, or beads and comprises: a) dissolving or dispersing a source of chitin in an ionic H3C NYS-G CHs O liquid and a co-solvent at a temperature of from about 10 OAc: 70° C. to about 130° C. to form a first solution: b) separating the undissolved material to form a second and Solution; dimethylsulfoxide at a temperature of from about 70° C. c) adding a coagulant to the second solution to form regen 15 to about 130° C.; and erated chitin; f) adding a coagulant and casting the regenerated chitin d) isolating the regenerated chitin; from step (e) into a film, a fiber, or a bead. e) dissolving the regenerated chitin in an ionic liquid at a Another example of this iteration relates to a process for temperature of from about 70° C. to about 130° C.; and preparing chitin films, fibers, or beads and comprises: f) adding a coagulant and casting the regenerated chitin a) dissolving or dispersing a source of chitin in 3-ethyl-1- from step (e) into a film, a fiber, or a bead. methyl-1H-imidazol-3-ium acetate, CamimOAc, hav One example of this iteration relates to a process for pre ing the formulae: paring chitin films, fibers, or beads and comprises: a) dissolving or dispersing a source of chitin in an ionic liquid and a co-solvent at a temperature of from about 25 HC n1-G CHs O 90° C. to about 110° C. to form a first solution; OAc: b) separating the undissolved material to form a second Solution; c) adding a coagulant to the second solution to form regen and erated chitin; 30 dimethylsulfoxide at a temperature of about 100° C. to d) isolating the regenerated chitin: form a first solution; e) dissolving the regenerated chitin in an ionic liquid at a b) separating the undissolved material to form a second temperature of from about 90° C. to about 110°C.; and Solution; f) adding a coagulant and casting the regenerated chitin c) adding a coagulant to the second solution to form regen from step (e) into a film, a fiber, or a bead. 35 erated chitin; Another example of this iteration relates to a process for d) isolating the regenerated chitin; preparing chitin films, fibers, or beads and comprises: e) dissolving the regenerated chitin in 3-ethyl-1-methyl a) dissolving or dispersing a source of chitin in an ionic 1H-imidazol-3-ium acetate, CamimOAc, having the formulae: liquid and a co-solvent at a temperature of about 100°C. 40 to form a first solution; b) separating the undissolved material to form a second Solution; H3C NYS-G CHs G c) adding a coagulant to the second solution to form regen OAc: erated chitin; d) isolating the regenerated chitin; 45 e) dissolving the regenerated chitin in an ionic liquid at a and temperature of about 100° C.; and dimethylsulfoxide at a temperature of about 100° C.; and f) adding a coagulant and casting the regenerated chitin f) adding a coagulant and casting the regenerated chitin from step (e) into a film, a fiber, or a bead. 50 from step (e) into a film, a fiber, or a bead. A further iteration of this aspect of the disclosed process A further aspect of the present disclosure relates to a pro relates to a process for preparing chitin films, fibers, or beads cess for preparing chitin films, fibers, or beads and comprises: and comprises: a) dissolving or dispersing a source of chitin in an ionic a) dissolving or dispersing a source of chitin in 3-ethyl-1- liquid and a co-solvent to form a first Solution; methyl-1H-imidazol-3-ium acetate, CamimOAc, hav 55 b) separating the undissolved material to form a second ing the formulae: Solution; c) adding a coagulant to the second solution to form regen erated chitin; HC NYS-Gb CHs O d) isolating the regenerated chitin; OAc: 60 e) dissolving the regenerated chitin in an ionic liquid to form a solution; f) adding an adjunct ingredient to the solution formed in and step (e) to form a chitin/adjunct ingredient admixture dimethylsulfoxide at a temperature of from about 70° C. Solution; and to about 130° C. to form a first solution; 65 g) adding a coagulant to the Solution of step (f) and casting b) separating the undissolved material to form a second the regenerated chitin/adjunct ingredient admixture into Solution; a film, a fiber, or a bead. US 9,096,743 B2 17 18 It is noted that while the above examples disclose the ionic a) dissolving or dispersing a source of chitin in an ionic liquid CamimOAc, the disclosed processes can use other liquid, a co-solvent, or a mixture of anionic liquid and an ionic liquids, for example, C.mimRCO, where n is an organic solvent to form a first solution; integer of from 1 to 8 and R is H or substituted or unsubsti b) separating the undissolved material to form a second tuted Cls alkyl. Solution; Organic Solvent Used for Dissolution of the Source of Chitin c) adding a coagulant to the second solution to form regen Another aspect of the present disclosure relates to a process erated chitin; for preparing chitin films, fibers, or beads and comprises: d) isolating the regenerated chitin; a) dissolving or dispersing a source of chitin in an ionic e) dissolving the regenerated chitin in an ionic liquid to 10 form a solution; liquid, a co-solvent, or a mixture of an ionic liquid and an f) adding an adjunct ingredient to the solution formed in organic solvent to form a first Solution; step (e) to form a chitin/adjunct ingredient admixture b) separating the undissolved material to form a second Solution; and Solution; g) adding a coagulant to the Solution of step (f) and casting c) adding a coagulant to the second solution to form regen 15 the regenerated chitin/adjunct ingredient admixture into erated chitin; a film, a fiber, or a bead. d) isolating the regenerated chitin; The following is a description of the process wherein the e) dissolving the regenerated chitin in an ionic liquid to resulting films, fibers, or beads comprise chitinous materials. form a solution; Step (a): Dissolving or Dispersing a Source of Chitin to Form f) dissolving one or more polymers in an ionic liquid to a First Solution form a solution; Step (a) of the disclosed process relates to dissolving or g) combining the solution from step (e) and step (f) to form dispersing a source of chitin. The Source of chitin can be an polymer admixture Solution; and chitinous biomass, pure chitin, technical or practical grade h) adding a coagulant to the polymer admixture solution of chitin, ground or pulverized exoskeleton of arthropods, i.e., step (g) and casting the polymer admixture from step (g) 25 crustaceans. In one embodiment, the Source of chitin is pure into a film, a fiber, or a bead. chitin, for example, pure chitin obtained from crab shells, One iteration of this aspect of the disclosed process relates C9752, available from SigmaTM St. Louis, Mo. In another to a process for preparing chitin films, fibers, or beads and embodiment, the source of chitin is practical grade chitin comprises: obtained from crab shells, C7170, available from SigmaTM St. a) dissolving or dispersing a source of chitin in an ionic 30 Louis, Mo. In a further embodiment, the source of chitin is chitinous biomass, such as shrimp shells that are removed liquid, a co-solvent, or a mixture of an ionic liquid and an from the meat by peeling and processed to insure all shrimp organic solvent to form a first Solution; meat is removed. However, any biomass comprising chitin or b) separating the undissolved material to form a second mixtures of chitin and chitosan, or mixtures of chitin, chito Solution; 35 san, and other polysaccharides can be used as the Source of c) adding a coagulant to the second solution to form regen chitin in step (a). erated chitin; When contemplating the source of chitin, the formulator d) isolating the regenerated chitin; can take into consideration the amount of chitin that com e) dissolving the regenerated chitin in an ionic liquid to prises the source of chitin. For example, "pure chitin' can form a solution; 40 comprise from about 75% to about 85% by weight of chitin. f) dissolving cellulose in an ionic liquid to form a solution; In one example, pure chitin comprises about 81.8% of chitin. g) combining the solution from step (e) and step (f) to form “Technical grade' or “practical grade chitin can comprise an polymer admixture Solution; and from about 70% to about 80% by weight of chitin. In one h) adding a coagulant to the polymer admixture solution of example, practical chitin comprises about 78.9% of chitin. As step (g) and casting the polymer admixture from step (g) 45 it relates to crude biomass sources, one example of shrimps into a film, a fiber, or a bead. skins or shells comprises 27.2% chitin, while, one example of Another iteration relates to a process for preparing chitin crab shells comprises 23.9% chitin by weight. films, fibers, or beads, and comprises: In one aspect of the disclosed process, high molecular a) dissolving or dispersing a source of chitin in an ionic weight chitin is obtained by directly dissolving or dispersing liquid, a co-solvent, or a mixture of an ionic liquid and an 50 a chitinous biomass in an ionic liquid. The chitin obtained by organic solvent to form a first Solution; this process is not broken down into Small polysaccharide b) separating the undissolved material to form a second chains as is the case with practical grade or pure grade chitin. Solution; As such, direct dissolution of chitin from a biomass allows the c) adding a coagulant to the second solution to form regen formulator to obtain high molecular weight chitin than can be erated chitin; 55 subsequently used to form films, fibers, or beads having dif d) isolating the regenerated chitin; ferent properties than in the case wherein the source of chitin e) dissolving the regenerated chitin in an ionic liquid to is not directly extracted from a chitinous biomass. In addition, form a solution; as disclosed herein, the biomass derived chitin can be f) dissolving poly(2-hydroxyethyl methacrylate) admixed with one or more adjunct ingredients to form poly (PHEMA) in an ionic liquid to form a solution; 60 meric compositions have properties not obtainable from pure g) combining the solution from step (e) and step (f) to form or practical grade chitin. an polymer admixture Solution; and The source of chitin can be dissolved in an ionic liquid h) adding a coagulant to the polymer admixture solution of alone, an organic solvent alone, or in a mixture of an ionic step (g) and casting the polymer admixture from step (g) liquid and an organic solvent. In one embodiment, the source into a film, a fiber, or a bead. 65 of chitin is dissolved in an ionic liquid. The source of chitin A further aspect of the present disclosure relates to a pro can be dissolved or dispersed at a temperature of from about cess for preparing chitin films, fibers, or beads and comprises: 70° C. to about 130°C. In one iteration of this embodiment, US 9,096,743 B2 19 20 the source of chitin can be dissolved or dispersed at a tem Other non-limiting examples of heterocyclic and het perature of from about 90° C. to about 110°C. In one par eroaryl units that can be alkylated to form cationic units ticular example, the source of chitin can be dissolved or include imidazole, pyrazoles, thiazoles, isothiazoles, azathio dispersed at a temperature of about 100° C. However, the Zoles, oXothiazoles, oxazines, oxazolines, oxazaboroles, Source of chitin can be dissolved or dispersed at any tempera dithioZoles, triazoles, selenozoles, oxahospholes, pyrroles, ture, for example, 70° C., 71° C., 72° C., 73° C., 74° C., 75° boroles, furans, thiphenes, phospholes, pentazoles, indoles, C., 76° C., 770 C., 780 C. 790 C., 80° C. 810 C., 820 C. 830 indolines, oxazoles, isothirazoles, tetrazoles, benzofurans, C., 840 C., 850 C., 86° C., 87° C., 88° C., 89° C., 90° C., 910 dibenzofurans, benzothiophenes, dibenzothoiphenes, thia C., 920 C., 93° C., 940 C., 95°C., 96° C., 97° C., 98° C. 990 diazoles, pyrdines, pyrimidines, pyrazines, pyridazines, pip C., 100° C., 101° C., 102°C., 103°C., 104°C., 105° C., 106° 10 erazines, piperidines, morpholines, pyrans, annolines, C., 1070 C., 1080 C., 109° C. 110° C. 111° C., 112°C., 1130 phthalazines, quinazolines, and quinoxalines. C., 114° C., 115° C., 116°C., 117°C., 118°C., 119°C., 120° The following are examples of heterocyclic units that are C., 121°C., 122°C., 123°C., 124°C., 125°C., 126° C. 127° suitable for forming a cyclic heteroalkyl cation unit of the C., 128° C., 129° C., and 130° C. In one embodiment of step (a), microwave heating is used 15 disclosed ionic liquids: to dissolve chitin when the source of chitin is a chitinous biomass, for example, shrimp shells. In one iteration, the chitinous biomass can be combined with an ionic liquid oran R4 ionic liquid/co-solvent. The mixture is charge to a source of R5 R4 microwave radiation and the mixture heated to extract the chitin. In one example, short 1 to 5 second pulses are used, J. R3 R5 however, and pulse time can be used to extract the biomass R61 NN1 YR3 and R71NN R6 chitin, i.e., 1 second, 2 seconds, 3 seconds, 4 seconds, or 5 M V / V seconds, or any fractional part thereof. For this embodiment, 25 the temperature can be critical, however, microwave heating pyrrollidinium piperidinium provides an efficient and desirable method for extracting high molecular weight chitin from a biomass. Ionic Liquids The following are further examples of heterocyclic units The following is a non-limiting disclosure of the ionic 30 that are suitable for forming a cyclic heteroalkyl cation unit of liquids Suitable for use in the disclosed process. the disclosed ionic liquids: Ionic liquids are a class of solvents composed of ionized species in contrast to traditional organic or aqueous solvents which are molecular non-ionics. Ionic liquids are salts that R4 R4 exist in the liquid phase at a temperature from about -70° C. to about 300° C. The ionic liquids of the present disclosure 35 comprise an organic cation and an organic or inorganic anion. The organic cation is typically formed by alkylation of a OO R5 OÖr R5 neutral organic species capable of holding a positive charge R 7 R6, R6 t s when a suitable anion is present. Cations 40 RI RI The organic cation of the ionic liquids disclosed hereincan pyridinium pyridazinium comprise a linear, branched, or cyclic heteroalkyl unit. The R4 term "heteroalkyl refers to a cation as disclosed herein com prising one or more heteroatoms chosen from nitrogen, oxy R3 N R4 gen, Sulfur, boron, or phosphorous capable of forming a cat 45 ion. The heteroatom can be a part of a ring formed with one or 2. N more other heteroatoms, for example, pyridinyl, imidazolinyl R6 O R5, R6 IOCNR5, rings, that can have Substituted or unsubstituted linear or RI RI branched alkyl units attached thereto. In addition, the cation can be a single heteroatom wherein a sufficient number of 50 pyrimidinium pyrazinium substituted or unsubstituted linear or branched alkyl units are R4 R5 R3 R4 attached to the heteroatom such that a cation is formed. For example, the cation Cimim where n is an integer of from 1 to 8 can be used. Preferably, ionic liquids with the cation Y O. Y O Camim can be used. A particularly useful ionic liquid is 55 R1 Y NR, R21 N21 NRs. 1-ethyl-3-methyl-1H-imidazol-3-ium acetate, CamimOAc, R3 having the formulae: imidazolium pyrazolium R5 R3 R4 R3 R4 R3 60 Hics -r -C2H5 O OAc: R1 Y O),Y R11 NS-2O,NY 'n n R2, 1Y NY.O. , is an example of an ionic liquid comprising a cyclic het 65 R4 k eroalkyl cation; a ring comprising 3 carbon atoms and 2 oxazolium 1,2,3-triazolium nitrogen atoms. US 9,096,743 B2 21 22 -continued 1,1-1,2-ethanediylbis(oxy-1,2-ethanediyl)bis3 R3 ? R5 R3 methyl-1H-imidazolium-1-yl) N O). N O S R1N1 NRs. 1 R2 R3 Y s 1,2,4-triazolium R4 R! 1. -- 1. R4 thiazolium NN S-Né N1 10 R5 R6 R7 R8 n = 3, 6, 9, 12

R5 R4 15 R R3

R7 R’ and R8 RI quinolium imidazolium and pyrrolidinium based di-cations

25 where R', R. R. and R' comprise a substituted or unsubsti tuted linear, branched, or cyclic C-C alkyl, or Substituted or unsubstituted linear, branched, or cyclic C-C alkoxy; each R. R. R', and R is, independently, hydrogen, substituted or R4 R3 unsubstituted linear, branched, or cyclic C-C alkyl, Substi R R9 30 tuted or unsubstituted linear, branched, or cyclic C-C, alkoxy, or substituted or unsubstituted linear or branched, C-C alkoxyalkyl. R6 O NR The following is a description of the short hand method used throughout the specification for referring to the imida R7 R8 35 Zolium-based ionic liquids disclosed herein. The template: isoquinolium Camim where each R" and R is, independently, a substituted or represents the cation portion of the ionic liquid wherein C, unsubstituted linear, branched, or cyclic C-C alkyl, or sub 40 represent an alkyl or Substituted alkyl moiety having n num stituted or unsubstituted linear, branched, or cyclic C-C, ber of carbon atoms. The term “mim” refers to “methyl sub alkoxy; each R,R,R,R,R,R, and R is, independently, stituted imidazolium. CmPy is likewise used to refer to hydrogen, Substituted or unsubstituted linear, branched, or Cn-methyl substituted pyridinium. Referring to the generic cyclic C-C alkyl, Substituted or unsubstituted linear, imidazolium formula: branched, or cyclic C-C alkoxy, or Substituted or unsubsti 45 tuted linear or branched, C-C alkoxyalkyl. The following comprises yet another set of examples of heterocyclic units that are suitable for forming heterocyclic dication units of the disclosed ionic liquids and are referred to 50 as such or as "geminal ionic liquids: See Armstrong, D.W. et al., Structure and properties of high stability geminal dica tionic ionic liquids, J. Amer: Chem. Soc. 2005; 127(2):593 604; and Rogers, R. D. et al., Mercury(II) partitioning from aqueous Solutions with a new, hydrophobic ethylene-glycol 55 wherein R. R. and Rare each hydrogen, can also be written functionalized bis-imidazolium ionic liquid, Green Chem. as follows: 2003; 5:129-135 included herein by reference in its entirety. F GE) GE) F 60 R11 NNaNR2 N or R11 N N1,NR2N N/ wherein either nitrogen can be depicted as having a positive charge. By the convention used herein the methyl group of 65 "mim” refers to the R' moiety and the C, substituent is the R moiety. Therefore Camim represents a cation having the formula: US 9,096,743 B2 23 24 One embodiment of ionic liquids comprise an anion cho sen from formate, acetate, propionate, butyrate, (CF)SO, (RO)S(=O).O. (RO)2P(=O)C; (RO)C(=O)C; and R'CO.; each R" is independently C-C alkyl. Anions that are chosen from R'CO have been found to be convenient in which can be equally well represented by the formula: forming the compositions of step (a) in the compositions and processes disclosed herein. The anion portion of the ionic liquid is written without the 10 charge, for example, OAc, CHO, Cl, Br, RCHOPO, and (O. PF. IL EXAMPLES Anions The choice of the anion in the ionic liquid can be particu 15 larly relevant to the rate and level of chitin dissolution. While The following are non-limiting examples of ionic liquids not wishing to be bound by theory, the primary mechanism of written in the short hand convention with the corresponding Solvation of carbohydrates by an ionic liquid is the anion's formula: ability to break the extensive hydrogen-bonding networks by i) CamimOAC having the formula: specific interactions with hydroxyl groups. Thus, it is believed that that the dissolution of chitin is enhanced by increasing the hydrogen bond acceptance and basicity of the anion. Anions that also formless viscous ionic liquids are also O OAc: preferred. By using anions that can accept hydrogen bonds and that are relatively basic, one can not only dissolve pure 25 chitin, but one can dissolve practical grade chitin and even extract chitin from raw chitinous biomass, as described ii) Camim (CHO)SO, having the formula: herein. Accordingly, preferred anions are substituted or unsubstituted acyl units R'CO, for example, formate 30 HCO, acetate CH-CO, proprionate, CHCH2CO, butyrate CHCH-CHCO, and benzylate, CHCO; Substituted or unsubstituted sulfates: (R'O)S(=O).O; substituted or unsubstituted sulfonates R'SO, for example (CF)SO; substituted or unsubstituted phosphates: (R'O)P(=O)C); 35 and substituted or unsubstituted carboxylates: (R'O)C(=O) O. Non-limiting examples of R' include hydrogen; substi tuted or unsubstituted linear branched, and cyclic alkyl; sub stituted or unsubstituted linear, branched, and cyclic alkoxy; substituted or unsubstituted aryl; substituted or unsubstituted 40 aryloxy; substituted or unsubstituted heterocyclic; substi tuted or unsubstituted heteroaryl; acyl: silyl; boryl; phos iii) CamimX, where X is chloride or bromide, having the phino; amino; thio; and seleno. In especially preferred embo formula: diuments, the anion is C. carboxylate. Still further examples of preferred anion are deprotonated 45 amino acids, for example, Isoleucine, Alanine, Leucine, xe Asparagine, Lysine, Aspartic Acid, Methionine, Cysteine, Phenylalanine, Glutamic Acid, Threonine, Glutamine, Tryp H3CN -\se-calls tophan, Glycine, Valine, Proline, Selenocysteine, Serine, Tyrosine, Arginine. Histidine, Ornithine, Taurine. 50 It is also contemplated that other anions, though not pre ferred, can still be used in some instances. However, in these instances, higher concentrations, longer mixing times, and iv) Camim RCHOPO, where RCHOPO is an alkane higher temperatures can be required. One can use halogens, phosphonate with R being an alkyl chain, having the formula: (i.e., F, Cl, Br, and I), CO: NO., NO, SO, CN, arsen 55 ate(V), ASX, AsF, and the like: Stibate(V) (antimony), SbX: SbF, and the like. Borides BX, wherein X represents halogen (i.e., BFBC1), and phosphates(V), PX; PF have, O however, been found not to work. o–– Other non-limiting examples of ionic liquidanions include 60 / substituted azolates, that is, five membered heterocyclic aro O matic rings that have nitrogenatoms in either positions 1 and 3 (imidazolates); 1, 2, and 3 (1.2.3-triazolates); or 1, 2, 4 HCN-a-calls (1,2,4-triazolate). Substitutions to the ring occurat positions that are not located in nitrogen positions (these are carbon 65 positions) and include CN (cyano-), NO (nitro-), and NH (amino) group appended to the heterocyclic azolate core. US 9,096,743 B2 25 26 V) Camim(CHsO)2PO having the formula: and xi) CamiPyX, where X is Clor Br. Py is pyrimidyl, having the formula: O

/ o f -O A Hs CHS O

N 1n GN1 CHs: 10

Of course, any of the anions in these specific examples can be combined with any other cations in these specific examples 15 to form ionic liquids suitable for use herein. In one iteration of this embodiment, 3-ethyl-1-methyl-1H-imidazol-3-ium acetate, CamimOAc, having the formulae:

OAc vii) AmimX, where A is allyl, and X is C1 or Br, having 25 is used to dissolve or disperse the Source of chitin in step (a) the formula: of the disclosed process. In another embodiment, the source of chitin is dissolved in an organic solvent. The Source of chitin can be dissolved or dispersed at a temperature of from about 0°C. to about 50° C. 30 In one iteration of this embodiment, the source of chitin can be dissolved or dispersed at a temperature of from about 15° C. to about 30° C. In one particular example, the source of chitin can be dissolved or dispersed at a temperature of about 25° C. However, the source of chitin can be dissolved or 35 dispersed at any temperature, for example, 0°C., 1C..., 2°C., viii) CamimX, where X is C1 or Br, having the formula: 3° C., 40 C., 50 C., 6° C., 70 C., 10 C. 20 C., 3° C., 40 C., 120 C., 13°C., 140 C., 15° C., 16° C. 17° C., 18°C., 19°C., 200 C., 21°C., 22° C. 230 C, 24°C. 250 C., 26°C., 27°C., 280 C., 299 C., 30° C., 31° C., 32° C., 33° C., 34° C., 35° C., 360 40 C., 37° C., 38° C., 39° C., 40° C., 41° C., 42°C., 43° C., 44° C., 45° C., 46° C., 47°C., 48° C., 49° C., and 50° C. Any organic solvent that effectively dissolves the chitin, HCN-ra-CHs. chitosan, other polysaccharides present in the source of chitin can be used for this step. What is meant by “effectively 45 dissolves” is at least about 25% by weight of the chitin present is solubilized. In one embodiment, at least about 45% of the iX) CamimOAC having the formula: chitin, chitosan, other polysaccharides present is solubilized. In another embodiment, at least about 60% of the chitin, chitosan, other polysaccharides present is solubilized. In a G OAc 50 further embodiment, at least about 75% of the chitin, chito san, other polysaccharides present is solubilized. In a still further embodiment, at least about 90% of the chitin, chito HCN/\s-CH, san, other polysaccharides present is solubilized. In one iteration of this embodiment, dimethylsulfoxide, 55 DMSO, is used as the organic solvent in step (a). Other suitable solvents include, dimethylformamide, DMF, hexam X) IC mimCHCO having the formula: ethyl-phosphoramide, HMPA, and the like. Inafurther embodiment, the source of chitin is dissolved in an admixture of an ionic liquid and a co-solvent. The source O 60 of chitin can be dissolved or dispersed at a temperature of CHCO from about 70° C. to about 130° C. In one iteration of this embodiment, the source of chitin can be dissolved or dis HCN/\s-CH, persed at a temperature of from about 90° C. to about 110°C. In one particular example, the source of chitin can be dis 65 solved or dispersed at a temperature of about 100° C. How ever, the source of chitin can be dissolved or dispersed at any temperature, for example, 70° C., 71°C., 72° C., 73°C., 74° US 9,096,743 B2 27 28 C., 750 C., 76° C., 770 C., 780 C. 790 C., 80° C. 810 C., 820 dispersing the source of chitin in Step (a). In one embodiment, C., 83°C., 840 C., 850 C., 86° C., 87° C., 88° C., 89° C.,90° the coagulant is water. In another embodiment, the coagulant C., 910 C., 920 C., 93° C., 94° C., 95° C., 96° C., 97° C., 98° is a C-C linear or branched alcohol, for example, methanol, C.,999 C., 100° C., 101° C., 102°C., 103°C., 104°C., 105° ethanol, propanol, iso-propanol, butanol, sec-butanol, iso C., 106° C., 107°C., 108°C., 109°C., 110°C., 111° C., 112 butanol, or tert-butanol. In one example, ethanol is used as the C., 113°C., 114°C., 115°C., 116°C., 117°C., 118°C., 119° coagulant. In a further embodiment, a mixture of water and a C., 120° C., 121°C., 122°C., 123° C. 124°C., 125° C., 126° C-C linear or branched alcohol can be used as a coagulant, C., 127°C., 128°C., 129° C., and 130° C. for example, water/methanol, water/ethanol, and the like. For The term “co-solvent as used herein means any suitable this embodiment, any ratio of water to solvent can be used, for solvent other than an ionic liquid, for example, DMSO. This 10 example, from about 5:95 water/solvent to 95:5 water/sol embodiment also includes multiple solvents, for example, Vent. two or more ionic liquids and one co-solvent, one ionic liquid The formulator can select the ionic liquid suitable for use in and two or more co-solvents, and two or more ionic liquids this step of the disclosed process by the one or more factors, and two or more co-solvents. For this embodiment, any ratio for example, solubility of the source of chitin and/or the of ionic liquid to co-solvent can be used, for example, from 15 naturally occurring or synthetic polymer used in the embodi about 5:95 ionic liquid/co-solvent to 95:5 ionic liquid/co ments which produce blended fibers, films, or beads. One Solvent weight/weight. In one example, the ratio of ionic method of determining the choice of ionic liquid is as follows. liquid to co-solvent is 25:1. The source of chitin is dissolved in an ionic liquid and heated In one aspect of the disclosed process, an adjunct ingredi in an oil at 100° C. for 19 hours in air. For example, practical ent can be added to the solution or dispersion obtained in step grade (1 g) or pure chitin (0.5 g) are dissolved in 10g of an (a), especially for embodiments wherein chitin is directly cast ionic liquid. After heating, the undissolved residues from the into films, fibers, or beads by the subsequent addition of a sample are diluted with a small amount of DMSO (to reduce coagulant. This aspect can be summarized as a process com the viscosity, as well as remove any dissolved substances prising: adsorbed or trapped within the solid texture), and then the a) contacting an ionic liquid with a chitinous biomass to 25 solids are separated by centrifugation, washed with DI water, form a residue and a chitin comprising solution; and then dried in an oven at 80° C. for 20 hours. b) adding an adjunct ingredient to the chitin comprising Table I below shows non-limiting examples of the solubil Solution; and ity of various grades of a suitable starting material in various c) adding a coagulant to the Solution formed in step (a) and ionic liquids at 100° C. wherein the solution is stirred for 19 casting the chitin comprising Solution into a film, a fiber, 30 hours. For pure chitin as the source of chitin, 0.5 g was or a bead. dissolved in 2 g of the corresponding ionic liquid. For prac The following are non-limiting examples of adjunct ingre tical grad and shrimps shells as the source of chitin, 1 g is dients that can be added to the solution in step (a) or to the dissolved in 10 g of the corresponding ionic liquid. process in any of the Succeeding steps. The disclosed process does not limit the time necessary to 35 TABLE I dissolve or disperse the source of chitin in step (a), nor does the presently disclosed process require that all of the source of Percent mass dissolved,96 chitin that can be solublized in step (a) must be solublized before proceeding to step (b). As such, the undissolved mate ComimCl CamimCl C2mimOAc rial separated in step (b), as disclosed herein below, can be 40 Pure Chitin 13.9 24.4 8O.O recycled back into step (a) and any unsolublized source of Practical Grade Chitin 4.2 6.8 15.2 chitin can Suffice as part of a feedstock source of chitin. Shrimp shells 9.7 1O.O 46.0 Step (b): Separating the Undissolved Material to Form a Second Solution. Surprisingly, CamimOAc dissolved over five times as much Step (b) relates to separating any non-solublized material 45 pure chitin, over three times as much practical grade chitin, from the solublized chitin, chitosan, or other polysaccharides and nearly five times as much chitin from shrimp shells as present. The non-solublized material can be inorganic matter, CamimCl. This data evidences the surprising effect the as can be the case when clam shells or shrimp skins/shells are nature of the anion has onionic liquid Solvation of chitin. This used as the Source of chitin. In one embodiment, the non data also shows that CamimCl provides better solvation solublized material is solublizable chitin, however, due to the 50 than CamimCl. It is also noted that in all cases more pure process conditions chosen by the formulator, the Solids are chitin dissolved than practical grade chitin, likely because of separated before all of the solublizable chitin is in solution. In the higher mineral content in the practical grade chitin. practice, undissolved chitin can be recycled into step (a) as Step (d): Isolating the Regenerated Chitin part of the source of chitin. Step (d) relates to isolating the regenerated chitin from the The undissolved material can be removed by any process 55 coagulant/ionic liquid phase. As disclosed herein above, the chosen by the formulator. For example, the material can be coagulant/ionic liquid phase may comprise coagulant/ionic removed by centrifugation, filtration, or by decanting the liquid, coagulant/ionic liquid co-solvent admixture, or coagu liquid phase. lant/organic Solvent. The regenerated chitin can be isolated in Step (c): Adding a Coagulant to the Second Solution to any manner chosen by the formulator, for example, the regen Regenerate the Solublized Chitin 60 erated chitin can be removed by centrifugation, filtration, or Step (c) of the disclosed process relates to adding a coagul by decanting the liquid phase. lant to the insoluble material-free solution obtained in step Step (e): Dissolving the Regenerated Chitin in an Ionic Liquid (b). The coagulant causes the Solubilized matter to be regen Step (e) relates to dissolving the regenerated chitin in an erated in Solid form. The formulator can use any coagulant ionic liquid. The regenerated chitin can be dissolved or dis suitable for the disclosed process. 65 persed at a temperature of from about 0°C. to about 50°C. In The coagulant can be water, a C-C linear or branched one iteration of this embodiment, the regenerated chitin can alcohol, or other organic solvent not suitable for dissolving or be dissolved or dispersed at a temperature of from about 15° US 9,096,743 B2 29 30 C. to about 30°C. In one particular example, the regenerated c) adding a coagulant to the second solution to form regen chitin can be dissolved or dispersed at a temperature of about erated chitin; 25° C. However, the regenerated chitin can be dissolved or d) isolating the regenerated chitin; dispersed at any temperature, for example, 0°C., 1C..., 2°C., e) dissolving the regenerated chitin in an ionic liquid to 3° C., 40 C., 50 C., 6° C., 70 C., 10 C. 20 C., 3° C., 40 C., 120 form a solution; C., 13°C., 140 C., 150 C., 16° C. 17° C., 18°C., 19°C., 20° f) dissolving one or more polymers in an ionic liquid to C., 21°C., 22° C. 230 C, 24°C. 250 C., 26°C., 27°C., 280 form a solution; C., 299 C., 30° C., 310 C., 32° C., 33° C., 34° C., 35° C., 36° g) combining the Solution from step (e) and step (f) to form C., 37° C., 38° C., 39° C., 40° C., 41° C., 42°C., 43° C., 44° a polymer admixture Solution; and 10 h) adding a coagulant to the polymer admixture solution of C., 45° C., 46° C., 47°C., 48° C., 49° C., and 50° C. step (g) and casting the polymer admixture from step (g) Any suitable ionic liquid as disclosed herein is suitable for into a film, a fiber, or a bead. use in dissolving the regenerated chitin in step (e). In one Steps (a) through (d) of this aspect can be conducted in the embodiment, the ionic liquid in step (e) is 3-ethyl-1-methyl same manner as disclosed herein above for films, fibers, and 1H-imidazol-3-ium acetate, CamimOAc, having the for 15 beads comprising chitinous material. mula: Steps (e) and (f) relate to separately dissolving regenerated chitin and a naturally occurring or synthetic polymer in an ionic liquid. These two steps can be done in any order. In one HCN-ra-cells O embodiment, however, the formulator can combine these two OAc. steps into one step by admixing the regenerated Source of chitin with a naturally occurring or synthetic polymer and dissolving the admixture in a one or more ionic liquids. When Step (f): Adding a Coagulant and Casting the Regenerated using this embodiment, step (g) of the disclosed process is Chitin into a Film, a Fiber, or a Bead. obviated. Step (f) relates to adding a coagulant to the solution formed 25 In one embodiment, the second polymeric material is a in step (e) and Subsequently casting the chitinous material naturally occurring polymer, for example, a cellulosic mate that regenerates into a film, a fiber, or a bead. The rate at which rial. As such, for this embodiment the regenerated chitin is the coagulant is added can be adjusted by the formulator to dissolved in a Suitable ionic liquid. The regenerated chitin can control the rate at which the chitinous material regenerates. be dissolved at a temperature of from about 70° C. to about 30 130°C. In one iteration of this embodiment, the regenerated The coagulant useful for step (f) can be water, a C-C, chitin can be dissolved or dispersed at a temperature of from linear or branched alcohol, or other organic solvent not suit about 90° C. to about 110°C. In one particular example, the able for dissolving or dispersing the source of chitin in step regenerated chitin can be dissolved or dispersed at a tempera (a). In one embodiment, the coagulant is water. In another ture of about 100° C. However, the regenerated chitin can be embodiment, the coagulant is a C-C linear or branched 35 dissolved or dispersed at any temperature, for example, 70° alcohol, for example, methanol, ethanol, propanol, iso-pro C. 710 C., 720 C., 73° C. 740 C., 750 C., 76° C., 770 C., 780 panol, butanol, Sec-butanol, iso-butanol, or tert-butanol. In C., 79° C., 80° C., 81° C., 82° C., 83° C., 840 C., 850 C., 86° one example, ethanol is used as the coagulant. In a further C., 87°C., 88° C., 89° C., 90° C., 910 C., 920 C., 93° C., 940 embodiment, a mixture of water and a C-C linear or C., 959 C., 96° C., 97° C., 98° C. 990 C., 100° C., 101° C., branched alcohol can be used as a coagulant, for example, 40 102°C., 103°C., 104°C., 105°C., 106° C., 107 C., 108°C., water/methanol, waterlethanol, and the like. For this embodi 109° C., 110° C., 111° C., 112°C., 113°C., 114°C., 115°C., ment, any ratio of water to solvent can be used, for example, 116° C., 117° C., 118°C., 119°C., 120° C. 121°C., 122°C., from about 5:95 water/solvent to 95:5 water/solvent. 123° C. 124°C., 125° C. 126° C. 127°C., 128°C., 129°C., The films, fibers, or beads can be formed by any process and 130°C., where any of the stated values can form an upper chosen by the formulator. The disclosed fibers can be manu 45 or lower endpoint of a range. factured by extrusion, i.e., by forcing the Solution in step (f) The cellulose can be dissolved at a temperature of from comprising regenerated chitinous material through the tiny about 70° C. to about 130° C. In one iteration of this embodi holes of a spinneret to form continuous filaments of semi ment, the cellulose can be dissolved or dispersed at a tem Solid polymer. The spinnerets used can be any chosen by the perature of from about 90° C. to about 110°C. In one par formulator that is consistent with the properties of the regen 50 ticular example, the cellulose can be dissolved or dispersed at erated chitinous mass and properties of the composition a temperature of about 100° C. However, the cellulose can be obtained in Step (f). For example, the spinneret may have from dissolved or dispersed at any temperature, for example, 70° one to several hundred holes. Because the disclosed process C. 710 C., 720 C., 73° C. 740 C., 750 C., 76° C., 770 C., 780 provides highly purified chitin, there are few, if any, impuri C., 79° C., 80° C., 81° C., 82° C., 83° C., 840 C., 850 C., 86° ties to occlude the tiny openings. Each of the four general 55 C., 87°C., 88° C., 89° C., 90° C., 910 C., 920 C., 93° C., 940 methods for spinning filament, for example, wet, dry, melt, C., 959 C., 96° C., 97° C., 98° C. 990 C., 100° C., 101° C., and gel spinning can be adapted for use with the present 102°C., 103°C., 104°C., 105°C., 106° C., 107 C., 108°C., process. 109° C., 110° C., 111° C., 112°C., 113°C., 114°C., 115°C., The following is a description of the process wherein the 116° C., 117° C., 118°C., 119°C., 120° C. 121°C., 122°C., resulting films, fibers, or beads comprise an admixture of 60 123° C. 124°C., 125° C. 126° C. 127°C., 128°C., 129°C., chitinous material and a naturally occurring or synthetic poly and 130°C., where any of the stated values can form an upper mer. In general, this aspect comprises: or lower endpoint of a range. a) dissolving or dispersing a source of chitin in an ionic In another embodiment, the second polymeric material is a liquid, a co-solvent, or a mixture of an ionic liquid and an synthetic polymer, for example, poly(2-hydroxyethyl meth organic solvent to form a first Solution; 65 acrylate) (poly-HEMA). As such, for this embodiment the b) separating the undissolved material to form a second synthetic polymer is dissolved in a Suitable ionic liquid. Solution; Depending upon the specific synthetic polymer, the tempera US 9,096,743 B2 31 32 ture at which the polymer is dissolved in an ionic liquid will vides highly purified chitin, there are few, if any, impurities to depend upon the solubility of the particular polymer or upon occlude the tiny openings. Each of the four general methods the concentration of polymer that is desired by the formulator. for spinning filament, for example, wet, dry, melt, and gel In one example, poly-HEMA is dissolved at a temperature of spinning can be adapted for use with the present process. from about 70° C. to about 130° C. In one iteration of this The following are non-limiting examples of several aspects embodiment, the poly-HEMA can be dissolved or dispersed of the disclosed process. These examples are not intended to at a temperature of from about 90° C. to about 110°C. In one circumscribe the full scope of the disclosed process, but to particular example, the poly-HEMA can be dissolved or dis provide the formulator with suitable examples that can serve persed at a temperature of about 100° C. However, the poly as the basis for executing the iterations, examples, and HEMA can be dissolved or dispersed at any temperature, for 10 embodiments embraced within the present disclosure. example, 70° C., 71°C., 72°C., 73°C., 74°C., 75° C., 76°C., The ionic liquids, i.e., CamimCl, CamimCl and 77° C., 78° C. 79° C., 80° C., 81° C., 82° C., 83° C., 840 C., CamimOAc (purity.95%) were obtained from BASFTM and 850 C., 86° C., 87° C., 88° C., 89° C., 90° C., 910 C., 920 C., dried in a vacuum oven at ~70° C. for 20 hours before use. 93°C., 94° C.,950 C., 96° C., 97° C., 98°C.,990 C., 100° C., Dimethylsulfoxide (DMSO) (>99.6%) and Poly(2-hydroxy 101° C., 102°C., 103°C., 104°C., 105°C., 106° C., 107°C., 15 ethyl methacrylate) (Poly-HEMA) were purchased from Ald 108°C., 109°C., 110°C., 111° C., 112°C., 113°C., 114°C., rich (St. Louis, Mo.) and used as received. Deionized (DI) 115° C., 116°C., 1170 C., 118°C., 119°C., 120° C. 121°C., water was obtained from a commercial deionizer (Culli 122°C., 123° C., 124°C., 125° C., 126°C., 127°C., 128°C., ganTM: Northbrook, Ill.) with specific resistivity of 17.25 129°C., and 130°C., where any of the stated values can form MS2-cm at 25° C. Pure chitin (from crab shells, Cat. No. an upper or lower endpoint of a range. C9752) and practical grade chitin (from crab shells, Cat. No. The ionic liquid used in steps (e) and (f) can be the same or C7170) were purchased from SigmaTM (St. Louis, Mo.) and different, for example, a first ionic liquid can be used to used directly without further purification. Frozen shrimp dissolve the regenerated chitin and a second ionic liquid can were obtained from Cox's Wholesale Seafood, Inc. (Tampa, be used to dissolve the naturally occurring or synthetic poly Fla.). The shrimp were thawed, carefully peeled to make sure mer. Alternatively, an admixture of ionic liquids can be used 25 no obvious shrimp meat was left, and the back and tail of the to dissolve separately both the regenerated chitin and the shells were retained. The shells were washed three times with polymer. The ratio of the two ionic liquids when mixtures are tap water and then dried in oven (Precision Econotherm used can be the same for the regenerated chitin and polymer, Laboratory oven) at 80° C. for 2 days. The dried shells were or the ratio can be different to aid in solublizing the respective ground for 1 minute using a Janke & KunkelTM mill (Ika ingredients. 30 Laborteehnik, Wilmington, N.C.) and separated using a sieve Step (g): Combining the Solution from Step (e) and Step (f) to into particle sizes of 0.125 to 0.5 mm. Crab legs were obtained Form a Polymer Admixture Solution from a local market and processed in a similar manner. Step (g) relates to combining the regenerated chitin Solu General Procedure for Determining the Amount of Regen tion with the polymer solution. As discussed herein above, erated Chitin Available From a Source of Chitin this step can be obviated if the formulator elects to combine 35 Approximately 1 g (m) of pure or practical grade chitin, or the regenerated chitin and polymer and dissolve the two in dried, groundchitinous biomass (shrimp shells or crab shells) one or more ionic liquids. Once combined, the temperature of is mixed with 10 g (m) of dried IL in a 50 mL PyrexTM glass the polymer admixture solution can be raised, lowered or held beaker. The mixture is vigorously stirred (-700 rpm) and constant such that the casting solution formed in step (h) has heated in an oil bath at 100°C. in air. One method of heating the desired properties for the product being formed, i.e., film, 40 can be accomplished by using a digital magnetic stirring hot fiber, or bead. plate, for example, an IsotempTM brand plate available from Step (h): Adding a Coagulant to the Polymer Admixture Solu Fisher Scientific. After heating for approximately 19 hours, or tion of Step (g) and Casting the Polymer Admixture from Step until the formulator is satisfied the chitin is fully dissolved, (g) into a Film, a Fiber, or a Bead the mixture is transferred to a 20 mL. glass vial, and about 10 The coagulant useful for step (h) can be water, a C-C2 45 mL of DMSO is added to the mixture to reduce the viscosity linear or branched alcohol, or other organic solvent not suit and remove any dissolved Substances adsorbed or trapped able for dissolving or dispersing the source of chitin in steps within the solid texture. The mixture is vortexed for 30 sec (e) and (f). In one embodiment, the coagulant is water. In onds then centrifuged at 100xg for 10 minutes. A Ther another embodiment, the coagulant is a C-C linear or molyneTM type 37600 mixer and a Clay AdamsTM Brand branched alcohol, for example, methanol, ethanol, propanol, 50 DYNAC centrifuge are suitable for this step. The undissolved iso-propanol, butanol, sec-butanol, iso-butanol, or tert-bu residue is then separated, washed with DI water (3x20 mL) tanol. In one example, ethanol is used as the coagulant. In a and dried in an oven at 80°C. for 20 hours. The dried residue further embodiment, a mixture of water and a C-C linear or is weighed and the dry mass (m) is used to calculate the branched alcohol can be used as a coagulant, for example, percent dissolved using equation 1 to calculate the amount of water/methanol, waterlethanol, and the like. For this embodi 55 chitin present and equation 2 to determine the amount of ment, any ratio of water to solvent can be used, for example, chitin dissolved in solution. from about 5:95 water/solvent to 95:5 water/solvent. The films, fibers, or beads can be formed by any process chosen by the formulator. The disclosed fibers can be manu Percent Dissolved= mi-mR x 100 Equation 1 factured by extrusion, i.e., by forcing the solution in step (h) 60 int comprising regenerated chitinous material and one or more in - mR Equation 2 polymers through the tiny holes of a spinneret to form con Dissolution (wt %) = x 100 tinuous filaments of semi-solid polymer. The spinnerets used in + (n - mR) can be any chosen by the formulator that is consistent with the properties of the regenerated chitinous/polymer mass and 65 where m is the initial mass of dried chitinous sample, and properties. For example, the spinneret may have from one to m, is the mass of IL used in the dissolution. The clear ionic several hundred holes. Because the disclosed process pro liquid solution is poured slowly into a beaker contains 200 US 9,096,743 B2 33 34 mL of coagulating solvent (DI water or ethanol) and a floc Example 2 culant will immediately form. Each mixture was then stirred at room temperature for 3 hours and poured into 4 separate 50 Crude chitin (practical grade) or shrimp? crab shells are mL glass vials for centrifugation. After centrifugation at pretreated by mixing 0.5 g chitinous sample with 10 g DMSO at room temperature until dissolved with occasional stirring. 100xg for 10 min, the settled flocculants are triply washed The mixture was transferred to a 20-mL glass vial and cen with DI water (100 mL), and dried at 80° C. for 20 hours in an trifuged at 100xg for 10 min. The light yellow DMSO was oven. The yield of reconstituted chitin is calculated using decanted and only the settled Solid chitinous sample was equation 3: collected. The wet pretreated chitinous sample was then mixed with 10 g freshCmimOAc and stirred at 100° C. for 10 1-2 hours until a viscous but clear dark red solution was X CRC Equation 3 Chitin Reconstitution Yield (wt %) = iRC x 100 obtained. mD X CDC Example 3 where in partial dissolution, m is the mass of dried recon 15 0.5 g Crude chitin (practical grade) or shrimp/crab shells stituted chitin and m, is the mass of dissolved chitinous was mixed with 10 g CmimOAc and 0.4 g DMSO in a material (m, m-m); and where in complete dissolution, 50-mL Pyrex(R) glass beaker. The mixture was stirred and m is the total amount of chitinous sample dissolved in IL. heated in an oil bath at 100°C. in air by a digital stirring hot C, is the chitin content (wt %) of the reconstituted chitin, plate till complete dissolution was reached (approximately C, is the chitin content (wt %) of the dissolved chitinous 1-2 hours). sample. Both C, and C were determined according to the Black and Schwartz methodology (See, M. Black, H. Example 4 Schwartz, Analyst, 1950, 75, 185-189). The Kjeldahl nitrogen A chitin/cellulose composite fiber/film/bead was made by analysis can also be used to obtain the amount of nitrogen dissolving each of pure chitin (0.3 g) and cellulose (0.39 g) in present, and hence the amount of chitin. See, for example, 25 3 g CmimOAc. The two mixtures were then mixed together Official Methods of Analysis of the Association of Official and stirred at 100° C. for 30 minutes to produce a homog Analytical Chemists, 13a ed.: Horwitz, W. Ed.; AOAC inter enous clear Solution containing chitin/cellulose (3:4, wit/wt) national: Washington, D.C., 1980, pp 14-15 and Rodde, R. wherein the total biomass concentration was 10.3 wt % in H.; Einbu, A.; Varum, K. M. Carbohydrate Polymers, 2008, 30 CamimOAc. The solution was used to produce chitin/cellu 71,388-393. lose composite fiber/film/bead by the methods described The following are non-limiting examples of preparing the herein. disclosed films, fibers, and beads by the disclosed process. Example 5 Uses: The disclosed compositions and solutions can have many 35 Cellulose (2 g) was dissolved in 10 gC.mimOAc at 100° uses. They can be fashioned into beads, fibers, films, aerosols, C. over a period of 2 hours to give a clear dissolution solution. or shaped into particles or otherforms. In a particularly useful Cleaned, pulverized shrimp shells (0.5 g) were mixed with 10 method, chitin fibers can be prepared according to the dis gCamimOAc and the mixture was stirred at 100° C. for 19 closed methods and be used in bandages, coated Sutures. hours. After heating, the Solution was centrifuged at 100xg Other medical applications include contact lenses. The dis 40 for 10 minutes, the upper layer (4.6 wt % of shrimp shell closed chitin compositions can also be impregnated with dissolved in CmimOAc, which equals to 1.25 wt % of chitin in CamimOAc was separated by decanting and mixed actives and be used for drug delivery. Still further, the dis with the produced cellulose C mimOAc solution. The mix closed compositions can be used in various cosmetic appli ture was stirred at 100°C. for 30 minutes to produce a homog cations, such as toothpaste, moisturizers, body creams, and enous clear solution contains chitin/cellulose (0.06:1, wit/wt) make-up. The disclosed compositions can be used in various 45 in the total biomass concentration of 9.6 wt % in IL. The food applications as preservatives, color stabilizers, or animal solution was used to produce a shrimp shell derived chitin/ feed additives. The disclosed compositions can be used in cellulose composite fiber/film/bead by the herein described various agricultural applications, such as a seed coating, leaf methods. coating, or for controlled agrochemical release. The disclosed compositions can be used in environmental applications. Such 50 Example 6 as water treatment, oil remediation, metalion removal, or as flocculants/coagulants. The disclosed compositions can be In the third example, pure chitin (0.2 g) and Poly(2-hy used in biotechnology, e.g., for cell immobilization and droxyethyl methacrylate (Poly-HEMA) (0.4 or 0.6 g) were recovery, protein separations, or glucose electrodes. dissolved in 2 g of CmimOAc, respectively. The two mix 55 tures were then mixed and stirred at 100° C. for 30 minto Example 1 produce a homogenous clear Solution contains chitin/Poly HEMA (2:3, wit/wt) in the total polymer concentration of Approximately 0.5 g (m) of crude chitin (pure or practical 13.0-16.7 wt % in IL. The solution was used to produce grade), or dried, ground chitinous biomass (shrimp shells or chitin/Poly-HEMA composite film by casting. Poly-HEMA crab shells) was mixed with 10 g (m) of dried CamimOAc 60 belongs to acrylics, which could be used as binders (the actual in a 50-mL Pyrex(R) glass beaker. The mixture was magneti film forming component of paint) to impart adhesion and bind cally vigorously stirred (~700 rpm) and heated in an oil bath the components together. at 100° C. in airby a digital stirring hotplate. After heating for 19 hours, the dissolved chitin was separated and reconstituted Example 7 by the method hereinabove. The dried reconstituted chitin 65 was then re-dissolved in 10 g fresh C-mimOAc and stirred One further advantage of the disclosed process is the ability at 100° C. until complete dissolution was achieved. to use microwave radiation as a source of heating the solu US 9,096,743 B2 35 36 tions. For example, approximately 0.04 g of practical grade polymers and polymer blends formed from chitin by the chitin was mixed with 2 g of dried CmimOAc in a 20 mL disclosed process and polymers comprising cellulose. pyrex vial. The mixture was heated in a domestic microwave The chitin-CmimOAc complete dissolution mixtures oven (SHARP Carousel R-209KK, Mahwah, N.J.) using 3 obtained in Examples 1-6 can be used to produce chitin fiber/ second pulses at full power (CAUTION: care must be taken to film/bead. Chitin fiber was produced by the dry jet wet spin avoid overheating the CamimOAc). Between each pulse, ning process (see, Sun, N.; Swatloski, R. P.; Maxim, M.: the vial was removed, the mixture was manually stirred by a Rahman, M.; Harland, A. G.; Hague, A.; Spear, S.K.; Daly, D. glass rod and then replaced in the microwave. Complete dis T.; Hague, A.; Harland, A. G.; Rogers, R. D. “Magnetite Solution was monitored by removing a drop of the mixture embedded cellulose fibers from ionic liquid'.J. Mater. Chem. 10 2008, 18, 283-290). and placing it in between two pieces of closely contacted Chitin film was produced by pouring the dissolution mix glass slides for observation of any undissolved residue using ture carefully on a glass plate, then casting into a film using an optical microscope (Reichert Stereo Star Zoom 580, RDS laboratory coating rod with winding wire on the rod Depew, N.Y.). After 40 pulses (total time of 2 minutes) the surface (Webster, N.Y.). The film thickness can be controlled Solution was homogeneous. This solution is used directly to 15 by the size of the winding wire on the rod, the bigger the wire form films, fibers, and beads. diameter, the thicker film can be cast. Chitin beads were made by dispersing the dissolution mix Example 8 ture into a mechanically vigorously stirring coagulate bath. DI water is used as the coagulant. The produced fiber/film/ Approximately 0.4 g of shrimp shells was mixed with 10 g bead was soaked in warm DI water for 1-2 days to remove the of dried CmimOAc in a 50 mL pyrex vial. The mixture was residue IL and then air dried. The diameters of the produce heated in a domestic microwave oven (SHARP Carousel dry fiber, film and bead were in the range of 0.12 mm to 0.2 R-209KK, Mahwah, N.J.) using 3 second pulses at full power mm, 0.05 mm to 0.2 mm and 0.25 mm to 1 mm, respectively. (CAUTION: care must be taken to avoid overheating the The disclosed process relates to forming films, fibers, and CamimOAc). Between each pulse, the vial was removed, 25 beads which comprise a mixture of chitin and one or more the mixture was manually stirred by a glass rod and then naturally occurring or synthetic polymers. In one iteration, replaced in the microwave. Complete dissolution was moni this aspect comprises tored by removing a drop of the mixture and placing it in a) dissolving or dispersing a source of chitin in an ionic between two pieces of closely contacted glass slides for liquid to form a first Solution; observation of any undissolved residue using an optical 30 b) adding one or more naturally occurring or synthetic microscope (Reichert Stereo Star Zoom 580, Depew, N.Y.). polymers to form a polymer admixture; and After 40 pulses (total time of 3 minutes) the solution was c) adding a coagulant to the solution of step (b) and casting homogeneous. This solution is used directly to form films, the chitin/one or more naturally occurring or synthetic fibers, and beads. polymers admixture into a film, a fiber, or a bead. Determination of the Amount of Biomass Dissolved in an 35 A further iteration of this aspect comprises: Ionic Liquid a) dissolving or dispersing a source of chitin in an ionic Samples of chitin obtained from various sources, interalia, liquid to form a first Solution; shrimp shells, practical grade chitin, were added in portions b) adding one or more naturally occurring or synthetic of 0.01 gata time to 10g on an ionic liquid in a 50 mL PyrexR) polymers to form a polymer admixture; glass beaker with a magnetic stir bar, causing a stepwise 40 c) separating any undissolved material in step (b) to form a increase of 0.1 wt % of chitin concentration in the ionic liquid second solution; solution. For dissolution of pure chitin, 0.1 wt % of pure chitin d) adding a coagulant to the second Solution to form a was mixed with 2 g of dried ionic liquid in a 20 mL. glass vial regenerated chitin/one or more naturally occurring or with a magnetic stir bar. The mixture was vigorously stirred synthetic polymers composition; (-700 rpm) and heated in an oil bath at 100° C. in air using a 45 e) dissolving the composition from step (d) in an ionic digital stirring hotplate (IsotempTM, Fisher Scientific, Dubu liquid to form a solution; and que, Iowa). Complete dissolution was monitored by using an f) adding a coagulant to the Solution of step (e) and casting optical microscope as explained above. After each portion the chitin/one or more naturally occurring or synthetic was completely dissolved, another portion was added to the polymers admixture into a film, a fiber, or a bead. mixture until complete dissolution could not beachieved. The 50 Anotheriteration of this aspect comprises maximum amount of biomass dissolved in IL Solution is a) dissolving or dispersing a source of chitin in an ionic reported in wt % and is calculated using eq. 3: liquid and a co-solvent to form a first Solution; b) adding one or more naturally occurring or synthetic polymers to form a polymer admixture; and Maximium amount of biomass dissolved in IL (wt %) = Equation 4 55 c) adding a coagulant to the solution of step (b) and casting the chitin/one or more naturally occurring or synthetic iD x 100 polymers admixture into a film, a fiber, or a bead. iii. -- inD A yet further iteration of this aspect comprises: a) dissolving or dispersing a source of chitin in an ionic where m is the mass of dissolved chitinous material and m. 60 liquid and a co-solvent to form a first Solution; is the mass of ionic liquic used in the dissolution. b) adding one or more naturally occurring or synthetic polymers to form a polymer admixture; Example 9 Comparative c) adding one or more adjunct ingredients to the polymer admixture; and A polymer comprising 11.5 weight% of cellulose is made 65 d) adding a coagulant to the solution of step (b) and casting by the process disclosed in Example 1. The resulting fibers, the chitin/one or more naturally occurring or synthetic films and beads are used to illustrate the difference between polymers admixture into a film, a fiber, or a bead. US 9,096,743 B2 37 38 The disclosed process can be used to make blended poly The PXRD diffractograms were measured using a Rigaku mers that comprise crosslinking agents or that do not com D/MAX-2BX horizontal X-ray diffractometer (Arlington prise a crosslinking agent. Examples of chitin blends com Heights, Ill.) in the scanning range of 5-40° with scanning prising a crosslinker include chitin/1,6-diisocyanatohexane, speed of 1°/min and step size of 0.1°. The samples were chitin/gluteraldehyde, chitin/glyoxal, chitin/starch?guteral stabilized on a silicon wafer Substrate using vacuum grease dehyde, and chitin/collagen?gluteraldehyde. Examples of and the silicon wafer was mounted on an aluminum sample chitin blends without a crosslinker includes chitin/starch/ holder with vacuum suction. The crystallinity index (Cri) was chitin/gelatin, chitin, collagen, chitin/poly(vinyl alcohol), determined according to the method proposed for chitin and chitin/poly(caprolactone) and chitin/polyethylene glycol. chitosan using eq. 5: Characterization of the Polymers Formed by the Disclosed 10 Crio-100x(I lo-I)/I11o (5) Process. where I is the maximum intensity of the (110) lattice dif The chitin used as a starting material and the regenerated fraction (in our case, it is located at 19.1°), and I is the chitin was characterized by elemental analysis, Energy Dis intensity of amorphous diffraction at 20=16. persive X-ray Spectroscopy (EDS), infrared spectroscopy 15 The chitin/IL solutions were characterized by CNMR at (IR), powder X-ray diffraction (PXRD), scanning electron 70° C. using a Bruker Avance 500 NMR spectrometer (Bil microscopy (SEM), and tensile strength testing. lerica, Mass.) with a 5 mm BBO probe. A total of 20,000 Elemental analyses (CHNO) of the source of chitin or of scans were collected at 125.76 MHz and spectra were pro reconstituted chitin were obtained from Galbraith Laborato cessed with a 10 Hz line-broadening factor. To prepare a ries, Inc (Knoxyille, Tenn.). EDS spectra were recorded on a chitinous solution NMR sample, chitinous material was dis Philips XL30 SEM-EDS (Eindhoven, Netherlands) where the solved in CamimOAc and then mixed with DMSO-d to SEM was equipped with elemental analysis capabilities. The final concentrations of 5 wt % chitinous material, 80 wt % IL, SEM images were taken with a Philips XL30 SEM instru and 15 wt % DMSO. ment. Samples were sputter-coated with gold to improve the The choice of coagulant by the formulator can be based on conductivity. IR spectroscopy was carried out on a Perki 25 either the properties of the regenerated chitin, the solubility of nElmer Spectrum 100 FT-IR spectrometer (Bucks, UK) the Source of chitin in a particular ionic liquid, the amount of equipped with an attenuated total reflectance (ATR) cell by chitin obtained when regenerating the chitin, or on the avail accumulation of 4 scans, with a resolution of 2 cm. The ability, cost, or other factors related to a particular ionic PXRD diffractograms were measured using a Rigaku liquid. For example, the recovery of chitin dissolved in D/MAX-2BX horizontal X-ray diffractometer (Arlington 30 CamimOAC using three different coagulants is depicted in Heights, Ill.) in the Scanning range of 5-40° with scanning Table II herein below. For pure chitin, 0.4 g was dissolved in speed of 1°/min and step size of 0.1°. The samples were 2g CmimOAC at 100° C. for 2 hour and complete disso stabilized on silicon wafer Substrate using vacuum grease and lution was achieved. For shrimp shells, 1 g was mixed with 10 the silicon wafer mounted on an aluminum sample holder g CamimOAc and the mixture heated at 100° C. for 19 with vacuum Suction. The tensile testing was applied on chitin 35 hours, which yielded partial dissolution. fibers using a MTS QTest/25 tensile testing machine attached As shown, for pure chitin from 77.5% to 92.5% wt %/wt % with a specially designed pneumatic grip Suitable for thin and of chitin is obtained from the original mass as regenerated flexible fiber testing. A gauge length of 72 mm was employed chitin. For the case wherein the source of chitin is shrimp for the measurements. A load cell of 22.4 Newton capacity shells, from 30% to 35% wt %fwt % is obtained from the was used for load measurement. The cross head speed was 40 original mass as regenerated chitin. Table II herein below maintained at 1.27 mm/min and the test data in terms of stress summarizes the effect of different coagulants on the effi and strain were obtained using a data acquisition system. For ciency of chitin regeneration. sample preparation, 25.4 cm long fibers were cut and used for each testing. At least three samples were tested in each cat TABLE II egory. For each fiber sample, the diameter was measured by a caliper at ten different position of the fiber and the average 45 Coagulant used was taken and used. The thermostability of the ILS was monitored by thermo DIWater Ethanol Methanol gravimetric analysis (TGA). The chitin/IL or IL solutions Pure chitin Mass dissolved, g O.40 O4O O.40 were characterized by C NMR. The chitin or regenerated Reconstituted chitin, (g) 0.37 O.31 O.35 chitin was characterized by elemental analysis, energy dis 50 Shrimp Mass dissolved, (g) O46 O43 O.45 persive X-ray spectroscopy (EDS), infrared (IR) spectros shells Reconstituted chitin, (g) O.08 O.12 O.14 copy, powder X-ray diffraction (PXRD), TGA, differential scanning calorimetry (DSC), and scanning electron micros Table III provides a summary of the elemental analysis of copy (SEM). the regenerated chitin depicted in Table II. IR spectroscopy was carried out using a PerkinElmer Spec 55 trum 100 FT-IR spectrometer (Bucks, UK) equipped with an TABLE III attenuated total reflectance (ATR) cell by accumulation of 4 Theoretical value for chitin C, 96 H, 9% N,9% O, 9% scans, with a resolution of 2 cm. The degree of acetylation Entry (C8H13NOs), 47.29 6.40 6.90 39.41 (DA) of chitinous samples was calculated using eq. 4: 60 1 Pure chitin Result 42.47 6.89 6.16 42.81 % error 10.19 7.66 10.72 8.63 Alo/A1120-0.3822+0.03133XDA (4) 2 Reconstituted Result 46.52 6.64 6.54 38.82 where A is the area under the peak at 1320 cm, and pure chitin by % error 1.63 3.75 S.22 1...SO HO Alao is the area under the peak at 1420 cm. The baselines 3 Reconstituted Result 45.66 6.51 6.86 40.58 were chosen according to the literature, See, J. Brugnerotto et 65 pure chitin by % error 3.45 1.72 O.S8 2.97 al., Polymer, 2001, 42,3569-3580) and the peak areas were EtOH calculated by the IR software. US 9,096,743 B2 39 40 TABLE III-continued TABLEV-continued Theoretical value for chitin C, 9.6 H, 9% N,9% O, 9% Conc. Entry (C8H13NOs), 47.29 6.40 6.90 39.41 of total Ultimate biomass StreSS Failure 4 Reconstituted Resu 44.95 6.40 6.69 40.92 (wt.%) (MPa) strain (%) pure chitin by % error 4.95 O.OO 3.04 3.83 MeOH DMSO co-solvent 42 1215 - 19.6 5 Practical grade Resu 44.25 6.89 5.89 39.28 PG chitin fiber 3.4 80.1 - 9.5 chitin % error 6.43 7.66 14.64 O.33 direct extraction 6 Reconstituted Resu 45.51 6.50 6.17 39.47 Shrimp shells fiber 3.8 133.8 - 12.9 practical grade 96 error 3.76 1.56 10.58 O.15 10 direct extraction 3.2 1961 - 15.3 chitin by H2O Pure chiting 11.5e 240.8 - 11.5 7 Reconstituted Resu 44.18 6.72 6.64 41.61 cellulose fiber 11.56 224.53.1 chitin from % error 6.58 S.OO 3.77 5.58 Shrimp shell/ 10.0° 1733 - 24.8 shrimp shells by cellulose fiber HO 8 Reconstituted Resu 34:47 S.48 5.46 35.00 15 The solution weight does not include the weight of DMSO, chitin from % error 27.11 14.38 20.87 1119 The solution weight includes weight of DMSO (4.6 wt %). shrimp shells by Pure chitin cellulose = 1:2 (wtwt). EtOH Pue chitin/cellulose = 3:4 (wt?wt) 9 Reconstituted Resu 39.65 5.77 8.73 28.07 Shrimp shells, cellulose = 1:4.3 (wt wt) chitin from % error 16.16 9.84 26.52 28.77 shrimp shells by These results show that the produced dry chitin fiber from MeOH either Example 2 or Example 3 yields a tensile strength of 107.7-289.9 MPa, breaking elongation of 5.2-9.1%, with Young's modulus of 4.3-11.3 GPa, suggesting this chitin fiber FIG. 4 depicts the CNMR spectra of reconstituted pure is stronger than a cellulose fiber (85.5 MPa) produced by the chitin dissolved in CamimOAc. NMR samples were pre disclosed process, or comparable with the pure cellulose fiber pared by first dissolving reconstituted pure chitin in Camim 25 prepared by the same cellulose concentration and same OAc at 100° C. for 1 hour resulting in a clear solution. method in literature (129 MPa) (See Sukhanova T. E. et al. DMSO-d6 was then added to make a 5% chitin solution for Vysokomol. Soedin. Ser. B31 (1989) 381; Chem. Abstr. 111 analysis. (20): 175985n). However, our chitin fibers are weaker than The chitin signals at 101.1 (C-1), 80.0 (C-4), 75.2 (C-5), other chitin fibers prepared by DMAc/LiCl (390 MPa with 72.2 (C-3), 63.0 (C-6), and 59.2 (C-2) ppm, are all well 30 3% elongation and 1 GPa initial modulus), or by TCA system resolved. The two signals at 75.2 and 72.2 ppm as well (e.g. 706 MPa with a 13% breaking elongation) as reported in resolved peaks, indicate the existence of C-chitin and are the literature. Our shrimp shell/cellulose composite fiber (159 attributed to the different configurations of C3 and C5 result MPa) is stronger than the cellulose fiber (85.5 or 129 MPa). ing from hydrogen bonds. The signals at 169.1 and 21.9 ppm Fiber production can be optimized to reach the target prop are from carbonyl and methyl carbons of acetate groups in 35 erty. acetylamine, respectively. All chemical shifts are comparable In addition, when DMSO (5 wt %) is added to the biomass/ to the values reported in the literature, in which either con ionic liquid solution, although the amount of chitin is low, for centrated HCl or NaOH with deuterated water were used as example 2.8 wt %, fibers can be pulled from this solution solvents, or when solid state 'CNMR was applied. All other directly. At a concentration of from about 0.68 wt % to about large signals can be attributed to the CamimOAc and 40 0.94 wt %, (based on the fact that shrimp shell comprise DMSO-d6. approximately 27.2 wt % of chitin), this process provides a Tables IV and V summarize the tensile strength of various method of directly providing fibers from a source of chitin polymers prepared by the disclosed process. having a low amount of chitin. TABLE IV

Conc. of Young's spinning Ultimate Stress Failure Modulus Example No. solution Composition (MPa) Strain (%) (GPa.) 2 7.14 wt % 100% chitin 107.7 17.1 5.2 0.8 43 O.7 3 3.67 wt % 100% chitin 289.931.5 9.1 2.9 43 O.7 3 4.2 wt % 100% chitin 144.1 + 41.6 7.5 - 1.2 8.23.2 10.3 wt % Chitin:Cellulose = 159.031.8 5.4 1.8 6.6 1.2 total biomass 1:15.8, (wt wt) Comparative 11.5 wt % 100% cellulose 85.5 - 14.O 8.0 - 1.8 6.0 - 1.5 Example 7 of cellulose

TABLEV FIG. 1 depicts the IR spectra of polymer films prepared by Conc. the disclosed process. Spectrum 1 A depicts the IR spectrum of total Ultimate Young's 60 of a polymer film comprising chitin derived from shrimp biomass StreSS Failure modulus shells according to Example 1. Spectrum 1B depicts the IR (wt.%) (MPa) strain (%) (GPa.) spectrum of a polymer film comprising practical grade chitin PG chitin fiber 3.9 260.1 - 29.2 1.90.0 15.3 1.7 according to Example 2. Spectrum 1C depicts the IR spec DMSO pre- 4.8 299.498.2 3.6 O.O 9.17.1 trum of a polymer film comprising practical grade chitin treatinent 7.1a 107.7 17.1 5.2 0.8 43 O.7 65 according to Example 3. The IR spectra of FIGS. 1A, 1B, and PG chitin fiber 3.7 271.8 + 3.8 10.4 + 2.6 10.3 22 1C have almost identical IR plots. The IR analysis in FIG. 1 confirms that the only component in the fibers is chitin, for US 9,096,743 B2 41 42 example, for the film produced by Example 2, no peaks Table VIII is a comparison of the thermostability of appeared at 1436 and 1406 cm indicating no residue DMSO CamimOAc under various conditions. left in the film. FIG. 2 depicts the comparison of the IR spectra of com TABLE VIII posite polymer fibers with fibers made from a single polymer. Spectrum 2A depicts a polymer comprising chitin/cellulose Mass lost in (3:4 wit/wt). Spectrum 2B depicts a polymer comprising Mass lost in 15h 19h Mass lost in 24h chitin derived from shrimp shell/cellulose (1:15.8 wit/wt). a. 100° C. in N- 1.2% 1.3% 1.4% Spectrum 2C. depicts a polymer comprising chitin. Spectrum b. 100°C. in air 1.2% 1.4% 1.7% 2D depicts a polymer comprising cellulose. The IR spectra in 10 c. 110° C. in N- 2.8% 3.1% 3.5% FIG. 2 show the existence of peaks of 1654 and 1621 cm', d. 110°C. in air 12.2% 14.3% 16.8% which are peaks due to C=O stretching mode of singly e. 130°C. in air 21.2% 26.5% 32.8% hydrogen-bonded to NH and doubly hydrogen-bonded to both NH and C(6)OH, respectively, in the composite chitin/ cellulose and shrimp shell/cellulose films confirming the 15 Table IX is a comparison of shrimp shells dissolution in air existence of chitin in the composite films. or under nitrogen, and reconstitution of chitin from the solu FIG.3 depicts the comparison of IR spectra obtained from tion by using DI water as coagulant. fibers comprising pure Poly-HEMA (3B), pure chitin (3C) and a blended polymer comprising 2:1 Poly-HEMA/chitin TABLE IX (3A). Both poly-HEMA and pure chitin peaks were found in the blend (3A), which confirms the blend structure is formed. Dissolution in air Dissolution under N Peaks at 1714 and 2942 cm are stretching of C=O, and Amount of chitin dissolved in 0.46g 0.43g alkyl from poly-HEMA. Peak at 3257, 3099, 1651, 1622, 10g CamimOAc Percent dissolved 4.6% 4.3% 1550cm are stretching of N H (asymmetric), N H (sym Reconstituted chitin from 0.08 g 0.08 g metric), amide I (singly H-bond), amide I (doubly H-bond), 25 shrimp shells and amide II from chitin, respectively. Chitin reconstitution yield 52.1% 55.59% Table VI provides a comparison of the EDS analysis of Experimental details: 1 g of shrimp shells was mixed with 10g ComimOAc, the reaction reconstituted chitin obtained by various methods versus con happened at 100°C, for 19h under the target environment, trol. Calculated by eq 1. Calculated by eq. 2, where chitin content for shrimp shells and reconstituted chitin from 30 shrimp shells are 27.2 wt % and 81.1%, individually, based on our result shown in Table VII. TABLE VI Ele Table X is a comparison of the chemical composition ment Weight% Atomic % Element Weight% Atomic 96 observed in the EDS analysis for chitinous samples and the Reconstituted practical grade 35 chitin reconstituted from them. Practical grade chitin chitin by the method of Example 2 TABLE X CK 31.01 - 1.06 36.56 - 1.17 CK 47.793.30 SS.243.37 NK 26.63 - 0.79 26.93 - 0.87 NK 4.98 - 1.02 4.94 - 1.05 Ele OK 40.34 - 0.23 35.71 - 0.29 OK 44.OS 2.35 38.25 2.35 ment Weight % Atomic % Element Weight% Atomic 96 SiK 0.43 - 0.01 0.22 + 0.01 Si K 3.19 O.06 1.58 0.02 40 Pure chitin Reconstituted pure chitin CK 0.75- 0.04 0.30 - 0.01 Total 1OO 100 CaK O.85 OO6 O3O O.O2 CK 30.06 1.06 35.18 1.12 CK 29.72 O.47 34.78 O.51 NK 27.09: O.08. 27.18 O.O1 NK 27.80 0.42 27.90 O.45 Total 1OO.O1 1OOOO OK 42.86 - 1.12 37.65 1.12 OK 42.49 O.04 37.33 OO6 Reconstituted practical grade chitin Reconstituted practical grade chitin 45 by using DMSO as co-solvent using microwave radiation heating Total 100.00 100.00 Total 1OOOO 100.00 Practical grade chitin Reconstituted practical grade chitin CK 48.01 - O.15 5555 - 0.13 CK 31.08 - 0.59 36.36 - 0.65 NK 5.21 OSO 515 O.47 NK 26.13 - 0.76 26.21 - 0.78 CK 31.01 - 1.06 36.56 - 1.17 CK 31.08 0.59 36.36 O.65 OK 43.77 O.S7 37.76 O.15 OK 42.36 O.30 37.21 O.21 NK 26.63 - 0.79 26.93 - 0.87 NK 26.13 - 0.76 26.21 O.78 SiK 3.01 - 0.07 1.54 - 0.04 Si K O44 - 0.2O O.22 O.10 OK 40.34 - 0.23 35.71 - 0.29 OK 42.36 O.30 37.21 O.21 50 SiK 0.43 - 0.01 0.22 + 0.01 Si K O44- 0.2O O.22O10 Total 100.00 100.00 Total 1OOOO 1OOOO CK 0.75- 0.04 0.30 - 0.01 Total 1OOOO 100.00 Table VII shows the compositional analysis (wt %) of CaK O.85 OO6 O3O O.O2 chitin and crustacean shells. Total 1OO.O1 1OOOO 55 Shrimp shells Reconstituted shrimp shell chitin

TABLE VII CK 22.SS O.79 28.95 0.74 CK 30.22 O.15 35.54 - 0.13 NK 27.31 O.54 30.06 0.31 NK 25.14 OSO 25.35 - O.47 Practical Shrimp Crustacean OK 37.20 O2S 35.85 - O.S7 OK 43.82 0.57 38.200.15 Pure chitin grade chitin shells shells SiK 0.23 - 0.04 0.13 - 0.02 Si K O.83 0.07 O42 (0.04 Moisture content 5.5 5.3 8.7 NA 60 Cal K. 12.19 0.98 4.69 0.42 Total 1OOOO 99.50 Ash content O.3 2.2 34.5 30-50 Chitin content 81.8 78.9 27.2 13-41 Mg K 0.53 + 0.06 0.33 + 0.04 Chitin content of the 87.1 84.7 81.1 NA reconstituted chitin Total 99.99 1OOOO from dissolution of each chitin source 65 Table XI is from microwave heating on practical grade chitin dissolution in CamimOAc. US 9,096,743 B2 43 TABLE XI TABLE XIV-continued Heating for 2 min Heating for 4 min DA,% CrI, 9% Amount dissolved, g O.04 O.04 Reconstituted practical grade chitin 80.61 64.O Percent dissolved, 96 1OO 1OO Reconstituted shrimp shells 83.29 70.9 Amount regenerated, g O.O264 O.O214 Chitin reconstitution yield, 9% 70.85 57.43 TABLE XV Table XII is a comparison of complete dissolution of chiti 10 Chitin re- Prac- Re- Re nous samples in CamimOAc. constituted tical constituted constituted Pure from pure grade practical shrimp shell TABLE XII chitin chitin chitin grade chitin chitin

Time to l"Tonse, 223.63 276.52 2.78.97 296.67 298.66 Maximum solubility reach Chitin 15 (° C.) chitinous sample complete reconstitution l"T5% onse, 181.33 248.19 225.69 237.33 237.44 dissolved, mass % dissolution yield, % (° C.) 2" Tense, 450.46 457.14 397.65 462.90 479.36 Pure chitin 17.5 4h 98.3 (° C.) Practical grade chitin' O.8 15 14.1 Char 6.66 5.89 2.23 O.81 1.39 Shrimp shells' 1.7 29 d 25.4 (wt %) Pure chitin was dissolved in 2 g IL; Chitin samples were dissolved in 10g IL, TABLE XVI Table XIII is a percent chitin dissolved in CamimOAc at 25 Re- Re 100° C. for 19 hand reconstitution yield of chitin coagulated Re- Practical constituted constituted with water Pure constituted grade practical shrimp shell chitin pure chitin chitin grade chitin chitin TABLE XIII T (C.) 177.94 133.97 175.35 129.98 195.51 Percent Dissolved, Chitin reconstitution yield, 30 % wt % Table XVII shows the relative viscosities of chitin in Pure chitin 8O.O 98.1 CamimOAc at 35° C. Practical grade chitin' 15.2 64.8 Shrimp shells' 46.0 (10.2) 52.1 (60.8) TABLE XVII 0.5g pure chitin was mixed with 2 g IL; 35 b1 g chitin sample was mixed with 10g IL; Conc. of chitin in Total heating time Relative Result of a study conducted at room temperature for 4 months with occasional stirring, Samples CamimOAc (%) (sec) Viscosity (n) ComimOAc O NA 1 Table XIV shows the degree of acetylation (DA) and crys Pure chitin O.21 120 1.13 PG-chitin O.21 120 2.02 tallinity of chitinous samples. Table XV shows the thermo 40 Shrimp shells O.21 120 1.55 stability of chitins. Table XVI shows the melting temperature Rec. pure O.21 60 1.10 of chitins. chitin Rec. PG-chitin O.21 60 1.28 Rec. shrimp O.21 60 1.43 TABLE XIV shell chitin 45 DA,% CrI, 9% Reconstitued chitin samples are easier to be completely dissolved than unprocessed chitin, thus less heating time was used. Pure chitin 91.35 70.7 (n) = flow time of the solution flow time of the solvent (ComimOAc). Reconstituted pure chitin 87.99 70.9 Practical grade chitin 80.43 68.2 Table XVIII contains data related to dissolution and recov ery of chitin from IL solution and resulting fiber properties. TABLE XVIII

Avail. Conc. Chitin Relative To pull Fiber Ultimate Failure Young's Recovered Viscosity fiber thickness stress strain modulus Samples (%) (m) (wt.%) (mm) (MPa) (%) (GPa.)

Pure chitin 40.2 1.13 — PG-chitin 87.4 2.02 3.4 0.13(3) 80(9) 5.0(9) 4.7(8) Shrimp shells 94.0 1.55 3.8 0.06(1) 133(13) 3.3(3) 8.6(2) Rec. pure chitin' 1.10 & Rec. PG-chitin? 1.28 4.0 0.09(1) 132(10) 6.9(4) 5.3(5) Rec. shrimp 1.43 2.1 0.07(1) 237 (26) 13(4) 10(1) shells US 9,096,743 B2 46 TABLE XVIII-continued

Avail. Conc. Chitin Relative To pull Fiber Ultimate Failure Young's Recovered Viscosity fiber thickness stress strain modulus Samples (%) (m) (wt.%) (mm) (MPa) (%) (GPa) Cellulose MCC 11.5 0.15(3) 129(17) 24(3) Cellulose pulp" 4.3 0.07(1) 217(17) 13(O) See ESIeq 2. "noi = tito (t; Flow time of solution, to flow time of DL (35°C.; same concentrations). Avg. five samples. Avg. three fibers. Fibers could not be formed. 'Second dissolution. 3Microcrystalline cellulose of DP = 270.18 Kraft pulp of degree of polymerization (DP) = 1056.

Adjunct Ingredients LOTANTM, COZAARTM, and HYZAARTM, and fosinopril, The following are non-limiting examples of adjunct ingre sold under the trade name MONOPRILTM, Atorvastatin, sold dient suitable for use in the disclosed process. under the trade name LIPITORTM, and pravastatin, sold under When pharmaceutical activity is a desired property of the the trade name PRAVACHOLTM, are used to treat cholesterol disclosed fibers, films, or beads, one or more of the adjunct and montelukast, which is used to treat asthma and is sold ingredients can be a pharmaceutical active. It is not intended under the trade name SINGULAIRTM. that the category be limited by the specific examples. Those of The following are further examples of pharmaceutical ordinary skill in the art will be able to readily identify those actives that are suitable for use informing the disclosed films, pharmaceutical actives that can be used in the disclosed meth 25 fibers, or beads. Prostaglandin E. Prostaglandin F2, Sulpro ods and compositions. For example, one can identify a com stone, Cetapril, BenZaepril, Captopril, Methylhexaneamine, pound with a given property or activity by consulting various Synephrine, Isoetharine, Methoxyphenamine, Tamsulosin, sources, such as the Merck Index (13" Edition, Wiley, 2001), Tolazoline, Bufuralol, Nadoxolol, Acetylsalicylic acid, The United States Pharmacopeia-National Formulary (USP 30 ammonium salicylate. Buthalital Sodium, Thiopental NF), and the FDA's Orange book, which are each incorpo Sodium, and Isobutyl p-Aminobenzoate. rated by reference herein at least for their teachings of phar Further examples of pharmaceutical actives that can be maceutical actives. Once a compound with a desired property used as adjunct ingredients include the following. Adrener is identified, the skilled artisan can determine the manner in gic: adrenalone, amidephrine mesylate, apraclonidine hydro which the compound can be combined with the chitin, the 35 chloride, brimonidine tartrate, dapiprazole hydrochloride, regenerated chitin, the admixture of chitin and one or more deterenol hydrochloride, diplivefrin, dopamine hydrochlo naturally occurring or synthetic polymers. Such determina ride, ephedrine Sulfate, epinephrine, epinephrine bitartrate, tions can be performed based on the compound's structure, epinephryl borate, esproquin hydrochloride, etafedrine which can readily be determined by consulting the sources hydrochloride, hydroxyamphetamine hydrobromide, mentioned herein or experimentally. Knowing a compounds 40 levonordefrin, mephentermine Sulfate, metaraminol bitar structure can readily reveal at what step in the process the trate, metizoline hydrochloride, naphazoline hydrochloride, adjunct ingredient can be added. Those of ordinary skill in the norepinephrine bitartrate, oxidopamine, oxymetazoline art will recognize numerous other compounds that fall within hydrochloride, phenylephrine hydrochloride, phenylpro the categories and that are useful according to the disclosed panolamine hydrochloride, phenylpropanolamine polistirex, films, fibers, beads, compositions and processes. 45 prenalterol hydrochloride, propylhexedrine, pseudoephe Some specific examples of pharmaceutical actives that can drine hydrochloride, tetrahydrozoline hydrochloride, trama be used in the disclosed process or as a component of a Zoline hydrochloride, Xylometazoline hydrochloride. resulting film, fiber, or bead include, but are not limited to, Adrenocortical Steroid: ciprocinonide, desoxycorticoster aspirin, LIBRIUMTM, isoniazid, penicillin, PRONTOSILTM, one acetate, desoxycorticosterone pivalate, dexamethasone cisplatin, 6-mercaptopurine, RITUXANTM, TAXOLTM, phe 50 acetate, fludrocortisone acetate, flumoxonide, hydrocorti nobarbital, PROZACTM, ALLEGRATM, VIOXXTM, quinine, Sone hemisuccinate, methylprednisolone hemisuccinate, ivermectin, L-dopa, THORAZINETM, salvarsan, TAGA naflocort, procinonide, timobesone acetate, tipredane. METTM, AZT, crixivan, salbutamol, digoxin, fluride, LOV Adrenocortical Suppressant: aminoglutethimide, trilos ASTATINTM, erythropoietin, hydrocortisone, insulin, oral tane. contraceptives, oxytocin, PREMARINTM, RU-486, thyrox 55 Alcohol deterrent: disulfuram. ine, thalidomide, cyclosporine, fentanyl, methadone, mor Aldosterone antagonist: canrenoate potassium, canrenone, phine, botox, vitamins, FOSAMAXTM, RITALINTM, and dicirenone, mexrenoate potassium, prorenoate potassium, VIAGRATM, including ionic derivatives thereof. spironolactone. Other examples of pharmaceutical actives include, but are Amino acid: alanine, aspartic acid, cysteine hydrochloride, not limited to, pantoprazole, sold under the trade names PRO 60 cystine, histidine, isoleucine, leucine, lysine, lysine acetate, TONIXTM and PANTOZOLTM, and rabeprazole, sold under lysine hydrochloride, methionine, phenylalanine, proline, the trade names ACIPHEXTM and PARIETTM, which are used serine, threonine, tryptophan, tyrosine, Valine. to treat gastrointestinal disorders. Risedronate, sold under the Ammonia detoxicant: arginine: arginine glutamate, argin trade name ACTONELTM, and alendronate, sold under the ine hydrochloride. trade name FOSAMAXTM, are used to treat osteoporosis and 65 Anabolic: bolandiol dipropionate, bolasterone, boldenone are further examples of suitable adjunct ingredients. Further undecylenate, bolenol, bolnantalate, ethylestrenol, meth examples include losartan, sold under the trade names NU enolone acetate, methenolone enanthate, mibolerone, nan US 9,096,743 B2 47 48 drolone cyclotate, norbolethone, pizotyline, quinbolone, chloride, cocaine, cocaine hydrochloride, cyclopropane, Stenbolone acetate, tibolone, Zeranol. desflurane, dexivacaine, diamocaine cyclamate, dibucaine, Analeptic: modafinil. dibucaine hydrochloride, dyclonine hydrochloride, enflu Analgesic: acetaminophen, alfentanil hydrochloride, ami rane, ether, ethyl chloride, etidocaine, etoxadrol hydrochlo nobenzoate potassium, aminobenzoate sodium, anidoxime, ride, euprocin hydrochloride, fluoroxene, halothane, isob anileridine, anileridine hydrochloride, anilopam hydrochlo utamben, isoflurane, ketamine hydrochloride, levoxadrol ride, anirolac, antipyrine, aspirin, benoxaprofen, benzy hydrochloride, lidocaine, lidocaine hydrochloride, mepiv damine hydrochloride, bici fadine hydrochloride, brifentanil acaine hydrochloride, methohexital sodium, methoxyflurane, hydrochloride, bromadoline maleate, bromfenac sodium, midazolam hydrochloride, midazolam maleate, minaxolone, buprenorphine hydrochloride, butacetin, butixirate, butor 10 phanol, butorphanol tartrate, carbamazepine, carbaspirin cal nitrous oxide, norflurane, octodrine, oxethazaine, phencycli cium, carbiphene hydrochloride, carfentanil citrate, ciprefa dine hydrochloride, pramoxine hydrochloride, prilocalne dol Succinate, ciramadol, ciramadol hydrochloride, hydrochloride, procaine hydrochloride, propanidid, propara clonixeril, clonixin, codeine, codeine phosphate, codeine Sul caine hydrochloride, propofol, propoxycaine hydrochloride, fate, conorphone hydrochloride, cyclazocine, dexoxadrol 15 pyrrocaine, risocaine, rodocaine, roflurane, Salicyl alcohol, hydrochloride, dexpemedolac, dezocine, diflunisal, dihydro sevoflurane, teflurane, tetracaine, tetracaine hydrochloride, codeine bitartrate, dimefadane, dipyrone, doXpicomine thiamylal, thiamylal Sodium, thiopental sodium, tiletamine hydrochloride, drinidene, enadoline hydrochloride, epirizole, hydrochloride, Zolamine hydrochloride. ergotamine tartrate, ethoxazene hydrochloride, etofenamate, Anorectic compounds including dexfenfluramine. eugenol, fenoprofen, fenoprofen calcium, fentanyl citrate, Anorexic: a minorex, amphecloral, chlorphentermine floctafenine, flufenisal, fluniXin, flunixin meglumine, flupir hydrochloride, clominorex, clortermine hydrochloride, tine maleate, fluproduaZone, fluradoline hydrochloride, flur diethylpropion hydrochloride, fenfluramine hydrochloride, biprofen, hydromorphone hydrochloride, ibufenac, indopro fenisorex, fluidorex, fluminorex, levamfetamine Succinate, fen, ketazocine, ketorfanol, ketorolac tromethamine, letimide mazindol, mefenorex hydrochloride, phenmetrazine hydro hydrochloride, levomethadyl acetate, levomethadyl acetate 25 chloride, phentermine, sibutramine hydrochloride. hydrochloride, levonantradol hydrochloride, levorphanol tar Antagonist: atipamezole, atosiban, bosentan, cimetidine, trate, lofemizole hydrochloride, lofentanil oxalate, lorcina cimetidine hydrochloride, clentiazem maleate, detirelix dol, lomoxicam, magnesium salicylate, mefenamic acid, acetate, devaZepide, donetidine, etintidine hydrochloride, menabitan hydrochloride, meperidine hydrochloride, famotidine, fenmetozole hydrochloride, flumazenil, icatibant meptazinol hydrochloride, methadone hydrochloride, meth 30 acetate, icotidine, isradipine, metiarnide, nadide, nalmefene, adyl acetate, methopholine, methotrimeprazine, metkepha nalmexone hydrochloride, naloxone hydrochloride, naltrex mid acetate, mimbane hydrochloride, mirfentanil hydrochlo one, nilvadipine, oxilorphan, oxmetidine hydrochloride, ride, molinaZone, morphine Sulfate, moxazocine, nabitan oXmetidine mesylate, quadazocine mesylate, ranitidine, ran hydrochloride, nalbuphine hydrochloride, nalmexone hydro itidine bismuth citrate, ranitidine hydrochloride, sufotidine, chloride, namoxyrate, nantradol hydrochloride, naproxen, 35 teludipine hydrochloride, tiapamil hydrochloride, tiotidine, naproxen Sodium, naproXol, nefopam hydrochloride, nexeri vapiprost hydrochloride, Zaltidine hydrochloride. dine hydrochloride, noracymethadol hydrochloride, ocfenta Anterior pituitary activator: epimestrol. nil hydrochloride, octaZamide, olvanil, oxetorone fumarate, Anterior pituitary Suppressant: danazol. oxycodone, oxycodone hydrochloride, oxycodone terephtha Anthelmintic: albendazole, anthelmycin, bromoxanide, late, oxymorphone hydrochloride, pemedolac, pentamor 40 bunamidine hydrochloride, butonate, cambendazole, carban phone, pentazocine, pentazocine hydrochloride, pentazocine tel lauryl Sulfate, clioxanide, closantel, cyclobendazole, lactate, phenazopyridine hydrochloride, phenyramidol dichlorvos, diethylcarbamazine citrate, dribendazole, hydrochloride, picenadol hydrochloride, pinadoline, pirfeni dymanthine hydrochloride, etibendazole, fenbendazole, done, piroxicam olamine, pravadoline maleate, prodilidine furodazole, hexylresorcinol, mebendazole, morantel tartrate, hydrochloride, profadol hydrochloride, propirarn fumarate, 45 niclosamide, nitramisole hydrochloride, nitrodan, oxantel propoxyphene hydrochloride, propoxyphene napsylate, pamoate, Oxfendazole, oxibendazole, parbendazole, pipera proxazole, proxazole citrate, proXorphan tartrate, pyrro mide maleate, piperazine, piperazine citrate, piperazine ede liphene hydrochloride, remifentanil hydrochloride, salcolex, tate calcium, proclonol, pyrantel pamoate, pyrantel tartrate, Salethamide maleate, Salicylamide, Salicylate meglumine, pyrvinium pamoate, rafoxanide, stilbazium iodide, tetrami Salsalate, Sodium salicylate, spiradoline mesylate, Sufentanil, 50 sole hydrochloride, thiabendazole, ticarbodine, tioxidazole, Sufentanil citrate, talmetacin, talniflumate, talosalate, tazad triclofenol piperazine, Vincofos, Zilantel. olene Succinate, tebufelone, tetrydamine, tifurac sodium, tili Anti-acne: adapalene, erythromycin Salnacedin, inocoter dine hydrochloride, tiopinac, tonazocine mesylate, tramadol One acetate, acCutane. hydrochloride, trefentanil hydrochloride, trolamine, Verado Anti-adrenergic: acebutolol, alprenolol hydrochloride, line hydrochloride, verilopam hydrochloride, volazocine, 55 atenolol, bretylium tosylate, bunolol hydrochloride, carteolol Xorphanol mesylate, Xylazine hydrochloride, Zenazocine hydrochloride, celiprolol hydrochloride, cetamolol hydro mesylate, Zomepirac sodium, Zucapsaicin. chloride, cicloprolol hydrochloride, dexpropranolol hydro Androgen: fluoxymesterone, mesterolone, methyltest chloride, diacetolol hydrochloride, dihydroergotamine mesy osterone, nandrolone decanoate, nandrolonephenpropionate, late, dilevalol hydrochloride, esmolol hydrochloride, nisterime acetate, Oxandrolone, oxymetholone, silandrone, 60 exaprolol hydrochloride, fenspiride hydrochloride, flestolol stanozolol, testosterone, testosterone cypionate, testosterone sulfate, labetalol hydrochloride, levobetaxolol hydrochlo enanthate, testosterone ketolaurate, testosterone phenylac ride, levobunolol hydrochloride, metalol hydrochloride, etate, testosterone propionate, trestolone acetate. metoprolol, metoprolol tartrate, nadolol, pamatolol Sulfate, Anesthesia, adjunct to: Sodium oxybate. penbutolol Sulfate, phentolamine mesylate, practolol, propra Anesthetic: alliflurane, benoximate hydrochloride, ben 65 nolol hydrochloride, proroxanhydrochloride, solypertine tai Zocaine, biphenamine hydrochloride, bupivacaine hydro trate, Sotalol hydrochloride, timolol, timolol maleate, tipre chloride, butamben, butamben picrate, chloroprocaine hydro nolol hydrochloride, tolamolol, Zollertine hydrochloride. US 9,096,743 B2 49 50 Anti-allergic: amlexanox, astemizole, azelastine hydro Solution, ardeparin Sodium, bivalirudin, bromindione, dalte chloride, eclaZolast, minocromil, nedocromil, nedocromil parin Sodium, desirudin, dicumnarol, heparin calcium, hep calcium, nedocromil sodium, nivimedone sodium, pemiro arin Sodium, lyapolate sodium, nafamo.stat mesylate, phen last potassium, pentigetide, pirquinozol, poisonoak extract, procoumon, tinzaparin Sodium, warfarin Sodium. probicromil calcium, proXicromil, repirinast, tetraZolast Anticoccidal: maduramicin. meglumine, thiazinamium chloride, tiacrilast, tiacrilast Anticonvulsant: albutoin, ameltolide, atolide, buramate, Sodium, tiprinast meglumine, tixanoX. carbamazepine, cinromide, citenamide, clonazepam, cyhep Anti-amebic: berythromycin, bialamicol hydrochloride, tamide, dezinamide, dimethadione, divalproex sodium, eter chloroquine, chloroquine hydrochloride, chloroquine phos obarb, ethosuximide, ethotoin, flurazepam hydrochloride, phate, clamoxyquin hydrochloride, clioquinol, emetine 10 fluzinamide, fosphenyloin Sodium, gabapentin, ilepcimide, hydrochloride, iodoquinol, paromomycin Sulfate, quinfa lamotrigine, magnesium sulfate, mephenyloin, mephobar mide, Symetime hydrochloride, teclozan, tetracycline, tetra bital, methetoin, methSuximide, millacemide hydrochloride, cycline hydrochloride. nabazenil, nafimidone hydrochloride, nitrazepam, phenace Anti-androgen: benorterone, cioteronel, cyproterone mide, phenobarbital, phenobarbital Sodium, phensuximide, acetate, delmadinone acetate, oxendolone, topterone, Zanot 15 phenyloin, phenyloin Sodium, primidone, progabide, ralito COC. line, remacemide hydrochloride, ropizine, sabeluzole, stirip Anti-anemic: epoetin alfa, epoetin beta, ferrous Sulfate, entol, Sulthiame, thiopental sodium, tiletamine hydrochlo dried, leucovorin calcium. ride, topiramate, trimethadione, Valproate sodium, Valproic Anti-anginal: amlodipine besylate, amlodipine maleate, acid, vigabatrin, ZonicleZole hydrochloride, Zonisamide. betaxolol hydrochloride, bevantolol hydrochloride, buto Antidepressant: adatanserin hydrochloride, adinazolam, prozine hydrochloride, carvedilol, cinepazet maleate, meto adinazolam mesylate, alaproclate, aletamine hydrochloride, prolol Succinate, molsidomine, monatepil maleate, primi amedalin hydrochloride, amitriptyline hydrochloride, amox dolol, ranolazine hydrochloride, tosifen, Verapamil apine, aptazapine maleate, azaloxan fumarate, azepindole, hydrochloride. azipramine hydrochloride, bipenamol hydrochloride, bupro Anti-anxiety agent: adatanserin hydrochloride, alpidem, 25 pion hydrochloride, butacetin, butriptyline hydrochloride, binospirone mesylate, bretazenil, glemanserin, ipsapirone caroxazone, cartazolate, ciclazindol, cidoxepin hydrochlo hydrochloride, mirisetron maleate, Ocinaplon, ondansetron ride, cilobamine mesylate, clodazon hydrochloride, clomi hydrochloride, panadiplon, pancopride, paZinaclone, Seraza pramine hydrochloride, cotinine fumarate, cyclindole, cype pine hydrochloride, tandospirone citrate, Zalospirone hydro namine hydrochloride, cyprolidol hydrochloride, chloride. 30 cyproximide, daledalin tosylate, dapoxetine hydrochloride, Anti-arthritic: lodelaben. daZadrol maleate, dazepinil hydrochloride, desipramine Anti-asthmatic: ablukast, ablukast sodium, azelastine hydrochloride, dexamisole, deximafen, dibenzepin hydro hydrochloride, bunaprolast, cinalukast, crornitrile Sodium, chloride, dioxadrol hydrochloride, dothiepin hydrochloride, cromolyn Sodium, enofelast, isamoxole, ketotifen fumarate, doxepin hydrochloride, dulloxetine hydrochloride, eclan levcromakalim, lodoxamide ethyl, lodoxamide 35 amine maleate, encyprate, etoperidone hydrochloride, fantri tromethamine, montelukast sodium, OntaZolast, oxarbazole, done hydrochloride, fehmetozole hydrochloride, fenmetra oXatomide, piriprost, piriprost potassium, pirolate, pobi mide, fezolamine fumarate, fluotracen hydrochloride, lukastedamine, quaZolast, repirinast, ritolukast, Sulukast, tet fluoxetine, fluoxetine hydrochloride, fluparoxan hydrochlo razolast meglumine, tiaramide hydrochloride, tibenelast ride, gamfexine, guanoxyfen Sulfate, imafen hydrochloride, Sodium, tomelukast, tranilast, Verlukast, Verofylline, Zar 40 imiloxan hydrochloride, imipramine hydrochloride, indelox irlukast. azine hydrochloride, intriptyline hydrochloride, iprindole, Anti-atherosclerotic: mifobate, timefuronc. isocarboxazid, ketipramine fumarate, lofepramine hydro Anticholelithic: monoctanoin. chloride, lortalamine, maprotiline, maprotiline hydrochlo Anticholelithogenic: chenodiol, ursodiol. ride, melitracen hydrochloride, millacemide hydrochloride, Anticholinergic: alverinc citrate, anisotropine methylbro 45 minaprine hydrochloride, mirtazapine, moclobemide, moda mide, atropine, atropine oxide hydrochloride, atropine Sul line Sulfate, napactadine hydrochloride, napamezole hydro fate, belladonna, benapryzine hydrochloride, benzetimide chloride, nefazodone hydrochloride, nisoxetine, nitrafudam hydrochloride, benzilonium bromide, biperiden, biperiden hydrochloride, nomifensine maleate, nortriptyline hydro hydrochloride, biperiden lactate, clidinium bromide, cyclo chloride, octriptyline phosphate, opipramol hydrochloride, pentolate hydrochloride, dexetimide, dicyclomine hydro 50 oxaprotiline hydrochloride, oxypertine, paroxetine, chloride, dihexyverine hydrochloride, domazoline fumarate, phenelZine Sulfate, pirandamine hydrochloride, pizotyline, elantrine, elucaine, ethybenztropine, eucatropine hydrochlo pridefine hydrochloride, prolintane hydrochloride, protrip ride, glycopyrrolate, heteronium bromide, homatropine tyline hydrochloride, quipazine maleate, rolicyprine, seproX hydrobromide, homatropine methylbromide, hyoscyamine, etine hydrochloride, sertraline hydrochloride, sibutramine hyoscyamine hydrobromide, hyoscyamine Sulfate, isopropa 55 hydrochloride, Sulpiride, Suritozole, tametraline hydrochlo mide iodide, mepenZolate bromide, methylatropine nitrate, ride, tampramine fumarate, tandamine hydrochloride, thiaz metoquizine, oxybutynin chloride, parapenzolate bromide, esim hydrochloride, thozalinone, tomoxetine hydrochloride, pentapiperium methylsulfate, phencarbamide, poldine meth trazodone hydrochloride, trebenzomine hydrochloride, trimi ylsulfate, proglumide, propantheline bromide, propenZolate pramine, trimipramine maleate, Venlafaxine hydrochloride, hydrochloride, Scopolamine hydrobromide, tematropium 60 viloxazine hydrochloride, Zimeldine hydrochloride, methylsulfate, tiquinamide hydrochloride, tofenacin hydro Zometapine. chloride, toguizine, triampyZine Sulfate, trihexyphenidyl Antidiabetic: acetohexamide, buformin, butoxamine hydrochloride, tropicamide. hydrochloride, camiglibose, chlorpropamide, ciglitaZone, Anticoagulant: ancrod, anticoagulant citrate dextrose solu englitaZone sodium, etoformin hydrochloride, gliamilide, tion, anticoagulant citrate phosphate dextrose adenine solu 65 glibornuride, glicetanile Sodium, gliflumide, glipizide, gluca tion, anticoagulant citrate phosphate dextrose solution, anti gon, glyburide, glyhexamide, glymidine sodium, glyocta coagulant heparin Solution, anticoagulant Sodium citrate mide, glyparamide, insulin, insulin, dalanated, insulin US 9,096,743 B2 51 52 human, insulin human, isophane, insulin human Zinc, insulin hydrochloride, brompheniramine maleate, carbinoxamine human Zinc, extended, insulin, isophane, insulin lispro, insu maleate, cetirizine hydrochloride, chlorpheniramine maleate, lin, neutral, insulin Zinc, insulin Zinc, extended, insulin Zinc, chlorpheniramine polistirex, cinnarizine, clemastine, clemas prompt, linogliride, linogliride fumarate, metformin, methyl tine fumarate, closiramine aceturate, cycliramine maleate, palmoxirate, palmoxirate Sodium, pioglitaZone hydrochlo cyclizine, cyproheptadine hydrochloride, dexbromphe ride, pirogliride tartrate, proinsulin human, Seglitide acetate, niramine maleate, dexchlorpheniramine maleate, dimethin tolaZamide, tolbutamide, tolpyrramide, troglitaZone, Zopolr dene maleate, diphenhydramine citrate, diphenhydramine estat, and Sitagliptin. hydrochloride, dorastine hydrochloride, doxylamine Succi Antidiarrheal: rolgamidine, diphenoxylate hydrochloride nate, ebastine, levocabastine hydrochloride, loratadine, (lomotil), metronidazole (flagyl), methylprednisolone 10 mianserin hydrochloride, noberastine, orphenadrine citrate, (medrol), Sulfasalazine (aZulfidine). pyrabrom, pyrilamine maleate, pyroxamine maleate, rocas Antidiuretic: argipressin tannate, desmopressin acetate, tine hydrochloride, rotoxamine, tazifylline hydrochloride, lypressin. temelastine, terfenadine, tripelennamine citrate, tripelen Antidote: dimercaprol, edrophonium chloride, fomepi namine hydrochloride, triprolidine hydrochloride, Zolamine Zole, leucovorin calcium, levoleucovorin calcium, methylene 15 hydrochloride. blue, protamine Sulfate. Antihyperlipidemic: cholestyramine resin, clofibrate, Antidyskinetic: selegiline hydrochloride. colestipol hydrochloride, crilvastatin, dalvastatin, dextrothy Anti-emetic: alosetron hydrochloride, batanopride hydro roxine sodium, fluvastatin Sodium, gemfibrozil, lecimibide, chloride, bemesetron, benzquinamide, chlorpromazine, chlo lovastatin, niacin, pravastatin Sodium, probucol, simvastatin, rpromazine hydrochloride, clebopride, cyclizine hydrochlo tiqueside, Xenbucin. ride, dimenhydrinate, diphenidol, diphenidol hydrochloride, Antihyperlipoproteinemic: acifran, beloxamide, beZafi diphenidol pamoate, dolasetron mesylate, domperidone, brate, boxidine, butoxamine hydrochloride, cetaben sodium, dronabinol, fluidorex, flumeridone, galdansetron hydrochlo ciprofibrate, gemcadiol, halofenate, lifibrate, meglutol, ride, granisetron, granisetron hydrochloride, lurosetron nafenopin, pimetime hydrochloride, theofibrate, tibric acid, mesylate, meclizine hydrochloride, metoclopramide hydro 25 treloxinate. chloride, metopimazine, ondansetron hydrochloride, panco Antihypertensive: alfuZosin hydrochloride, alipamide, pride, prochlorperazine, prochlorperazine edisylate, prochlo althiazide, amiquinsin hydrochloride, amlodipine besylate, rperazine maleate, promethazine hydrochloride, amlodipine maleate, anaritide acetate, atiprosin maleate, bel thiethylperazine, thiethylperazine malate, thiethylperazine fosdil, bemitradine, bendacalol mesylate, bendroflumethiaz maleate, trimethobenzamide hydrochloride, Zacopride 30 ide, benzthiazide, betaxolol hydrochloride, bethanidine sul hydrochloride. fate, bevantolol hydrochloride, biclodil hydrochloride, Anti-epileptic: felbamate, loreclezole, tolgabide. bisoprolol, bisoprolol fumarate, bucindolol hydrochloride, Anti-estrogen: clometherone, delmadinone acetate, bupicomide, buthiazide: candoXatril, candoxatrilat, captopril, nafoxidine hydrochloride, nitromifene citrate, raloxifene carvedilol, ceronapril, chlorothiazide Sodium, cicletanine, hydrochloride, tamoxifen citrate, toremifene citrate, triox 35 cilaZapril, clonidine, clonidine hydrochloride, clopamide, ifene mesylate. cyclopenthiazide, cyclothiazide, darodipine, debrisoquin Sul Antifibrinolytic: nafamo.stat mesylate. fate, delapril hydrochloride, diapamide, diazoxide, dilevalol Antifungal: acrisorcin, ambruticin, amphotericin b, aza hydrochloride, diltiazem malate, ditekiren, doxazosin mesy conazole, azaserine, basifungin, bifonazole, biphenamine late, ecadotril, enalapril maleate, enalaprilat, enalkiren, hydrochloride, bispyrithione magSulfex, butoconazole 40 endralazine mesylate, epithiazide, eprosartan, eprosartan nitrate, calcium undecylenate, candicidin, carbol-fuchsin, mesylate, fenoldopam mesylate, flavodilol maleate, flo chlordantoin, ciclopiroX, ciclopiroX olamine, cillofungin, rdipine, floseduinan, fosinopril sodium, fosinoprilat, guana cisconazole, clotrimazole, cuprimyxin, denofungin, dipy benz, guanabenZ acetate, guanacline Sulfate, guanadrel Sul rithione, doconazole, econazole, econazole nitrate, enilcona fate, guancydine, guanethidine monosulfate, guanethidine Zole, ethonam nitrate, fenticonazole nitrate, filipin, flucona 45 Sulfate, guanfacine hydrochloride, guanisoquin Sulfate, gua Zole, flucytosine, fungimycin, griseofulvin, hamycin, noclor Sulfate, guanoctine hydrochloride, guanoxabenz, gua isoconazole, itraconazole, kalafungin, ketoconazole, noxan Sulfate, guanoxyfen Sulfate, hydralazine hydrochlo lomofimgin, lydimycin, mepartricin, miconazole, micona ride, hydralazine polistirex, hydroflumethiazide, Zole nitrate, monensin, monensin Sodium, naftifine hydro indacrinone, indapamide, indolaprif hydrochloride, chloride, neomycin undecylenate, nifuratel, nifurmerone, 50 indoramin, indoramin hydrochloride, indorenate hydrochlo nitralamine hydrochloride, nystatin, octanoic acid, orcona ride, lacidipine, leniquinsin, levcromakalim, lisinopril, Zole nitrate, oxiconazole nitrate, oxifungin hydrochloride, lofexidine hydrochloride, losartan potassium, losulazine parconazole hydrochloride, partricin, potassium iodide, pro hydrochloride, mebutamate, mecamylamine hydrochloride, clonol, pyrithione Zinc, pyrrolnitrin, rutamycin, sangui medroxalol, medroxalol hydrochloride, methalthiazide, narium chloride, Saperconazole, scopafungin, selenium Sul 55 methyclothiazide, methyldopa, methyldopate hydrochloride, fide, sinefungin, Sulconazole nitrate, terbinafine, terconazole, metipranolol, metolaZone, metoprolol fumarate, metoprolol thiram, ticlatone, tioconazole, tolciclate, tolindate, tolnaftate, Succinate, metyrosine, minoxidil, monatepil maleate, triacetin, triafungin, undecylenic acid, viridofulvin, Zinc muZolimine, nebivolol, nitrendipine, oftormine, pargyline undecylenate, Zinoconazole hydrochloride. One specific anti hydrochloride, paZoxide, pelanserin hydrochloride, perin fungal that is Suitable is itraconazole. 60 dopril erbumine, phenoxybenzamine hydrochloride, pinaci Antiglaucoma agent: alprenoXime hydrochloride, col dil, pivopril, polythiazide, prazosin hydrochloride, primi forsin, dapiprazole hydrochloride, dipivefrin hydrochloride, dolol, prizidilol hydrochloride, quinapril hydrochloride, naboctate hydrochloride, pilocarpine, pimabine. quinaprilat, quinaZosin hydrochloride, quinelorane hydro Antihemophilic: antihemophilic factor. chloride, quinpirole hydrochloride, quinuclium bromide, Antihemorrhagic: poliglusam. 65 ramipril, rauwolfia serpentina, reserpine, Saprisartan potas Antihistaminic: acrivastine, antazoline phosphate, astemi sium, Saralasin acetate, Sodium nitroprusside, Sulfinalol Zole, azatadine maleate, barmastine, bromodiphenhydramine hydrochloride, tasosartan, teludipine hydrochloride, temoca US 9,096,743 B2 53 54 pril hydrochloride, terazosin hydrochloride, terlakiren, tia talniflumate, talosalate, tebufelone, tenidap, tenidap Sodium, menidine, tiamenidine hydrochloride, ticrynafen, tinabinol, tenoxicam, tesicam, tesimide, tetrydamine, tiopinac, tiXocor tiodazosin, tipentosin hydrochloride, trichlormethiazide, tri tol pivalate, tolmetin, tolmetin Sodium, triclonide, triflumi maZosin hydrochloride, trimethaphan camsylate, trimoxam date, Zidometacin, Zomepirac sodium. ine hydrochloride, tripamide, Xipamide, Zankiren hydrochlo Antikeratinizing agent: doretinel, linarotene, pelretin. ride, Zofenoprilat arginine. Antimalarial: acedapsone, amodiaquine hydrochloride, Antihypotensive: ciclafrine hydrochloride, midodrine amduinate, arteflene, chloroquine, chloroquine hydrochlo hydrochloride. ride, chloroquine phosphate, cycloguanil pamoate, enpiroline Anti-infective: difloxacin hydrochloride, lauryl isoquino phosphate, halofantrine hydrochloride, hydroxychloroquine linium bromide, moxalactam disodium, ornidazole, pentiso 10 Sulfate, mefloquine hydrochloride, menoctone, mirincamy micin, Sarafloxacin hydrochloride, protease inhibitors of hiv cin hydrochloride, primaquine phosphate, pyrimethamine, and other retroviruses, integrase inhibitors of hiv and other quinine Sulfate, tebuquine. retroviruses, cefaclor (CECLORTM), acyclovir (ZOVI Antimicrobial: aztreonam, chlorhexidine gluconate, imi RAXTM), norfloxacin (NOROXINTM), cefoxitin (ME durea, lycetamine, nibroxane, piraZmonam sodium, propi FOXINTM), cefuroxime axetil (CEFTINTM), ciprofloxacin 15 onic acid, pyrithione sodium, Sanguinarium chloride, tige (CIPROTM). monam dicholine. Anti-infective, topical: alcohol, aminacrine hydrochloride, Antimigraine: dolasetron meSylate, naratriptanhydrochlo benzethonium chloride: bithionolate sodium, bromchlo ride, Sergolexole maleate, Sumatriptan Succinate, Zatosetron renone, carbamide peroxide, cetalkonium chloride, cetylpy maleate. ridinium chloride: chlorhexidine hydrochloride, clioquinol, Antimitotic: podofilox. domiphen bromide, fenticlor, fludazonium chloride, fuchsin, Antimycotic: amorolfine. basic, furazolidone, gentian violet, halquinols, hexachlo Antinauseant: buclizine hydrochloride, cyclizine lactate, rophene: hydrogen peroxide, ichthammol, imidecyl iodine, naboctate hydrochloride. iodine, isopropyl alcohol, mafenide acetate, meralein Antineoplastic: acivicin, aclarubicin, acodazole hydro Sodium, mercufenol chloride, mercury, ammoniated, methyl 25 chloride, acronine, adoZelesin, aldesleukin, altretamine, benzethonium chloride, nitrofuraZone, nitromersol, octeni ambomycin, ametantrone acetate, aminoglutethimide, amsa dine hydrochloride, oxychlorosene, oxychlorosene Sodium, crine, anastroZole, anthramycin, asparaginase, asperlin, aza parachlorophenol, camphorated, potassium permanganate, citidine, azetepa, azotomycin, batimastat, benzodepa, poVidone-iodine, sepazonium chloride, silver nitrate, Sulfa bicalutamide, bisantrene hydrochloride, bisnafide dimesy diazine, silver, Symclosene, thimerfonate Sodium, thimero 30 late, bizelesin, bleomycin Sulfate, brequinar Sodium, bropir sal: troclosene potassium. imine, buSulfan, cactinomycin, calusterone, caracemide, car Anti-inflammatory: acetominophen, alclofenac, alclom betimer, carboplatin, carmustine, carubicin hydrochloride, etaSone dipropionate, algestone acetonide, alpha amylase, carzelesin, cedefingol, chlorambucil, cirolemycin, cisplatin, amcinafal, amcinafide, amfenac sodium, amiprilose hydro cladribine, crisinatol mesylate, cyclophosphamide, cytara chloride, anakinra, anirolac, anitraZafen, apaZone, bal 35 bine, dacarbazine, dactinomycin, daunorubicin hydrochlo Salazide disodium, bendazac, benoxaprofen, benzydamine ride, decitabine, dexormaplatin, deZaguanine, deZaguanine hydrochloride, bromelains, broperamole, budesonide, car mesylate, diaziquone, docetaxel, doxorubicin, doxorubicin profen, cicloprofen, cintaZone, cliprofen, clobetasol propi hydrochloride, droloxifene, droloxifene citrate, dromo onate, clobetasone butyrate, clopirac, cloticaSone propionate, stanolone propionate, duaZomycin, edatrexate, eflomithine cormethasone acetate, cortodoxone, deflazacort, desonide, 40 hydrochloride, elsamitrucin, enloplatin, enpromate, epipro desoximetasone, dexamethasone dipropionate, diclofenac pidine, epirubicin hydrochloride, erbulozole, esorubicin potassium, diclofenac sodium, diflorasone diacetate, diflumi hydrochloride, estramustine, estramustine phosphate done sodium, diflunisal, difluprednate, diftalone, dimethyl Sodium, etanidazole, ethiodized oil I 131, etoposide, etopo Sulfoxide, drocinonide, endrysone, enlimomab, enolicam side phosphate, etoprine, fadrozole hydrochloride, faZara Sodium, epirizole, etodolac, etofenamate, felbinac, fenamole, 45 bine, fenretinide, floxuridine, fludarabine phosphate, fluo fenbufen, fenclofenac, fenclorac, fendosal, fenpipalone, fen rouracil, fluorocitabine, fosquidone, fostriecin Sodium, tiazac, flazalone, fluazacort, flufenamic acid, flumizole, gemcitabine, gemcitabine hydrochloride, gold au 198, flunisolide acetate, flunixin, flunixin meglumine, fluocortin hydroxyurea, idarubicin hydrochloride, ifosfamide, ilmofos butyl, fluorometholone acetate, fluguaZone, flurbiprofen, ine, interferon alfa-2a, interferon alfa-2b, interferon alfa-N1, fluretofen, fluticasone propionate, furaprofen, furobufen, hal 50 interferon alfa-N3, interferon beta-la, interferon gamma-Ib, cinonide, halobetasol propionate, halopredone acetate, iproplatin, irinotecan hydrochloride, lanreotide acetate, letro ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol, Zole, leuprolide acetate, liarozole hydrochloride, lometrexol ilonidap, indomethacin, indomethacin Sodium, indoprofen, Sodium, lomustine, losoxantrone hydrochloride, masoprocol, indoxole, intrazole, isoflupredone acetate, isoxepac, isoxi maytansine, mechlorethamine hydrochloride, megestrol cam, ketoprofen, lofemizole hydrochloride, lornoxicam, 55 acetate, melengestrol acetate, melphalan, menogaril, mercap loteprednol etabonate, meclofenamate sodium, meclofe topurine, methotrexate, methotrexate sodium, metoprine, namic acid, meclorisone dibutyrate, mefenamic acid, meturedepa, mitindomide, mitocarcin, mitocromin, mitogil mesalamine, meseclaZone, methylprednisolone Suleptanate, lin, mitomalcin, mitomycin, mitosper, mitotane, mitox morniflumate, nabumetone, naproxen, naproxen Sodium, antrone hydrochloride, mycophenolic acid, nocodazole, naproxol, nimaZone, olSalazine sodium, orgotein, orpanoxin, 60 nogalamycin, Ormaplatin, oxiSuran, paclitaxel, pegaspargase, oxaprozin, oxyphenbutaZone, paranyline hydrochloride, pen peliomycin, pentamustine, peplomycin Sulfate, perfosfa tosan polysulfate sodium, phenbutaZone sodium glycerate, mide, pipobroman, piposulfan, piroXantrone hydrochloride, pirfenidone, piroxicam, piroxicam cinnamate, piroxicamola plicamycin, plomestane, porfimer sodium, porfiromycin, mine, pirprofen, prednazate, prifelone, prodolic acid, produa prednimustine, procarbazine hydrochloride, puromycin, Zone, proxazole, proxazole citrate, rimexolone, romazarit, 65 puromycin hydrochloride, pyrazofurin, riboprine, rogletim salcolex, Salnacedin, Salsalate, sanguinarium chloride, secla ide, safmgol, Safingol hydrochloride, Semustine, simtraZene, Zone, Sermetacin, Sudoxicam, Sulindac, Suprofen, talmetacin, sparfosate Sodium, sparsomycin, spirogermanium hydro US 9,096,743 B2 55 56 chloride, Spiromustine, spiroplatin, streptonigrin, StreptoZo inhibiting factor, leukocyte alpha interferon, leuprolide--es cin, strontium chloride Sr 89, Sulofenur, talisomycin, taxane, trogen-progesterone, leuprorelin, levamisole, liarozole, lin taxoid, tecogalan Sodium, tegafur, teloxantrone hydrochlo ear polyamine analogue, lipophilic disaccharide peptide, ride, temoporfin, teniposide, teroxirone, testolactone, thiami lipophilic platinum compounds, lissoclinamide 7, lobaplatin, prine, thioguanine, thiotepa, tiazofurin, tirapazamine, topo lombricine, lometrexol, lonidamine, losoxantrone, lovasta tecan hydrochloride, toremifene citrate, trestolone acetate, tin, loxoribine, lurtotecan, lutetium texaphyrin, lysofylline, triciribine phosphate, trimetrexate, trimetrexate glucuronate, lytic peptides, maitansine, mannostatin A, marimastat, maso triptorelin, tubulozole hydrochloride, uracil mustard, ure procol, maspin, matrilysin inhibitors, matrix metalloprotein depa, Vapreotide, Verteporfin, vinblastine Sulfate, Vincristine ase inhibitors, menogaril, merbarone, meterelin, methioni Sulfate, vindesine, Vindesine Sulfate, vinepidine Sulfate, Ving 10 nase, metoclopramide, MIF inhibitor, mifepristone, lycinate sulfate, vinleurosine sulfate, vinorelbine tartrate, miltefosine, mirimostim, mismatched double stranded RNA, Vinrosidine Sulfate, Vinzolidine Sulfate, Vorozole, Zeniplatin, mitoguaZone, mitolactol, mitomycin analogues, mitonafide, Zinostatin, Zorubicin hydrochloride. mitotoxin fibroblast growth factor-Saporin, mitoxantrone, Other anti-neoplastic compounds include: 20-epi-1.25 mofarotene, molgramostim, monoclonal antibody, human dihydroxyvitamin D3, 5-ethynyluracil, abiraterone, aclarubi 15 chorionic gonadotrophin, monophosphoryllipid A+myobac cin, acylfulvene, adecypenol, adoZelesin, aldesleukin, ALL terium cell wall sk, mopidamol, multiple drug resistance TKantagonists, altretamine, ambamustine, amidox, amifos genie inhibitor, multiple tumor Suppressor 1-based therapy, tine, aminolevulinic acid, amrubicin, atrsacrine, anagrelide, mustard anticancer agent, mycaperoxide B, mycobacterial anastroZole, andrographolide, angiogenesis inhibitors, cell wall extract, myriaporone, N-acetyldinaline, N-substi antagonist D, antagonist G, antarelix, anti-dorsalizing mor tuted benzamides, nafarelin, nagrestip, naloxone +pentaZo phogenetic protein-1, antiandrogen, prostatic carcinoma, cine, napavin, naphterpin, nartograstim, nedaplatin, nemoru antiestrogen, antineoplaston, antisense oligonucleotides, bicin, neridronic acid, neutral endopeptidase, nilutamide, aphidicolin glycinate, apoptosis gene modulators, apoptosis nisamycin, nitric oxide modulators, nitroxide antioxidant, regulators, apurinic acid, ara-CDP-DL-PTBA, arginine nitrullyn, O6-benzylguanine, octreotide, okicenone, oligo deaminase, asulacrine, atamestane, atrimustine, axinastatin 25 nucleotides, onapristone, ondansetron, ondansetron, oracin, 1, axinastatin 2, axinastatin 3, aZasetron, azatoxin, azaty oral cytokine inducer, ormaplatin, osaterone, Oxaliplatin, rosine, baccatin III derivatives, balanol, batimastat, BCR/ oxaunomycin, paclitaxel analogues, paclitaxel derivatives, ABL antagonists, benzochlorins, benzoylstaurosporine, beta palauamine, palmitoylrhizoxin, pamidronic acid, panax lactam derivatives, beta-alethine, betaclamycin B, betulinic ytriol, panomifene, parabactin, paZelliptine, pegaspargase, acid, bFGF inhibitor, bicalutamide, bisantrene, bisaziridinyl 30 peldesine, pentosan polysulfate sodium, pentostatin, pentro spermine, bisnafide, bistratene A, bizelesin, breflate, bropir Zole, perflubron, perfosfamide, perillyl alcohol, phenazino imine, budotitane, buthionine sulfoximine, calcipotriol, mycin, phenylacetate, phosphatase inhibitors, picibanil, pilo calphostin C, camptothecin derivatives, canarypox IL-2, carpine hydrochloride, pirarubicin, piritrexim, placetin A, capecitabine, carboxamide-amino-triazole, carboxyamidot placetin B, plasminogen activator inhibitor, platinum com riazole, CaRest M3, CARN 700, cartilage derived inhibitor, 35 plex, platinum compounds, platinum-triamine complex, por carzelesin, casein kinase inhibitors (ICOS), castanospermine, fimer Sodium, porfiromycin, propyl bis-acridone, prostaglan cecropin B. cetrorelix, chlorins, chloroquinoxaline Sulfona din J2, proteasome inhibitors, protein A-based immune mide, cicaprost, cis-porphyrin, cladribine, clomifene ana modulator, protein kinase Cinhibitor, protein kinase Cinhibi logues, clotrimazole, collismycin A, collismycin B, combre tors, microalgal, protein tyrosine phosphatase inhibitors, tastatin A4, combretastatin analogue, conagenin, 40 purine nucleoside phosphorylase inhibitors, purpurins, pyra crambescidin 816, crisinatol, cryptophycin 8, cryptophycin A Zoloacridine, pyridoxylated hemoglobin polyoxyethylene derivatives, curacin A, cyclopentanthraquinones, cyclo conjugate, rafantagonists, raltitrexed, ramosetron, ras farne platam, cypemycin, cytarabine ocfosfate, cytolytic factor, syl protein transferase inhibitors, ras inhibitors, ras-GAP cytostatin, dacliximab, decitabine, dehydrodidemnin B, inhibitor, retelliptine demethylated, rhenium Re 186 etidr deslorelin, dexifosfamide, dexraZOxane, dexVerapamil, diazi 45 onate, rhizoxin, ribozymes, RII retinamide, rogletimide, rohi quone, didemnin B, didox, diethylnorspermine, dihydro-5- tukine, romurtide, roquinimex, rubiginone B1, ruboxyl, saf azacytidine, dihydrotaxol. 9-dioxamycin, diphenyl spiro ingol, Saintopin, SarCNU, sarcophytol A, SargramoStim, Sdi mustine, docosanol, dolasetron, doxifluridine, droloxifene, 1 mimetics, semustine, Senescence derived inhibitor 1, sense dronabinol, duocannycin SA, ebselen, ecomustine, edelfos oligonucleotides, signal transduction inhibitors, signal trans ine, edrecolomab, eflornithine, elemene, emitefur, epirubicin, 50 duction modulators, single chain antigen binding protein, epristeride, estramustine analogue, estrogen agonists, estro sizofuran, Sobuzoxane, sodium borocaptate, sodium pheny gen antagonists, etanidazole, etoposide phosphate, exemes lacetate, Solverol. Somatomedin binding protein, Sonermin, tane, fadrozole, faZarabine, fenretinide, filgrastim, finas sparfosic acid, Spicamycin D, Spiromustine, splenopentin, teride, flavopiridol, flezelastine, fluasterone, fludarabine, spongistatin 1, squalamine, stem cell inhibitor, stem-cell divi fluorodaunorunicin hydrochloride, forfenimex, formestane, 55 sion inhibitors, stipiamide, Stromelysin inhibitors, Sulf fostriecin, fotemustine, gadolinium texaphyrin, gallium mosine, Superactive vasoactive intestinal peptide antagonist, nitrate, galocitabine, ganirelix, gelatinase inhibitors, gemcit Suradista, Suramin, Swainsonine, synthetic glycosaminogly abine, glutathione inhibitors, hepsulfam, heregulin, hexam cans, tallimustine, tamoxifen methiodide, tauromustine, taZ ethylene bisacetamide, hypericin, ibandronic acid, idarubi arotene, tecogalan Sodium, tegafur, tellurapyrylium, telom cin, idoxifene, idramantone, ilmofosine, illomastat, 60 erase inhibitors, temoporfin, temozolomide, teniposide, imidazoacridones, imiquimod, immunostimulant peptides, tetrachlorodecaoxide, tetrazomine, thaliblastine, thalido insulin-like growth factor-1 receptor inhibitor, interferon mide, thiocoraline, thrombopoietin, thrombopoietin mimetic, agonists, interferons, interleukins, iobenguane, iododoxoru thymalfasin, thymopoietin receptor agonist, thymotrinan, bicin, ipomeanol, 4-irinotecan, iroplact, irsogladine, isoben thyroid stimulating hormone, tin ethyl etiopurpurin, tira gazole, isohomohalicondrin B, itasetron, jasplakinolide, 65 paZamine, titanocene dichloride, topotecan, topsentin, kahalalide F, lamellarin-N triacetate, lanreotide, leinamycin, toremifene, totipotent stem cell factor, translation inhibitors, lenograstim, lentinan Sulfate, leptolstatin, letrozole, leukemia tretinoin, triacetyluridine, triciribine, trimetrexate, triptore US 9,096,743 B2 57 58 lin, tropisetron, turosteride, tyrosine kinase inhibitors, tyr ride, naranol hydrochloride, neflumozidehydrochloride, oca phostins, UBC inhibitors, ubenimex, urogenital sinus-de peridone, olanzapine, oxiperomide, penfluridol, pentiapine rived growth inhibitory factor, urokinase receptor maleate, perphenazine, pimozide, pinoxepin hydrochloride, antagonists, vapreotide, variolin B. vector system, erythro pipamperone, piperacetazine, pipotiazine palniitate, piquin cyte gene therapy, Velaresol, Veramine, Verdins, verteporfin, done hydrochloride, prochlorperazine edisylate, prochlor Vinorelbine, Vinxaltine, vitaxin, Vorozole, Zanoterone, Zeni perazine maleate, promazine hydrochloride, remoxipride, platin, Zilascorb, Zinostatin stimalamer. remoxipride hydrochloride, rimcazole hydrochloride, seperi Anti-cancer Supplementary potentiating agents: tricyclic dol hydrochloride, sertindole, Setoperone, spiperone, thior anti-depressant drugs (e.g., imipramine, desipramine, amit idazine, thioridazine hydrochloride, thiothixene, thiothixene ryptyline, clomiprainine, trimipramine, doxepin, nortrip 10 hydrochloride, tioperidone hydrochloride, tiospirone hydro tyline, protriptyline, amoxapine and maprotiline), non-tricy chloride, trifluoperazine hydrochloride, trifluperidol, triflu clic anti-depressant drugs (e.g., Sertraline, traZodone and promazine, triflupromazine hydrochloride, Ziprasidone citalopram), Ca' antagonists (e.g., Verapamil, nifedipine, hydrochloride. nitrendipine and caroverine), calmodulin inhibitors (e.g., pre Antirheumatic: auranofin, aurothioglucose, bindarit, nylamine, trifluoroperazine and clomipramine), amphoteri 15 lobenzarit Sodium, phenylbutaZone, piraZolac, prinomide cin B, triparanol analogues (e.g., tamoxifen), antiarrhythmic tromethamine, Seprilose. drugs (e.g., quinidine), antihypertensive drugs (e.g., reser Antischistosomal: becanthone hydrochloride, hycanthone, pine), thiol depleters (e.g., buthionine and Sulfoximine) and lucanthone hydrochloride, niridazole, oxamniquine, pararo Multiple Drug Resistance reducing agents such as Crema saniline pamoate, teroxalene hydrochloride. phor EL. Antiseborrheic: chloroxine, piroctone, piroctone olamine, Antineutropenic: filgrastim, lenograstim, molgramostim, resorcinol monoacetate. antisecretory: arbaprostil, deprostil, regramos tim, Sargramostim. fenoctimine Sulfate, octreotide, octreotide acetate, omepra Antiobsessional agent: fluvoxamine maleate. Zole Sodium, rioprostil, trimoprostil. Antiparasitic: abamectin, clorSulon, ivermectin. Antispasmodic: stilonium iodide, tizanidine hydrochlo Antiparkinsonian: benztropine mesylate, biperiden, 25 ride. biperiden hydrochloride, biperiden lactate, carmantadine, Antithrombotic: anagrelide hydrochloride, bivalirudin, ciladopa hydrochloride, dopamantine, ethopropazine hydro dalteparin Sodium, danaparoid sodium, daZOXiben hydro chloride, lazabemide, levodopa, lometraline hydrochloride, chloride, efegatran Sulfate, enoxaparin Sodium, ifetroban, mofegiline hydrochloride, naxagolide hydrochloride, parep ifetroban Sodium, tinzaparin sodium, trifenagrel. tide Sulfate, procyclidine hydrochloride, quinetorane hydro 30 Antitussive: benzonatate, butamirate citrate, chlophedi chloride, ropinirole hydrochloride, selegiline hydrochloride, anol hydrochloride, codeine polistirex, codoxime, dex tolcapone, trihexyphenidyl hydrochloride. antiperistaltic: tromethorphan, dextromethorphan hydrobromide, dex difenoximide hydrochloride, difenoxin, diphenoxylate tromethorphan polistirex, ethyl dibunate, guaiapate, hydrochloride, fluperamide, lidamidine hydrochloride, lop hydrocodone bitartrate, hydrocodone polistirex, levopro eramide hydrochloride, malethamer, nufenoXole, paregoric. 35 poxyphene napsylate, noscapine, pemerid nitrate, Antipneumocystic: atovaquone. pipazethate, SuXemerid Sulfate. Antiproliferative agent: piritreximisethionate. Anti-ulcerative: aceglutamide aluminum, cadexomer Antiprostatic hypertrophy: sitogluside. iodine, cetraxate hydrochloride, enisoprost, isotiquimide, Antiprotozoal: amodiaquine, azanidazole, bamidazole, lansoprazole, lavoltidine Succinate, misoprostol, nizatidine, carnidazole, chlortetracycline bisulfate, chlortetracycline 40 nolinium bromide, pantoprazole, pifamine, pirenzepine hydrochloride, flubendazole, flunidazole, halofuginone hydrochloride, rabeprazole sodium, remiprostol, roXatidine hydrobromide, imidocarb hydrochloride, ipronidazole, met acetate hydrochloride, Sucralfate. Sucrosofate potassium, ronidazole, misonidazole, moXnidazole, nitarSone, partricin, tolimidone. puromycin, puromycin hydrochloride, ronidazole, Sulnida Anti-urolithic: cysteamine, cysteamine hydrochloride, Zole, tinidazole. 45 tricitrates. Antipruritic: cyproheptadine hydrochloride, methdilazine, Appetite Suppressant: dexfenfluramine hydrochloride, methdilazine hydrochloride, trimeprazine tartrate. phendimetrazine tartrate, phentermine hydrochloride. Antipsoriatic: acitretin, anthralin, azaribine, calcipotriene, Benign prostatic hyperplasia therapy agent: tamsulosin cycloheximide, enaZadrem phosphate, etretinate, liaroZole hydrochloride. fumarate, lonapalene, tepoxalin. 50 Blood glucose regulators: human insulin, glucagon, tolaza Antipsychotic: acetophenazine maleate, alentemol hydro mide, tolbutamide, chloropropamide, acetohexamide and bromide, alpertine, azaperone, batelapine maleate, benperi glipizide. dol, benzindopyrine hydrochloride, brofbxine, bromperidol, Bone resorption inhibitor: alendronate sodium, etidronate bromperidol decanoate, butaclamol hydrochloride, butapera disodium, pamidronate disodium. Zine, butaperazine maleate, carphenazine maleate, carvotro 55 Bronchodilator: albuterol, albuterol sulfate, azanator male line hydrochloride, chlorpromazine, chlorpromazine hydro ate, bamifylline hydrochloride, bitolterol mesylate, butap chloride, chlorprothixene, cinperene, cintriamide, clomacran rost, carbuterol hydrochloride, clorprenaline hydrochloride, phosphate, clopenthixol, clopimozide, clopipazan mesylate, colterol mesylate, doxaprost, doxofylline, dyphylline, cloroperone hydrochloride, clothiapine, clothixamide male enprofylline, ephedrine, ephedrine hydrochloride, fenoterol, ate, clozapine, cyclophenazine hydrochloride, droperidol. 60 fenprinast hydrochloride, guaithylline, hexoprenaline Sul etazolate hydrochloride, fenimide, flucindole, flumezapine, fate, hoquizil hydrochloride, ipratropium bromide, isoet fluiphenazine decanoate, fluiphenazine enanthate, fluphena harine, isoetharine hydrochloride, isoetharine mesylate, iso Zine hydrochloride, fluspiperone, fluspirilene, flutroline, gev proterenol hydrochloride, isoproterenol Sulfate, otroline hydrochloride, halopemide, haloperidol, haloperidol metaproterenol polistirex, metaproterenol Sulfate, nisbuterol decanoate, illoperidone, imidoline hydrochloride, lenperone, 65 mesylate, oxtriphylline, picumeterol fumarate, piquizil maZapertine Succinate, mesoridazine, mesoridazine besylate, hydrochloride, pirbuterol acetate, pirbuterol hydrochloride, metiapine, milemperone, millipertine, molindone hydrochlo procaterol hydrochloride, pseudoephedrine Sulfate, quaZod US 9,096,743 B2 59 60 ine, quinterenol Sulfate, racepinephrine, racepinephrine fluorescein Sodium, gadobenate dimeglumine, gadoteridol. hydrochloride, reproterol hydrochloride, rimiterol hydrobro gadodiamide, gadopentetate dimeglumine, gadoversetamide, mide, Salmeterol, Salmeterol Xinafoate, Soterenol hydrochlo histoplasmin, impromidine hydrochloride, indigotindisul ride, sulfonterol hydrochloride, Suloxifen oxalate, terbutaline fonate sodium, indocyanine green, lobenguane sulfate I'', Sulfate, theophylline, Xanoxate sodium, Zindotrine, Zinterol iobenzamic acid, iocarmate meglumine, locarmic acid, ioc hydrochloride. etamic acid, iodamide, lodamide megiumine, iodipamide Carbonic anhydrase inhibitor: acetazolamide, acetazola meglumine, iodixanol, iodoxamate meglumine, iodoxamic mide sodium, dichlorphenamide, dorzolamide hydrochlo acid, ioglicic acid, ioglucol, ioglucomide, ioglycamic acid, ride, methazolamide, seZolamide hydrochloride. iogulamide, lohexyl, iomeprol, iopamidol, iopanoic acid, Cardiac depressant: acecamide hydrochloride, acetylcho 10 iopentol, iophendylate, iprofenin, iopronic acid, ioprocemic line chloride, actisomide, adenosine, amiodarone, aprindine, acid, iopydol, iopydone, iosefamic acid, io.seric acid, ioSula aprindine hydrochloride, artilide fumarate, azimilide mide meglumine, ioSumetic acid, iotasul, iotetric acid, Dihydrochloride, bidisomide, bucamide maleate, bucro iothalamate meglumine, iothalamate sodium, iothalamic marone, butoprozine hydrochloride, capobenate Sodium, acid, iotrolan, iotroxic acid, ioversol, ioxaglate meglumine, capobenic acid, cifenline, cifenline Succinate, clofilium phos 15 ioxagiate Sodium, ioxaglic acid, ioxilan, ioxotrizoic acid, ipo phate, disobutamide, disopyramide, disopyramide phos date calcium, ipodate sodium, isosulfan blue, leukocyte typ phate, dofetilide, drobuline, edifolone acetate, emilium tosy ing serum, lidofenin, mebrofenin, meglumine, metrizamide, late, encamide hydrochloride, flecamide acetate, ibutilide metrizoate sodium, metyrapone, metyrapone tartrate, mumps fumarate, indecamide hydrochloride, ipazilide fumarate, skin test antigen, pentetic acid, propyliodone, quinaldine lorajmine hydrochloride, lorcamide hydrochloride, meoben blue, sermorelin acetate, sodium iodide I'', sprodiamide, tine Sulfate, mexiletine hydrochloride, modecamide, mori Stannous pyrophosphate, Stannous Sulfur colloid. Succimer, cizine, oxiramide, pirmenol hydrochloride, pirolazamide, teriparatide acetate, tetrofosmin, tolbutamide Sodium, tuber pranolium chloride, procainamide hydrochloride, pro culin, tyropanoate sodium, Xylose. pafenone hydrochloride, pyrinoline, quindonium bromide, Diuretic: ambuphylline, ambuside, amiloride hydrochlo quinidine gluconate, quinidine Sulfate, recainam hydrochlo 25 ride, azolimine, azosemide, brocrinat, bumetanide, chlorothi ride, recainam tosylate, risotilide hydrochloride, ropitoin azide, chlorthalidone, clazolimine, clorexolone, ethacrynate hydrochloride, sematilide hydrochloride, Suricamide male Sodium, ethacrynic acid, etoZolin, fenduizone, furosemide, ate, tocamide, tocamide hydrochloride, transcamide. hydrochlorothiazide, isosorbide, mannitol, mefruside, oZoli Cardioprotectant: dexraZoxane, draflazine. none, piretanide, spiroXasone, torsemide, triamterene, triflo Cardiotonic: actodigin, aminone, bemoradan, butopamine, 30 cin, urea. carbazeran, carsatirin Succinate, deslanoside, digitalis, digi Dopaminergic agent: ibopamine. toxin, digoxin, dobutamine, dobutamine hydrochloride, dob Ectoparasiticide: nifluridide, permethrin. utamine lactobionate, dobutamine tartrate, enoXimone, ima Emetic: apomorphine hydrochloride. Zodan hydrochloride, indolidan, isomazole hydrochloride, Enzyme inhibitor: acetohydroxamic acid, alrestatin levdobutamine lactobionate, lixazinone sulfate, medorinone, 35 Sodium, aprotinin, benazepril hydrochloride, benazeprilat, milrinone, pelrinone hydrochloride, pimobendan, piroxi benurestat, bromocriptine, bromocriptine mesylate, cilastatin mone, prinoXodan, proscillaridin, quaZinone, tazolol hydro Sodium, fluorofamide, lergotrile, lergotrile mesylate, levcy chloride, Vesnarinone. closerine, libenzapril, pentopril, pepstatin, perindopril, polig Cardiovascular agent: dopexamine, dopexamine hydro nate Sodium, sodium amylosulfate, Sorbinil, spirapril hydro chloride. 40 chloride, spiraprilat, taleranol, teprotide, tolfamide, Choleretic: dehydrocholic acid, fencibutirol, hymec Zofenopril calcium. romone, piprozolin, sincalide, tocamphyl. Estrogen: chlorotrianisene, dienestrol, diethylstilbestrol, Cholinergic: aceclidine, bethanechol chloride, carbachol, diethylstilbestrol diphosphate, equilin, estradiol, estradiol demecarium bromide, dexpanthenol, echothiophate iodide, cypionate, estradiol enanthate, estradiol undecylate, estradiol isofluorophate, methacholine chloride, neostigmine bromide, 45 Valerate, estraZinol hydrobromide, estriol, estrofurate, estro neostigmine methylsulfate, physostigmine, physostigmine gens, conjugated, estrogens, esterified, estrone, estropipate, salicylate, physostigmine Sulfate, pilocarpine, pilocarpine ethinyl estradiol, fenestrel, mestranol, nylestriol, quinestrol. hydrochloride, pilocarpine nitrate, pyridostigmine bromide. Fibrinolytic: anistreplase, bisobrin lactate, brinolase. Cholinergic agonist: Xanomeline, Xanomeline tartrate. Free oxygen radical scavenger: pegorgotein. Cholinesterase deactivator: obidoxime chloride, prali 50 Gastrointestinal motility agents: cisapride (PROPUL doXime chloride, pralidoxime iodide, pralidoxime mesylate. SIDTM), metoclopramide (REGLANTM), hyoscyamine Coccidiostat: arprinocid, narasin, semduramicin, semdu (LEVSINTM). ramicin Sodium. Glucocorticoid: amcinonide, beclomethasone dipropi Dognition adjuvant: ergoloid mesylates, piracetam, onate, betamethasone, betamethasone acetate, betametha pramiracetam hydrochloride, pramiracetam Sulfate, tacrine 55 Sone benzoate, betamethasone dipropionate, betamethasone hydrochloride. Sodium phosphate, betamethasone Valerate, carbenoXolone Cognition enhancer: besipirdine hydrochloride, linopird Sodium, clocortolone acetate, clocortolone pivalate, clopred ine, sibopirdine. nol, corticotropin, corticotropin, repository, corticotropin Depressant: omeprazole. Zinc hydroxide, cortisone acetate, cortivaZol, descinolone Diagnostic aid: aminohippurate Sodium, anazolene 60 acetonide, dexamethasone, dexamethasone sodium phos Sodium, arclofenin, arginine, bentiromide, benzylpenicilloyl phate, diflucortolone, diflucortolone pivalate, flucloronide, polylysine, butedronate tetrasodium, butilfenin, coccidioidin, flumethasone, flumethasone pivalate, flunisolide, fluocino corticorelin ovine triflutate, corticotropin, repository, corti lone acetonide, fluocinonide, fluocortolone, fluocortolone cotropin Zinc hydroxide, diatrizoate meglumine, diatrizoate caproate, fluorometholone, fluperolone acetate, flupredniso Sodium, diatrizoic acid, diphtheria toxin for Schick test, dis 65 lone, fluprednisolone Valerate, flurandrenolide, formocortal, ofenin, edrophonium chloride, ethiodized oil, etifenin, exam hydrocortisone, hydrocortisone acetate, hydrocortisone etazime, ferristenc, ferumoxides, ferumoXsil, fluorescein, buteprate, hydrocortisone butyrate, hydrocortisone sodium US 9,096,743 B2 61 62 phosphate, hydrocortisone sodium Succinate, hydrocortisone Immunoregulator: azarole, fanetizole mesylate, frentizole, Valerate, medrysone, methylprednisolone, methylpredniso oxamisole hydrochloride, ristianol phosphate, thymopentin, lone acetate, methylprednisoloime sodium phosphate, meth tilomisole. ylprednisolone sodium Succinate, nivaZol, paramethasone Immunostimulant: loxoribine, teceleukin. acetate, prednicarbate, prednisolone, prednisolone acetate, Immunosuppressant: azathioprine, azathioprine Sodium, prednisolone hemisuccinate, prednisolone sodium phos cyclosporine, daltroban, gusperimus trihydrochloride, siroli phate, prednisolone sodium Succinate, prednisolone tebutate, mus, tacrolimus. prednisone, prednival, ticabesone propionate, tralonide, tri Impotence therapy adjunct: deleguamine hydrochloride. amcinolone, triamcinolone acetonide, triamcinolone Inhibitor: acarbose, atorvastatin calcium, benserazide, bro acetonide Sodium, triamcinolone diacetate, triamcinolone 10 cresine, carbidopa, clavulanate potassium, daZmegrel, doce hexacetonide. benone, epoprostenol, epoprostenol Sodium, epristeride, fin Gonad-stimulating principle: buserelin acetate, clomi asteride, flurbiprofen sodium, furegrelate sodium, lufironil, phene citrate, ganirelix acetate, gonadorelin acetate, gona miglitol, orlistat, pimagedine hydrochloride, pirmagrel, dorelin hydrochloride, gonadotropin, chorionic, menotro ponalrestat, ridogrel, Sulbactam benzathine, Sulbactampiv pins. 15 oxil, Sulbactam Sodium, Suronacrine maleate, taZobactam, Hair growth stimulant: minoxidil. taZobactam Sodium, ticlopidine hydrochloride, tirilazad Hemostatic: aminocaproic acid, oXamarin hydrochloride, mesylate, tolrestat, Velnacrine maleate, Zifrosilone, Zileuton. Sulmarin, thrombin, tranexarnic acid. Keratolytic: alcloxa, aldioxa, benzoyl peroxide, diben Histamine H2 receptor antagonists: ranitidine (ZAN Zothiophene, etarotene, isotretinoin, motretinide, picotrin TACTM), famotidine (PEPCIDTM), cimetidine (TAGA diolamine, resorcinol, resorcinol monoacetate, Salicylic acid, METTM), nizatidine (AXIDTM). Sumarotene, tazarotene, tetroquinone, tretinoin. Hormone: diethylstilbestrol, progesterone, 17 hydroxy LHRL agonist: deslorelin, goserelin, histrelin, lutrelin progesterone, medroxyprogesterone, norgestrel, norethyno acetate, nafarelin acetate. drel, estradiol, megestrol (megace), norethindrone, levonorg Liver disorder treatment: malotilate. estrel, ethyndiol, ethinyl estradiol, mestranol, estrone, equi 25 Luteolysin: femprostalene. lin, 17 alpha dihydroequilin, equilenin, 17 alpha Memory adjuvant: dimoxamine hydrochloride, ribaminol. dihydroequilenin, 17 alpha estradiol, 17 beta estradiol, leu Mental performance enhancer: aniracetam. prolide (LUPRONTM), glucagon, testolactone, clomiphene, Mood regulator: fengabine. human menopausal gonadotropins, human chorionic gona Mucolytic: acetylcysteine, carbocysteine, domiodol. dotropin, urofollitropin, bromocriptine, gonadorelin, lutein 30 Mucosal protective agents: misoprostol (CYTOTECTM). izing hormone releasing hormone and analogs, gonadotro Mydriatic: berefrine. pins, danazol, testosterone, dehydroepiandrosterone, Nasal decongestant: nemazoline hydrochloride, pseu androstenedione, dihydroestosterone, relaxin, oxytocin, doephedrine polistirex. vasopressin, folliculostatin, follicle regulatory protein, gona Neuroleptic: duoperone fumarate, risperidone. doctrinins, oocyte maturation inhibitor, insulin growth factor, 35 Neuromuscular blocking agent: atracurium besylate, cisa follicle stimulating hormone, luteinizing hormone, tamox tracurium besylate, doxacurium chloride, gallamine triethio ifen., corticorelin ovine trifiutate, cosyntropin, metogest, dide, metocurine iodide, mivacurium chloride, pancuronium pituitary, posterior, seractide acetate, Somalapor, somatrem, bromide, pipecuronium bromide, rocuronium bromide, Suc Somatropin, somenopor, somidobove. cinylcholine chloride, tubocurarine chloride, vecuronium Hypocholesterolemic: lifibrol. 40 bromide. Hypoglycemic: darglitaZone sodium: glimepiride. Neuroprotective: dizocilpine maleate. Hypolipidemic: azalanstat dihydrochloride, colestolone, NMDA antagonist: selfotel. Surfomer, Xenalipin. Non-hormonal sterol derivative: pregnenolone succinate. Hypotensive: viprostol. Oxytocic: carboprost, carboprost methyl, carboprost Hmgcoa reductase inhibitors: lovastatin (MEVACORTM), 45 tromethamine, dinoprost, dinoprost tromethamine, dinopro simvastatin (ZOCORTM), pravastatin (PRAVACHOLTM), flu stone, ergonovine maleate, meteneprost, methylergonovine vasatin (LESCOLTM). maleate, oxytocin, Sparteine Sulfate. Immunizing agent: antirabies serum, antivenin (latrodec Plasminogen activator: alteplase, urokinase. tus mactans), antivenin (micrurus fulvius), antivenin (crotal Platelet activating factor antagonist: lexipafant. idae) polyvalent, BCG vaccine, botulism antitoxin, cholera 50 Platelet aggregation inhibitor: acadesine, beraprost, bera vaccine, diphtheria antitoxin, diphtheria toxoid, diphtheria prost sodium, ciprostene calcium, itaZigrel, lifarizine, toxoid adsorbed, globulin, immune, hepatitis b immune OXagrelate. globulin, hepatitis B virus Vaccine inactivated, influenza virus Post-stroke and post-head trauma treatment: citicoline vaccine, measles virus vaccine live, meningococcal polysac Sodium. charide vaccine group A, meningococcal polysaccharide vac 55 Potentiator: pentostatin, talopram hydrochloride. cine group C, mumps virus vaccine live, pertussis immune Progestin: algestone acetophenide, amadinone acetate, globulin, pertussis vaccine, pertussis vaccine adsorbed, anagestone acetate, chlormadinone acetate, cingestol, cloge plague vaccine, poliovirus vaccine inactivated, poliovirus stone acetate, clomegestone acetate, desogestrel, dimethister vaccine live oral, rabies immune globulin, rabies vaccine, Rh one, dydrogesterone, ethynerone, ethynodiol diacetate, (D) immune globulin, rubella virus vaccine live, Smallpox 60 etonogestrel, fluorogestone acetate, gestaclone, gestodene, vaccine, tetanus antitoxin, tetanus immune globulin, tetanus gestonorone caproate, gestrinone, haloprogesterone, hydrox toxoid, tetanus toxoid adsorbed, typhoid vaccine, yellow yprogesterone caproate, levonorgestrel, lynestrenol, fever vaccine, Vaccinia immune globulin, varicella-Zoster medrogestone, medroxyprogesterone acetate, methynodiol immune globulin. diacetate, norethindrone, norethindrone acetate, norethyno Immunomodulator: dimepranol acedoben, imiquimod, 65 drel, norgestimate, norgestomet, norgestrel, oxogestone interferon beta-Ib, lisofylline, mycophenolate mofetil, preza phenpropionate, progesterone, quingestanol acetate, tide copper acetate. quingestrone, tigestol. US 9,096,743 B2 63 64 Prostaglandin: cloprostenol Sodium, fluprostenol Sodium, Selective adenosine alantagonist: apaxifylline. gemeprost, prostalene, Sulprostone. Serotonin antagonist: altanserin tartrate, amesergide, ket Prostate growth inhibitor: pentomone. anserin, ritanserin. Prothyrotropin: protirelin. Serotonin inhibitor: cinanserin hydrochloride, fenclonine, Psychotropic: minaprine. fonazine mesylate, Xylamidine tosylate. Pulmonary surface: beractant, colfosceril palmitate. Serotonin receptor antagonist: tropanserin hydrochloride. Radioactive agent: fibrinogen I'', fludeoxyglucose F. Steroid: dexamethasone aceflirate, mometasone furoate. fluorodopa F, insulin I°, insulin I'', iobenguane I'', Stimulant: amfonelic acid, amphetamine Sulfate, ampyZine iodipamide sodium I'% iodoantipyrine I'96 iodocholes Sulfate, arbutamine hydrochloride, azabon, caffeine, ceru terol I'9% iodohippurate sodium I', iodohippurate sodium 10 letide, ceruletide diethylamine, cisapride, dazopride fuma I', iodohippurate sodium I'9% iodopyracet I', iodopy rate, dextroamphetamine, dextroamphetamine Sulfate, racet I'', iofetamine hydrochloride I'', iomethin I'', difluanine hydrochloride, dimefline hydrochloride, dox iomethin I'9%iothalamate sodium I'', iothalamate sodium apram hydrochloride, etryptamine acetate, ethamivan, fen I'', iotyrosine I'', liothyronine I'', liothyronine I''9% ethylline hydrochloride, flubanilate hydrochloride, fluo merisoprolacetate Hg', merisoprolacetate Hg", meriso 15 rothyl, histamine phosphate, indriline hydrochloride, prol Hg'7, selenomethionine Se7, technetium Tc'" anti mefexamide, methamphetamine hydrochlo ride, meth mony trisulfide colloid, technetium Tc'" bicisate, techne ylphenidate hydrochloride, pemoline, pyrovalerone hydro tium Tc'" disofenin, technetium Tc" etidronate, chloride, Xamoterol. Xamoterol fumarate. technetium Tc'" exametazime, technetium Tc'" furifos Suppressant: amfhutizole, coXchicine, taZofelone. min, technetium Tc" gluceptate, technetium Tc" lidofe Symptomatic multiple Sclerosis: fampiridine. nin, technetium Tc’" mebrofenin, technetium Tc" medr Synergist: proadifen hydrochloride. onate, technetium Tc" medronate disodium, technetium Thyroid hor move: levothyroxine sodium, liothyronine Tc" mertiatide, technetium Tc'" oxidronate, technetium Sodium, liotrix. Tc'" pentetate, technetium Tc'" pentetate calcium triso Thyroid inhibitor: methimazole, propylthiouracil. dium, technetium Tc" sestamibi, technetium Tc'" 25 Thyromimetic: thyromedan hydrochloride. siboroxime, technetium Tc" succimer, technetium Tc'" Tranquilizer: bromazepam, buspirone hydrochloride, sulfur colloid, technetium Tc" teboroxime, technetium chlordiazepoxide, claZolam, clobazam, cloraZepate dipotas Tc" tetrofosmin, technetium Tc" tiatide, thyroxine I'', sium, cloraZepate monopotassium, demoxepam, dexmedeto thyroxine I'', tolpovidone I'', triolein I'', triolein I''. midine, enciprazine hydrochloride, gepirone hydrochloride, Regulator: calcifediol, calcitonin, calcitriol, clodronic 30 hydroxyphenamate, hydroxy Zine acid, dihydrotachysterol, etidronic acid, oxidronic acid, piri Hydrochloride, hydroxy Zine pamoate, ketazolam, dronate sodium, risedronate sodium, secalciferol. lorazepam, lorzafone, loxapine, loxapine succinate, Relaxant: adiphenine hydrochloride, alcuronium chloride, medazepam hydrochloride, nabilone, nisobamate, aminophylline, azumolene sodium, baclofen, benzoctamine oxazepam, pentabamate, piremperone, ripazepam, roliprarn, hydrochloride, carisoprodol, chlorphenesin carbamate, chlo 35 Sulazepam, taciamine hydrochloride, temazepam, trifluba rZoxazone, cinflumide, cinnamedrine, clodanolene, Zam, tybamate, Valnoctamide. cyclobenzaprine hydrochloride, dantrolene, dantrolene Amyotrophic lateral Sclerosis agents: riluzole. sodium, femalamide, fenyripol hydrochloride, fetoxylate Cerebral ischemia agents: dextrorphan hydrochloride. hydrochloride, flavoxate hydrochloride, fletazepam, flume Paget’s disease agents: tiludronate disodium. tramide.-flurazepam hydrochloride, hexafluorenium bro 40 Unstable angina agents: tirofiban hydrochloride. mide, isomylamine hydrochloride, lorbamate, mebeverine UricoSuric: benzbromarone, irtemazole, probenecid, hydrochloride, meSuprine hydrochloride, metaxalone, Sulfinpyrazone. methocarbamol, methixene hydrochloride, nafomine malate, Vasoconstrictor: angiotensin amide, fely pressin, methy neleZaprine maleate, papaverine hydrochloride, pipoxolan. Sergide, methysergide maleate. Hydrochloride, quinctolate, ritodrine, ritodrine hydrochlo 45 Vasodilator: alprostadil, azaclorzine hydrochloride, bam ride, rolodine, theophylline sodium glycinate, thiphenamil ethan sulfate, bepridil hydrochloride, buterizine, cetiedil cit hydrochloride, xilobam. rate, chromonar hydrochloride, clonitrate, diltiazem hydro Repartitioning agent: cimaterol. chloride, dipyridamole, droprenilamine, erythrityl Scabicide: amitraz, crotamiton. tetranitrate, felodipine, flunarizine hydrochloride, fostedil, Sclerosing agent: ethanolamine oleate, morrhuate Sodium, 50 hexobendine, inositol niacinate, iproxamine hydrochloride, tribenoside. isosorbide dinitrate, isosorbide mononitrate, isoXSuprine Sedative: propiomazine. hydrochloride, lidoflazine, mefenidil, mefenidil fumarate, Sedative-hypnotic: allobarbital, alonimid, alprazolam, mibefradil dihydrochloride, mioflazine hydrochloride, mixi amobarbital sodium, bentazepam, brotizolam, butabarbital, dine, nafronyl oxalate, nicardipine hydrochloride, nicer butabarbital sodium, butalbital, capuride, carbocloral, chloral 55 goline, nicorandil, nicotinyl alcohol, nifedipine, nimodipine, betaine, chloral hydrate, chlordiazepoxide hydrochloride, nisoldipine, Oxfenicine, Oxprenolol hydrochloride, pen cloperidone hydrochloride, clorethate, cyprazepam, dex taerythritol tetranitrate, pentoxifylline, pentrinitrol, perhexy clamol hydrochloride, diazepam, dichloralphenaZone, esta line maleate, pindolol, pirsidomine, prenylamine, propatyl Zolam, ethchlorVynol, etomidate, fenobam, flunitrazepam, nitrate, Suloctidil, terodiline hydrochloride, tipropidil hydro fosazepam, glutethimide, halazepam, lormetazepam, meclo 60 chloride, tolaZoline hydrochloride, Xanthinol niacinate. qualone, meprobamate, methaqualone, midaflur, paralde Vulnerary: allantoin. hyde, pentobarbital, pentobarbital sodium, perlapine, Wound healing agent: erSofermin. prazepam, quazepam, reclazepam, roletamide, secobarbital, Xanthine oxidase inhibitor: allopurinol, oxypurinol. secobarbital Sodium, Suproclone, thalidomide, tracazolate, Other pharmaceutical agents include: 1-decpyrrolidinone, trepipam maleate, triazolam, tricetamide, triclofos Sodium, 65 1-dodecpyrrolidinone, 16C.-fluoroestradiol, 16-epiestriol, trimetozine, uldazepam, Zaleplon, Zolazepam hydrochloride, 16C.-gitoxin, 17C. estradiol, 17 Bestradiol. 1 alpha-hydroxyvi Zolpidem tartrate. tamin D2,2'-nor-cGMP, 20-epi-1.25 dihydroxyvitamin D3, US 9,096,743 B2 65 66 22-oxacalcitriol, 20VV, 3-isobutyl GABA, 6-FUDCA, clarithromycin, clausenamide, clebopride, clinafloxacin, clo 7-methoxytacrine, abamectin, abanoquil, abecarnil, abirater bazam, clobetaSone butyrate, clodronic acid, clomethiazole, one, acadesine, acamprosate, acarbose, aceclofenac, aceman clopidogrel, clotrimazole, colestimide, colfosceril palmitate, nan, acetomepregenol, acetyl-L-carnitine, acetylcysteine, collismycin A, collismycin B, combretastatin A4, complesta N-acetylmethadol, acifran, acipimoX, acitemate, acitretin, tin, conagenin, contignasterol, contortrostatin, cosalane, cos aclarubicin, aclatonium, napadisilate, aconiazide, acrivasti tatolide, cotinine, coumermycin A1, cucumariosid, curacin net, adafenoxate, adapalene, adatanserin, adecypenol, ade A, curdlan sulfate, curiosin, cyclazosin, cyclic HPMPC, fovir dipivoxil, adelmidrol, ademetionine, adinazolam, adi cyclobenzaprine, cyclobut A, cyclobut G, cyclocapron, cyclo posin, adoZelesin, adrafinil, alacepril, aladapcin, alaptide, platam, cyclosin, cyclothialidine, cyclothiazomycin, cype albendazole, albolabrin, aldecalmycin, aldesleukin, allen 10 mycin, cyproterone, cytarabine ocfosfate, cytochalasin B, dronic acid, alentemol, alfacalcidol, alfuizosin, alglucerase, dacliximab, dactimicin, daidzein, daidzin, dalfopristin, dalte alinastine, alosetron, alpha idoSone, alprostadil, altretamine, parin Sodium, danaparoid, daphnodorin A, dapiprazole, dapi altromycin B. ambamustine, amelometaSone, ameSergide, tant, darifenacin, darlucin A, darsidomine, ddOTP, decitab amezinium metilsulfate, amfebutamone, amidox, amifloxa ine, deferiprone, deflazacort, dehydrodidemnin B, cin, amifostine, amiodarone, amisulpride, amlexanox, amlo 15 dehydroepiandrosterone, delapril, deleduanine, delfapra dipine, amlodipine, ampiroxicam, aminone, amrubicin, Zine, delmopinol, delphinidin, deoxypyridinoline, depro amsacrine, amylin, amythiamicin, anagrelide, anakinra, done, depsidomycin, deramciclane, dermatan Sulfate, desflu ananain, anaritide, anastroZole, andrographolide, anordrin, rane, desirudin, deslorelin, desmopressin, desogestrel, apadoline, apafant, apaxifylline, aphidicolin glycinate, apra desoxoarniodarone, detajmium bitartrate, dexifosfamide, clonidine, aprosulate Sodium, aptiganel, apurinic acid, arani dexketoprofen, dexloxiglumide, dexmedetomidine, dex dipine, arbekacin, arbidol, arbutamine, ardeparin Sodium, pemedolac, dexraZoxane, dexSotalol, dextrin2-Sulphate, dex arecatannin B1, argatroban, aripiprazol, arotinolol, asimado Verapamil, dezinamide, dezocine, diaziquone, diclofenac line, aspalatone, asperfuran, aspoxicillin, astemizole, asula digolil, diclofenac potassium, dicranin, didemnin B, didox, crine, atamestanie, atenolol, S-atevirdine, atosiban, atova dienogest, diethylhomospermine, diethylnorspermine, dihy quone, atpenin B, atrimustine, atrinositol, aureobasidin A, 25 drexidine, dihydro-5-azacytidine, dimethyl prostaglandin azadirachtine, azasetron, azatyrosine, azelaic acid, azelas A1, dimethylhomospermine, dimiracetam, dioxamycin, tine, azelnidipine, azimilide, azithromycin, aZosemide, aztre diphency prone, diphenyl spiromustine, diprafenone, dipro onam, baccatin III, bacoside A, bacoside B, bactobolamine, pylnorspermine, dirithromycin, discodermolide, disulfuram, balaZipone, balhimycin, balofloxacin, balsalazide, bam ditekiren, docarpamine, docosanol. 1-dofetilide, dolasetron, buterol, baohuoside 1, bamidipine, basifungin, batebulast, 30 domitroban, dopexamine, dorzolamide, doSmalfate, dotariz batimastat, beauvericin, becaplermin, becliconazole, ine, doxacurium chloride, doxazosin, doxifluridine, doxofyl befloxatone, belfosdil, bellenamine, benflumetol, benidipine, line, draculin, draflazine, droloxifene, dronabinol, drosperi benzisoxazole, benzochlorins, benzoidazoxan, benzoylstau done, drotaverine acephyllinate, droxicam, ebiratide, rosporine, benztropine, bepridil, beractant, beraprost, ber ebrotidine, ebselen, ecabapide, ecabet, ecadotril, ecdlisteron, lafenone, bertosamil, besipirdine, beta-alethine, betaclamy 35 echicetin, echistatin, ecomustine, ecteinascidin 722, ectein cin B, betamipron, betaxolol, betulinic acid, bevantolol, ascidin 729, ecteinascidin 743, edaravone, edelfosine, edoba bicalutamide, bifemelane, birnakalim, bimithil, binospirone, comab, edrecolomab, efegatran, eflornithine, efonidipine, bioxalomycin alpha2, biriperone, bis-benzimidazole A, bis egualen, elcatonin, eletriptan, elgodipine, eliprodil, eltenac, benzimidazole B, bisantrene, bisaramil, bisaziridinylsper emakalim, emedastine, emiglitate, emitefur, emoctakin, ena mine, bisnafide, bisoprolol, bistramide D, bistramide K, bis 40 doline hydrochloride, enalapril, enaZadrem, englitaZone, tratene A, boldine, bopindolol, brefeldin, breflate, enlimomab, enoxacin, enoxaparin sodium, enoXimone, enta brimonidine, bromfenac, bromperidol, bropirimine, bucin capone, enterostatin, epoprostenol, epoxymexrenone, epris dolol, budesonide, budipine, budotitane, bunaprolast, teride, eprosartan, eptastigmine, erdosteine, ersentilide, erso bunaZosin, butenafine, buthionine Sulfoximine, butiXocort fermin, erytlritol, esuprone, etanidazole, etanterol, ethacizin, propionate, cadexomer iodine, calanolide A, calcipotriol, 45 ethinylestradiol, etizolam, etodolac, etoposide phosphate, calphostin C, camonagrel, candesartan, candesartan cilexetil, etrabamine, everninomicin, examorelin, exemestane, fadro candoXatril, candoXatrilat, capecitabine, capromab, capsai Zole, faerieflungin, famciclovir, fampiridine, fantofarone, faro cin, captopril, carbazomycin C, carbetocin, carbovir, car penem, fasidotril, fasudil, fazarabine, fedotozine, felbamate, boxamide-amino-triazole, carboxyamidotriazole, carboxym fenofibrate, fenoldopam, fenretinide, fenspiride, fenticona ethylated B-1,3-glucan, carperitide, carteolol, carumonam, 50 Zole, fepradinol, ferpifosate sodium, ferristene, ferrixan, carvedilol, carvotroline, carZelesin, castanospermine, ferumoxsil, fexofenadine, flavopiridol, flecamide, fle cebaracetam, cecropin B, cefcapene pivoxil, cefdaloXime robuterol, fleroxacin, flesinoxan, flezelastine, flobufen, flo pentexiltosilate, cefdinir, cefditoren pivoxil, cefepime, cefe moxef, florfenicol, florifenine, flosatidil, fluasterone, flu tamet, cefetamet pivoxil, cefixime, cefluprenam, cefimneta conazole, fludarabine, flumazenil, flumecinol, flumequine, Zole, cefimninox, cefodizime, cefoselis, cefotetan, cefotiam, 55 flunarizine, fluocalcitriol, fluorodaunorunicin hydrochloride, cefotiam hexetil, cefoZopran, cefpimizole, cefpiramide, cef fluoxetine, R-fluoxetine, S-fluparoxan, flupirtine, flurbipro pirome, cefpodoxime proxetil, cefprozil, cefsulodin, fen axetil, flurithromycin, fluticasone propionate, flutrima cefteram, ceftibuten, cefiriaxone, cefuroxime axetil, cellas Zole, fluvastatin, fluvoxamine, forasartan, forfenimex, form trol, celikalim, celiprolol, cepacidine A, cericlamine, ceriv estane, formoterol, formoterol, R.R-fosfomycin, trometamol. astatin, ceronapril, certoparin Sodium, cetiedil, cetirizine, 60 fosinopril, fosphenyloin, fostriecin, fotemustine, gabapentin, chloroorienticin A, chloroorienticin B, chloroquinoxaline gadobenic acid, gadobutrol, gadodiamide, gadodiamide Sulfonamide, cibenzoline, cicaprost, ciclesonide, cicletanine, EOB-DTPA, gadolinium texaphyrin, gadoteric acid, gadot cicloprolol, cidofovir, cilansetron, cilaZapril, cilnidipine, eridol, gadoversetamide, galantamine, galdansetron, gallo cilobradine, cilostazol, cimetropium bromide, cinitapride, pamil, galocitabine, gamolenic acid, ganirelix, gepirone, cinolazepam, cioteronel, ciprofibrate, ciprofloxacin, cipros 65 gestrinone, girisopam, glaspimod, glaucocalyxin A, glutapy tene, cis-porphyrin, cisapride, cisatracurium besilate, cistin rone, glycopine, glycopril, granisetron, grepafloxacin, hali exine, citalopram, citicoline, citreamicin alpha, cladribine, chondrin B, halofantrine, halomon, halopredone, hatomami US 9,096,743 B2 67 68 cin, hatomarubigin A, hatomarubigin B, hatomarubigin C, pamicogrel, pamidronic acid, panamesine, panaxytriol, hatomarubigin D, ibogaine, ibopamine, ibudilast, illi panipenem, panipenum, pannorin, panomifene, pantethine, maquinone, ilmofosine, illomastat, illoperidone, iloprost, imi pantoprazole, parabactin, pamaparin Sodium, paroxetine, dapril, imidazenil, indinavir, indolidan, indometacin farnesil, parthenolide, paZelliptine, paZufloxacin, pefloxacin, pegas indometacin, tropine ester, indoramin, inocoterone, inogat pargase, peldesine, pemedolac, pemirolast, penciclovir, pen ran, inolimomab, interferon alfa, interferon alfa-2a, inter tafuside, pentamidine, pentamorphone, pentigetide, pen feron alfa-2B, interferon alfa-N 1, interferon alfa-N3, inter tosan, pentostatin, pentroZole, perflubron, perfosfamide, feron B, interferon B-1 A1, interferon B-1B, interferon pergolide, perindoprilat, peroSpirone, phenaridine, phenazi gamma-1A, interferon gamma-1B, interferon omega, inter nomycin, phenserine, phensuccinal, phentolamine mesilate, feron, consensus, interleukin-1, interleukin-1 alpha, interleu 10 phenylacetate, phenylalanylketoconazole, picenadol, piciba kin-1 B, interleukin-10, interleukin-11, interleukin-12, inter nil, picroliv, picumeterol, pidotimod, pilocarpine hydrochlo leukin-12, interleukin-15, interleukin-2, interleukin-3, ride, pilsicamide, pimagedine, pimilprost, pimobendan, pina interleukin-4, interleukin-5, interleukin-7, interleukin-8, cidil, pinocebrin, pioglitaZone, pipecuronium bromide, iobenguane, iobitridol, iodoamiloride, iododoxorubicin, iof pirarubicin, piretanide, pirfenidone, piritrexim, pirlindole, ratol, iomeprol, iopentol, iopromide, iopyrol, iotriside, iover 15 pirmagrel, pirmenol, pirodavir, pirodomast, piroXicam cin Sol, ioxilan, ipazilide, IpdR, ipenoxaZone, ipidacrine, namate, propagermanium, propentofylline, propionylcam ipomeanol, 4-ipriflavone, ipsapirone, irbesartan, irinotecan, itine, L-propiram, propiram +paracetamol, propiverine, pro irloxacin, irsogladine, irtemazole, isalsteine, isbogrel, isepa pyl bis-acridone, prostaglandin J2, prostratin, protegrin, micin, isobengaZole, isofloxythepin, isohomohalicondrin B, protoSufloxacin, prulifloxacin, pyrazoloacridine, quazepam, isopropyl unoprostone, isradipine, itameline, itasetron, ito quetiapine, quiflapon, quinagolide, quinapril, quinfamide, pride, itraconazole, ketoprofen, R-ketoprofen, S-ketorolac, quinupristin, raloxifene, raltitrexed, ramatroban, ramipril, lacidipine, lactitol, lactivicin, laennec, lafutidine, lamel ramosetron, ranelic acid, ranitidine bismuth citrate, ranola rarin-N triacetate, lamifiban, lamivudine, lamotrigine, lano Zine, recainam, regavirumab, relaxin, repirinast, resinfera conazole, lanperisone, lanreotide, lanSoprazole, latanoprost, toxin, reticulon, reviparin sodium, revizinone, ricasetron, lateritin, laurocapram, lazabemide, lemefloxacin, lemil 25 ridogrel, rifabutin, rifapentine, rifaximin, rilopiroX, riluzole, dipine, leminoprazole, lenercept, lenograstim, lentinan Sul rimantadine, rimexolone, rimoprogin, riodipine, ripisartan, fate, leptin, leptolstatin, lercanidipine, lerisetron, lesopitron, risedronic acid, rispenzepine, risperidone, ritanserin, riti letraZuril, letrozole, leucomyzin, leuprorelin, levcromakalim, penem, ritipenemacoxil, ritolukast, ritonavir, rizatriptan ben levetiracetam, levobetaxolol, levobunolol, levobupivacaine, Zoate, rohitukine, rokitamycin, ropinirole, ropivacaine, levocabastine, levocamitine, levodropropizine, levofloxacin, 30 roquinimex, roXatidine, roXindole, roXithromycin, rubigi levomoprolol, levonorgestrel, leVormeloxifene, levosimen none B1, ruboxyl, rufloxacin, rupatidine, ruzadolane, Safin dan, levosulpiride, linotroban, linsidomine, lintitript, linto gol, safironil, saintopin, salbutamol, R-salmeterol, salme pride, liothyronine sodium, lirexapride, lisinopril, lobaplatin, terol, R-sainacedin, Sameridine, Sampatrilat, Sanfetrinem, lobucavir, lodoxamide, lombricine, lomefloxacin, lomeriZ Saprisartan, sapropterin, saquinavir, sarcophytol A Sargra ine, lometrexol, lonazolac, lonidamine, loracarbef, lorata 35 mostim, Sarpogrelate, Saruplase, Saterinone, satigrel, Satumo dine, lorglumide, lornoxicam, losartan, losigamone, losox mab pendetide, selegiline, selenium thiosemicarbazone, antrone, loteprednol, loviride, loxoribine, lubeluzole, sematilide, semduramicin, Semotiadil, Semustine, sermore lurtotecan, luteinizing hormone, lutetium, luZindole, lydica lin, Sertaconazole, sertindole, Sertraline, setiptiline, mycin, lysofylline, lysostaphin, magainin2 amide, magnolol. Sevirumab, sevoflurane, seZolamide, silipide, silteplase, sim mallotochromene, mallotojaponin, malotilate, mangafodipir, 40 endan, simvastatin, sinitrodil, sinnabidol, sipatrigine, siroli manidipine, maniwamycin A, mannostatin A, manumycin E, mus, sizofuran, Somatomedin B. Somatomedin C. Somatrem, manumycin F. mapinastine, marimastat, masoprocol, Somatropin, Sonermin, Stalol, staurosporine, stavudine, maspin, massetolide, meterelin, methoxatone, methylhista stepronin, stipiamide, Stiripentol, Stobadine, Succibun, mine, R-alpha, methylinosine monophosphate, methylpred Sucralfate, Sulfasalazine, Sulfmosine, Sulfoxamine, nisolone aceponate, methylprednisolone Suleptanate, metipa 45 Sulopenem, Sultamicillin, Sultopride, Sulukast, Sumatriptan, mide, metoclopramide, metoprolol. S-metrifonate, Symakalim, tandospirone, tapgen, taprostene, tasosartan, mibefradil, michellarnine B, microcolin A, midodrine, mife taZanolast, tazarotene, teicoplanin, telenzepine, tellurapyry pristone, miglitol, millacemide, milameline, mildronate, mil lium, telmesteine, telmisartan, temocapril, temoporfin, temo nacipran, milrinone, miltefosine, minaprine, miokamycin, Zolomide, tenidap, teniposide, tenosal, tenoxicam, tepirin mipragoside, mirfentanil, mirimostim, mirtazapine, miso 50 dole, tepoxalin, teraZosin, terbinafine, terfenadine, prostol, mitoguaZone, mitolactol, mitonafide, mitoxantrone, terflavoxate, terguride, terlakiren, terlipressin, terodiline, ter mivacurium chloride, mivaZerol, mixanpril, mizolastine, tatolol, testosterone buciclate, tetrachlorodecaoxide, tetra mizoribine, moclobemide, modafinil, moexipril, mofarotene, Zomine, thaliblastine, thalidomide, thiocoraline, thiofedrine, mofeZolac, molgramoStim, mometasone, montirelin, mopi thiomarinol, thioperamide, thyroid stimulating hormone, damol, moracizine, mosapramine, mosapride, motilide, mox 55 tiagabine, tianeptine, tiapafant, tibolone, ticlopidine, tienox iraprine, moxonidine, nadifloxacin, nadroparin calcium, olol, tilisolol, tilnoprofen arbamel, tiludronic acid, tinzaparin nafadotride, nafamo.stat, nafarelin, naftopidil, naglivan, Sodium, tiotropium bromide, tipredane, tiqueside, tirandaly nagreStip, nalmefene, naphterpin, napsagatran, naratriptan, digin, tirapazamine, tirilazad, tirofiban, tiropramide, topsen nartograstim, nasaruplase, nateplase, niperotidine, nirav tin, torasemide, toremifene, to Sufloxacin, trafermin, trandola oline, nisamycin, nisin, nisoldipine, nitazoxanide, niteca 60 pril, traXanox, tretinoin, tretinoin tocoferil, triacetyluridine, pone, nitrendipine, nitrendipine, S-nitrofurantoin monohy tricaprilin, trichohyalin, trichosanthin, alpha, triciribine, tri drate, nitrullyn, nizatidine, ofloxacin, okicenone, olanzapine, entine, triflavin, trimegestone, triptorelin, troglitaZone, trom olopatadine, olprinone, olSalazine, omeprazole, onapristone, bodipine, tropisetron, trospectomycin, trovafloxacin, troVir ondansetron, ondansetron, R-OntaZolast, oracin, otenZepad, dine, tucaresol, tulobuterol, tylogenin, urapidil, uridine oxaliplatin, oxamisole, Oxandrolone, oxaprozin, oxaunomy 65 triphosphate, Valaciclovir, Valproate magnesium, valproate cin, oXcarbazepine, oxiconazole, oxiracetam, oxodipine, oza semisodium, Valsartan, Vamicamide, Vanadeine, Vaminolol. grel, palauamine, palinavir, palmitoylrhizoxin, pamaqueside, Vapreotide, variolin B. velaresol, Venlafaxine, Veramine, US 9,096,743 B2 69 70 Verapamil, S-Verdins, Veroxan, Verteporfin, Vesnarinone, nine, flumequine, fosfomycin, fosfomycin tromethamine, Vexibinol, vigabatrin, vinbumine citrate, vinburnine resinate, fumoxicillin, furazolium chloride, furazolium tartrate, fusi Vinconate, Vinorelbine, Vinpocetine, Vinpocetine citrate, Vin date Sodium, fusidic acid, gentamicin Sulfate, gloXimonam, toperol, Vinxaltine, Voriconazole, Vorozole, Voxergolide, gramicidin, haloprogin, hetacillin, hetacillin potassium, Xemilofiban, Ximoprofen, yangambin, Zabicipril, Zacopride, hexedine, ibafloxacin, imipenem, isoconazole, isepamicin, Zacopride, R-Zafirlukast, Zalcitabine, Zaleplon, Zalospirone, isoniazid, josamycin, kanamycin Sulfate, kitasamycin, levo Zaltoprofen, Zanamivir, Zankiren, Zanoterone, Zatebradine, furaltadone, levopropylcillin potassium, lexithromycin, lin Zatosetron, Zenarestat, Zeniplatin, Zifrosilone, Zilascorb, comycin, lincomycin hydrochloride, lomefloxacin, lom Zileuton, Zinostatin stimalamer, Ziprasidone, Zoledronic acid, efloxacin hydrochloride, lomefloxacin mesylate, loracarbef, Zolmitriptan, Zolpidem, Zonisamide, Zopiclone, Zopiclone, 10 mafenide, meclocycline, meclocycline Sulfosalicylate, mega S-Zopolrestat, Zotepine. lomicin potassium phosphate, medulidox, meropenem, meth When antibacterial activity is a desired property of the acycline, methacycline hydrochloride, methenamine, meth disclosed films, fibers, or beads, one or more of the following enamine hippurate, methenamine mandelate, methicillin can be an used as an adjunct ingredient. Further examples of Sodium, metioprim, metronidazole hydrochloride, metron Suitable antibacterial agents include, but are not limited to, 15 idazole phosphate, mezlocillin, meZlocillin Sodium, minocy acedapsone, acetosulfone sodium, alamecin, alexidine, amdi cline, minocycline hydrochloride, mirincamycin hydrochlo nocillin, amdinocillin pivoxil, amicycline, amifloxacin, ami ride, monensin, monensin Sodiumr, nafcillin Sodium, floxacin meSylate, amikacin, amikacin Sulfate, aminosali nalidixate sodium, nalidixic acid, natainycin, nebramycin, cylic acid, aminosalicylate Sodium, amoxicillin, neomycin palmitate, neomycin Sulfate, neomycin unde amphomycin, amplicillin, amplicillin Sodium, apalcillin cylenate, netilmicin Sulfate, neutramycin, nifuiradene, Sodium, apramycin, aspartocin, astromicin Sulfate, avilamy nifuraldezone, nifuratel, nifuratrone, nifurdazil, nifurimide, cin, avoparcin, azithromycin, azlocillin, azlocillin Sodium, nifiupirinol, nifurquinazol, nifurthiazole, nitrocycline, nitro bacampicillin hydrochloride, bacitracin, bacitracin methyl furantoin, nitromide, norfloxacin, novobiocin Sodium, ene disalicylate, bacitracin Zinc, bambermycins, benzoylpas ofloxacin, onnetoprim, oxacillin Sodium, oximonam, oxi calcium, berythromycin, betamicin Sulfate, biapenem, binira 25 monam Sodium, oxolinic acid, oxytetracycline, oxytetracy mycin, biphenamine hydrochloride, bispyrithione mag cline calcium, oxytetracycline hydrochloride, paldimycin, Sulfex, butikacin, butirosin Sulfate, capreomycin Sulfate, car parachlorophenol, paulomycin, pefloxacin, pefloxacin mesy badox, carbenicillin disodium, carbenicillin indanyl Sodium, late, penamecillin, penicillin G benzathine, penicillin G carbenicillin phenyl Sodium, carbenicillin potassium, caru potassium, penicilling procaine, penicilling sodium, peni monam sodium, cefaclor, cefadroxil, cefamandole, cefaman 30 cillin V, penicillin V benzathine, penicillin V hydrabamine, dole nafate, cefamandole Sodium, cefaparole, cefatrizine, penicillin V potassium, pentizidone sodium, phenyl ami cefazafiur sodium, cefazolin, cefazolin sodium, cefbupera nosalicylate, piperacillin sodium, pirbenicillin sodium, piri Zone, cefdinir, cefepime, cefepime hydrochloride, cefetecol, dicillin Sodium, pirlimycin hydrochloride, pivampicillin cefixime, cefimenoXime hydrochloride, cefimetazole, hydrochloride, pivampicillin pamoate, pivampicillin cefnetazole Sodium, cefonicid monosodium, cefonicid 35 probenate, polymyxin B sulfate, porfiromycin, propikacin, Sodium, cefoperaZone sodium, ceforanide, cefotaxime pyrazinamide, pyrithione Zinc, quindecamine acetate, quinu Sodium, cefotetan, cefotetan disodium, cefotiam hydrochlo pristin, racephenicol, ramoplanin, ranimycin, relomycin, ride, cefoxitin, cefoxitin Sodium, cefpimizole, ce?pimizole repromicin, rifabutin, rifametane, rifamexil, rifamide, Sodium, cefpiramide, ce?piramide Sodium, cefpirome Sulfate, rifampin, rifapentine, rifaximin, rollitetracycline, rollitetracy cefpodoxime proxetil, cefprozil, cefroxadine, cefsulodin 40 cline nitrate, rosaramicin, rosaramicin butyrate, rosaramicin Sodium, ceftazidime, ceftibuten, ceftizoxime Sodium, ceftri propionate, rosaramicin Sodium phosphate, rosaramicin aXone sodium, cefuroxime, cefuroxime axetil, cefuroxime Stearate, roSoxacin, roXarsone, roXithromycin, sancycline, pivoxetil, cefuroxime Sodium, cephacetrile sodium, cephal Sanfetrinem Sodium, Sarmoxicillin, Sarpicillin, scopafungin, exin, cephalexin hydrochloride, cephaloglycin, cephalori Sisomicin, Sisomicin Sulfate, sparfloxacin, spectinomycin dine, cephalothin Sodium, cephapirin Sodium, cephradine, 45 hydrochloride, spiramycin, stallimycin hydrochloride, Steffi cetocycline hydrochloride, cetophenicol, chloramphenicol, mycin, Streptomycin Sulfate, streptonicoZid, SulfabenZ, Sul chloramphenicol palmitate, chloramphenicol pantothenate fabenzamide, Sulfacetamide, Sulfacetamide Sodium, Sulfacy complex, chloramphenicol sodium Succinate, chlorhexidine tine, Sulfadiazine, Sulfadiazine sodium, Sulfadoxine, phosphanilate, chloroxylenol, chlortetracycline bisulfate, Sulfalene, Sulfamerazine, Sulfameter, Sulfamethazine, Sul chlortetracycline hydrochloride, cinoxacin, ciprofloxacin, 50 famethizole, Sulfamethoxazole, Sulfamonomethoxine, Sulfa ciprofloxacin hydrochloride, cirolemycin, clarithromycin, moXole, Sulfanilate Zinc, Sulfanitran, SulfaSalazine, Sulfa clinafloxacin hydrochloride, clindamycin, clindamycin Somizole, Sulfathiazole, Sulfazamet, Sulfisoxazole, hydrochloride, clindamycin palmitate hydrochloride, clinda Sulfisoxazole acetyl, Sulfisboxazole diolamine, Sulfomyxin, mycin phosphate, clofazimine, cloxacillin benZathine, clox Sulopenem, Sultamricillin, Suncillin sodium, talampicillin acillin Sodium, cloxyquin, colistimethate sodium, colistin 55 hydrochloride, teicoplanin, temafloxacin hydrochloride, Sulfate, coumermycin, coumermycin Sodium, cyclacillin, temocillin, tetracycline, tetracycline hydrochloride, tetracy cycloserine, dalfopristin, dapsone, daptomycin, demeclocy cline phosphate complex, tetroXoprim, thiamphenicol, cline, demeclocycline hydrochloride, demecycline, denofun thiphencillin potassium, ticarcillin cresyl Sodium, ticarcillin gin, diaveridine, dicloxacillin, dicloxacillin Sodium, dihy disodium, ticarcillin monosodium, ticlatone, tiodonium chlo drostreptomycin Sulfate, dipyrithione, dirithromycin, 60 ride, tobramycin, tobramycin Sulfate, to Sufloxacin, trimetho doxycycline, doxycycline calcium, doxycycline fosfatex, prim, trimethoprim Sulfate, trisulfapyrimidines, troleando doxycycline hyclate, droxacin Sodium, enoxacin, epicillin, mycin, trospectomycin Sulfate, tyrothricin, Vancomycin, epitetracycline hydrochloride, erythromycin, erythromycin Vancomycin hydrochloride, Virginiamycin, and Zorbamycin. acistrate, erythromycin estolate, erythromycin ethylsucci Penicillin G, which is used as an antibacterial agent for infec nate, erythromycin gluceptate, erythromycin lactobionate, 65 tions including pneumonia, meningitis, and skin, bone, joint, erythromycin propionate, erythromycin Stearate, ethambutol stomach, blood, and heart valve infections, is a particular hydrochloride, ethionamide, fleroxacin, floxacillin, fludala example suitable for use herein. tazobactum, sold under the US 9,096,743 B2 71 72 trade names ZOSYNTM and TAZOCINTM, ceftrioxone, sold sulfuron, rimsulfuron, thifensulfuron-methyl, triflusulfuron, under the trade name ROCEPHINTM, and metronidazol, sold N-(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl-2-dim under the trade name FLAGYLTM, are also used to treat ethylaminocarbonyl-5-formylaminobenzenesulfonamide bacterial infections and are further examples of suitable com (Foramsulfuron), and the like. Still further, suitable herbi pounds that can be used to prepare the disclosed ionic liquids. cides include inhibitors of the photosynthesis electron trans When antiviral activity is a desired property of the dis port Such as ametryne, atrazine, bromoxynil, cyanazine, diu closed films, fibers or beads, one or more of the following ron, hexaZinone, metribuzin, pyridate, terbuthylazine, and the antivirals can be used as an adjunct ingredient. Examples of like. In yet further examples, suitable herbicides for the dis suitable antiviral actives include, but are not limited to, ace closed ionic liquids include synthetic auxins such as copy mannan, acyclovir, acyclovir Sodium, adefovir, alovudine, 10 ralid, dicamba, diflufenZopyr, fluoroxypyr, and the like. alvircept Sudotox, amantadine hydrochloride, aranotin, aril Inhibitors offatty acid biosynthesis, such as butylate, EPTC, done, atevirdine mesylate, pyridine, cidofovir, cipamfylline, fenoxaprop-P-ethyl, and the like, can also be used in the cytarabine hydrochloride, delavirdine mesylate, desciclovir, disclosed ionic liquid compositions. In other examples, Suit didanosine, disoxaril, edoxudine, enviradene, enviroXime, able herbicides can include inhibitors of cell division such as famciclovir, famotine hydrochloride, fiacitabine, fialuridine, 15 acetochlor, alachlor, dimethenamid, flufenacet, mefenacet, fosarilate, foScarnet sodium, fosfonet Sodium, ganciclovir, metolachlor, S-metolachlor, thenylchlor, and the like. In still ganciclovir Sodium, idoxuridine, kethoxal, lamivudine, lobu other examples, the herbicide can be an inhibitor of protopor cavir, memotine hydrochloride, methisaZone, nevirapine, phyrinogen oxidase, Such as fluthiacet-methyl, carfentra penciclovir, pirodavir, ribavirin, rimantadine hydrochloride, Zone-ethyl, and the like. Inhibitors of hydroxyphenylpyruvate saquinavir meSylate, Somantadine hydrochloride, Sorivudine, dioxygenase, Such as isoxaflutole, mesotrione, Sulcotrione, statolon, stavudine, tillorone hydrochloride, trifluridine, Vala 4-(4-trifluoromethyl-2-methylsulfonylbenzoyl)-5-hydroxy cyclovir hydrochloride, Vidarabine, Vidarabine phosphate, 1-methyl-3-methylpyrazole, and the like, can also be used. Vidarabine Sodium phosphate, ViroXime, Zalcitabine, Zidovu Further examples of suitable herbicides include, but are not dine, Zinviroxime, and Tamiflu. limited to, glyphosate, pendimethalin, trifluralin, asulam, tri When pesticidal activity is a desired property of the dis 25 aziflam, diflufenican, glufosinate-ammonium, and the like. closed films, fibers, or beads, one or more of the following Clofencet, fluoroxpyr, mesosulfuron, diflufenzopyr are fur pesticides can be used as an adjunct ingredient. Included ther examples of suitable herbicides and they are FDA within the meaning of "pesticide' are insecticides and fungi approved. cides. Examples of suitable pesticides include, but are not In addition to the pharmaceutical, antibacterial, antiviral, limited to, carfentraZone-ethyl, SulfentraZone, clomaZone, 30 pesticidal, and herbicidal ingredients disclosed herein, other diclofop-methyl, oxamyl propargite, prosulfuron, pyridate, compounds that are Suitable as adjunct ingredients include pyriftalid, S-metolachlor, simazine, terbuthylazine, ter the food additives Allura Red AC (FD&C Red No. 40), Tar butryn, triasulfuron, trifloxysulfuron, trinexapac-ethyl, trazine (FD&C Yellow No. 5), Indigotine (FD&C Blue No. ametryn, atrazine, benoxacor, bifenthrin, butafenacil, choline 2), Erythrosine (FD&C Red No. 3), and Sunset Yellow azide, chlortoluron, cinosulfuron, clodinafop, cloquintocet, 35 (FD&C Yellow No. 6), which are FDA-approved color addi DEET, desmetryn, dicamba, dimethachlor, dimethametryn, tives for food use. Further, nutraceuticals such as fatty acids, DTPA NaFe, EDDHA NaFe, fenclorim, flumetralin, flu cholesterols, vitamins, minerals, and trace elements can be ometuron, fluthiacetimethyl, halosulfuron, isoproturon, meto adjunct ingredients. bromuron, metolachlor, norflurazon, oxasulfuron, pipero Agrochemicals, neutraceuticals, oil dispersant can also phos, pretilachlor, primisulfuron, prometryn, propaquizafop, 40 been used as an adjunct ingredients. Other Suitable active acilbenzolar-s-methyl, chlorothalonil, cyproconazole, ingredients that can be used as adjunct ingredients herein are cyprodinil, difenoconazole, fempropidin, fenpropimorph, disclosed in U.S. Application 20070093462, which is incor furalaxyl, metalaxyl, metalaxyl-m, oxadixyl, penconazole, porated by reference herein in its entirety for its teachings of propiconazole, pyrifenox, thiabendazol, abamectin, bro active Substances. mopropylate, cypermethrin, cypermethrin high-cis, cyro 45 Other advantages which are obvious and which are inher mazine, diafenthiuron, diazinon, dichlorvos, disulfoton, ema ent to the invention will be evident to one skilled in the art. It mectinbenzoate, fenoxycarb, formothion, furathiocarb, will be understood that certain features and sub-combinations lufenuron, methidathion, permethrine, codilemone, phospha are of utility and may be employed without reference to other midon, profenofos, pymetrozine, quinalphos, terrazole, thia features and Sub-combinations. This is contemplated by and methoxam, thiocyclam, thiometon, triallate, trifloxystrobin, 50 is within the scope of the claims. Since many possible Vinclozolin, Zetacy permethrin, and the like. Prohexadione is a embodiments may be made of the invention without depart FDA approved reduced risk fungicide and is also useful for ing from the scope thereof, it is to be understood that all the disclosed ionic liquids. Further examples of suitable pes matter herein set forth or shown in the accompanying draw ticides can be found in The Pesticide Manual, 11" Edition, ings is to be interpreted as illustrative and not in a limiting British Crop Protection Council, 1997, which is incorporated 55 SS. by reference herein at least for its teaching of pesticides. When herbicidal activity is a desired property of the dis What is claimed is: closed films, fibers or beads, one or more of the ions in the 1. A process for preparing chitin films, fibers, or beads, disclosed ionic liquids can be a herbicide. Examples of Suit comprising: able herbicides include, but are not limited to, carfentraZone, 60 a) contacting an ionic liquid with a chitinous biomass to imazapyr, benefin, acifluorfen, and 2-2-chloro-3-(2.2.2-trif form a residue and a chitin comprising solution, wherein luoroethoxymethyl)-4-methylsulfonylbenzoyl-cyclohex the ionic liquid comprises a cation and an anion, wherein ane-1. the cation is 3-ethyl-1-methyl-1H-imidazol-3-ium and Other suitable herbicides include inhibitors of the biosyn the anion is a Cls carboxylate; thesis of branched amino acids such as ethoxysulfuron, flu 65 b) adding a coagulant to the solution formed in step (a) and metSulam, halosulfuron, imaZamox, imazapyr, imaZaquin, casting the chitin comprising Solution into a film, a fiber, imazethapyr, metoSulam, nicosulfuron, primisulfuron, pro or a bead. US 9,096,743 B2 73 74 2. The process according to claim 1, further comprising 13. The process according to claim 10, wherein in step (b) adding an adjunct ingredient to the chitin comprising Solu the second solution is free of undissolved solids. tion, wherein the adjunct ingredient is one or more pharma 14. The process according to claim 10, wherein the first ceuticals, herbicides, insecticides, food ingredient, antibiotic, coagulant is chosen from water or a C-C linear or branched fatty acid, vitamin, or mineral. 3. The process according to claim 1, wherein the ionic alcohol. liquid is 3-ethyl-1-methyl-1H-imidazol-3-ium acetate. 15. The process according to claim 10, wherein the first 4. The process according to claim 1, wherein the chitinous coagulant is a mixture of water and one or more C-C linear biomass is chosen from practical grade chitin, shrimp shells, or branched alcohols. or crab shells. 16. The process according to claim 10, wherein the regen 5. The process according to claim 1, wherein the chitinous 10 erated chitin in step (d) is isolated by filtration or centrifuga biomass is dissolved or dispersed in the ionic liquid at a tion. temperature of from about 70° C. to about 130° C. 17. The process according to claim 10, wherein the second 6. The process according to claim 1, wherein the coagulant ionic liquid is 3-ethyl-1-methyl-1H-imidazol-3-ium acetate. is chosen from water or a C-C linear or branched alcohol. 18. The process according to claim 10, wherein the regen 7. The process according to claim 1, wherein the coagulant 15 is a mixture of water and one or more C-C linear or erated chitin is dissolved or dispersed in step (e) in the second branched alcohols. ionic liquid at a temperature of from about 70° C. to about 8. The process according to claim 1, wherein a co-solvent 130° C. is added in step (a). 19. The process according to claim 10, wherein the second 9. The process according to claim8, wherein the co-solvent coagulant is chosen from water or a C-C linear or branched is dimethylsulfoxide, DMSO. alcohol. 10. A process for preparing chitin films, comprising: 20. The process according to claim 10, wherein the second a) dissolving or dispersing a source of chitin inan first ionic coagulant is a mixture of water and one or more C-C linear liquid to form a first solution wherein the ionic liquid or branched alcohols. comprises a cation and an anion, wherein the cation is 3-ethyl-1-methyl-1H-imidazol-3-ium and the anion is a 25 21. A mixture of chitinous biomass and an ionic liquid, Cs carboxylate; wherein the ionic liquid comprises a cation and an anion, b) separating any undissolved material to form a second wherein the cation is 3-ethyl-1-methyl-1H-imidazol-3-ium Solution; and the anion is a Cls carboxylate. c) adding a first coagulant to the second solution to form 22. The mixture of claim 21, wherein the ionic liquid is regenerated chitin; 30 3-ethyl-1-methyl-1H-imidazol-3-ium acetate. d) isolating the regenerated chitin; 23. The mixture of claim 22, wherein the chitinous biomass e) redissolving the regenerated chitin in a second ionic is selected from the group consisting of practical grade chitin, liquid; and shrimp shells, and crab shells. f) adding a second coagulant and casting the regenerated 24. A chitin fiber, wherein the fiber is pulled from a mixture chitin from step (e) into a film, a fiber, or a bead. 35 11. The process according to claim 10, wherein the source of crustacean shells and the ionic liquid is 3-ethyl-1-methyl of chitin is chosen from practical grade chitin, shrimp shells, 1H-imidazol-3-ium acetate. or crab shells. 25. The mixture of claim 21, further comprising an adjunct 12. The process according to claim 10, wherein the source ingredient, wherein the adjunct ingredient is one or more of of chitin is dissolved or dispersed in the organic solvent or 40 pharmaceutical, herbicide, insecticide, food ingredient, anti first ionic liquid at a temperature of from about 0°C. to about biotic, fatty acid, vitamin, or mineral. 500 C. k k k k k