US007452555B2

(12) United States Patent (10) Patent No.: US 7452,555 B2 Childs (45) Date of Patent: Nov. 18, 2008

(54) COCRYSTALLIZATION International Search Report and Written Opinion, dated Jul.18, 2005, from International Application No. PCT/US04/01699. (75) Inventor: Scott L. Childs, Atlanta, GA (US) Aakeroy, C. B. Acta Crystallogr: Sect. B-Struct. Sci. 1997, 53, 569 586. (73) Assignee: S.S.C.I., Inc., West Lafayette, IN (US) Aakeroy, C.B.; Evans, T. A.; Seddon, K. R.; Palinko, I. New J. Chem. 1999, 23, 145-152. Aullon, G.; Bellamy, D.; Brammer, L.; Bruton, E. A.; Orpen, A. G. (*) Notice: Subject to any disclaimer, the term of this Chem. Commun. 1998, 653-654. patent is extended or adjusted under 35 Bartoszak-Adamska, E.; Wojciechowski. G.; Jaskolski. M.; U.S.C. 154(b) by 513 days. Brzezinski. M.; Journal of Molecular Structure 595 (2001) 21-28. Bettinetti, G.; Caira, M. R.; Callegari, A.; Merli. M.; Sorrenti. M.; (21) Appl. No.: 10/763.987 Tadini, C.J. Pharm. Sci. 2000, 89, 478-489. Bettis, J. W.; Lach, J. L.; Hood, J. American Journal of Hospital (22) Filed: Jan. 21, 2004 Pharmacy 1973, 30, 240-243. Bilton, C.; Allen, F. H.; Shields, G. P.; Howard, J. A. K. Acta (65) Prior Publication Data logr: Sect. B-Struct. Sci. 2000, 56, 849-856. Braga, D.; CoaZZi, G.; Abati, A.; Maini. L.; Polito, M.; Scaccianoce, US 2004/0176335A1 Sep. 9, 2004 L.; also T.S.O.E.", 2000, 3969-3975. O O Braga, D: Draper S.M.; Champeil. E.; Grepioni. F.; Journal of Related U.S. Application Data Organometallic Chemistry 573 (1999) 73-77. (60) Provisional application No. 60/441,561, filed on Jan. Braga, D.; Maini. L.; Polito, M.; Grepioni, F. Chem. Commun. 2002, 21, 2003, provisional application No. 60/441,557. 2302-23.03. filed on Jan. 21, 2003. (Continued) (51) Int. Cl. Primary Examiner Johann Richter A6 IK3I/60 (2006.01) Assistant Examiner Yevegeny Valenrod A6 IK3I/I9 (2006.01) (74) Attorney, Agent, or Firm Nixon Peabody LLP; Jeffrey (52) U.S. Cl...... 424/666; 562/.405 A. Lindeman (58) Field of Classification Search ...... None See application file for complete search history. (57) ABSTRACT (56) References Cited The present disclosure relates to novel cocrystals and novel U.S. PATENT DOCUMENTS methods for cocrystallization. In particular, the disclosure includes cocrystals comprising a of an active agent, Such 2,665,277 A * 1/1954 Homeyer et al...... 546,44 as a chloride Salt of an active pharmaceutical ingredient. The 5,080,832 A 1/1992 Etter et al. present disclosure also relates to methods of preparing coc rystals and methods for Screening for Solid state phases. OTHER PUBLICATIONS Gavezzotti Acc. Chem. Res. 1994, 27, 309-314.* 11 Claims, 5 Drawing Sheets (C)=()K)\ AAA XX CS)K)=( wa?yOXX) AP Structure 1:2 API:guest co-crystal US 7,452,555 B2 Page 2

OTHER PUBLICATIONS O'Dowd, C.; Kennedy, J. D.; Thornton-Pett, M.J. Organomet. Chem. 2002, 657, 20-39. Cheung, E.Y. et al., J. Am. Chem. Soc., 2003, 125, 14658-59. Orita, A.; Jiang, L. S.; Nakano, T.; Ma, N. C.; Otera, J. Chem. Cheung, E., et al.; “Direct Structure Determination of a Commun. 2002, 1362-1363. Multicomponent Molecular Crystal Prepared by a Solid-State Grind Oswald, I. D. H.; Allan, D. R.; McGregor, P. A.; Motherwell, W. D. S.; ing Procedure.” J. Am. Chem. Soc. XXXX.XXX (2003). Parsons, S.; Pulham, C. R. Acta Crystallogr: Sect. B-Struct. Sci. Coe, S.; Kane, J. J.; Nguyen, T. L.; Toledo, L. M.; Wininger, E.; (2002) 58, 1057-1066. Fowler, F. W.; Lauher, J. W. J. Am. Chem. Soc. 1997, 119,86-93. Pierpont, C. G.; Lang, S. A. Acta Crystallogr: Sect. C-Cryst. Struct. Dalhus, B., Gorbitz, C. H. Acta Crystallogr. Sect. C-Cryst. Struct. Commun. 1986, 42, 1085-1087. Commun. 1999, 55, 1547-1555. Rai, U. S.; George, S. Thermochim. Acta 1994, 243, 17-25. Datta, S.; Grant, D.J.W.; Nature, Jan. 2004, vol. 3, 42-57. Reddy, L.S.; Nangia, A.; Lynch, V.M.; Crystal Growth & Design, Dega-Szafran, Z. Katrusiak, A.; Szafran, M. J. Mol. Struct. 2001, "Phenyl-Perfluorophenyl Synthon Mediated Cocrystallization of 570, 165-174. Carboxylic and Amides.” XXXX, vol. 0. No. 0, 1-6 2003. Deng, J. et al.; Tetrahedron: Asymmetry 11 (2000) 1729-1732. Remenar, J.F. et al.; Organic Process Research & Development 2003, Desiraju, G. R. The Royal Society of Chemistry 2003, 466-467. 7,990-996. Dunitz, J.D.: The Royal Society of Chemistry 2003, 506. Remenar, J. F.; Morissette, S. L.; Peterson, M. L.; Moulton, B.; Edwards, M. R.; Jones, W.; Motherwell, W. D. S. Cryst. Eng 2002, 5, MacPhee, J. M. Guzman, H. R.; Almarsson, O. J. Am. Chem. Soc. 25-36. 2003, 125, 8456-8457. Fleischman, S. G.; Kuduva, S. S.; McMahon, J. A.; Moulton, B.: Rothenberg, G.; Downie, A. P.; Raston, C. L.; Scott, J. L. J. Am. Walsh, R. D. B.; Rodriguez-Hornedo, N.; Zaworotko, M. J. Cryst. Chem. Soc. 2001, 123, 8701-8708. Growth Des. 2003, 3,909-919. Schauer, C.L. et al., J. Chem. Soc., 1997, 119, 10245-10246. Shan, N.; Toda, F.; Jones, W. Chem. Commun. 2002, 2372-2373. Goldberg, I.; J. Am. Chem. Soc. 1982, 104,7077-7084. Steiner, T. Acta Crystallogr: Sect. B-Struct. Sci. 1998, 54, 456-463. Gorbitz, C. H.; Hersleth, H. P. Acta Crystallogr: Sect. B-Struct. Sci. Steiner, T. New J. Chem. 1998, 22, 1099-1 103. 2000, 56,526-534. Thallapally, P. K.; Nangia, A. Crystengcomm 2001, art. No. 27. Gorbitz, C. H. Acta Crystallogr. Sect. C-Cryst. Struct. Commun. TransForm Pharmaceuticals, Inc. Press Release, Lexington, MA, 2000, 56,500-502. Nov. 3, 2003. Hu, Z-Q et al., Acta Cryst. (2002) C58, o612-o614. Videnova-Adrabinska, V. Acta Cryst. 1996, B52, 1048-1056. Hubschle, C.B., et al., Acta Cryst., (2002) C58, o540-o542. Vishweshwar, P.; Nangia, A.; Lynch, V. M. Cryst. Growth Des. 2003, Iimura, N.; Ohashi, Y.; Hirata, H. Bull. Chem. Soc. Jpn. 2000, 73. 3,783-790. 1097-1103. Vishweshwar, P.; Nangia, A.; Lynch, V. M. Crystengcomm 2003, Karlsson, R.; Acta Cryst., (1972) B28, 2358. 164-168. Kumar, V. S. S.; Nangia, A.; Katz, A. K.; Carrell, H. L. Cryst. Growth Walsh, R. D. B.: Bradner, M. W.; Fleischman, S.; Morales, L. A.; Des. 2002, 2, 313-318. Moulton, B.; Rodriguez-Hornedo, N.; Zaworotko, M.J. Chem. Com Kuroda, R.: Imai.Y.; Tajima, N. Chem. Commun. 2002, 2848-2849. mun. 2003, 186-187. Morgan, T.K. et al.; 1986 American Chemical Society, 1398-1405. Wang, K.W.; Pan, Y. J.; Jin, Z. M.Z. Krist.-New Cryst. Struct. 2002, Nangia, A.; Desiraju, G. R. Acta Crystallogr: Sect. A 1998, 54,934 217,435-436. 944. * cited by examiner U.S. Patent Nov. 18, 2008 Sheet 1 of 5 US 7452,555 B2

(q) XIXY (TXIX XXIX |e?SÁuo-oo?sen6:IdVZ:|| I9.InáH

3.In?On!!SIdV/ (e) U.S. Patent Nov. 18, 2008 Sheet 2 of 5 US 7452,555 B2

a R Ne/

en C9

CD o s

O an CS Ne/ U.S. Patent Nov. 18, 2008 Sheet 3 of 5 US 7452,555 B2

an R Yso

ef 39 -1 s W. N. D 0. f {5

Of O

aa

L s L O O W U.S. Patent Nov. 18, 2008 Sheet 4 of 5 US 7452,555 B2

e

i

g U.S. Patent Nov. 18, 2008 Sheet 5 of 5 US 7452,555 B2

Caeº,O~*~~~~ÕH(~~~~~~

WHN US 7,452,555 B2 1. 2 COCRYSTALLIZATION include identifying a crystal comprising a salt of an active agent, wherein the Salt comprises the active agent and a nega CROSS-REFERENCE TO RELATED tive counterion. One may identify coordination of the nega APPLICATIONS tive counterion (for example, its hydrogen bond interactions within that crystal). One may then select a guest to coordinate This application claims the benefit under 35 U.S.C. S 119 (e) of U.S. Provisional Application Nos. 60/441,557 and more strongly with the negative counterion than the coordi 60/441,561, filed Jan. 21, 2003. These applications are incor nation within the crystal. Based upon the evaluation of the porated by reference herein. nonbonded interactions involving one component of an active 10 agent and/or guest, one selects another molecule or molecules FIELD OF THE INVENTION or a salt that will coordinate well, or interact strongly with a hydrogen bond acceptor site that has been identified as being The present disclosure describes cocrystals comprising involved in a weak hydrogenbond. If the acceptor site has the active agents, especially active pharmaceutical ingredients ability to interact with stronger hydrogen bond donors, and (APIs), and methods relating to cocrystals. In particular, 15 novel cocrystals are provided of a salt of an active pharma thus form a more energetically favorable interaction, yet it is ceutical ingredient (Such as a salt having chloride as the presently involved in a weak interaction, then the opportunity counterion) and a guest that forms a relatively strong interac exists to replace the weak donor with a stronger one. For tion with the counterion. Methods are provided for searching example, if a strong hydrogen bond acceptor is interacting for possible Solid state phases of a sample and include Solidi with a weak hydrogen bond donor in a crystal, a cocrystal fying the sample as a cocrystal. Methods are also provided for could be created by adding a strong hydrogen bond donor screening a sample for Solid state phases and include Solidi molecule to the system which would replace the weak donor fying the sample as a cocrystal. and bond to the strong acceptor site in the resulting cocrystal. After the selection of a Suitable guest, a solution, melt, or BACKGROUND OF THE INVENTION 25 physical mixture comprising the active agent, the counterion, and the guest may be prepared. The Solution or melt is Sub Cocrystals are that contain two or more non-iden jected to a process. Such as evaporation, cool tical molecules. Examples of cocrystals may be found in the ing, or any of the many well-known processes for forming a Cambridge Structural Database. Examples of cocrystals may crystal from a solution or melt. The physical mixture can be also be found at Etter, Margaret C., and Daniel A. Adsmond 30 (1990) “The use of cocrystallization as a method of studying ground to form the cocrystal. A cocrystal is formed compris hydrogen bond preferences of 2-aminopyridine” J. Chem. ing the salt of the active agent and the guest. Soc., Chem. Commun. 1990 589-591, Etter, Margaret C., As another aspect, the present disclosure provides a coc John C. MacDonald, and Joel Bernstein (1990a) “Graph-set rystallization method that produces a novel type of chloride analysis of hydrogen-bond patterns in organic crystals' Acta 35 salt cocrystal structure. The method can be useful for gener Crystallogr., Sect. B, Struct. Sci. B46256-262, Etter, Marga ating beneficial solid chloride of APIs in cases where the ret C. Zofia Urbanczyk-Lipkowska, Mohammad Zia-Ebra chloride salt was previously disfavored. himi, and Thomas W. Panunto (1990b) “Hydrogen bond As yet another aspect, novel forms of salts of active phar directed cocrystallization and molecular recognition proper maceutical ingredients are provided. For example, the present ties of diarylureas”.J. Am. Chem. Soc. 1128415-8426, which 40 are incorporated herein by reference in their entireties. The disclosure provides novel cocrystals of fluoxetine HCl and following articles are also incorporated herein by reference in benzoic ; fluoxetine HCl and succinic acid; and fluoxetine their entireties: Carl Henrik Górbotz and Hans-Petter Hers HCl and fumaric acid. Novel forms or solid state phases of leth, 2000, “On the inclusion of solvent molecules in the active pharmaceutical ingredients may be prepared for which crystal structures of organic compounds’ Acta Cryst. (2000), 45 there are no known polymorphs, Solvates or hydrates, or B56, 625-534; and V. S. Senthil Kumar, Ashwini Nangia, where Such polymorphs, Solvates or hydrates were disfa Amy K. Katz, and H. L. Carrell, 2002, “Molecular Complexes vored. of Some Mono- and Dicarboxylic Acids with trans-1,4,- As a further aspect, a method of modifying one or more Dithiane-1,4-dioxide American Chemical Society, Crystal physical properties of a drug formulation or drug composition Growth & Design, Vol. 2, No. 4, 2002. 50 which comprises an API, the method comprising forming a The identification of an optimal composition, formulation, series of cocrystals of the API with a plurality of guests. The and/or solid state phase is important in the pharmaceutical method may further comprise measuring a physical property field, as well as in other fields including nutraceuticals, agri of the cocrystal and/or adjusting the drug formulation or drug cultural chemicals, dyes, explosives, polymer additives, composition. lubricant additives, photographic chemicals, and structural 55 and electronic materials. The new methods described herein As yet another aspect, an improved method for Screening may be useful in any of these fields as well as others where or selecting the optimal Solid state phase for active agents, Solid materials are used. particularly active pharmaceutical ingredients, and salts thereof, is provided. The screening method comprises crys SUMMARY OF THE INVENTION 60 tallizing or attempting to crystallize the free base of the active agent, a chloride salt of the active agent, and optionally other As one aspect, novel cocrystals are provided. The novel salts of the active agent, and cocrystallizing or attempting to cocrystals comprise one or more active agents, particularly of cocrystallize the free base of the active agent, a chloride salt the salts of Such active agents. of the active agent, and optionally other salts of the active As another aspect, novel cocrystallization methods are pro 65 agent. The method may further comprise evaluating one or vided which have increased probability of successful cocrys more properties of the Solid forms, such as one or more tallization. A suitable method of cocrystallization may physical properties. US 7,452,555 B2 3 4 BRIEF DESCRIPTION OF THE DRAWINGS even though those stronger interactions may be relatively weak themselves, compared to other interactions. For FIGS. 1(a) and (b) illustrate a crystal structure of an active example, an undercoordinated chloride may have one strong pharmaceutical ingredient and a cocrystal structure contain hydrogen bond donor and several weak hydrogen bond ing the same API with a guest molecule. donors or two strong hydrogen bond donors and several weak FIGS. 2(a) and (b) are drawings of two-dimensional and hydrogen bond donors. In a cocrystal, weaker interactions three-dimensional models of a cocrystal of fluoxetine HCl may be replaced by stronger interactions, although those and benzoic acid (1:1). stronger interactions may still be weaker than the strong FIGS. 3(a) and (b) are drawings of two-dimensional and interactions (charge-assisted hydrogen bonds) present in flu three-dimensional models of a cocrystal of fluoxetine HCl 10 oxetine HCl crystals. The strongest interactions involving and Succinic acid (2:1). chloride in crystal structures of organic salts are the FIGS. 4(a) and (b) show a two-dimensional drawing of charge assisted hydrogen bonds that invariably form between nabumetone and 2.3-naphthalenediol and a three-dimen the protonated nitrogen base and the chloride . The stron sional model of a cocrystal of nabumetone and 2.3-naphtha gest interactions between neutral molecular groups and the lenediol (1:1). 15 chloride ion involve acids and the chloride ion. Carboxylic FIG. 5 shows examples of general classes of guests. acids, for instance, have strong interactions with chloride ions. It can be seen that a combination of carboxylic acids and DETAILED DESCRIPTION OF THE INVENTION hydrochloride salts of nitrogen containing bases are espe cially well suited to cocrystal formation (as demonstrated by The present disclosure provides a way of investigating the examples included). Furthermore, it can be anticipated cocrystals and a way of creating new solid state phases in that different combinations of these elements could lead to which one or more active agents are cocrystallized with a other cocrystals. For example, the active molecule of interest guest. By cocrystallizing an active agent with a guest Such as may contain either the neutral moiety or the a pharmaceutically acceptable compound, one can create new protonated nitrogen. The potential exists to cocrystallize an Solid state phases which may have improved properties over 25 API having a neutral carboxylic acid moiety with a guest that existing Solid State phases of that active agent. For example, is a hydrochloride Salt of a nitrogen-containing organic base. new drug formulations comprising cocrystals of active phar It is further contemplated that the nature of the protonated maceutical ingredients may have Superior properties over nitrogen base will affect the potential for cocrystallization. existing drug formulations. The active agent and guest will Numerous strong hydrogen bond donor groups will compete vary depending on the industry. For example, in the pharma 30 with the carboxylic acid guest for the open acceptor sites on ceutical field, the active agent or guest may be an API, and the the chloride ion. In order to favor cocrystal formation, the other component of the cocrystal must be a pharmaceutically nitrogen base is preferably a tertiary amine because this pre acceptable compound. The present techniques are also appli sents a situation where only one strong charged hydrogen cable to active agents from other fields including nutraceuti bond donor exists and thus will only occupy one site on the cals, agricultural chemicals, pigments, dyes, explosives, 35 chloride acceptor. Additionally, systems that have only this polymer additives, lubricant additives, photographic chemi one tertiary amine and no other strong donors present an cals, and structural and electronic materials. especially favorable system for potential cocrystallization. Broadly speaking, one aspect relates to the use of under Protonated secondary amines with two N H donor groups coordinated counterions to facilitate cocrystallization. While are also favored, although protonated primary amines may the inventor does not wish to be bound to theory, the inventor 40 also be used. Special consideration must be taken for systems believes excellent cocrystals may beformed using hydrochlo with additional strong hydrogen bond donor and acceptor ride salts and similar salts which are strong hydrogen bond sites in order to determine the potential for cocrystallization acceptors yet contain relatively undercoordinated ions. and the optimal guest molecule type for cocrystallization. The “Undercoordinated in this case refers to ions, for example a potential for cocrystallization involving a carboxylic acid and chloride ion, that are able to form a number of strong hydro 45 a hydrochloride salt may be reduced as the number of avail gen bonds. An undercoordinated counterion may have hydro able strong donors in the system is increased. Additional gen bonds within a crystal of that salt, but it could form guidance as to evaluating undercoordination may be found in additional hydrogen bonds in a cocrystal and/or form rela the inventor's prior work (which is incorporated by reference tively stronger hydrogen bonds in a cocrystal with a guest. An herein in its entirety), particularly in its discussion of non ion is “undercoordinated when the system is limited in the 50 bonded motifs: Scott L. Childs, “Nonbonded Interactions. In number of hydrogen bond donors that are available and Molecular Crystal Structures”. Emory Univ., USA, available bonded to the ion. In these cases, the extra hydrogen bond from UMI, Order No. DA3009424 (288 pp.), Dissertation acceptor sites are typically filled by weakly interacting Abstract Int. Ref. B2001, 62(3), 1394. In some circum donors such as C-H groups. Chloride ions are strong hydro stances, the undercoordination can be determined by measur gen bond acceptors in a crystal structure. In a crystal structure 55 ing distances, comparing profiles in the Cambridge Structural such as fluoxetine hydrochloride, the chloride ion coordinates Database, measuring the pKa of the donors and acceptors, or to the two strong hydrogen bond donors available in the evaluating the ratio of strong hydrogen bond donors to avail system, and the chloride ion also has three weaker CH Cl able acceptors. Other crystal engineering theories may also be interactions resulting in a pseudo-octahedral coordination used. environment. There is an opportunity for bonding with these 60 The formation of cocrystals is very unpredictable. It is coordination sites, by displacing the weak CH donors that the difficult to foresee structural changes as a function of changes chloride has recruited to fill its coordination sphere with in molecular substitution patterns or in molecular geometry. Somewhat stronger hydrogen bond donors from a guest Such However, the present disclosure provides greater predictabil as benzoic acid, Succinic acid, fumaric acid, or another car ity and better probability of Success in designing and forming boxylic acid. 65 cocrystals. It is useful informing cocrystals to recognize that relatively The present techniques may be employed to generate a weak interactions may be replaced by stronger interactions, wide variety of cocrystals of active agents and guests. For US 7,452,555 B2 5 6 example, the present techniques may be used to generate thermore, new types of HCl salt structures may be prepared. cocrystals of a salt of an active agent. Such as a salt of an active The properties of hydrochloride salts can be tuned and per pharmaceutical ingredient, with a neutral guest. Alterna fected. New, unique, stable, and marketable phase of hydro tively, a cocrystal of a neutral or Zwitterionic active agent (or chloride salts may be prepared. One can choose whether to a salt of an active agent) may be generated with a guest salt, make the formulation more soluble or less soluble. which includes a positive ion and a negative ion of its own. As another aspect, the present techniques may also be used Where the active agent is provided in a salt, it may be posi to remove or reduce the water of hydration, and/or to prepare tively or negatively charged and have a negative or positive a cocrystal substantially free of water of hydration. A hydrate counterion. As an example, for fluoxetine HCl, the active may be viewed as a cocrystal having water as the guest. Water agent fluoxetine is positively charged by virtue of accepting a 10 and guest acids perform a similar role in the stabilization of proton from HCl to form a protonated amine, and chloride is the crystal structure. In fact, about 28% of the hydrochloride present as a negative counterion. Furthermore, some of the salts of API in the Cambridge Structure Database are present methods may be employed with a neutral or Zwitte hydrates, compared to about 8% of all other organic struc rionic active agent to form a cocrystal with a neutral guest or tures. This indicates an affinity for hydration. The present ionic guest. 15 techniques both capitalize and rectify this affinity, in that an The present techniques provide an opportunity to create a affinity for cocrystallization (as evidence by hydration) is stable solid state phase of a hydrochloride salt of an API that likely indicated, and this affinity for cocrystallization may be was previously found to have properties that were unsuitable employed for the formation of cocrystals with a suitable for development. Opportunities for continued development in guest, Such as an acid, for example a carboxylic acid. Indeed, such a situation have often relied on the fortuitous formation in many cocrystals, an acid may have stronger interactions of a stable hydrate or solvate, but the present techniques than water molecules and may displace the water of hydration present the ability to systematically examine alternative for during the formation of the cocrystal. Accordingly, the mulations of the hydrochloride salt by cocrystallizing the present techniques provide a method of preparing a cocrystal hydrochloride salt of the API with appropriate guest mol from a hydrate. A hydrate of a salt is provided, and the hydrate ecules. 25 comprises water of hydration. A guest is selected to coordi Cocrystallization may bean attractive technique for salts of nate with the counterion. Preferably, the guest coordinates APIs that have been rejected due to problems relating to more strongly with the counterion than the solvent does. A physical properties. Since cocrystals may have different Solution, melt or physical mixture is prepared which com physical properties than the individual components, APIs prises the hydrate and the guest. The Solution or melt is with unfavorable physical properties can be cocrystallized 30 Subjected to a crystallization process, or the physical mixture with Suitable guest molecules and the physical properties of is subjected to grinding, and a cocrystal comprising the salt of the resulting crystalline solids can be evaluated. the active agent and the guest is formed, and the salt com The cocrystals of fluoxetine HCl provide examples of the prises the active agent and a counterion. Similarly, the present modification of a physical property () of an API salt. techniques provide a method of preparing a cocrystal from a Cocrystals of fluoxetine HCl:benzoic acid are less soluble 35 Solvate. A Solvate of a salt is provided, and the Solvate com and have a lower dissolution rate than crystals of fluoxetine prises solvent molecules coordinated with the salt. A guest is HCl, while cocrystals of fluoxetine HCl:Succinic acid are selected to coordinate with the counterion. Preferably, the more soluble and have a faster dissolution rate than crystals of guest coordinates more strongly with the counterion than the fluoxetine HC1. Solvent does. A Solution, melt or physical mixture is prepared Other physical properties of APIs or their salts that may be 40 comprising the Solvate and the guest. The Solution or melt is modified by forming a cocrystal include: melting point, den Subjected to a crystallization process, or the physical mixture sity, hygroscopicity, crystal morphology, loading Volume, is subjected to grinding, and a cocrystal comprising the salt of compressibility, and shelf life. Furthermore, other properties the active agent and the guest is formed. The salt comprises Such as bioavailability, toxicity, taste, physical stability, the active agent and a counterion. chemical stability, production costs, and manufacturing 45 FIGS. 2(a) and (b) are drawings of two-dimensional and method may be modified by the use of the present cocrystal three-dimensional models of a cocrystal of fluoxetine HCl lization techniques. and benzoic acid (1:1). FIG. 2(a) shows a two-dimensional An active agent can be screened for possible cocrystals model in which the chloride ion interacts with the hydrogens where polymorphic forms, hydrates or Solvates are especially of the amine group of fluoxetine and of the hydroxyl group of problematic. A neutral compound that can only be isolated as 50 benzoic acid. Through these interactions, which may be char amorphous material could be cocrystallized. Forming a coc acterized as hydrogen bonding, fluoxetine hydrochloride and rystal may up-grade the performance of a drug formulation of benzoic acid form a Supramolecular structure that may be the an active pharmaceutical ingredient by changing physical basis of a cocrystal. FIG. 2(b) shows a three-dimensional properties. Some APIs are problematic during wet granula model of the Supramolecular organization of fluoxetine tion and compression stages. A bioequivalent cocrystal could 55 hydrochloride and benzoic acid. rectify this problem. FIG. 3(a) and (b) are drawings of two-dimensional and three-dimensional models of a cocrystal of fluoxetine HCl A cocrystal can be used to isolate or purify a compound and succinic acid (2:1). FIG. 3(a) shows a two-dimensional during manufacturing. If it is desirable to identify all of the model in which the chloride ion interacts with the hydrogens Solid state phases of an active pharmaceutical ingredient, then 60 of the group of fluoxetine and of the hydroxyl cocrystallization may be particularly desirable. group of Succinic acid. Through these interactions, which The present techniques provide new methods of develop may be characterized as hydrogenbonding, two molecules of ing and screening active pharmaceutical ingredients. Non fluoxetine hydrochloride and one molecule of succinic acid toxic cocrystalline forms of neutral active pharmaceutical form a Supramolecular structure that may be the basis of a ingredients may be prepared, screened, tested, and commer 65 cocrystal. FIG.3(b) shows a three-dimensional model of the cialized. Screening based on cocrystal formation is equiva Supramolecular organization of the molecules of fluoxetine lent in many respects to a salt-screen for neutral APIs. Fur hydrochloride and Succinic acid. US 7,452,555 B2 7 FIGS. 4(a) and (b) show a two-dimensional drawing of glycerophosphoric acid nabumetone and 2.3-naphthalenediol and a three-dimen ethanesulfonic acid sional model of a cocrystal of nabumetone and 2.3-naphtha hydroiodic acid lenediol (1:1). The present techniques also extend beyond salts as starting Active Agent 5 materials and also include many weak bases that may have The active agent is the molecule whose activity is desirable been marketed as neutral forms because the known salts did or the object of interest. It is contemplated that one or more not have appropriate properties. These salts could be revisited active agents may be employed in a cocrystal, according to and attempts could be made to cocrystallize the HCl salt. For any of the present techniques. For example, where the active example, a drug formulation marketed as a salt of an agent is an active pharmaceutical ingredient, the pharmaceu 10 API could be reformulated by cocrystallizing the HCl salt of tical activity of the active agent is desirable. Other active the active molecule with an appropriate guest molecule. Thus, agents may be nutraceuticals, agricultural chemicals, pig cocrystallization could make a useful HC1 cocrystal out of the ments, dyes, explosives, polymer additives, lubricant addi API that is currently marketed as a tartrate, sulfate, or other tives, photographic chemicals, or structural and electronic salt formulation. For this reason the present disclosure materials. 15 includes APIs that are not HCl salts as starting materials. The active agent may be provided as a salt. It is contem Furthermore, the present techniques relate to salts other plated that one or more salts may be employed in a cocrystal, than chloride salts. It is contemplated that hydrobromide salts according to any of the present techniques. The salt may be and salts of APIs may especially benefit from the prepared from the active agent or obtained from a commercial present techniques, since they form relatively strong non Source. Hydrochloride salts of active pharmaceutical ingre bonded interactions. For example, the hydrobromide salts dients, especially of amine APIs, are especially preferred in citalopram hydrobromide and galantamine hydrobromide are the pharmaceutical industry. contemplated for cocrystallization with benzoic acid. Suc In general, it is contemplated that the present techniques cinic acid, and other guests compatible with hydrochloride will have particularly good results as applied to amine HCl salts. salts as well as other ammonium salts as described in more 25 The present techniques may be employed to form cocrys detail herein. In ammonium acid salts, the active agent has at tals of Sodium salts of APIs such as, for example, naproxen least one amine moiety which is relatively basic (at least one Sodium, tolmetin Sodium, and warfarin Sodium. When a relatively basic nitrogen), and a salt is formed with an acid Sodium salt (or other salt of an API having a positive counte that reacts with the amine moiety. Cocrystals may be then rion) is employed, different guests are expected to be suitable formed between the ammonium salts and guests which act as 30 for cocrystallization than when a hydrochloride salt (or other hydrogen-bond donors to the salts. Cocrystals may beformed anionic salt) of an API is employed. of chloride salts of APIs, for example buspirone hydrochlo Anions and Cations ride, fluoxetine hydrochloride, and metforminhydrochloride. As one aspect, the active agent is provided as a salt. A salt The present cocrystals may comprise salts other than chlo 35 of the active agent is formed. Alternatively or additionally, the ride salts—the hydrochloride API salts that are listed above guest is provided as a salt or a salt of the guest is formed. The are only a sampling of the relevant compounds because the salt may comprise the active agent and a counterion that is starting material need not be a known hydrochloride. Indeed, either a cation or an anion. Among the preferred cations many relevant APIs are salts that are not HCl salts because the (including cations as well as compounds that can form cat HCl salt was not believed to be an appropriate material and a 40 ions) are aluminum, ammonium, benzathine, calcium, different salt was commercialized instead. The present tech diethanolamine, diethylamine, dimeglumine, disodium, niques may enable one to employ an HCl salt of an API that is lithium, lysine, magnesium, meglumine, , Sodium, marketed as another type of salt. Alternatively, it may be and zinc. Among the preferred anions are acetate, L-aspartate, desirable to employ a salt other than an HCl salt, by replacing besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, the HCl or by forming a salt comprising an active agent that 45 citrate, edisylate, fumarate, gluconate, hydrobromide/bro acts as a base with an acid other than HC1. The following acids mide, hydrochloride/chloride, D-lactate, L-lactate, DL-lac provide anionic counterions that would be used to replace tate, D.L-malate, L-malate, meSylate, pamoate, phosphate, chlorine. These are relatively strong acids, and includebut are Succinate, Sulfate, D-tartrate, L-tartrate, D.L-tartrate, meso not limited to acids, and the carboxylic acid guest is tartrate, benzoate, gluceptate, D-glucuronate, hybenzate, expected to form one or more hydrogen bonds with a hydro 50 isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, gen bond acceptor on the anionic counterion. The list is the conjugate acid that would react with a basic active agent to nitrate, orotate, Stearate, tosylate, acefyllinate, aceturate, ami form a salt: nosalicylate, ascorbate, ascorbate, borate, butyrate, camphor Sulfuric acid ate, camphocarbonate, decanoate, hexanoate, cholate, cypi phosphoric acid onate, dichloroacetate, edentate, ethyl Sulfate, furate, 55 fusidate, galactarate (mucate), galacturonate, gallate, genti hydrobromic acid sate, glutamate, glutamate, glutarate, glycerophosphate, hep nitric acid tanoate (enanthate), hydroxybenzoate, hippurate, phenylpro pyrophosphoric acid pionate, iodide, Xinafoate, lactobionate, laurate, maleate, methanesulfonic acid mandelate, methanesufonate, myristate, napadisilate, oleate, thiocyanic acid 60 oxalate, palmitate, picrate, pivalate, propionate, pyrophos naphthalene-2-sulfonic acid phate, Salicylate, Salicylsulfate, Sulfosalicylate, Sulfosalicy 1.5-naphthalenedisulfonic acid late, tannate, terephthalate, thiosalicylate, tribrophenate, Val cyclamic acid erate, valproate, adipate, 4-acetamidobenzoate, camsylate, p-toluenesulfonic acid octanoate, estolate, esylate, glycolate, thiocyanate, and unde maleic acid 65 cylenate. L-aspartic acid When a metal cation is employed as a counterion of the 2-hydroxy-ethanesulfonic acid active agent, the interaction between guest and cation is not a US 7,452,555 B2 9 10 hydrogen bond but rather is an intermolecular interaction Table 3 sets forth the group comprising molecules believed between an electron rich group Such as a carbonyl and the at present to be suitable guests. It is contemplated that the metal cation. This interaction is often not as strong as a guests set forth in the Table may be arranged in Subgroups hydrogenbond, but is still a favorable interaction and thus can based upon molecular structure and/or physiological effect. contribute to the stabilization of a cocrystal. 5 Furthermore, the foregoing list is intended to provide a writ The HCl salt of an active pharmaceutical ingredient is ten description of any Sublist that omits one or more guests. especially preferred to create a new type of cocrystal. In this Ionic guests are salts themselves, and may be formed from type of solid state phase, one can cocrystallize the HCl salt bases and acids prior to being used to form cocrystals. For with a neutral guest molecule. By doing this one can create example, the following bases and acids may be reacted to Solid state phases with specific properties. For instance one 10 form ionic guests: can make a solid comprising an active pharmaceutical ingre dient having greater or lesser intrinsic solubility and/or a Bases faster or slower dissolution rate, depending on the guest com pound that is chosen. Ammonia 15 L-Arginine Guests Benethamine The guest is present in order to form the cocrystal with the Benzathine active agent. It is contemplated that one or more guests may Betaine be employed in a cocrystal, according to any of the present Calcium Hydroxide techniques. Accordingly, the guest is not required to have an Choline activity of its own, although it may have some activity that Deanol does not overly derogate from the desired activity of the active Diethanolamine agent. In some situations, the guest may have the same activ Diethylamine ity as or an activity complementary to that of the active agent. 2-(Diethylamino) The guest may be another API. For example, Some guests may 25 2-Aminoethanol facilitate the therapeutic effect of an active pharmaceutical Ethylenediamine ingredient. For pharmaceutical formulations, the guest may N-Methylglucamine be any pharmaceutically acceptable molecule(s) that forms a Hydrabamine cocrystal with the API or its salt. The RTECS database is a 1H-Imidazole useful source for toxicology information, and the GRAS list 30 Lysine contains about 2500 relevant compounds. Magnesium Hydroxide The guest may be neutral (such as benzoic acid and suc Morpholine cinic acid in the examples below) or ionic (such as sodium 4-(2-Hydroxyethyl)Morpholine benzoate or sodium Succinate). Neutral guests are nonionic piperazine guests. Ionic guests are compounds or complexes having 35 ionic bonds. FIG. 5 shows several general classes of guests Pyrrolidine (organic bases, organic salts, alcohols & aldehydes, amino 1-(2-Hydroxyethyl)Pyrrolidine acids, Sugars, ionic inorganics, aliphatic esters & ketones, Sodium Hydroxide organic acids, and aromatic esters & ketones). Triethanolamine The guest may be an acid that forms hydrogen bonds with 40 Tromethamine the chloride (or other anion). For example, Suitable guests Zinc Hydroxide which are acids include (but not are not limited to): ascorbic acid Acids glucoheptonic acid Sebacic acid 45 (+)-L- alginic acid 1.2.2-Trimethyl-1,3-cyclopentanedicarboxylic Acid cyclamic acid 10-Undecylenic Acid ethane-1,2-disulfonic acid 1-Hydroxy-2-naphthoic Acid 2-hydroxyethanesulfonic acid (+)-Camphor-10-sulfonic Acid 50 2,5-Dihydroxybenzoic Acid 2-oxo-glutaric acid 2-Furancarboxylic Acid naphthalene-1,5-disulfonic acid 2-Mercaptobenzoic Acid nicotinic acid 3-Cyclopentylpropionic Acid pyroglutamic acid 3-Phenylpropionic Acid 4-acetamidobenzoic acid 55 4-Aminosalicylic Acid Table 1 sets forth a group of presently preferred guests. It is 4-Hydroxybenzoic Acid contemplated that the guests set forth in the Table may be arranged in Subgroups based upon molecular structure and/or Adipic Acid physiological effect. Furthermore, the foregoing list is alpha-Hydroxypropionic Acid intended to provide a written description of any sublist that 60 Benzenesulfonic Acid omits one or more guests. Benzoic Acid Table 2 sets forth another group of preferred guests. It is Carbonic Acid contemplated that the guests set forth in the Table may be Cholic Acid arranged in Subgroups based upon molecular structure and/or Citric Acid physiological effect. Furthermore, the foregoing list is 65 (-)-D-Tartaric Acid intended to provide a written description of any sublist that (+)-D-Camphoric Acid omits one or more guests. (+)-D-Malic Acid US 7,452,555 B2 11 12 (+)-L-Malic Acid pounds having alcohol, ketone, ester, and/or carboxylic acid 2,2-Dichloroacetic Acid functionalities. Suitable guests may include organic acids, DL-10-Camphorsulfonic Acid organic bases, organic salts, alcohols, aldehydes, amino DL-Glutamic Acid acids, Sugars, ionic inorganic compounds, aliphatic esters and DL-Malic Acid ketones, and aromatic esters and ketones. DL-Tartaric Acid Among the presently preferred neutral guests are those Dodecylsulfuric Acid which are not liquids at room temperature. Also among the Ethanesulfonic Acid presently preferred neutral guests are carboxylic acids having Ethylenediaminetetraacetic Acid at least three carbon atoms, alternatively at least four carbon Ethylsulfuric Acid 10 atoms, and which do not form solvates. For example, if the Fumaric Acid following acids were combined with active agents, the com Galactaric Acid bination would more properly be considered a solvate than a Gallic Acid cocrystal: acetic acid, propionic acid, and butyric acid. How Gluconic Acid ever, in certain embodiments of the present invention (for Glutaric Acid 15 example, in certain cocrystals, cocrystallization methods, and Glycolic Acid screening methods), the use of solvents and Solvates may still Hippuric Acid be desirable, and the use of solvents and solvates is not Hydriodic Acid excluded from the scope of any cocrystal or method except Hydrobromic Acid where explicitly stated. Hydrochloric Acid (-)-L-Apple Acid Detection of Cocrystals (+)-L-Lactic Acid Cocrystals may be detected by X-ray diffraction analysis or (+)-L-Tartaric Acid other suitable techniques. The observation of physical prop D.L-Lactic Acid erties of a solid (particularly its melting point) which differ Lactobionic Acid 25 from the physical properties of the starting materials and the L-Aspartic Acid polymorphs and/or Solvates and/or hydrates of the starting Lauric Acid materials, is an indicator that a cocrystal has been formed. L-Glutamic Acid A method of crystal engineering is described. An active Maleic Acid pharmaceutical ingredient Such as fluoxetine hydrochloride is (-)-L-Malic Acid 30 recognized as possessing a strong hydrogen bond acceptor. Malonic Acid The API is screened against a library of strong hydrogenbond D.L-Mandelic Acid donors or other possible guest compounds. Such a library is Methanesulfonic Acid selected and ordered based upon nontoxicity, physical prop Naphthalene-2-sulfonic acid erty, and the availability and geometric arrangement of hydro n-Butyric Acid 35 gen bond donors that are complementary to the API. n-Decanoic Acid The results from a cocrystal screen of fluoxetine hydro n-Hexanoic Acid chloride demonstrate a new class of cocrystal that is broadly Nitric acid applicable to a wide variety of hydrochloride salts of APIs. n-Tetradecanoic Acid This new approach is a general method that allows creation of Octanoic Acid 40 cocrystals starting with the hydrochloride salt of the API. Oleic Acid Starting with the hydrochloride retains the advantages of the Orotic , yet one is still able to use the cocrystal method to alter the Orthoboric Acid physical properties of the resulting Solid by adding guest Oxalic Acid molecules. 4-Acetamidobenzoic Acid 45 Palmitic Acid EXAMPLE 1. Pamoic Acid Phosphoric Acid Cocrystallization of Fluoxetine HCl and Benzoic Picric Acid Acid Pivalic Acid 50 Propionic Acid Cocrystals of fluoxetine HCl: benzoic acid were formed p-Toluenesulfonic Acid using the following procedures. In one preparation, a 505 mg Pyrophosphoric Acid sample of fluoxetine HCl and 178 mg of benzoic acid were Salicylic Acid dissolved with heating in 5 mL of acetonitrile. The solution Stearic Acid 55 was allowed to crystallize in a small crystallization dish. Succinic Acid Well-formed crystalline material formed within 7 minutes. Sulfosalicylic Acid This material was isolated on filter paper and dried in the air Sulfuric Acid to yield 546 (80%) of fluoxetine HCl:benzoic acid (1:1) coc Terephthalic Acid rystal. Thiocyanic Acid 60 In another preparation, a 5.00 g sample of fluoxetine HCl Valeric Acid and 1.76 g of benzoic acid were dissolved in 50 mL of aceto Valproic Acid nitrile with heating. The solution was allowed to crystallize in Typically, Suitable guests will have complementary ability a large evaporating dish. The resulting solid was isolated on to noncovalently bond to the active agent or its salt, for filter paper and dried in the air to yield 5.40 g (92%) of example the ability to form hydrogen bonds with the active 65 fluoxetine HCl:benzoic acid (1:1) cocrystal. agent or its salt. Suitable guests for active agents having The cocrystal had a relatively slow dissolution rate and negative counterions include, but are not limited to, com lower water solubility. The measured melting point was 134° US 7,452,555 B2 13 14 C.+/-2°C. for the cocrystal. The cocrystal is expected to have hydrogen bond donors on the guest molecule are able to form a good toxicology profile, since benzoic acid is known to be stronger intermolecular interaction between the API and safe and appears on the GRAS list from the U.S. and guest, compared to the interactions between molecules of the Drug Administration. API. The resulting cocrystal is a ternary system comprising the protonated API base, the chloride ion, and the neutral guest EXAMPLE 4 molecule. The present inventor believes there are no known solvates Crystal Structure Analysis of fluoxetine HCl:benzoic or hydrates of fluoxetine hydrochloride. Thus, the formation Acid Cocrystal (1:1) of a cocrystal of fluoxetine hydrochloride constitutes a sur 10 prising achievement and provides a unique composition. A suitable cocrystal of fluoxetine HCl:benzoic acid (1:1) was coated with Paratone N oil, suspended in a small fiber EXAMPLE 2 loop and placed in a cooled nitrogen gas stream at 100K on a Bruker D8 SMART APEX CCD sealed tube diffractometer Cocrystallization of Fluoxetine HCl and Succinic 15 with graphite monochromated MoK (0.71073A) radiation. Acid Data were measured using a series of combinations of phi and omega Scans with 10 second frame exposures and 0.3° frame Cocrystals of fluoxetine HCl and succinic acid were pre widths. Data collection, indexing and initial cell refinements pared as follows. In one preparation, a 458 mg sample of were all carried out usingSMART software (SMARTVersion fluoxetine HCl was dissolved in 8 mL of acetonitrile by 5.624, 2000, Bruker AXS, Inc., Analytical X-ray Systems, heating the Solution gently. A 78 mg sample of Succinic acid 54.65 East Cheryl Parkway, Madison Wis. 537.11-5373). was added to the warm solution and dissolved. The solution Frame integration and final cell refinements were done using was allowed to evaporate rapidly in a crystallization dish. SAINT software (SAINT Version 6.02, 2000, Bruker AXS, Well-formed crystals as blocks formed as the solvent evapo Inc., Analytical X-ray Systems, 54.65 East Cheryl Parkway, rated over 8 minutes. The product was collected on filter 25 Madison Wis. 537.11-5373). The final cell parameters were paper and dried to yield 401 mg of fluoxetine HCl:Succinic determined from least-squares refinement on 5435 reflec acid (2:1) cocrystal (75% yield). tions. The SADABS program was used to carry out absorp In another preparation, a 5.00 g sample of fluoxetine HCl tion corrections (SADABS Version 2.03, 2001, George and 0.85g of succinic acid were dissolved in acetonitrile with Sheldrick, University of Göttingen). heating. The solution was allowed to crystallize in an open 30 The structure was solved using Direct methods and differ evaporating dish over a 15 minute period. The solid material ence Fourier techniques (SHELXTL V5.10, 2000, Bruker was isolated on filter paper and dried to yield 5.40 g (92% AXS, Inc., Analytical X-ray Systems, 54.65 East Cheryl Park yield) of fluoxetine HCl:Succinic acid (2:1) cocrystal. way, Madison Wis. 537.11-5373). Hydrogen atoms were The measured melting points were 158°C. for fluoxetine placed their expected chemical positions using the HFIX HCl, 184°C. for succinic acid, and 137° C. for the cocrystal. 35 command and were included in the final cycles of least The cocrystal is expected to have a good toxicology profile, squares with isotropic U's related to the atom's ridden upon. since Succinic acid is known to be safe and appears on the The C-H distances were fixed at 0.93 A (aromatic and Generally Recognized As Safe (“GRAS) list from the U.S. amide), 0.98 A (methine), 0.97 A (methylene), or 0.96 A Food and Drug Administration. (methyl). All non-hydrogen atoms were refined anisotropi 40 cally. Scattering factors and anomalous dispersion correc EXAMPLE 3 tions are taken from A. J. C. Wilson (ed), Cocrystallization of Nabumetone and International Tables for X-ray Crystallography, Volume C. 2,3-naphthalenediol Kynoch, Academic Publishers, Dordrecht, 1992, Tables 45 6.1.1.4 (pp. 500-502) and 4.2.6.8 (pp. 219-222) the Interna As a demonstrative example, a cocrystal comprising a neu tional Tables for X-ray Crystallography. Structure solution, tral API is described in this example. Cocrystals of nabume refinement, graphics and generation of publication materials tone (a neutral API) and 2.3-naphthalenediol were prepared were performed by using SHELXTL, V5.10 software. Addi as follows. A 4.01 g sample of 2.3-naphthalenediol and 5.7g tional details of data collection and structure refinement are of nabumetone were dissolved in 50 mL of nitromethane with 50 given in Table 4 which follows. heating. A Solid was formed as the solution cooled and was allowed to stand overnight. The solid was filtered from the EXAMPLE 5 remaining solvent and dried in the air to yield 6.61 g (68%) of nabumetone:2.3-naphthalenediol (1:1) cocrystal. Crystal Structure Analysis of fluoxetine HCl:Succinic The resulting cocrystal had a 1:1 molar ratio of nabume 55 Acid Cocrystal (2:1) tone to 2.3-naphthalienediol. The measured melting points were 80° C. for nabumetone, 162° C. for 2.3-naphthaliene A suitable cocrystal of fluoxetine HC1-succinic acid (2:1) diol, and 98°C. for the cocrystal. The cocrystal is expected to was coated with Paratone N oil, suspended in a small fiber have a relatively poor toxicology profile. However, this loop and placed in a cooled nitrogen gas stream at 100K on a example demonstrates one basis for the selection of guest 60 Bruker D8 SMART APEX CCD sealed tube diffractometer molecules: molecular structural similarities. In this case the with graphite monochromated MoK (0.71073A) radiation. molecular recognition of the naphthalene moieties of the API Data were measured using a series of combinations of phi and and the guest contribute to the stability of the cocrystal. In omega Scans with 10 second frame exposures and 0.3° frame addition, the stronger alcohol to ketone hydrogen bonds widths. Data collection, indexing and initial cell refinements formed by the cocrystal contribute to the stability of the 65 were all carried out usingSMART software (SMARTVersion cocrystal. The only hydrogen bond donors available in the 5.624, 2000, Bruker AXS, Inc., Analytical X-ray Systems, API crystal structure are weak C-H groups. The stronger 54.65 East Cheryl Parkway, Madison Wis. 537.11-5373). US 7,452,555 B2 15 16 Frame integration and final cell refinements were done using formed by using SHELXTL, V5.10 software. Additional SAINT software (SAINT Version 6.02, 2000, Bruker AXS, details of data collection and structure refinement are given in Inc., Analytical X-ray Systems, 54.65 East Cheryl Parkway, Table 6 which follows. Madison Wis. 537.11-5373). The final cell parameters were determined from least-squares refinement on 5435 reflec EXAMPLE 7 tions. The SADABS program was used to carry out absorp tion corrections (SADABS Version 2.03, 2001, George Cocrystals of Active Agent Salts and Guests Sheldrick, University of Göttingen). The experiments of Examples 1 and 2 are repeated, using The structure was solved using Direct methods and differ 10 conditions similar to those of those previous Examples, with ence Fourier techniques (SHELXTL V5.10, 2000, Bruker each possible combination of the salts of active agents and AXS, Inc., Analytical X-ray Systems, 54.65 East Cheryl Park guests identified earlier in this disclosure. Cocrystals are way, Madison Wis. 537.11-5373). Hydrogen atoms were formed which have utility according to the known activity of placed their expected chemical positions using the HFIX the active agent. command and were included in the final cycles of least squares with isotropic U's related to the atom's ridden upon. 15 EXAMPLE 8 The C-H distances were fixed at 0.93 A (aromatic and amide), 0.98 A (methine), 0.97 A (methylene), or 0.96 A Cocrystals of Active Agents and Guest Salts (methyl). All non-hydrogen atoms were refined anisotropi cally. Scattering factors and anomalous dispersion correc The experiments of Example 3 are repeated, using condi tions are taken from A.J. C. Wilson (ed), International Tables tions similar to those of those previous Examples, with each for X-ray Crystallography, Volume C. Kynoch, Academic possible combination of the neutral or Zwitterionic active Publishers, Dordrecht, 1992, Tables 6.1.1.4 (pp. 500-502) agents and guest salts identified earlier in this disclosure. and 4.2.6.8 (pp. 219-222). Structure solution, refinement, Cocrystals are formed which have utility according to the graphics and generation of publication materials were per known activity of the active agent. formed by using SHELXTL, V5.10 software. Additional 25 details of data collection and structure refinement are given in EXAMPLE 9 Table 5 which follows. Cocrystallization of Fluoxetine HCl and Fumaric Acid EXAMPLE 6 30 Crystal Structure Analysis of Nabumetone: Cocrystals of fluoxetine HCl and succinic acid were pre 2,3-naphthalenediol Cocrystal (1:1) pared as follows. A 6.00 g sample of fluoxetine HCl and 1.01 g of fumaric acid were dissolved in 20 mL of ethanol with heating. The Solution was filtered through a 0.2 Lum nylon A suitable cocrystal of nabumetone:2.3-naphthalenediol 35 filter, concentrated to a Volume of 8 mL, and cooled in an ice (1:1) was coated with Paratone N oil, suspended in a small bath for 6 hours. The solid material was isolated on filter fiber loop and placed in a cooled nitrogen gas stream at 100K paper and allowed to dry in the air to give 5.74 g (82% yield) on a Bruker D8 SMART 1000 CCD sealed tube diffractome of fluoxetine HCl:fumaric acid (2:1) cocrystal. The measured ter with graphite monochromated CuK (1.54178 A) radia melting points were 158° C. for fluoxetine HCl, >300° C. tion. Data were measured using a series of combinations of 40 (decomposes) for fumaric acid, and 164°C. for the cocrystal. phi and omega Scans with 10 second frame exposures and 0.3° The cocrystal is expected to have a good toxicology profile, frame widths. Data collection, indexing and initial cell refine since fumaric acid is known to be safe and appears on the ments were all carried out using SMART software (SMART Generally Recognized As Safe (“GRAS) list from the U.S. Version 5.55, 2000, Bruker AXS, Inc., Analytical X-ray Sys Food and Drug Administration. tems, 54.65 East Cheryl Parkway, Madison Wis. 537.11-5373). 45 Frame integration and final cell refinements were done using EXAMPLE 10 SAINT software (SAINT Version 6.02, 1999, Bruker AXS, Inc., Analytical X-ray Systems, 54.65 East Cheryl Parkway, Crystal Structure Analysis of fluoxetine HCl:fumaric Madison Wis. 537.11-5373). The final cell parameters were Acid Cocrystal (2:1) determined from least-squares refinement on 2869 reflec 50 tions. A suitable cocrystal of fluoxetine HCl and fumaric acid The structure was solved using Direct methods and differ was coated with Paratone N oil, suspended in a small fiber ence Fourier techniques (SHELXTL V5.10, 1997, Bruker loop and placed in a cooled nitrogen gas stream at 100K on a AXS, Inc., Analytical X-ray Systems, 54.65 East Cheryl Park Bruker D8 SMART 1000 CCD sealed tube diffractometer way, Madison Wis. 537.11-5373). Hydrogen atoms were 55 with graphite monochromated CuK (1.54178 A) radiation. placed their expected chemical positions using the HFIX Data were measured using a series of combinations of phi and command and were included in the final cycle's of least omega Scans with 10 second frame exposures and 0.3° frame squares with isotropic U's related to the atom's ridden upon. widths. Data collection, indexing and initial cell refinements The C-H distances were fixed at 0.93 A (aromatic and were all carried out usingSMART software (SMARTVersion amide), 0.98 A (methine), 0.97 A (methylene), or 0.96 A 60 5.55, 2000, Bruker AXS, Inc., Analytical X-ray Systems, (methyl). All non-hydrogen atoms were refined anisotropi 54.65 East Cheryl Parkway, Madison Wis. 537.11-5373). cally. Scattering factors and anomalous dispersion correc Frame integration and final cell refinements were done using tions are taken from A.J. C. Wilson (ed), International Tables SAINT software (SAINT Version 6.02, 1999, Bruker AXS, for X-ray Crystallography, Volume C. Kynoch, Academic Inc., Analytical X-ray Systems, 54.65 East Cheryl Parkway, Publishers, Dordrecht, 1992, Tables 6.1.1.4 (pp. 500-502) 65 Madison Wis. 537.11-5373). The final cell parameters were and 4.2.6.8 (pp. 219-222). Structure solution, refinement, determined from least-squares refinement on 5625 reflec graphics and generation of publication materials were per tions. US 7,452,555 B2 18 The structure was solved using Direct methods and differ ence Fourier techniques (SHELXTL V5.10, 1997, Bruker TABLE 1-continued AXS, Inc., Analytical X-ray Systems, 54.65 East Cheryl Park ethanesulfonic acid, 2-hydroxy way, Madison Wis. 537.11-5373). All the hydrogen atoms ethylenediaminetetraacetic acid were located from difference Fouriers and included in the 5 ethylsulfuric acid final cycles of least squares with isotropic U.'s. All non fumaric acid hydrogen atoms were refined anisotropically. Scattering fac galactaric acid gallic acid tors and anomalous dispersion corrections are taken from A. gentisic acid J. C. Wilson (ed), International Tables for X-ray Crystallog glucoheptonic acid raphy, Volume C. Kynoch, Academic Publishers, Dordrecht, 10 gluconic acid glutamic Acid 1992, Tables 6.1.1.4 (pp. 500-502) and 4.2.6.8 (pp. 219-222). glutamine Structure Solution, refinement, graphics and generation of glutaric acid publication materials were performed by using SHELXTL, glutaric acid, 2-oxo V5.10 software. Additional details of data collection and glycine glycolic acid structure refinement are given in Table G which follows. 15 hippuric acid All patents, test procedures, and other documents cited histidine herein, including priority documents, are fully incorporated hydroxyproline by reference to the extent such disclosure is not inconsistent isoleucine lactobionic acid with this invention and for all jurisdictions in which such lauric acid incorporation is permitted. leucine While the present invention has been described and illus levulinic acid trated by reference to particular embodiments, it will be lysine maleic acid appreciated by those of ordinary skill in the art that the inven malic acid tion lends itself to many different variations not illustrated malonic acid herein. For these reasons, then, reference should be made 25 mandelic acid solely to the appended claims for purposes of determining the m-methoxybenzoic acid naphthalene-1,5-disulfonic acid true scope of the present invention. naphthalene-2-sulfonic acid Although the appendant claims have single appendencies n-decanoic acid in accordance with U.S. patent practice, each of the features niacin nicotinic acid in any of the appendant claims can be combined with each of 30 n-tetradecanoic acid the features of other appendant claims or the main claim. oleic acid O-methylbenzoic acid TABLE 1. orotic acid orthoboric acid 10-camphorsulfonic acid 35 o-toluic acid 10-undecylenic acid p-acetamidobenzoic acid 1-hydroxy-2-naphthoic acid palmitic acid 2,4-dihydroxybenzoic acid pamoic acid 2,5-dihydroxybenzoic acid phenoxyacetic acid 2-aminopropionic acid phenylacetic acid 2-ethylbutyrinc acid phenylalanine 2-furancarboxylic acid 40 picric acid 2-mercaptobenzoic acid pivalic acid 3-methylbutanoic acid proline 3-phenylpropionic acid p-toluenesulfonic acid 4-aminobenzoic acid pyroglutamic acid 4-aminosalicylic acid pyruvic acid 4-hydroxybenzoic acid 45 Salicylic acid adipic acid Sebacic acid alginic acid serine anisic acid Sorbic acid arginine Stearic acid ascorbic acid Succinic acid asparagine 50 Sulfosalicylic acid aspartic acid tartaric acid aspirin terephthalic acid benzenesulfonic acid thiocyanic acid benzoic acid threonine 4-acetamidobenzoic acid tiglic acid beta-alanine 55 camphoric acid tryptophan camphorsulfonic acid tyrosine carbonic acid Valeric acid cholic acid valine cinnamic acid citric acid cyclamic acid 60 cyclohexanecarboxylic acid TABLE 2 cyclohexylacetic acid cysteine Name CAS if diphenylacetic acid dodecylsulfonic acid Potassium bicarbonate 298-14-6 ethane-1,2-disulfonic acid 65 S84-08-7 ethanesulfonic acid 7447-40-7 US 7,452,555 B2 19 20

TABLE 2-continued TABLE 2-continued

Name CAS if Name CAS if Potassium hydroxide 1310-58-3 Benzyl acetate 140-11-4 Potassium metabisulfite 16731-55-8 6-Methyl-5-hepten-2-one 110-93-0 Potassium nitrate 7757-79-1 Butyl acetate 123-86-4 Potassium nitrite 77S8-09-0 Ethyl acetoacetate 141-97-9 Potassium permanganate 7722-64-7 SopentylAcetate 123-92-2 Potassium persulfate 7727-21-1 Cinnamaldehyde 104-55-2 Potassium phosphate, dibasic 2139900 10 Methylbenzoate 93-58-3 Potassium Phosphate Monobasic 7778-77-0 Butyl sulfide 544-40-1 potassium phosphate, tribasic, 7778-53-2 Ethylbenzoate 93-89-0 n-hydrate 24-Hexadienoic acid, 24634-61-5 Potassium sulfate 7778-80-5 potassium salt, (EE)- 144-55-8 Potassium bittartrate 868-14-4 Sodium bisulfite 7631-90-5 15 Lauric acid 143-07-7 Sodium borohydride 16940-66-2 Benzyl benzoate 120-51-4 Sodium carbonate 497-19-8 Picric acid 88-89-1 Sodium Carbonate Monohydrate 1486118 Benzoyl peroxide 94-36-0 Sodium chloride 7647-14-5 Palmitic acid 57-10-3 Sodium dithionite 7775-14-6 Dibutyl phthalate 84–74-2 Sodium fluoride 7681-49-4 Stearic acid 57-11-4 Sodium hexametaphosphate 1O124-56-8 Succinic anhydride 108-30-5 Sodium hydroxide 1310-73-2 Diethylenetriamine 111-40-0 Sodium hypochlorite 7681-52-9 Diethanolamine 111-42-2 Sodium Metabisulfite 7681-57-4 Benzaldehyde 1 OO-52-7 Disodium metasilicate 6834-92-0 Phenethylamine 64-04-0 sodium monophosphate 7681-53-0 Salicylylaldehyde 90-02-8 Sodium nitrate 7631-99-4 25 Sodium benzoate S32-32-1 Sodium nitrite 7632-OO-O Cinnamic acid 621-82-9 sodium hydrogen phosphate 7558-79-4 Triethanolamine O2-71-6 Sodium Phosphate Monobasic 7558-80-7 L-(+)-Tartaric Acid Sodium Pyrophosphate 7722-88-5 Eugenol 344-09-8 D-mannitol Sodium Sulfate Decahydrate 30 Butyl paraben Sodium sulfite Benzoin Sodium Thiosulfate Diethyl phthalate Pentahydrate Oleic acid Calcium acetate Sodium lactate Calcium Carbonate Indole Dihydrate OO35-04-8 35 ethyl lactate 299-28-5 quinoline Calcium hydroxide 3OS-62-0 Thymol Calcium oxide 305-78-8 Methyl anthranilate Calcium phosphate, dibasic Methyl salicylate Calcium Phosphate Monobasic Diethylmalonate Calcium sulfate Citric acid 40 Magnesium hydroxide 309-42-8 Sodium dodecyl sulfate Magnesium Sulfate Heptahydrate OO34-99-8 Morpholine Aluminum 7429-90-5 Furfural Aluminum ammonium sulfate 7784-26-1 Niacin Aluminum chloride 7446-70-0 Choline chloride 67-48-1 Aluminum hydroxide 21645-51-2 L-Menthol 221 6-51-5 Aluminum potassium sulfate, 7784-24-9 45 Meso-inositol 87-89-8 dodecahydrate ethylenediaminetetraacetic 60-00-4 Orthoboric acid 10043-35-3 acid formaldehyde SO-OO-O EDTA, calcium derivative, 62-33-9 DL-Isoleucine 443-79-8 disodium salt (2S,7S)-(-)-Cystine S6-89-3 Calcium pantothenate 137-08-6 DL-Alanine 302-72-7 50 Riboflavin 83-88-5 beta-Alanine 107-95-9 Zinc carbonate 3486-3S-9 (S)-(+)-Arginine 74-79-3 Amyl alcohol 71-41-0 (S)-(-)-Cysteine 52-90-4 Mineral oil 8O12-95-1 DL-Glutamic acid 617-6S-2 Triton(R) X-100 90O2-93-1 Glycine 56-40-6 Acetaldehyde 75-07-0 (S)-(-)-Histidine 71-OO-1 55 Acetic Acid 64-19-7 (S)-(+)-Lysine S6-87-1 Acetone 67-64-1 DL-Methionine 59-51-8 Acetophenone 98-86-2 DL-Phenylalanine 150-30-1 4-Aminobenzoic acid 150-13-0 (S)-(-)-Phenylalanine 63-91-2 Anisole 1OO-66-3 D-(+)-Proline 344-25-2 Vitamin C SO-81-7 (S)-(-)-Tryptophan 73-22-3 Benzoic Acid 6S-8S-O (S)-(-)-Tyrosine 60-18-4 60 Biphenyl 92-52-4 Carvone 99-49-0 2-Methyl-1-propanol 78-83-1 Citral S392-40-5 n-Butanol 71-36-3 Ethylbutyrate 105-54-4 n-Butylamine 109-73-9 Isobutyl propionate 540-42-1 ethyl acetate 141-78-6 Methylbutyrate 623-42-7 Caffeine 58-08-2 n-Propyl acetate 109-60-4 65 Chloroacetic Acid 79-11-8 Isobutyl formate 542-55-2 Dichloroacetic Acid 79-43-6 US 7,452,555 B2 21 22

TABLE 2-continued TABLE 2-continued

Name CAS if Name CAS if Diethylamine 109-89-7 D-(+)-Xylose 58-86-6 Ethanol Amine 141-43-5 Pectin Sugar S328-37-O n-Butyric Acid 107-92-6 D-(+)-Lactose 63-42-3 Ethylenediamine 107-15-3 Camphene 79-92-5 Formic acid 64-18-6 Isoquinoline 119-65-3 n-Hexanol 111-27-3 2,4-Dimethylphenol 105-67-9 Methanol 67-5 6-1 10 2,5-Dimethylphenol 95-87-4 Methyl Acetate 79-20-9 2,6-Dimethylphenol 576-26-1 Methyl 4-hydroxybenzoate 99-76-3 Methanesulfonic Acid 75-75-2 m-Cresol 108-39-4 o-Methoxybenzoic Acid 579-75-9 p-Cresol 106-44-5 Saccharin 81-07-2 Phenol 108-95-2 Thiazole 288-47-1 n-Propanol 71-23-8 15 Trifluoromethanesulfonic Acid 1493-13-6 Propionic Acid 79-09-4 Trimethylamine 75-50-3 Salicylic acid 69-72-7 Coumarin 91-64-5 57-50-1 Dimethylamine 124-40-3 Vanillin 121-33-5 Ethyl Alcohol 64-17-5 Vitamin E 59-02-9 Butylbenzyl phthalate 85-68-7 , monohydrate 153414.6 2,6-dimethylpyrazine 108-SO-9 p-toluenesulfonic acid 61.92-52-5 taurocholic acid 81-24-3 monohydrate geraniol 106-24-1 D-(+)-Maltose linalool 78-70-6 Tetrasodium ethyl isovalerate 108-64-5 ethylenediaminetetraacetate ethyl 2-methylbutyrate 7452-79-1 Saccharin sodium 128-44-9 1-octen-3-ol 3391-86-4 Trihydrate 6.131-90-4 25 ethyl 2-trans-4-cis 3O25-30-7 Quinine Sulfate, dihydrate 6119-70-6 decadienoate Sulfosalicylic acid, dihydrate 5965-83-3 Dihydromyrcenol 18479-58-8 L-(+)-Arginine 1119-34-2 citronellal 106-23-0 monohydrochloride linallyl acetate 115-95-7 Procaine hydrochloride S1-05-8 8-mercapto-p-menthan-3-one 384-62-22-5 Pyridoxine Hydrochloride 58-56-O 30 Ammonium citrate 3O12-65-S Thiamine hydrochloride 67-03-8 Ammonium bicarbonate 1066-33-7 Propionaldehyde 123-38-6 Ammonium chloride 121.25-02-9 Urea 57-13-6 Ammonium hydroxide 1336-21-6 2-Propanol 67-63-0 Ammonium persulfate 7727-54-0 Pyrrole 109-97-7 Ammonium phosphate, dibasic 7783-28-0 Sodium formate 141-53-7 35 Ammonium Phosphate Monobasic 7722-76-1 Pyrrollidine 123-75-1 Ammonium sulfate 7783-20-2 Methyl ethyl ketone 78-93-3 Ammonium sulfide 2135-76-1 Ethyl formate 109-94-4 Hydrazine Propylene glycol 57-55-6 Nitric acid Thiourea 62-56-6 phosphoric acid Ammonium acetate 631-61-8 Phosphorus oxychloride 40 Benzene 71-43-2 Hydriodic acid Sodium acetate 27-09-3 Hydrobromic acid Cyclopentanone 20-92-3 Hydrochloric acid Cyclohexane 10-82-7 hydrogen peroxide piperidine 10-89-4 Periodic Acid 2-Pentanone O7-87-9 Sulfamic acid 1O-54-3 45 Sulfuric acid Soamyl Alcohol Sulfurous acid Lactic acid Dexpanthenol 2-Ethoxyethanol 4-oxoisophorone Propionic acid, sodium salt Copper(II) sulfate Potassium acetate erric chloride cyclohexylamine 50 Ferric oxide 309-37-1 methyl methacrylate erric sulfate OO28-22-5 methyl isobutyl ketone ron (II) Sulfate Heptahydrate Acetic anhydride Oil IsopropylAcetate Manganese (II) Sulfate OO34-96-5 2,2'-Oxybisethanol Monohydrate Benzyl alcohol 55 Nickel 7440-02-0 Resorcinol Titanium dioxide 3463-67-7 2-Butoxy ethanol Zinc chloride 7646-85-7 Cumene Zinc oxide 314-13-2 2-Amino-2-(hydroxymethyl)-1,3- 1,1-Azobisformamide 23-77-3 propanediol 1,3-Butanediol Phenethyl alcohol 60-12-8 1-Methylnaphthalene 2-Ethyl-1-hexanol 104-76-7 60 2,6-Di-tert-Butyl-p-Cresol 2-Octanol 123-96-6 2,6-Dimethylpyridine 2-(2-Ethoxyethoxy) ethanol 111-90-0 Disodium 2,6-Dimethyl-4-heptanone 108-83-8 cyanodithioimidocarbonate Benzophenone 119-61-9 3-Methyl-2-Cyclopentene-2-ol-one 80-71-7 D-(-)- 57-48-7 6-Methylcoumarin 92-48-8 D- SO-99-7 65 acetoin 513-86-0 D-Ribose 50-69-1 alpha-Phellandrene 99-83-2 US 7,452,555 B2 23 24

TABLE 2-continued TABLE 2-continued

Name CAS if Name CAS if alpha-Terpinene 99-86-5 methylpropionate 554-12-1 Benzenesulfonic Acid 98-11-3 methyl valeraldehyde Benzothiazole 95-16-9 nitrosyl chloride borates, tetrasodium salts 330-43-4 octafluorocyclobutane Butylbutyrate 09-21-7 peroxyacetic acid Butyl Mercaptain O9-79-5 propyl formate Butyraldehyde 10 propyl mercaptain Capsaicin Sodium aluminate Chloromethyl Methyl Ether sodium chlorite Cymene Terephthalic Acid Diallyl Disulfide allyl isothiocyanate Diethylaminoethanol Vitamin B1 dimethyldisulfide 15 Valproic acid Dimethyl Succinate Ethoxyquin Dimethyl Sulfate n-Amyl Ethyl Ketone Dimethyl Sulfide Nabam Dipropyl Disulfide Sodium sulfide Dipropyl Ketone Thiocyanic acid Ethyl Acrylate 2-Methyl-5-(1-methylethenyl)- Ethyl Butyl Ketone 2-cyclohexene-1-one Ethyl Propionate 4-(2,6,6-Trimethyl-2- 27-41-3 Furfuryl Alcohol cyclohexen-1-yl)-3-buten-2-one gamma-Butyrolactone 4-(2,6,6-trimethyl-1- 4901-07-6 Glutaraldehyde cyclohexen-1-yl)-3-buten-2-one glycerin Isoamyl propionate OS-68-0 Glycolic Acid 25 3-Methylbutanoic acid SO3-74-2 sobutyl Acetate L-Menthone 4O73-97-3 sobutyl Isobutyrate 4-Ethylphenol 23-07-9 sobutyraldehyde 78-84-2 o-cresol Soheptanol 543-49-7 dimethyl-Carbamodithioic acid, 78-59-1 sodium salt Sopropyl Mercaptain 75-33-2 30 Anethole Methyl isobutenylketone Dimethylterephthalate Methyl n-amylketone propyl gallate methyl acrylate L-Ascorbic Acid Sodium Salt Methyl Isobutyrate 4-Hexylresorcinol Methyl Mercaptain Estragole N,N-Dimethylethanolamine 35 L-monosodium glutamate 42-47-2 n-Butyl Lactate Malonaldehyde, Sodium salt 24382-04-5 n-Hexyl Acetate Butylated hydroxyanisole 25013-16-5 n-Valeraldehyde allyl 3-methylbutyrate 2835-39-4 Nitrous Oxide DL-monosodium glutamate 32221-81-1 p-Anisaldehyde 23-11-5 3-Acetyl-6-methyl-2,4- 520-45-6 2-Methylcyclohexanone pyrandione 40 Octanoic Acid L-Glutamic Acid 56-86-O Oxalic Acid DL-alpha-tocopheryl acetate 58-95-7 Phenyl ether D-limonene S989-27-5 Phenylmercaptain Calcium Acetate 62-54-4 Propargyl Alcohol Erythorbic Acid Monosodium 6381-77-7 Propyl paraben Salt sec-Butyl Alcohol 45 Ethyl methylphenylglycidate 77-83-8 Sodium Gluconate 527-07-1 2.4.6-Trinitro-1,3-dimethyl-5- 81-15-2 Sodium Tripolyphosphate 7758-29-4 ert-butylbenzene Tetrahydro-2-furanmethanol 97-99-4 Dimethoxane 828-OO-2 Valeric Acid 109-52-4 3,5-Di-tert-butyl-4- 88-26-6 3,4-xylenol 95-6S-8 hydroxybenzyl alcohol 3-hexanol 623-37-0 50 6-Methylquinoline 91-62-3 3-methyl-1-pentanol S89-35-5 alpha-Methylbenzyl alcohol 98-85-1 1,1-diethoxyethane 105-57-7 Nicotinamide 98-92-0 Aluminum Sulfate 10043-01-3 3,4-Dihydrocoumarin 119-84-6 ammonium sulfite 10196-04-0 GeranylAcetate 105-87-3 amylbutyrate 540-18-1 Sodium(2-Ethylhexyl)Alcohol 126-92-1 borneol 507-70-0 55 Sulfate butyl formate S92-84-7 Cyclohexanol, 5-methyl-2-(1- 89-78-1 calcium peroxide 1305-79-9 methylethyl)-, n-Hexanoic Acid 142-62-1 (1alpha2beta,5alpha)- cyclohexyl acetate 622-45-7 (+)-Camphor 464-49-3 diacetyl 431-03-8 (1S)-(-)-alpha-Pinene 7785-26-4 dimethyl carbonate 616-38-6 1,3-Dihydroxy-5-methylbenzene 504-15-4 ethylbutyraldehyde 97-96-1 60 1,5-Naphthalenedisulfonic Acid 1655-29-4 Ethyl crotonate 623-70-1 Disodium Salt ethyl isobutyrate 97-62-1 1-Hydroxy-2-naphthoic Acid 86-48-6 ethyl nitrite 109-95-S 1-Penten-3-ol 616-25-1 fumaric acid 110-17-8 1-Phenyl-1-propanol 93-54-9 hexaldehyde 66-25-1 10-Undecylenic Acid 112-38-9 isobutyric acid 79-31-2 65 2'-Hydroxyacetophenone 118-93-4 methyl isovalerate 556-24-1 2,4-Dihydroxybenzoic Acid 89-86-1 US 7,452,555 B2 25 26

TABLE 2-continued TABLE 2-continued

Name CAS if Name CAS if 2-Acetylfuran 1192-62-7 disodium salt 2-Furancarboxylic Acid 88-14-2 Heliotropine 120-57-O 2-Isopropylphenol 88-69-7 Hippuric Acid 495-69-2 2-Ketoglutaric Acid 328-50-7 Hydroquinone Dimethyl Ether 1SO-78-7 2-Ketovaline 759-05-7 nosine-5'-monophosphate 4691-65-O 2-n-Propylphenol 644-35-9 Sodium Salt 2-Naphthalenethiol 91-60-1 10 iso-Amyl Mercaptain 541-31-1 2-Phenyl-1-propanol 1123-85-9 Soamyl Salicylate 87-20-7 3,3'-Thiodipropionic Acid 111-17-1 iso-Butyl n-Hexanoate 105-79-3 3,5,5-Trimethylhexanal S435-64-3 isovaleraldehyde 590-86-3 3-Phenyl-1-propanol 122-97-4 Soamyl Benzoate 94-46-2 3-Phenylpropionic Acid SO1-52-0 soamyl Formate 11O-45-2 4-Aminosalicylic Acid 65-49-6 15 Soamyln-Butyrate 106-27-4 4-Ethoxyphenol 622-62-8 Soamylamine 107-85-7 4-Hydroxybenzoic Acid 99-96-7 sobutyl n-Butyrate S39-90-2 4-Phenyl-2-butanol 2344-70-9 Socaproic Acid 646-07-1 4-tert-Octylphenol 140-66-9 Soeugenol 97-54-1 Allyl Cinnamate 1866-31-5 Sopropyl Benzoate 939-48-0 Allyl Mercaptain 870-23-5 Sopropyl Formate 625-5S-8 alpha-L-Rhamnose 3615-41-6 sopropyl N-Butyrate 638-11-9 Alpha-Terpineol 98-55-S Sopropyl Propionate 637-78-5 Anisic Acid 100-09-4 isobutyl Mercaptain 513-44-0 Benzalacetone 122-57-6 L-(+)-Isoleucine 73-32-5 Benzaldehyde Dimethylacetal 1125-88-8 L-(-)-Apple Acid 97-67-6 Benzyl Ether 103-50-4 L-2-Aminopropionic Acid 56-41-7 Benzyl Formate 104-57-4 25 L-Aspartic acid 56-84-8 Benzyl Mercaptain 100-53-8 L-Carnitine 541-15-1 Benzyl Salicylate 118-58-1 L-Cysteine Hydrochloride 52-89-1 Calcium Citrate 813-94-5 L-Glutamic Acid Hydrochloride 138-15-8 Calcium Glycerophosphate 27214-OO-2 L-Glutamine S6-85-9 Calcium Hypophosphite 7789-79-9 L-Hydroxyproline S1-35-4 Calcium Iodate 7789-80-2 30 L-Proline 147-85-3 Propanoic acid, 2-hydroxy-, 814-8O-2 L-Serine 56-45-1 calcium salt (2:1) L-Threonine 72-19-5 Calcium Phosphate Tribasic 7758-87-4 L-Valine 72-18-4 Calcium Propionate 4075-81-4 N-Acetylglycine 543-24-8 Calcium Pyrophosphate 7790-76-3 n-Amyl Formate 638-49-3 Cholic Acid 81-25-4 35 n-Amyl n-Caproate S4O-07-8 Choline 23-41-1 n-Butyl n-Caproate 626-82-4 Choline Bitaritrate 87-67-2 n-Butyl Propionate 590-01-2 trans-Cinnamic Aldehyde 4371-10-9 n-Butyl Salicylate 2052-14-4 Cinnamyl Alcohol O4-54-1 n-Decanoic Acid 334-48-5 Citronellol n-Hexyl Mercaptain 111-31-9 2315-68-6 Copper(I) Iodide 40 n-Propyl Benzoate D-(+)-Glucono-1,5-lactone n-Propyl Isobutyrate 644-49-5 D-(-)-Tartaric Acid n-Tetradecanoic Acid 544-63-8 D-Isoascorbic Acid Nitrillotriacetic Acid 5064-31-3 D-Tyrosine Trisodium Salt Sodium dehydroacetate o-Toluenethiol 137-06-4 Deoxycholic Acid Orotic Acid 65-86-1 Dibenzyl Ketone 45 p-Acetamidobenzoic Acid SS6-08-1 Diethyl L-(+)-Tartrate p-Anise Alcohol 105-13-5 Diethyl Succinate Phenoxyacetic Acid 122-59-8 Dimethylacetal PhenylAcetate 122-79-2 DL-Cystine Piperine 94-62-2 DL-Proline Pivalic Acid 75-98-9 DL-Tartaric Acid 50 Potassium Benzoate S82-25-2 DL-Tyrosine Potassium Diphosphate 7320-34-5 DL-Valine Potassium Hypophosphite 7782-87-8 Enantholic Acid Potassium Metaphosphate 7790-53-6 Erythorbic Acid Sodium Salt Potassium Sulfite 101.17-38-1 Ethyl 2-Aminobenzoate Quinine Hydrochloride 130-89-2 Ethyl Cinnamate 55 sec-Amyl Alcohol 6032-29-7 Ethyl n-Valerate Sodium D-Pantothenate 867-81-2 Ethyl Phenylacetate Di (2-ethylhexyl)sulfosuccinic 577-11-7 Ethyl Salicylate acid, sodium salt Ethyl Sulfide Sodium Sorbate 7757-81-5 Ethyl Vanillin Succinic acid, disodium salt 1SO-90-3 Ethylene Mercaptain Sodium Taurocholate 145-42-6 Farnesene 60 Taurine 107-35-7 Folic acid Thiamine Nitrate 532-43-4 gamma-Nonanolactone Thioanisole 100-68-5 gamma-Valerolactone Tiglic Acid 80-59-1 Gluconic Acid Tri-n-butyrin 60-01-5 Gluconic Acid Potassium Salt Triacetin 102-76-1 Glutaric Acid 65 Trisodium Citrate 68-04-2 Guanosine-5'-monophosphate, 333479 Veratraldehyde 120-14-9

US 7,452,555 B2 39 40

TABLE 2-continued TABLE 3

Name CAS if Name CAS if

entanone Sodium Metabisulfite 7681-57-4 Neryl butyrate 999-40-6 sodium hydrogen phosphate 7558-79-4 Neryl formate 2142-94-1 Sodium Phosphate Monobasic 7558-80-7 Neryl isovalerate 3915-83-1 Sodium thiosulfate 7772-98-71 4430-31-3 Orthoboric acid 10043-35-3 Phenethyl 2-furoate 7149-32-8 Diethanolamine 111-42-2 -Phenyl-2-pentanol 705-73-7 10 Benzaldehyde 1 OO-52-7 Phenylacetaldehyde 68345-22-2 Sorbic acid 110-44-1 diisobutylaceta L-(+)-Tartaric Acid 87-69-4 Phenylacetaldehyde glyceryl 2989S-73-6 D-mannitol 69-65-8 Butyl paraben 94-26-8 2-(3-Phenylpropyl)pyridine 2110-18-1 Thymol 89-83-8 Propyl phenylacetate 4606-15-9 15 Methyl salicylate 119-36-8 Pyrazineethanethiol 352SO-53-4 Citric acid 77-92-9 Ethyl 2-methyl pentanoate 392SS-32-8 Creatinine 60-27-5 Methyl 2,4-decadienoate 4493-42-9 Vitamin C SO-81-7 alpha-Isomethyl ionone 127-51-5 Benzoic Acid 6S-8S-O 5-Methylhexanoic acid 628-46-6 Methyl 4-hydroxybenzoate 99-76-3 Ethyl 3-methyl pentanoate S870-68-8 m-Cresol 108-39-4 Ethyl 2-methyl-3,4- 60S23-21-9 p-Cresol 106-44-5 pentadienoate Aspirin SO-78-2 3-Nonen-2-one 14309-57-O Phenol 108-95-2 5-Methyl-3-hexen-2-one S166-53-0 Sucrose 57-50-1 Maltol propionate 68SSS-63-5 Potassium citrate, monohydrate 153414.6 2-Methyl-3-(2-furyl) acrolein 874-66-8 Sodium acetate 127-09-3 Ethyl 3(2-furyl)propanoate 10O31-90-0 25 Lactic acid SO-21-5 2-Phenyl-3-(2-furyl)-propenal S7568-60-2 Propionic acid, sodium salt 6S-85 4-Methyl-2-pentyl-1,3- 1599-49-1 Benzyl alcohol 100-51-6 dioxolane Phenethyl alcohol 60-12-8 2-Ethyl-4,5-dimethyl oxazole S3833-30-0 Cholesterol 57-88-5 Isobornyl isovalerate 7779-73-9 D-Glucose SO-99-7 Theophylline-7-acetic acid 652-37-9 30 Sorbitol SO-70-4 Ethyl trans-2-octenoate 7367-82-O Aspartame 22839-47-O DL-Arginine 72OO-25-1 Saccharin 81-07-2 Allyl Crotonate 20474-93-5 2,6-Di-tert-Butyl-p-Cresol 128-37-0 2-Methoxystyrene 612-15-7 4-Chloro-3-methylphenol 59-50-7 Magnesium Fumarate 7704-71-4 glycerin 56-81-5 2-Propionylpyrrole 1073-26-3 35 Propyl paraben 94-13-3 2-methyl-1,3-dithiolane S616-51-3 fumaric acid 110-17-8 2-ethyl-5-methyl pyrazine 13360-64-0 dabco 280-57-9 2-methyl-3-(dimercaptomethyl)- 6SSOS-17-1 p-Phenylenediamine 106-50-3 8 Anethole 418O-23-8 Magnesium gluconate 3632-91-5 propyl gallate 121-79-9 Manganese gluconate 6485-39-8 142-47-2 40 L-monosodium glutamate Erythritol 149-32-6 Butylated hydroxyanisole 25013-16-5 D-Arabinose 28697-53-2 Cyclohexanol, 5-methyl-2-(1- 89-78-1 D-Galactose 59-23-4 methylethyl)-, D-(+)-Mannose 3458-28-4 (1alpha, 2beta, 5alpha)- SO-70-4 alpha-Thioglycerol 96-27-5 22839-47-O Sodium dehydroacetate 4418-26-2 1OO-88-9 45 Ethyl 4-hydroxybenzoate 120-47-8 150-69-6 Ethyl Vanillin 121-32-4 Glucose-1-phosphate 29732-59-0 Triacetin 102-76-1 Dipotassium Salt Potassium sorbate 590-00-1 L-(+)-Arabinose 87-72-9 Triethylcitrate 77-93-0 Fructose-6-Phosphate 643-13-0 (S)-(+)-Arginine 74-79-3 D-Maltose Monohydrate 6363-53-7 50 Glycine 56-40-6 Ribose 24259-59-4 (S)-(-)-Histidine 71-OO-1 Fructose 1,6-Diphosphate 26177-85-5 (S)-(+)-Lysine S6-87-1 Disodium Salt Quinone Saccharin sodium, dihydrate 6155-57-3 Naphthalene, 2-ethoxy 2-Benzisothiazol-3(2H)-one 6485-34-3 Methanesulfonic Acid 1-dioxide, calcium salt 55 DL-Tartaric Acid 2-Benzisothiazolin-3-one 10332-51-1 Cyclamic acid 1-dioxide, potassium salt (S)-(-)-Phenylalanine Zeranol 26538-44-3 (S)-(-)-Tyrosine beta-D-fructopyranose 7660-25-S Carvone D-fructose 1,6-bisphosphate 488-69-7 Ethylbutyrate Ribose 5-phosphate 4300-28-1 6-Methyl-5-hepten-2-one Arabinose 147-81-9 60 Ethyl acetoacetate Saccharin, sodium salt hydrate 82385-42-O Methylbenzoate Maltitol S85-88-6 Phenylacetic Acid D-Fructose 1-phosphate 15978-08-2 Adipic acid D-Sorbitol 6-phosphate 108392-12 Ethylbenzoate alpha-D-Xylose 3.11.78-70-8 Benzyl benzoate nositol 1-phosphate 573-35-3 65 Pyruvic acid Succinic acid

US 7,452,555 B2 43 44

TABLE 3-continued TABLE 3-continued

Name CAS if Name CAS if Dimethyl anthranilate 85-91-6 Sodium , 6381-59-5 1,1-Dimethoxy-2-phenylpropane 90-87-9 tetrahydrate 4-hexanolide 695-06-7 L-(+)-Arginine 1119-34-2 Dimethylbenzylcarbinyl acetate 151-05-3 monohydrochloride Benzyl isobutyrate 103-28-6 Ethylenediamine 333-18-6 Acetyl isoeugenol 93-29-8 dihydrochloride 2-Acetyl-5-methylfuran 1193-79-9 10 Sodium formate 141-53-7 Alpha-methyl-p- 103-95-7 Sodium acetate 127-09-3 isopropylphenylpropanaldehyde Potassium acetate 127-08-2 Benzylcarbinyl formate 104-62-1 Ammonium citrate 3O12-65-S p-Cresyl alpha-toluate 101-94-0 Ammonium bicarbonate 1066-33-7 7646-93-7 Ammonium chloride 121.25-02-9 Potassium carbonate S84-08-7 15 Ammonium nitrate 6484-52-2 Potassium chloride 7447-40-7 Ammonium persulfate 7727-54-0 Potassium hydroxide 1310-58-3 Ammonium sulfate 7783-20-2 Ethyl tiglate 5837-78-5 Zinc chloride 7646-85-7 Nerol oxide 1786-08-9 Sulfuric acid, Zinc salt 744-6-2O-O DL-Tetrohydrofurfuryl 637-6S-O (1:1), heptahydrate propionate Sodium Tripolyphosphate 7758-29-4 Benzaldehyde propylene glycol 2568-25-4 ammonium benzoate 863-63-4 acetal ammonium bisulfite O192-30-0 2-Methyl-3-(2-furyl) acrolein 874-66-8 5-Naphthalenedisulfonic Acid 655-29-4 vanillin 121-33-5 Disodium Salt Cholic acid 81-25-4 4-Hydroxybenzoic Acid R-Carvone 6485-40-1 Diphenylacetic Acid Potassium nitrate 7757-79-1 25 Glutaric Acid Potassium permanganate 7722-64-7 L-(-)-Fucose Potassium persulfate 7727-21-1 L-Cysteine Hydrochloride Potassium phosphate, dibasic 2139900 L-Histidine Hydrochloride Potassium Phosphate Monobasic 7778-77-0 Monohydrate Potassium sulfate 7778-80-5 o-Toluic Acid Sodium bicarbonate 144-55-8 30 Pivalic Acid Sodium bisulfite 7631-90-5 Pyruvic Acid Sodium Salt Sodium carbonate 497-19-8 Sodium chloride 7647-14-5 Sodium Dithionate Dihydrate Sodium dithionite 7775-14-6 Sodium Malonate Sodium hydroxide 1310-73-2 Trisodium Citrate 68-04-2 Sodium nitrite 7632-OO-O 35 Potassium Sodium Tartrate 3O4-59-6 Sodium Pyrophosphate 7722-88-5 Potassium Citrate 866-84-2 Sodium sulfate 7757-82-6 D-Maltose Monohydrate 6363-53-7 Sodium sulfite 7757-83-7 Cyclohexaamylose 10016-20-3 Sodium thiocyanate S4O-72-7 Dodecyl sulfate, lithium salt 2O44-56-6 Calcium Carbonate 471-34-1 Manganese chloride 2145.076 Calcium chloride 10043-52-4 methyl-urea 598-SO-5 40 Calcium gluconate 299-28-5 beta-Cyclodextrin 7585-39-9 Calcium hydroxide 1305-62-O Triphosphoric acid, 13845-36-8 Calcium phosphate, dibasic 7757-93-9 pentapotassium salt Calcium sulfate 7778-18-9 Glycine ethyl ester 623-33-6 N-Methyl-D-glucamine 6284-40-8 hydrochloride Calcium oxide 1305-78-8 L-Histidine methyl ester 7389-87-9 Calcium Phosphate Monobasic 7758-23-8 45 ihydrochloride hexahydrate 7791-18-6 L-Leucine methyl ester 7517-19-3 Magnesium sulfate 7487-88-9 hydrochloride Magnesium Sulfate Heptahydrate 10O34-99-8 D-Lysine hydrochloride 7274-88-6 Aluminum chloride hexahydrate 7784-13-6 2-Naphthalenesulfonic acid S32-02-5 aluminum nitrate nonahydrate 7784-27-2 sodium salt Aluminum potassium sulfate, 7784-24-9 50 calcium nitrate tetrahydrate 13477-34-4 dodecahydrate Vitamin B1 59-43-8 Aluminum Sulfate, 7784-31-8 Zinc Acetate Dihydrate 5970-45-6 octadecahydrate 7789-23-3 (S)-(-)-Cysteine 52-90-4 Potassium iodate 2139718 p-Toluenesulfonic Acid 104-15-4 7681-11-0 Potassium 868-14-4 55 333-20-0 DL-aspartic acid 617-45-8 Sodium bromide 7647-15-6 p-Dimethylaminobenzaldehyde 100-10-7 Sodium fluoride 7681-49-4 Sodium salicylate 54-21-7 Sodium iodide 7681-82-5 Benzoin 119-53-9 Sodium nitrate 7631-99-4 Sodium dodecyl sulfate 151-21-3 Calcium acetate S743-26-0 L-Menthol 221 6-51-5 Trichloroacetic acid 76-03-9 Tiron 149-45-1 60 Ammonium acetate 631-61-8 Riboflavin 83-88-5 Ammonium fluoride 121.25-01-8 Sodium Acetate Trihydrate 6.131-90-4 DL-malic acid 617-48-1 Disodium Succinate Hexahydrate 6106-21-4 t-Butyl Alcohol 75-6S-O Disodium 6381-92-6 beta-Alanine 107-95-9 ethylenediaminetetraacetate (S)-(-)-Tryptophan 73-22-3 dihydrate 65 Malonic acid 141-82-2 sodium citrate, dihydrate 15458O1 Phenethylamine 64-04-0 US 7,452,555 B2 45 46

TABLE 3-continued TABLE 3-continued

Name CAS if Name CAS if Salicylylaldehyde 90-02-8 Diethylamine 109-89-7 Sodium benzoate S32-32-1 Diethylaminoethanol 100-37-8 Mandelic acid 90-64-2 N-(2-Hydroxyethyl)Morpholine 622-40-2 Calcium pantothenate 137-08-6 Octanoic Acid 124-07-2 Chloroacetic Acid 79-11-8 isobutyric acid 79-31-2 Ethanol Amine 141-43-5 Anisic Acid 100-09-4 Salicylic acid 69-72-7 10 Betaine 107-43-7 Saccharin sodium 128-44-9 Enantholic Acid 111-14-8 Thiamine hydrochloride 67-03-8 Hippuric Acid 495-69-2 2,2'-Oxybisethanol 111-46-6 Tiglic Acid 80-59-1 Resorcinol 108-46-3 Cyclohexanecarboxylic acid 98-89-5 2-Amino-2-(hydroxymethyl)-1,3- 77-86-1 m-Methoxybenzoic acid S86-38-9 propanediol 15 D-(+)-Camphoric acid 124-83-4 2,5-Dimethylphenol 95-87-4 N-(2-Hydroxyethyl)pyrrollidine 29SS-88-6 Ammonium Phosphate Monobasic 7722-76-1 Sodium Metabisulfite 7681-57-4 1,3-Butanediol 107-88-0 sodium hydrogen phosphate 7558-79-4 Glycolic Acid 79-14-1 Sodium Phosphate Monobasic 7558-80-7 Sodium Gluconate 527-07-1 Sodium thiosulfate 7772-98-71 Terephthalic Acid 100-21-0 Orthoboric acid 10043-35-3 L-Ascorbic Acid Sodium Salt 134-03-2 Diethanolamine 111-42-2 3-Acetyl-6-methyl-2,4- 520-45-6 Benzaldehyde 1 OO-52-7 pyrandione Sorbic acid 110-44-1 Calcium Acetate 62-54-4 L-(+)-Tartaric Acid 87-69-4 Nicotinamide 98-92-0 D-mannitol 69-65-8 -Hydroxy-2-naphthoic Acid 86-48-6 Butyl paraben 94-26-8 2-Isopropylphenol 88-69-7 25 Thymol 89-83-8 4-Aminosalicylic Acid 65-49-6 Methyl salicylate 119-36-8 Calcium Glycerophosphate 27214-OO-2 Citric acid 77-92-9 Erythorbic Acid Sodium Salt 7378-23-6 Creatinine 60-27-5 Gluconic Acid Potassium Salt 299-27-4 Vitamin C SO-81-7 Orotic Acid 65-86-1 Benzoic Acid 6S-8S-O p-Anise Alcohol 105-13-5 30 Methyl 4-hydroxybenzoate 99-76-3 Potassium Benzoate S82-25-2 m-Cresol 108-39-4 Taurine 107-35-7 p-Cresol 106-44-5 Thiamine Nitrate 532-43-4 Aspirin SO-78-2 3,3,5-Trimethyl-1-cyclohexanol 116-O2-9 Phenol 108-95-2 ert-Butylhydroquinone 1948-33-O Sucrose 57-50-1 Sulfosalicylic acid 97-05-2 35 Potassium citrate, monohydrate 153414.6 Gallic acid 149-91-7 Sodium acetate 127-09-3 L-borneo 464-45-9 Lactic acid SO-21-5 Soborneo 124-76-5 Propionic acid, sodium salt 6S-85 2,5-Dihydroxybenzoic acid, 490-79-9 Benzyl alcohol 100-51-6 Gentisic acid Phenethyl alcohol 60-12-8 5-hydroxy-6-methyl-3,4- Cholesterol 57-88-5 40 pyridinedimethanol D-Glucose SO-99-7 Naphthalene-2-sulfonic acid 20-18-3 Sorbitol SO-70-4 Ethanesulfonic acid, 2 562-OO-1 Aspartame 22839-47-O hydroxy-, monosodium salt Saccharin 81-07-2 Pamoic acid 2,6-Di-tert-Butyl-p-Cresol 128-37-0 2,4-Dimethylphenol 4-Chloro-3-methylphenol 59-50-7 3,5-Dihydroxyacetophenone 45 glycerin 56-81-5 Eugenol Propyl paraben 94-13-3 n-Butyric Acid fumaric acid 110-17-8 Hydroquinone dabco 280-57-9 Propionic Acid p-Phenylenediamine 106-50-3 meta-Phenylenediamine Anethole 418O-23-8 Oxalic Acid 50 propyl gallate 121-79-9 n-Hexanoic Acid L-monosodium glutamate 142-47-2 2-Furancarboxylic Acid Butylated hydroxyanisole 25013-16-5 4'-Nitroacetanilide Cyclohexanol, 5-methyl-2-(1- 89-78-1 D-(-)-Tartaric Acid methylethyl)-, p-Acetamidobenzoic Acid (1alpha2beta,5alpha)- Galactaric acid 55 alpha-Thioglycerol 96-27-5 D-glucuronate Sodium dehydroacetate 4418-26-2 Lactobionic acid Ethyl 4-hydroxybenzoate 120-47-8 p-Formylacetanilide Ethyl Vanillin 121-32-4 2-Mercaptobenzoic acid Triacetin 102-76-1 Propanoic acid, 2-hydroxy-, Potassium sorbate 590-00-1 calcium salt (2:1), (S)- Triethylcitrate 77-93-0 D(+)-10-Camphorsulfonic acid 60 (S)-(+)-Arginine 74-79-3 3-Cyclopentylpropionic acid Glycine 56-40-6 R-(-)-Camphorsulfonic acid (S)-(-)-Histidine 71-OO-1 DL-Lysine (S)-(+)-Lysine S6-87-1 Cinnamic acid Quinone 106-51-4 Naphthalene, 2-ethoxy 93-18-5 65 Methanesulfonic Acid 75-75-2 Dichloroacetic Acid DL-Tartaric Acid 133-37-9

US 7,452,555 B2 49 50

TABLE 3-continued TABLE 3-continued

Name CAS if Name CAS if 4-Methoxyphenylacetone 122-84-9 DL-aspartic acid 617-45-8 (-)-Myrtenal 564-94-3 p-Dimethylaminobenzaldehyde 100-10-7 3-Phenylpropionaldehyde 104-53-0 Sodium salicylate 54-21-7 -Phenylethyl propionate 120-45-6 Benzoin 119-53-9 2-Methyltetrahydrofuran-3-one 3188-OO-9 Sodium dodecyl sulfate 151-21-3 Cinnamyl acetate 103-54-8 L-Menthol 221 6-51-5 Styrallyl acetate 93-92-5 10 Tiron 149-45-1 Ethyl 4-methoxybenzoate 94-30-4 Riboflavin 83-88-5 Benzylpropionate 122-63-4 Sodium Acetate Trihydrate 6.131-90-4 Phenylpyruvate 156-O6-9 Disodium Succinate Hexahydrate 6106-21-4 uraneol 3658-77-3 Disodium 6381-92-6 methyl 2-methylbutanoate 868-57-5 ethylenediaminetetraacetate Benzeneacetaldehyde, alpha 93-53-8 15 dihydrate methyl sodium citrate, dihydrate 15458O1 Dimethyl anthranilate 85-91-6 Sodium potassium tartrate, 6381-59-5 ,1-Dimethoxy-2-phenylpropane 90-87-9 tetrahydrate 4-hexanolide 695-06-7 L-(+)-Arginine 1119-34-2 Dimethylbenzylcarbinyl acetate 151-05-3 monohydrochloride Benzyl isobutyrate 103-28-6 Ethylenediamine 333-18-6 Acetyl isoeugenol 93-29-8 dihydrochloride 2-Acetyl-5-methylfuran 1193-79-9 Sodium formate 141-53-7 Alpha-methyl-p 103-95-7 Sodium acetate 127-09-3 isopropylphenylpropanaldehyde Potassium acetate 127-08-2 Benzylcarbinyl formate 104-62-1 Ammonium citrate 3O12-65-S p-Cresyl alpha-toluate 101-94-0 Ammonium bicarbonate 1066-33-7 Potassium bisulfate 7646-93-7 25 Ammonium chloride 121.25-02-9 Potassium carbonate S84-08-7 Ammonium nitrate 6484-52-2 Potassium chloride 7447-40-7 Ammonium persulfate 7727-54-0 Potassium hydroxide 1310-58-3 Ammonium sulfate 7783-20-2 Ethyl tiglate 5837-78-5 Zinc chloride 7646-85-7 Nerol oxide 1786-08-9 Sulfuric acid, Zinc salt 744-6-2O-O DL-Tetrohydrofurfuryl 637-6S-O 30 (1:1), heptahydrate propionate Sodium Tripolyphosphate 7758-29-4 Benzaldehyde propylene glycol 2568-25-4 ammonium benzoate 863-63-4 acetal ammonium bisulfite O192-30-0 2-Methyl-3-(2-furyl) acrolein 874-66-8 5-Naphthalenedisulfonic Acid 655-29-4 vanillin 121-33-5 Disodium Salt 81-25-4 35 4-Hydroxybenzoic Acid 6485-40-1 Diphenylacetic Acid Potassium nitrate 7757-79-1 Glutaric Acid Potassium permanganate 7722-64-7 L-(-)-Fucose Potassium persulfate 7727-21-1 L-Cysteine Hydrochloride Potassium phosphate, dibasic 2139900 L-Histidine Hydrochloride 7778-77-0 Monohydrate Potassium Phosphate Monobasic 40 Potassium sulfate 7778-80-5 o-Toluic Acid Sodium bicarbonate 144-55-8 Pivalic Acid Sodium bisulfite 7631-90-5 Pyruvic Acid Sodium Salt Sodium carbonate 497-19-8 Potassium bromide Sodium chloride 7647-14-5 Sodium Dithionate Dihydrate Sodium dithionite 7775-14-6 Sodium Malonate Sodium hydroxide 1310-73-2 45 Trisodium Citrate Sodium nitrite 7632-OO-O Potassium Sodium Tartrate 3O4-59-6 Sodium Pyrophosphate 7722-88-5 Potassium Citrate 866-84-2 Sodium sulfate 7757-82-6 D-Maltose Monohydrate 6363-53-7 Sodium sulfite 7757-83-7 Cyclohexaamylose 10016-20-3 Sodium thiocyanate S4O-72-7 Dodecyl sulfate, lithium salt 2O44-56-6 Calcium Carbonate 471-34-1 50 Manganese chloride 2145.076 Calcium chloride 10043-52-4 methyl-urea 598-SO-5 Calcium gluconate 299-28-5 beta-Cyclodextrin 7585-39-9 Calcium hydroxide 1305-62-O Triphosphoric acid, 13845-36-8 Calcium phosphate, dibasic 7757-93-9 pentapotassium salt Calcium sulfate 7778-18-9 Glycine ethyl ester 623-33-6 N-Methyl-D-glucamine 6284-40-8 55 hydrochloride Calcium oxide 1305-78-8 L-Histidine methyl ester 7389-87-9 Calcium Phosphate Monobasic 7758-23-8 dihydrochloride Magnesium chloride hexahydrate 7791-18-6 L-Leucine methyl ester 7517-19-3 Magnesium sulfate 7487-88-9 hydrochloride Magnesium Sulfate Heptahydrate 10O34-99-8 D-Lysine hydrochloride 7274-88-6 Aluminum chloride hexahydrate 7784-13-6 2-Naphthalenesulfonic acid S32-02-5 aluminum nitrate nonahydrate 7784-27-2 60 sodium salt Aluminum potassium sulfate, 7784-24-9 calcium nitrate tetrahydrate 13477-34-4 dodecahydrate Vitamin B1 59-43-8 Aluminum Sulfate, 7784-31-8 Zinc Acetate Dihydrate 5970-45-6 octadecahydrate Potassium fluoride 7789-23-3 (S)-(-)-Cysteine 52-90-4 Potassium iodate 2139718 p-Toluenesulfonic Acid 104-15-4 65 Potassium iodide 7681-11-0 Potassium bitartrate 868-14-4 Potassium thiocyanate 333-20-0 US 7,452,555 B2 51 52

TABLE 3-continued TABLE 3-continued

Name CAS if Name CAS if Sodium bromide 7647-15-6 D-glucuronate Sodium fluoride 7681-49-4 Lactobionic acid Sodium iodide 7681-82-5 p-Formylacetanilide Sodium nitrate 7631-99-4 2-Mercaptobenzoic acid Calcium acetate S743-26-0 Propanoic acid, 2-hydroxy-, Trichloroacetic acid 76-03-9 calcium salt (2:1), (S)- Ammonium acetate 631-61-8 10 D(+)-10-Camphorsulfonic acid 3144-16-9 Ammonium fluoride 2125-O1-8 3-Cyclopentylpropionic acid 40-77-2 DL-malic acid 617-48-1 R-(-)-Camphorsulfonic acid 35963-20-3 t-Butyl Alcohol DL-Lysine beta-Alanine Cinnamic acid (S)-(-)-Tryptophan Malonic acid 15 Phenethylamine Dichloroacetic Acid Salicylylaldehyde Diethylamine Sodium benzoate Diethylaminoethanol Mandelic acid N-(2-Hydroxyethyl)Morpholine Calcium pantothenate Octanoic Acid Chloroacetic Acid isobutyric acid Ethanol Amine Anisic Acid Salicylic acid Betaine Saccharin sodium Enantholic Acid Thiamine hydrochloride Hippuric Acid 2,2'-Oxybisethanol Tiglic Acid Resorcinol Cyclohexanecarboxylic acid 2-Amino-2-(hydroxymethyl)-1,3- 25 m-Methoxybenzoic acid S86-38-9 propanediol D-(+)-Camphoric acid 24-83-4 2,5-Dimethylphenol N-(2-Hydroxyethyl)pyrrollidine 29SS-88-6 Ammonium Phosphate Monobasic Sodium Metabisulfite 7681-57-4 1,3-Butanediol sodium hydrogen phosphate 7558-79-4 Glycolic Acid Sodium Phosphate Monobasic 7558-80-7 Sodium Gluconate 30 Sodium thiosulfate 7772-98-71 Terephthalic Acid Orthoboric acid 10043-35-3 L-Ascorbic Acid Sodium Salt Diethanolamine 111-42-2 3-Acetyl-6-methyl-2,4- 520-45-6 Benzaldehyde 1 OO-52-7 pyrandione Sorbic acid 110-44-1 Calcium Acetate 62-54-4 L-(+)-Tartaric Acid 87-69-4 Nicotinamide 98-92-0 35 D-mannitol 69-65-8 -Hydroxy-2-naphthoic Acid 86-48-6 Butyl paraben 94-26-8 2-Isopropylphenol 88-69-7 Thymol 89-83-8 4-Aminosalicylic Acid 65-49-6 Methyl salicylate 119-36-8 Calcium Glycerophosphate 27214-OO-2 Citric acid 77-92-9 Erythorbic Acid Sodium Salt 7378-23-6 Creatinine 60-27-5 Gluconic Acid Potassium Salt 299-27-4 Vitamin C SO-81-7 40 Orotic Acid 65-86-1 Benzoic Acid 6S-8S-O p-Anise Alcohol OS-13-5 Methyl 4-hydroxybenzoate 99-76-3 Potassium Benzoate m-Cresol 108-39-4 Taurine p-Cresol 106-44-5 Thiamine Nitrate Aspirin SO-78-2 3,3,5-Trimethyl-1-cyclohexanol Phenol 108-95-2 ert-Butylhydroquinone 45 Sucrose 57-50-1 Sulfosalicylic acid Potassium citrate, monohydrate 153414.6 Gallic acid Sodium acetate 127-09-3 L-borneo Lactic acid SO-21-5 Soborneo Propionic acid, sodium salt 6S-85 2,5-Dihydroxybenzoic acid, Benzyl alcohol 100-51-6 Gentisic acid 50 Phenethyl alcohol 60-12-8 5-hydroxy-6-methyl-3,4- Cholesterol 57-88-5 pyridinedimethanol D-Glucose SO-99-7 Naphthalene-2-sulfonic acid 20-18-3 Sorbitol SO-70-4 Ethanesulfonic acid, 2 562-OO-1 Aspartame 22839-47-O hydroxy-, monosodium salt Saccharin 81-07-2 Pamoic acid 55 2,6-Di-tert-Butyl-p-Cresol 128-37-0 2,4-Dimethylphenol 4-Chloro-3-methylphenol 59-50-7 3,5-Dihydroxyacetophenone glycerin 56-81-5 Eugenol Propyl paraben 94-13-3 n-Butyric Acid fumaric acid 110-17-8 Hydroquinone dabco 280-57-9 Propionic Acid p-Phenylenediamine 106-50-3 meta-Phenylenediamine 60 Anethole 418O-23-8 Oxalic Acid propyl gallate 121-79-9 n-Hexanoic Acid L-monosodium glutamate 142-47-2 2-Furancarboxylic Acid Butylated hydroxyanisole 25013-16-5 4'-Nitroacetanilide Cyclohexanol, 5-methyl-2-(1- 89-78-1 D-(-)-Tartaric Acid 47-71-7 methylethyl)-, p-Acetamidobenzoic Acid SS6-08-1 65 (1alpha, 2beta, 5alpha)- Galactaric acid 526-99-8 alpha-Thioglycerol 96-27-5 US 7,452,555 B2 53 54

TABLE 3-continued TABLE 3-continued

Name CAS if Name CAS if Sodium dehydroacetate 4418-26-2 Alpha-Terpineol 98-55-S Ethyl 4-hydroxybenzoate 120-47-8 Benzaldehyde Dimethylacetal 1125-88-8 Ethyl Vanillin 121-32-4 Benzyl Ether 103-50-4 Triacetin 102-76-1 Benzyl Formate 104-57-4 Potassium sorbate 590-00-1 Benzyl Salicylate 118-58-1 Triethylcitrate 77-93-0 Cinnamyl Alcohol 104-54-1 (S)-(+)-Arginine 74-79-3 10 D-(+)-Glucono-1,5-lactone 4253-68-3 Glycine 56-40-6 D-Isoascorbic Acid 89-65-6 (S)-(-)-Histidine 71-OO-1 2,3-Naphthalenediol 92-44-4 (S)-(+)-Lysine Diethyl Succinate 123-25-1 Quinone Ethyl 2-Aminobenzoate 87-25-2 Naphthalene, 2-ethoxy Ethyl Cinnamate 103-36-6 Methanesulfonic Acid 15 Ethyl Phenylacetate 101-97-3 DL-Tartaric Acid Ethyl Salicylate 118-61-6 Cyclamic acid gamma-Valerolactone 108-29-2 (S)-(-)-Phenylalanine Hydroquinone Dimethyl Ether 1SO-78-7 (S)-(-)-Tyrosine Socaproic Acid 646-07-1 Carvone Soeugenol 97-54-1 Ethylbutyrate Sopropyl Benzoate 939-48-0 6-Methyl-5-hepten-2-one L-(+)-Isoleucine 73-32-5 Ethyl acetoacetate L-Malic acid 97-67-6 Methyl benzoate L-2-Aminopropionic Acid 56-41-7 Phenylacetic Acid L-Carnitine 541-15-1 Adipic acid L-Glutamine S6-85-9 Ethyl benzoate L-Hydroxyproline S1-35-4 Benzyl benzoate 25 L-Proline 147-85-3 Pyruvic acid L-Serine 56-45-1 Succinic acid L-Threonine 72-19-5 indole L-Valine 72-18-4 Methyl anthranilate Phenoxyacetic Acid 122-59-8 Diethyl malonate Weratrole 91-16-7 Niacin 30 2-Ethylbutyric acid 88-09-5 Meso-inositol 2-Methylpyrazine 109-08-0 4-Aminobenzoic acid o-methoxybenzaldehyde 135-02-4 Anisole L-Leucine 61-90-5 Urea L-Asparagine 70-47-3 Pyrrollidine propiophenone 93-SS-O Cyclopentanone 35 5-isopropyl-2-methyl-phenol 499-75-2 Acetic anhydride Xylitol 87-99-0 Benzophenone ethyl 4-oxopentanoate S39-88-8 D-(-)-Fructose methyl cinnamate 103-26-4 D-(+)-Xylose culmic alcohol S36-60-7 o-Methoxybenzoic Acid methyl 2-naphthyl ketone 93-08-3 inalool 1-methyl-4-(1-methylethyl)- 99-85-4 40 1,4-Cyclohexadiene en-ethylene diamine Caffeine 58-08-2 5-methylfurfural 620-02-0 furfuryl acetate 623-17-6 terpinen-4-ol 10482-56-1 45 phenylethanal 122-78-1 4-Methoxyacetophenone 100-06-1 D-Fenchone 4695-62-9 1-Methoxy-4-methylbenzene 104-93-8 O-methylamisole 578-58-5 Acetylacetaldehyde dimethyl 5436-21-5 50 acetal p-methylacetophenone 122-OO-9 Ethyl crotonate 623-70-1 Methyl phenylacetate 101-41-7 ethyl isobutyrate 97-62-1 4-Ethoxybenzaldehyde 10O31-82-0 methyl isovalerate 556-24-1 p-tolyl acetate 140-39-6 methylpropionate 554-12-1 2,6-Dimethoxyphenol 91-10-1 methyl valeraldehyde 123-15-9 55 Methyl 2-methoxybenzoate 606-45-1 4-(2,6,6-Trimethyl-2- 127-41-3 alpha-methylcinnamaldehyde 101-39-3 cyclohexen-1-yl)-3-buten-2-one 2-methoxycinnamaldehyde 6O125-24-8 4-(2,6,6-trimethyl-1- 14901-07-6 Potassium bicarbonate 298-14-6 cyclohexen-1-yl)-3-buten-2-one piperonyl acetate 326-61-4 Maleic acid 110-16-7 2,3-hexanedione 3848-24-6 3-Methylbutanoic acid SO3-74-2 urfural acetone 623-15-4 L-Glutamic Acid 56-86-O 60 trans beta-(2-furyl)acrolein 623-30-3 D-limonene S989-27-5 carveol 99-48-9 1-Phenyl-1-propanol 93-54-9 Methyl nicotinate 93-60-7 2'-Hydroxyacetophenone 118-93-4 Ethylbenzoylacetate 94-O2-0 2,4-Dihydroxybenzoic Acid 89-86-1 Methyl 4-methoxybenzoate 121-98-2 2-Phenyl-1-propanol 1123-85-9 Levulinic acid 123-76-2 3-Phenylpropionic Acid SO1-52-0 65 m-Dimethoxybenzene 151-10-0 4-Ethoxyphenol 622-62-8 2-acetylpyridine 1122-62-9 US 7,452,555 B2 55 56

TABLE 3-continued TABLE 3-continued

Name CAS if Name CAS if tetramethyl-pyrazine 1124-11-4 Calcium oxide 1305-78-8 2,3-dimethyl-pyrazine 591 O-89-4 Calcium Phosphate Monobasic 7758-23-8 trimethyl-pyrazine 14667-SS-1 Magnesium chloride hexahydrate 7791-18-6 2-ethyl-3-methyl-pyrazine 15707-23-0 Magnesium sulfate 7487-88-9 5-Methyl-3H-furan-2-one 591-12-8 Magnesium Sulfate Heptahydrate 10O34-99-8 2-Methoxy-4-methylphenol 93-51-6 Aluminum chloride hexahydrate 7784-13-6 piperazine 110-85-0 10 aluminum nitrate nonahydrate 7784-27-2 2-Methoxy-4-propylphenol 2785-87-7 Aluminum potassium sulfate, 7784-24-9 Naphthalene, 2-(2- 2173-57-1 dodecahydrate methylpropoxy)- Aluminum Sulfate, 7784-31-8 2-Acetyl-1-methylpyrrole 932-16-1 octadecahydrate 3,3-Dimethylacrylic acid 541-47-9 (S)-(-)-Cysteine 52-90-4 Ethyl sorbate 2396-84-1 15 p-Toluenesulfonic Acid 104-15-4 4-(4-Hydroxyphenyl)-2-butanone S471-51-2 Potassium bittartrate 868-14-4 4-Methoxyphenylacetone 122-84-9 DL-aspartic acid 617-45-8 (-)-Myrtenal 564-94-3 p-Dimethylaminobenzaldehyde 100-10-7 3-Phenylpropionaldehyde 104-53-0 Sodium salicylate 54-21-7 -Phenylethyl propionate 120-45-6 Benzoin 119-53-9 2-Methyltetrahydrofuran-3-one 3188-OO-9 Sodium dodecyl sulfate 151-21-3 Cinnamyl acetate 103-54-8 L-Menthol 221 6-51-5 Styrallyl acetate 93-92-5 Tiron 149-45-1 Ethyl 4-methoxybenzoate 94-30-4 Riboflavin 83-88-5 Benzylpropionate 122-63-4 Sodium Acetate Trihydrate 6.131-90-4 Phenylpyruvate 156-O6-9 Disodium Succinate Hexahydrate 6106-21-4 uraneol 3658-77-3 Disodium 6381-92-6 methyl 2-methylbutanoate 868-57-5 25 ethylenediaminetetraacetate Benzeneacetaldehyde, alpha 93-53-8 dihydrate methyl sodium citrate, dihydrate 15458O1 Dimethyl anthranilate 85-91-6 Sodium potassium tartrate, 6381-59-5 ,1-Dimethoxy-2-phenylpropane 90-87-9 etrahydrate 4-hexanolide 695-06-7 L-(+)-Arginine 1119-34-2 Dimethylbenzylcarbinyl acetate 151-05-3 30 monohydrochloride Benzyl isobutyrate 103-28-6 Ethylenediamine 333-18-6 Acetyl isoeugenol 93-29-8 dihydrochloride 2-Acetyl-5-methylfuran 1193-79-9 Sodium formate 141-53-7 Alpha-methyl-p- 103-95-7 Sodium acetate 127-09-3 isopropylphenylpropanaldehyde Potassium acetate 127-08-2 Benzylcarbinyl formate 104-62-1 35 Ammonium citrate 3O12-65-S p-Cresyl alpha-toluate 101-94-0 Ammonium bicarbonate 1066-33-7 Potassium bisulfate 7646-93-7 Ammonium chloride 121.25-02-9 Potassium carbonate S84-08-7 Ammonium nitrate 6484-52-2 Potassium chloride 7447-40-7 Ammonium persulfate 7727-54-0 Potassium hydroxide 1310-58-3 Ammonium sulfate 7783-20-2 Ethyl tiglate 5837-78-5 Zinc chloride 7646-85-7 40 Nerol oxide 1786-08-9 Sulfuric acid, Zinc salt 744-6-2O-O DL-Tetrohydrofurfuryl 637-6S-O (1:1), heptahydrate propionate Sodium Tripolyphosphate 7758-29-4 Benzaldehyde propylene glycol 2568-25-4 ammonium benzoate 863-63-4 acetal ammonium bisulfite O192-30-0 2-Methyl-3-(2-furyl) acrolein 874-66-8 5-Naphthalenedisulfonic Acid 655-29-4 vanillin 121-33-5 45 Disodium Salt Cholic aci 81-25-4 4-Hydroxybenzoic Acid R-Carvone 6485-40-1 Diphenylacetic Acid Potassium nitrate 7757-79-1 Glutaric Acid Potassium permanganate 7722-64-7 L-(-)-Fucose Potassium persulfate 7727-21-1 L-Cysteine Hydrochloride Potassium phosphate, dibasic 2139900 50 L-Histidine Hydrochloride Potassium Phosphate Monobasic 7778-77-0 Monohydrate Potassium sulfate 7778-80-5 o-Toluic Acid Sodium bicarbonate 144-55-8 Pivalic Acid Sodium bisulfite 7631-90-5 Pyruvic Acid Sodium Salt Sodium carbonate 497-19-8 Potassium bromide Sodium chloride 7647-14-5 55 Sodium Dithionate Dihydrate Sodium dithionite 7775-14-6 Sodium Malonate Sodium hydroxide 1310-73-2 Trisodium Citrate Sodium nitrite 7632-OO-O Potassium Sodium Tartrate Sodium Pyrophosphate 7722-88-5 Potassium Citrate Sodium sulfate 7757-82-6 D-Maltose Monohydrate 6363-53-7 Sodium sulfite 7757-83-7 Cyclohexaamylose OO16-20-3 Sodium thiocyanate S4O-72-7 60 Dodecyl sulfate, lithium salt 2O44-56-6 Calcium Carbonate 471-34-1 Manganese chloride 2145.076 Calcium chloride 10043-52-4 methyl-urea 598-SO-5 Calcium gluconate 299-28-5 beta-Cyclodextrin 7585-39-9 Calcium hydroxide 1305-62-O Triphosphoric acid, 13845-36-8 Calcium phosphate, dibasic 7757-93-9 pentapotassium salt Calcium sulfate 7778-18-9 65 Glycine ethyl ester 623-33-6 N-Methyl-D-glucamine 6284-40-8 hydrochloride US 7,452,555 B2 58

TABLE 3-continued TABLE 3-continued

Name CAS if Name CAS if L-Histidine methyl ester 7389-87-9 2,4-Dimethylphenol OS-67-9 dihydrochloride 3,5-Dihydroxyacetophenone 51863-6O-6 L-Leucine methyl ester 7517-19-3 Eugenol 97-53-0 hydrochloride n-Butyric Acid O7-92-6 D-Lysine hydrochloride 7274-88-6 Hydroquinone 23-31-9 2-Naphthalenesulfonic acid S32-02-5 Propionic Acid 79-09-4 sodium salt 10 meta-Phenylenediamine O8-45-2 calcium nitrate tetrahydrate 13477-34-4 Oxalic Acid 44-62-7 Vitamin B1 59-43-8 n-Hexanoic Acid 42-62-1 Zinc Acetate Dihydrate 5970-45-6 2-Furancarboxylic Acid 88-14-2 Potassium fluoride 7789-23-3 4'-Nitroacetanilide 04-04-1 Potassium iodate 2139718 D-(-)-Tartaric Acid 47-71-7 Potassium iodide 7681-11-0 15 p-Acetamidobenzoic Acid SS6-08-1 Potassium thiocyanate 333-20-0 Galactaric acid 526-99-8 Sodium bromide 7647-15-6 D-glucuronate 7OO908 Sodium fluoride 7681-49-4 Lactobionic acid 96-82-2 Sodium iodide 7681-82-5 p-Formylacetanilide 22-85-O Sodium nitrate 7631-99-4 2-Mercaptobenzoic acid 47-93-3 Calcium acetate S743-26-0 Propanoic acid, 2-hydroxy-, 283OS-2S-1 Trichloroacetic acid 76-03-9 calcium salt (2:1), (S)- Ammonium acetate 631-61-8 D(+)-10-Camphorsulfonic acid 3144-16-9 Ammonium fluoride 121.25-01-8 3-Cyclopentylpropionic acid 40-77-2 DL-malic acid 617-48-1 R-(-)-Camphorsulfonic acid 35963-20-3 t-Butyl Alcohol 75-6S-O DL-Lysine 70-54-2 beta-Alanine 107-95-9 Cinnamic acid 621-82-9 (S)-(-)-Tryptophan 73-22-3 25 Triethanolamine O2-71-6 Malonic acid 141-82-2 Acetic Acid 64-19-7 Phenethylamine 64-04-0 Dichloroacetic Acid 79-43-6 Salicylylaldehyde 90-02-8 Diethylamine O9-89-7 Sodium benzoate S32-32-1 Diethylaminoethanol OO-37-8 Mandelic acid 90-64-2 N-(2-Hydroxyethyl)Morpholine 622-40-2 Calcium pantothenate 137-08-6 30 Octanoic Acid 24-07-2 Chloroacetic Acid 79-11-8 isobutyric acid 79-31-2 Ethanol Amine 141-43-5 Anisic Acid OO-09-4 Salicylic acid 69-72-7 Betaine O7-43-7 Saccharin sodium 128-44-9 Enantholic Acid 11-14-8 Thiamine hydrochloride 67-03-8 Hippuric Acid 495-69-2 2,2'-Oxybisethanol 111-46-6 35 Tiglic Acid 80-59-1 Resorcinol 108-46-3 Cyclohexanecarboxylic acid 98-89-5 2-Amino-2-(hydroxymethyl)-1,3- 77-86-1 propanediol m-Methoxybenzoic acid S86-38-9 2,5-Dimethylphenol 95-87-4 D-(+)-Camphoric acid 124-83-4 Ammonium Phosphate Monobasic 7722-76-1 N-(2-Hydroxyethyl)pyrrollidine 29SS-88-6 107-88-0 1,3-Butanediol 40 Glycolic Acid 79-14-1 Sodium Gluconate 527-07-1 Terephthalic Acid 100-21-0 TABLE 4 L-Ascorbic Acid Sodium Salt 134-03-2 3-Acetyl-6-methyl-2,4- 520-45-6 Crystal data and structure refinement for pyrandione Fluoxetine HCl:Benzoic acid (1:1). Calcium Acetate 62-54-4 45 Nicotinamide 98-92-0 Identification code Fluoxetine HCl:Benzoic acid (1:1) -Hydroxy-2-naphthoic Acid 86-48-6 Empirical formula C24 H2S C1 F3 NO3 2-Isopropylphenol 88-69-7 Formula weight 467.90 4-Aminosalicylic Acid 65-49-6 Temperature 100(2) K Calcium Glycerophosphate 27214-OO-2 Wavelength 0.71073 A Erythorbic Acid Sodium Salt 7378-23-6 50 Crystal system Monoclinic Gluconic Acid Potassium Salt 299-27-4 Space group P2(1)/n Orotic Acid 65-86-1 Unit cell dimensions a = 14.806(5) A C = 90°. p-Anise Alcohol 105-13-5 b = 13.179(4) A B = 97.738(13). Potassium Benzoate S82-25-2 c = 24.417(7) A y = 90°. Taurine 107-35-7 Volume 4721(2) A Thiamine Nitrate 532-43-4 55 Z. 8 3,3,5-Trimethyl-1-cyclohexanol 116-O2-9 Density (calculated) 1.317 Mg/m ert-Butylhydroquinone 1948-33-O Absorption coefficient 0.210 mm Sulfosalicylic acid 97-05-2 F(000) 1952 Gallic acid 149-91-7 Crystal size 0.47 x 0.15 x 0.10 mm L-borneo 464-45-9 Theta range for data collection 1.52 to 33.07. Soborneo 124-76-5 Index ranges -22 <= h <= 22, -20 <= k <= 20, 2,5-Dihydroxybenzoic acid, 490-79-9 60 -37 &= 1 &= 37 Gentisic acid Reflections collected 82494 5-hydroxy-6-methyl-3,4- Independent reflections 17030 R(int) = 0.0751) pyridinedimethanol Completeness to theta = 33.07 95.0% Naphthalene-2-sulfonic acid 120-18-3 Absorption correction None Ethanesulfonic acid, 2 1562-OO-1 Refinement method Full-matrix least-squares on F? hydroxy-, monosodium salt 65 Data restraints, parameters 1703.O.O.S81 Pamoic acid 130-85-8 Goodness-of-fit on F2 1.053 US 7,452,555 B2 59 60

TABLE 4-continued TABLE 6-continued Crystal data and structure refinement for Crystal data and structure refinement for Fluoxetine HCl:Benzoic acid (1:1). Nabumetone:2,3-naphthalenediol (1:1). Final R indices I is 2sigma(I) R1 = 0.0853, wR2 = 0.1933 Final R indices I is 2sigma(I) R1 = 0.0528, wR2 = 0.1332 Rindices (all data) R1 = 0.1330, wR2 = 0.2168 Rindices (all data) R1 = 0.1116, wR2 = 0.1692 Largest diff. peak and hole 2.571 and -0.689 e - A Largest diff peak and hole 0.277 and -0.325e. A

10 TABLE 5 TABLE 7 Crystal data and structure refinement for Fluoxetine Crystal data and structure refinement for Fluoxetine HCl-Succinic acid (2:1). HC-fumaric acid (2:1). 15 Identification code Identification code Fluoxetine HCl-succinic acid (2:1) Empirical formula Empirical formula C38H42 C12 F6N2O6 Formula weight Formula weight 807.64 Temperature Temperature 100(2) K 173(2) K 0.71073 A Wavelength 1.54178 A Wavelength Orthorhombic Orthorhombic Crystal system Crystal system Space group Pbcn Space group Pbcn Unit cell dimensions a = 26.6914(8) A C = 90°. Unit cell dimensions a = 26.620(2) A b = 7.1807(3) A B = 90°. b = 7.2147 (7) A c = 20.6546(7) A B = 90°. c = 20.8315(19) A Volume Volume 3958.7 (2) A 4000.8(6) A Z. 4 Z. 4 Density (calculated) 1.355 Mg/m Density (calculated) 1.341 Mg/m 25 Absorption coefficient 2.130 mm Absorption coefficient 0.236 mm 1680 F(000) 1680 F(000) Crystal size 0.21 x 0.18 x 0.09 mm Crystal size 0.20 x 0.14 x 0.08 mm Theta range for data collection 3.31 to 58.93. Theta range for data collection 1.53 to 27.50. index ranges -24 <= h <= 29, -7 <= k <= 7. index ranges -34 <= h <= 34, -9 <= k <= 9, -21 <= 1 <= 22 -26 <= 1 <= 27 30 Reflections collected 15698 Reflections collected 37123 independent reflections 2823 R(int) = 0.1693) independent reflections 4600 R(int) = 0.0748) 99.7% 100.0% Completeness to theta = 58.93 Completeness to theta = 27.50° Absorption correction None Absorption correction Semi-empirical from equivalents Refinement method Max. and min. transmission 1.000 and 0.813837 Full-matrix least-squares on F. 2823 O.246 Refinement method Data restraints parameters Full-matrix least-squares on F. 35 Goodness-of-fit on F2 1.018 Data restraints parameters 46000249 Goodness-of-fit on F2 1.156 Final R indices I is 2sigma(I) R1 = 0.0469, wR2 = 0.0927 Rindices (all data) R1 = 0.0940, wR2 = 0.1197 Final R indices I is 2sigma(I) R1 = 0.0786, wR2 = 0.1782 Largest diff peak and hole 0.583 and -0.750 e - A Rindices (all data) R1 = 0.0911, wR2 = 0.1852 Largest diff. peak and hole 0.682 and -0.499 e - A 40 What is claimed is: TABLE 6 1. A method of Screening for a cocrystal of a hydrochloric Crystal data and structure refinement for acid salt of an active agent, comprising the steps of Nabumetone:2,3-naphthalenediol (1:1). 45 selecting a carboxylic acid having at least 4 carbons to Identification code Nabumetone:2,3-naphthalenediol (1:1) coordinate via hydrogen bonding with the chloride Empirical formula anion of the hydrochloric acid salt of the active agent, Formula weight Temperature 100(2) K preparing a solution, melt, or physical mixture of the Wavelength 1.54178 A hydrochloric acid salt of the active agent and the car Crystal system Monoclinic 50 boxylic acid, Space group P2(1)/n Subjecting the Solution or melt to a crystallization process, Unit cell dimensions a = 17.1585 (7) A C = 90°. b = 5.5168(3) A B = 91.319(3). or the physical mixture to grinding, and c = 20.7083 (9) A y = 90°. determining whether a cocrystal of the hydrochloric acid Volume 1959.73(16) A salt of the active agent and the carboxylic acid has Z. 4 55 Density (calculated) 1.317 Mg/m formed. Absorption coefficient 0.710 mm 2. The method of claim 1 wherein the carboxylic acid F(000) 824 Crystal size 0.21 x 0.08 x 0.025 mm having at least 4 carbons is selected from benzoic acid, Suc Theta range for data collection 3.31 to 66.15. cinic acid, and fumaric acid. Index ranges -17 <= h <= 19, -6 <= k <= 5, 3. The method of claim 1 wherein the active agent is an -24 <= 1 <= 23 60 active pharmaceutical ingredient. Reflections collected 8803 Independent reflections 3063 R(int) = 0.0801) 4. The method of claim 1 wherein the active agent is a Completeness to theta = 66.15° 89.1% nitrogen containing base. Absorption correction None 5. The method of claim 4 wherein the nitrogen containing Refinement method Full-matrix least-squares on F. Data restraints, parameters 3063 2.266 65 base is a tertiary amine. Goodness-of-fit on F2 1.019 6. The method of claim 4 wherein the nitrogen containing base is a secondary amine. US 7,452,555 B2 61 62 7. The method of claim 4 wherein the nitrogen containing 10. The method of claim 1 wherein the preparing step base is a primary amine. comprises preparing a melt of the hydrochloric acid salt of the 8. The method of claim 1 wherein X-ray diffraction is used active agent and the carboxylic acid. to determine whether a cocrystal of the hydrochloric acid salt 11. The method of claim 1 wherein the preparing step of the active agent and the carboxylic acid has formed. comprises preparing a physical mixture of the hydrochloric 9. The method of claim 1 wherein the preparing step com acid salt of the active agent and the carboxylic acid. prises preparing a solution of the hydrochloric acid salt of the active agent and the carboxylic acid. k k k k k