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US 2011 0160273A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0160273 A1 Buschmann et al. (43) Pub. Date: Jun. 30, 2011

(54) CO-CRYSTALS OF DULOXETINE AND (30) Foreign Application Priority Data COX-INHIBITORS FOR THE TREATMENT OF PAN May 21, 2008 (EP) ...... O8384009.O (76) Inventors: Helmut Heinrich Buschmann, Publication Classification Walheim (DE); Lluis Solá (51) Int. Cl. Carandell, Tarragona (ES); Jordi A63L/38 (2006.01) Benet Buchholz, Tarragona (ES); A6II 3/40 (2006.01) Jordi Carles Ceron Bertran, Tarragona (ES); Jesis Ramirez A6IP 25/00 (2006.01) Artero, Tarragona (ES) A6IP 9/02 (2006.01) (52) U.S. Cl...... 514/423: 514/438 (21) Appl. No.: 12/991,420 (57) ABSTRACT (22) PCT Filed: May 20, 2009 The present invention relates to co-crystals of dulloxetine and (86). PCT No.: PCT/EP2009/003617 co-crystal formers selected from COX-INHIBITORs, pro cesses for preparation of the same and their uses as medica S371 (c)(1), ments or in pharmaceutical formulations, more particularly (2), (4) Date: Mar. 18, 2011 for the treatment of pain.

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US 2011/O160273 A1 Jun. 30, 2011

CO-CRYSTALS OF OULOXETINE AND 0006 Thus it was the objective of the current invention to COX-INHIBITORS FOR THE TREATMENT provide new means of improving the properties of dulloxetine, OF PAN especially in regard to the treatment of pain, by providing new drugable forms of dulloxetine. 0007 Especially desirable improvements/advantages of the new drugable form would include: 0001. The present invention relates to co-crystals of 0008 improvement of physicochemical properties in dulloxetine and co-crystal formers selected from COX-IN order to facilitate the formulation, the manufacture, or to HIBITORs, processes for preparation of the same and their enhance the absorption and/or the bioavailability: uses as medicaments or in pharmaceutical formulations, 0009 thus more particularly for the treatment of pain. 0.010 being more active when compared to dulloxetine 0002 Pain is a complex response that has been function base or hydrochloride salt; or ally categorized into sensory, autonomic, motor, and affective 0.011 providing a form of dulloxetine with a further components. The sensory aspect includes information about active agent having a beneficial pharmacological effect stimulus location and intensity while the adaptive component in itself, thus allowing for a highly efficient dose/weight may be considered to be the activation of endogenous pain relation of the final active principle or even modulation and motor planning for escape responses. The 0012 allowing the use of a lower therapeutic dose of affective component appears to include evaluation of pain either dulloxetine and the further active agent or of both; unpleasantness and stimulus threat as well as negative emo 0013 having a synergistic effect through the combina tions triggered by memory and context of the painful stimu tion of dulloxetine and the further actice agent in the lus. same new drugable form; or 0003. In general, pain conditions can be divided into 0014 further chronic and acute. Chronic pain includes neuropathic pain 0.015 being easily obtainable, easy to manufacture or and chronic inflammatory pain, for example arthritis, or pain 0016 allowing more flexibility informulating, or facili of unknown origin, as fibromyalgia. Acute pain usually fol tating its formulation, lows non-neural tissue injury, for example tissue damage 0017 being highly soluble, thus allowing better disso from Surgery or inflammation, or migraine. lution rates, especially if dissolving in an aqueous physi 0004 (+)-(S)- N-Methyl-N-3-(naphthalene-1-yloxy)- ological Surrounding, or 3-(2-thienyl)-propylamine, having the INN-name Duloxet 0018 reducing hygrosciplicity: ine and being also described as (+)-(S)-Duloxetine or (S)- 0.019 improving stability; Duloxetine is known to be a potent serotonin and 0020 allowing new routes of administration; norepinephrine reuptake inhibitor (SNRI). Duloxetine is mar 0021 also keted for the treatment of a variety of diseases like anxiety and 0022 allowing to combine dulloxetine with a chemi depression but also including pain, especially diabetic periph cally usually non-compatible active agent in the same eral neuropathy. formulation or even in immediate contact, without hav ing to isolate dulloxetine; examples would include an acidic active agents and the acid labile dulloxetine; 7 S 0023 or finally le 0024 minimizing/reducing the side effects, especially the severe side effects, assigned to dulloxetine. 0025 Most desirably the new drugable forms should com i bine more than one, or even most of these advantages. 0026. This objective was achieved by providing new co crystals of dulloxetine. It was found that Duloxetine was able to form Co-crystals with COX-INIBITORs. These co-crys tals show improved properties if compared to dulloxetine Duloxetine? (S)-Duloxetine alone, and also good activity. The co-crystals thus obtained have a specific Stoichiometry which depends upon the structure of each co-crystal former. Under the proper 0005 Duloxetine is a commonly used drug. The usual circumstance this is also another advantage of these new solid application route is orally with capsules containg dulloxetine drugable forms possibly achieving some modulation of the hydrochloride in enterically coated pellets being applied with pharmacological effects. While APIs (Active Pharmaceutical doses of 20, 30 and 60 mg of active duloxetine. The enteric Ingredients) like dulloxetine in general have been recognized coating is necessary as dulloxetine is acid labile and therefore to form crystalline polymorphs, Solvates, hydrates and amor would have been in danger to become degenerated in the acid phous forms for a number of years, there is little knowledge environment of the stomach. The main side effects, nausea, about which APIs will form co-crystals. Co-crystals are a Somnolence, insomnia and dizzines, are occurring in 10 to specific type of crystalline form which provide a new avenue 20% of the patients. In addition a number of severe side to modulate the API form and thus to modulate API proper effects have been reported. Being as said above a wildly ties. Co-crystals contain an API and at least one other com used drug there is a continuous need to improve its properties ponent which crystallize together. Selection of the other com to achieve a number of effects like improved formulations, ponent helps determine whether a co-crystal will form and higher efficacy, reduction of side effects e.g. through reduc what properties the co-crystal will have. Just as a polymorph, tion of the necessary dosis etc. solvate, hydrate or amorphous form of an API can modulate US 2011/O160273 A1 Jun. 30, 2011 stability, solubility, and hygroscopicity, a co-crystal can not necessarily the case so that there are symptoms of allo modulate those same properties. dynia not connected to neuropathic pain though rendering 0027 Thus the main object of the present invention is a allodynia in some areas broader then neuropathic pain. co-crystal comprising dulloxetine and at least one co-crystal 0034. The IASP further draws the following difference former selected from COX-INHIBITORs. The group of between “allodynia”, “hyperalgesia” and “hyperpathia COX-INHIBITORs include the NSAIDs (Nonsteroidal anti (IASP. Classification of chronic pain, 2'' Edition, IASP Press inflammatory drugs). (2002), 212): 0028 “COX-INHIBITORs are defined by the basis of their activity being inhibition of (COX), one of the two activities of prostaglandine endoperoxide synthase (PGHS). PGHS is a key enzyme in the path Allodynia Lowered threshold Stimulus and response mode differ way. Some preferred co-crystal formers in the sense of this Hyperalgesia Increased response Stimulus and response application are those (COX-INHIBITORS/NSAIDs) with a rate are the same carboxylic acid function, with examples including salicy Hyperpathia Raised threshold: Stimulus and response lates, anthranilates, arylacetic acids/arylalkanoic acids, and Increased response rate may be the same or arylpropionic acids, but also including Coxibs. different 0029 “Drugable form (of dulloxetine) as used herein is defined as any form (salt, amorphous crystal, Solution, dis 0035. According to the IASP"neuropathy” is defined as “a persion, mixture etc.) that dulloxetine might take which still primary lesion or dysfunction in the nervous system’ (IASP. can be formulated into a pharmaceutical formulation usable Classification of chronic pain, 2" Edition, IASP Press as a medicament to treat a disease or a symptom, especially (2002), 211). Neuropathic pain may have central or periph pain. eral origin. 0030 "Co-Crystal as used herein is defined as a crystal 0036. In one embodiment of the co-crystal according to line material comprising two or more compounds of which at the invention the co-crystal former or one of the co-crystal least two are held together by weak interaction, wherein at formers has at least one functional group from the group least one of the compounds is a co-crystal former. Weak consisting of ether, thioether, alcohol, thiol, aldehyde, ketone, interaction is being defined as an interaction which is neither thioketone, nitrate ester, phosphate ester, thiophosphate ester, ionic nor covalent and includes for example: hydrogen bonds, ester, thioester, Sulfate ester, carboxylic acid, phosphonic Vander Waals forces, and U-TL interactions. Solvates of duloX acid, phosphinic acid, Sulfonic acid, amide, primary amine, etine that do not further comprise a co-crystal former are not secondary amine, ammonia, tertiary amine, thiocyanate, co-crystals according to the present invention. The co-crys cyanamide, oxime, nitrile, diazo, organohalide, nitro, S-het tals may however, include one or more Solvate molecules in erocyclic ring, thiophene, n-heterocyclic ring, pyrrole, o-het the crystalline lattice. Just for the sake of clarity the distinc erocyclic ring, furan, epoxide, peroxide, hydroxamic acid, tion between crystalline salt and a co-crystal has to be stressed imidazole, and pyridine; here. An API bound to another compound forming a salt by preferably wherein the co-crystal former has at least one means of ionic interaction can be considered as one "com functional group from the group consisting of alcohol, thiol, pound according to the invention, but it cannot be considered ester, carboxylic acid, primary amine, secondary amine, ter as two compounds by itself. tiary amine. 0031. In scientific literature there is currently some dis cussion on the proper use of the word co-crystal (see for 0037. In one embodiment of the co-crystal according to example Desiraju, Cryst Eng Comm, 2003, 5(82), 466-467 the invention, the co-crystal former or one of the co-crystal and Dunitz, Cryst Eng Comm, 2003, 5(91), 506). A recent formers has at least one functional group from the group article by Zawarotko (Zwarotko, Crystal Growth & design, consisting of ether, thioether, alcohol, thiol, aldehyde, ketone, Vol. 7, No. 1, 2007, 4-9) gives a definition of co-crystal which thioketone, nitrate ester, phosphate ester, thiophosphate ester, is in line with the definition given above and thus also is a ester, thioester, Sulfate ester, carboxylic acid, phosphonic definition of “co-crystal’ according to this invention. Accord acid, phosphinic acid, Sulfonic acid, amide, primary amine, ing to this article “a co-crystal is a multiple component crystal secondary amine, ammonia, tertiary amine, thiocyanate, in which all components are solid under ambient conditions cyanamide, oxime, nitrile, diazo, organohalide, nitro, S-het when in their pure form. These components consist of a target erocyclic ring, thiophene, n-heterocyclic ring, pyrrole, o-het molecule Orion and a molecular co-crystal former(s); when erocyclic ring, furan, epoxide, peroxide, hydroxamic acid, in a co-crystal, they coexist at a molecular level within a imidazole, and pyridine; single crystal.' preferably wherein the co-crystal former or one of the co 0032 “Pain' is defined by the International Association crystal formers has at least one functional group from the for the Study of Pain (IASP) as “an unpleasant sensory and group consisting of alcohol, thiol, ester, carboxylic acid, pri emotional experience associated with actual or potential tis mary amine, secondary amine, tertiary amine; Sue damage, or described in terms of Such damage (IASP. most preferably wherein the co-crystal former or one of the Classification of chronic pain, 2" Edition, IASP Press co-crystal formers has at least one functional group being a (2002), 210). Even though pain is always subjective its causes carboxylic acid. or syndromes can be classified. 0038. In another embodiment the co-crystal former or one 0033. According to the IASP “allodynia” is defined as “a of the co-crystal formers has at least one functional group pain due to a stimulus which does not normally provoke pain' from the group consisting of alcohol, ester, or carboxylic acid. (IASP. Classification of chronic pain, 2" Edition, IASP Press In a further embodiment the co-crystal former or one of the (2002), 210). Even though the symptoms of allodynia are co-crystal formers has at least one functional group being a most likely associated as symptoms of neuropathic pain this is carboxylic acid. US 2011/O160273 A1 Jun. 30, 2011

0039. In a further embodiment of the co-crystal according NSAID being an arylacetic acid/arylalkanoic acid; or d) a to the invention the co-crystal former/s is/are chosen in Such co-crystal comprising dulloxetine and at least one co-crystal a way that if compared to either dulloxetine alone or to a former selected from an NSAID being an arylpropionic acid. mixture of dulloxetine and the corresponding active agent/s 0054 Examples of salicylates are: Acetylsalicylic acid, 0040 the solubility of the co-crystal is increased; and/or , , , , Fosfosal, 0041 the dose response of the co-crystal is increased; and Benorylate. Examples of anthranilates are: , and/or , , , Niflu mic acid, and . Examples of arylacetic acids/ 0042 the efficacy of the co-crystal is increased; and/or arylalkanoic acids are: , , Glucameta 0043 the dissolution of the co-crystal is increased; and/ cin, , , , Alcofenac, O , Indomethacin, , , Tolimetin, 0044 the bioavailability of the co-crystal is increased; Amtolimetin guacil, , , , and/or , and . Examples of arylpropionic acids are: 0045 the stability of the co-crystal is increased; and/or , Flurbiprofen axetil, , , 0046 the hygroscopicity of the co-crystal is decreased; , , , , Feno and/or profen, , , , and Clidanac. 0047 the form diversity of the co-crystal is decreased; 0055. In a further embodiment of the co-crystal according and/or to the invention the co-crystal former or one of the co-crystal 0048 the morphology of the co-crystal is modulated. formers is selected from 0056 Acetylsalicylic acid, Diflunisal, Ethenzamide, 0049 “Mixture of dulloxetine and the corresponding Salicylamide, Triflusal, Fosfosal, Benorylate, Etofe active agent/s is defined as a mixture of the active agent or namate, Flufenamic acid, Meclofenamic acid, Mefe agents in question (the co-crystal former/s) with dulloxetine namic acid, , Tolfenamic acid, Acemeta which is only a physical mixture without any coupling inter cin, Oxametacin, Glucametacin, Proglumetacin, actions between the compounds and thus neither includes BufeXamac, Diclofenac, Alcofenac, Aceclofenac, salts nor another co-crystal. Indomethacin, Lonazolac, Sulindac, Tolimetin, Amtol 0050. The term "salt' is to be understood as meaning any metin guacil, MofeZolac, Bromfenac, Nabumetone, form of dulloxetine or the co-crystal former according to the Fentiazac, Felbinac, Flurbiprofen, Flurbiprofen axetil, invention in which this assumes an ionic form or is charged Ibuprofen, Ketoprofen, Naproxen, Tiaprofenic acid, and is coupled with a counter-ion (a cation or anion) or is in Zaltoprofen, Pirprofen, , Vedaprofen, solution. By this are also to be understood complexes of Nepafenac, Amfenac, and Clidanac; or their stereoiso dulloxetine or the co-crystal former with other molecules and mers, salts or metabolites. ions, in particular complexes which are complexed via ionic 0057. Other examples of NSAIDs are the Coxibs, selec interactions. This also includes physiologically acceptable tive COX-2 Inhibitors. Therefore, another preferred embodi salt. ment of the invention is a co-crystal comprising dulloxetine 0051. The term “solvate” according to this invention is to and at least one co-crystal former selected from an NSAID be understood as meaning any form of the dulloxetine or being a Coxib. Examples of Coxibs are: , Etori co-crystal former in which the compound has attached to it coxib, , , , , and via non-covalent binding another molecule (most likely a . polar solvent) especially including hydrates and alcohol Sol 0058. Further examples of the co-crystal former are para Vates, e.g. methanol Solvate. aminophenol derivatives. Therefore, another preferred 0052. In a further embodiment of the co-crystal according embodiment of the invention is a co-crystal comprising to the invention the molar ratio between dulloxetine and the dulloxetine and at least one co-crystal former selected from a co-crystal former or at least one of the co-crystal formers is para-aminophenol derivative. Examples of para-aminophe different from 1. This might have the advantage of allowing nol derivatives are: , , and Pheni the development of a non-equimolar ratio between dulloxetine dine. and the active agent/s in a fixed dose with all the advantages 0059. In a further embodiment of the co-crystal according of the co-crystal. to the invention the co-crystal former or one of the co-crystal 0053. The co-crystal formers are selected from COX-IN formers is selected from HIBITORs (which include the NSAIDs), preferably those 0060 Acetylsalicylic acid, Diflunisal, Ethenzamide, with a carboxylic acid function. Preferred examples include Salicylamide, Triflusal, Fosfosal, Benorylate, Paraceta salicylates, anthranilates, arylacetic acids/arylalkanoic acids, mol, Propacetamol, Phenidine, Etofenamate, Flufe and arylpropionic acids. Therefore, a preferred embodiment namic acid, Meclofenamic acid, Mefenamic acid, Niflu of the invention is a co-crystal comprising dulloxetine and at mic acid, Tolfenamic acid, Acemetacin, Oxametacin, least one co-crystal former selected from NSAIDs, preferably Glucametacin, Proglumetacin, Bufexamac, Diclofenac, from NSAIDs with a carboxylic acid function. Another pre Alcofenac, Aceclofenac, Indomethacin, Lonazolac, ferred embodiment of the invention is a co-crystal comprising Sulindac, Tolimetin, Amtolimetin guacil, MofeZolac, dulloxetine and at least one co-crystal former selected from Bromfenac, Nabumetone, Fentiazac, Felbinac, Flurbi NSAIDs, selected from salicylates, anthranilates, arylacetic profen, Flurbiprofen axetil, Ibuprofen, Ketoprofen, acids/arylalkanoic acids, or arylpropionic acids. Other pre Naproxen, Tiaprofenic acid, Zaltoprofen, Pirprofen, ferred embodiment of the invention area) a co-crystal com Fenoprofen, Vedaprofen, Nepafenac, Amfenac, Clid prising dulloxetine and at least one co-crystal former selected anac, Metamizol, Propylphenazone, , Mofeb from an NSAID being a salicylate; b) a co-crystal comprising utaZone, , , ApaZone, dulloxetine and at least one co-crystal former selected from an , , , , Ketoro NSAID being a anthranilate; c) a co-crystal comprising lac, , Oxaprozine, Ditazole, , dulloxetine and at least one co-crystal former selected from an , , Celecoxib, , US 2011/O160273 A1 Jun. 30, 2011

Lumiracoxib, Parecoxib, Rofecoxib, Valdecoxib, Cimi 0068 Thus, another very preferred aspect of the invention coxib; or their stereoisomers, salts or metabolites: relates to a co-crystal according to the invention, wherein the 0061 or co-crystal former is naproxen, its enantiomers or salts 0062 Acetylsalicylic acid, Diflunisal, Ethenzamide, thereof. Especially it refers to a co-crystal according to the Salicylamide, Triflusal, Fosfosal, Benorylate, Paraceta invention, wherein the co-crystal former is (S)-naproxen. mol, Propacetamol, Phenidine, Etofenamate, Flufe 0069. As illustrated in more detail below dulloxetine forms namic acid, Meclofenamic acid, Mefenamic acid, Niflu co-crystals with (S)-naproxen. Generally co-crystals mic acid, Tolfenamic acid, Acemetacin, Oxametacin, obtained have a specific Stoichiometry which depends upon Glucametacin, Proglumetacin, Bufexamac, Diclofenac, the structure of each co-crystal former. In this specific case of Alcofenac, Aceclofenac, Indomethacin, Lonazolac, the co-crystal with (S)-naproxen being the co-crystal former Sulindac, Tolimetin, Amtolimetin guacil, MofeZolac, the molecular ratio between dulloxetine and (S)-naproxen is 2 Bromfenac, Nabumetone, Fentiazac, Felbinac, Flurbi to 3. profen, Flurbiprofen axetil, Ibuprofen, Ketoprofen, 0070. In this specific co-crystal of duloxetine and (S)- Naproxen, Tiaprofenic acid, Zaltoprofen, Pirprofen, naproxen according to the invention the endothermic sharp Fenoprofen, Vedaprofen, Nepafenac, Amfenac, Clid peak corresponding to the melting point has an onset at 124° anac, Metamizol, Propylphenazone, KebuZone, Mofeb C. utaZone, OxyphenbutaZone, PhenylbutaZone, ApaZone, 0071. This specific co-crystal of dulloxetine and (S)- Isoxicam, Lornoxicam, PiroXicam, Tenoxicam, Ketoro naproxen according to the invention shows an X-Ray powder lac, ProquaZone, Oxaprozine, Ditazole, Etodolac, diffraction pattern with peaks expressed in d-Value in A at Meloxicam, Nimesulide, Celecoxib, Etoricoxib, 12.889, 10.733, 10.527, 9,194, 8.541, 7.594, 7.430, 6.656, Lumiracoxib, Parecoxib, Rofecoxib, Valdecoxib, Cimi 6.444, 6.082, 5.975, 5.754, 5.436, 5.346, 5.259, 5.182, 5.131, coxib; Bermoprofen; Pelubiprofen; Tenosal; Ace 4.953, 4.930, 4.817, 4.766, 4.739, 4.690, 4.654, 4.638, 4.597, neuramic acid: Pirazolac; Xinoprofen; Flobufen; Aniro 4.434, 4.293, 4.266, 4.174, 4.068, 4.005, 3.984, 3.940, 3.886, lac, Zoliprofen; Bromfenac: Pemedolac, 3.795, 3.769, 3.735, 3.715, 3.641, 3.577, and 3.533. Dexpemedolac. Bindarit; Romazarit: (S)-Naproxen; 0072 This specific co-crystal of dulloxetine and (S)- Tiaprofenic acid: : Fenoprofen; Flobufen; naproxen according to the invention further has a triclinic unit , or their stereoisomers, salts or metabolites; cell with the following dimensions 0063 preferably is selected from 0.073 a=10.9284(4) A 0064 Acetylsalicylic Acid; Triflusal; HTB (2-hydroxy 0.074 b=12.1480(6) A 4-trifluoromethyl benzoic acid); Diflunisal; Meclofe 0075 c=13.5613(7) A namic acid; Mefenamic acid; Niflumic acid; Flufenamic 0076 C-107.477(3) acid; Diclofenac, Lonazolac, Acemetacin; Indometha 0.077 B=99.792(3) cin; Tolimetin; Sulindac.; Etodolac; , Flurbi 0078 y=95.382(2) profen; (RS)-Flurbiprofen; Esflurbiprofen; Ibuprofen; (0079 Another highly interesting COX-INHIBITOR to be (RS)-Ibuprofen; S-(+)-Ibuprofen; Ketoprofen; (rac)- the co-crystal former with duloxetine is the marketed drug Ketoprofen; R-(-)-Ketoprofen; Bermoprofen; Pelubi , whose chemical name is 1-methyl-5-(4-methyl profen, Tenosal; Aceneuramic acid; PiraZolac, Xinopro benzoyl)-1H-pyrrol-2-yl) and which is also fen; Flobufen; Anirolac; Zoliprofen; Bromfenac: described as a physiologically acceptable salt. Pemedolac, Dexpemedolac. Bindarit; Romazarit; Naproxen; (S)-Naproxen; Tiaprofenic acid: Fenbufen; Fenoprofen; Flobufen: Oxaprozin; their stereoisomers O or salts; HO N 0065 more preferably is Acetylsalicylic acid, Paraceta mol; Naproxen, (S)-Naproxen; Ibuprofen, (RS)-Ibupro fen, S-(+)-Ibuprofen; or one of their salts. \ / 0066. In general, all of these co-crystal formers which Tolimetin have at least one Stereogenic center are to be understood as being included herein in their racemic form or as diastereoi Somers or enantiomers or mixtures thereof. 0080 Thus, another very preferred aspect of the invention 0067. A highly interesting COX-INHIBITOR to be the relates to a co-crystal according to the invention, wherein the co-crystal former with dulloxetine is the marketed drug co-crystal former is tolmetin, or salts thereof. naproxen, whose chemical name is (S)-(6-methoxy-2-naph 0081. As illustrated in more detail below dulloxetine forms tyl), and which is also described as a physi co-crystals with tolmetin. Generally co-crystals obtained ologically acceptable salt. It has an empirical formula of have a specific Stoichiometry which depends upon the struc ture of each co-crystal former. In this specific case of the CHO, an Mp of 153°C. and a pKa of 4.2. co-crystal with tolmetin being the co-crystal former the CH3 molecular ratio between dulloxetine and tolmetin is 1 to 2. I0082 In this specific co-crystal of dulloxetine and tolmetin OH according to the invention the endothermic sharp peak corre sponding to the melting point has an onset at 111° C. I0083. This specific co-crystal of dulloxetine and tolmetin No O O according to the invention shows an X-Ray powder diffrac Naproxen tion pattern with peaks expressed in d-Value in A at 13.774, 12.845, 11.510, 9.146, 8.909, 8.462, 7.662, 6.856, 6.435, US 2011/O160273 A1 Jun. 30, 2011

6.329, 6.019, 5.881, 5.715, 5.571, 5.259, 5.010, 4.928, 4.888, 0108. The molecular ratio between dulloxetin and the co 4.569, 4.443, 4.274, 4.216, 4.136, 4.032, 3.951, 3.896, 3.830 crystal formerlies between 10:1 to 1:10; preferably 5:1 to 1:5, and 3.757. more preferably from 3:1 to 1:3 and most preferably from 1:1 0084. In another preferred embodiment of the co-crystal to 1:2. according to the invention the co-crystal former is ibuprofen, 0109 Preferably the dulloxetine-solution in step (c) (Alter its enantiomers or salts thereof. native I) or (a) (Alternative II) has a concentration of between 0085. In a further preferred embodiment of the co-crystal 3 and 0.01 mM. according to the invention the co-crystal former is (S)-ibu 0110. The parts of the co-crystal according to the inven profen. tion are well-known drugs with analgesic properties some I0086. Another embodiment of the present invention times used for a long time worldwide. Due to this a further relates to a process for the production of a co-crystal accord object of the present invention is a medicament comprising a ing to the invention as described above comprising the steps co-crystal according to the invention. of: 0111. Thus the invention also concerns a medicament I0087 (a) dissolving or suspending a co-crystal former comprising at least one co-crystal according to the invention in a solvent; and as described above and optionally one or more pharmaceuti I0088 (b) heating the solution or dispersion to a tem cally acceptable excipients. perature above ambient temperature and below the boil 0112 The invention also relates to a pharmaceutical com ing point of the solution or dispersion; position that comprises a therapeutically effective amount of I0089 (c) dissolving together with, or after, or before the co-crystal according to the invention in a physiologically acceptable medium. Physiologically acceptable medium is step (a) dulloxetine either as a free base or as a salt in a defined as especially comprising pharmaceutically accept Solvent, able auxiliary Substances (additives/excipients), especially 0090 (d) adding the solution of (c) to the heated solvent those suitable for a solid pharmaceutical formulation, of of (b) and mixing them; which one or more may be part of the pharmaceutical formu 0091 (e) cooling the mixed solution/dispersion of step lation. (d) to ambient temperature; 0113. The association of two active principles in the same 0092 (f) filtering-off the resulting co-crystals. crystal exhibits several advantages. Being linked, they often 0093. Another embodiment of the present invention behave as a single chemical entity, thus facilitating the treat relates to a process for the production of a co-crystal accord ments, formulation, dosage etc. In addition to that, with both ing to the invention as described above comprising the steps dulloxetine and the co-crystal formers being active of: these co-crystals are highly useful in the treatment of pain, (0094) either (Alternative I): especially also not losing any activity/weight by the addition 0.095 (a) dissolving or suspending a co-crystal former of pharmacologically useless counterions as in salts with no in a solvent; and API. In addition the two active principles are complementing 0096 (b) heating the solution or dispersion to a tem each other in the treatment especially of pain, but possibly perature above ambient temperature and below the boil also of various other diseases or symptoms. Thus, the co ing point of the solution or dispersion; crystals according to the invention do combine a high number 0097 (c) dissolving together with, or after, or before of advantages over the State of the art. step (a) dulloxetine either as a free base or as a salt in a 0114. Another advantage is that the association of two active principles into one unique species seems to allow for a Solvent, better Pharmacokinetic/Pharmacodynamic (PKPD) includ 0.098 (d) adding the solution of (c) to the heated solvent ing also a better penetration of the blood-brain barrier, which of (b) and mixing them; helps in the treatment of pain. (0099 or (Alternative II): 0.115. In general in most embodiments in which the co 0100 (a) dissolving or suspending a co-crystal former crystals of dulloxetine are used (e.g. for the treatment of pain and duloxetine in a solvent; and etc.) these co-crystals would be formulated into a convenient 0101 (b) heating the solution or dispersion to a tem pharmaceutical formulation or a medicament. Accordingly a perature above ambient temperature and below the boil desirable advantage of a co-crystal of dulloxetine would show ing point of the solution or dispersion; improved pharmaceutical properties and features, especially 0102 (d) adding a solvent to the heated solvent of (b) when compared to the free base or dulloxetine hydrochloride. and mixing them; Thus, the co-crystal of dulloxetine according to the invention (0103 followed by (for both Alternatives I and II) should desirably show at least one, preferably more, of the 0104 (e) cooling the mixed solution/dispersion of step following features: (d) to ambient temperature; 0116 to have a very small particle size, e.g. from 300 0105 (f) filtering-off the resulting co-crystals. um or lower; or 0106 “Ambient temperature' is defined here as a tempera 0.117 to be and/or remain essentially free of agglomer ture between 20 and 25°C., preferably being 20° C. ates; or 0107 The solvents usable in this process include water or 0118 to be less or not very hygroscopic; or organic solvents, preferably solvents selected from acetone, 0119 to help informulating controlled release or imme isobutyl acetate, acetonitrile, ethyl acetate, 2-butanol, dim ethylcarbonate, chlorobenzene, butylether, diisopropylether, diate release formulations; or dimethylformamide, ethanol, water, hexane, isopropanol, 0120 to have a high chemical stability; or methyl ethyl ketone, methanol, methyl t-butyl ether, 3 pen 0121 if given to a patient tanone, toluene and 1,1,1-trichloroethane, most preferably 0.122 to decrease the inter- and intra-subject variability including alcohols, like ethanol. It is preferable but not in blood levels; or necessary—that the solvents in steps (a) and (c) for Alterna 0123 to show a good9. absorption rate (e.g.9. increases in tive I are identical. plasma levels or AUC); or US 2011/O160273 A1 Jun. 30, 2011

0.124 to show a high maximum plasma concentration (except attached to heteroatoms) were omitted in the sake of (e.g. Cna); or clarity. 0.125 to show decreased time to peak drug concentra 0.136 FIG. 1 is showing the structure formed by 3 mol tions in plasma (t); or ecules of (S)-naproxene and 2 molecules of (S)-duloxetine. 0.126 to show changes in half life of the compound 0.137 The measured crystal was selected using a Zeiss (t), in whichever direction this change is preferably Stereomicroscope using polarized light and prepared under directed. inert conditions immersed in perfluoropolyether as protecting 0127. The medicament or pharmaceutical compositions oil for manipulation. Crystal structure determination was car according to the present invention may be in any form Suitable ried out using a Bruker-Nonius diffractometer equipped with for the application to humans and/or animals, preferably a APPEX 24K CCD area detector, a FR591 rotating anode humans including infants, children and adults and can be with Moe radiation, Montel mirrors as monochromator and produced by standard procedures known to those skilled in a Kryoflex low temperature device (T=100K). Fullsphere the art. The medicament of the present invention may for data collection omega and phi scans. Programs used: Data example be administered parenterally, including intramuscu collection Apex2 V. 1.0-22 (Bruker-Nonius 2004), data lar, intraperitoneal, or intravenous injection, transmucosal or reduction Saint--Version 6.22 (Bruker-Nonius 2001) and Sublingual application; or orally, including administration as absorption correction SADABSV.2.10 (2003). Crystal struc tablets, pellets, granules, capsules, lozenges, aqueous or oily ture Solution was achieved using direct methods as imple Solutions, Suspensions, emulsions, sprays or as reconstituted mented in SHELXTL Version 6.10 (Sheldrick, Universtität dry powdered form with a liquid medium. Göttingen (Germany), 2000) and visualized using XP pro 0128. Typically, the medicaments according to the present gram. Missing atoms were Subsequently located from differ invention may contain 1-60% by weight of one or more of the ence Fourier synthesis and added to the atom list. Least co-crystals as defined herein and 40-99% by weight of one or squares refinement on Fousing all measured intensities was more auxiliary Substances (additives/excipients). carried out using the program SHELXTL Version 6.10 0129. The compositions of the present invention may also (Sheldrick, Universtität Göttingen (Germany), 2000). All non be administered topically or via a Suppository. hydrogenatoms were refined including anisotropic displace 0130. The daily dosage for humans and animals may vary ment parameters depending on factors that have their basis in the respective species or other factors, such as age, sex, weight or degree of 0138 FIG. 2: illness and so forth. The daily dosage for humans preferably 0.139 Powder X-Ray diffraction pattern of an (S)-dulox is in the range of 5 to 500 milligrams of dulloxetine to be etine-(S)-naproxene (2:3) co-crystal. Approximately 20 mg administered during one or several intakes per day. of the samples were prepared in standard sample holders 0131) A further aspect of the invention relates to the use of using two foils of polyacetate. Powder diffraction patterns co-crystal according to the invention as described above for were acquired on a D8 Advance Series 2Theta/Theta powder the treatment of pain, preferably acute pain, chronic pain, diffraction system using Cu-radiation in transmission neuropathic pain, hyperalgesia, allodynia or cancer pain, geometry. The system is equipped with a VANTEC-1 single including diabetic neuropathy or osteoarthritis or fibromyal photon counting PSD, a Germanium monochromator, a gia. Preferably this use is provided for in form of a medica ninety positions auto changer sample stage, fixed divergence ment or a pharmaceutical composition according to the inven slits and radial soller. Programs used: Data collection with tion as described above. Also another aspect of the invention DIFFRAC plus XRD Commander V.2.4.1 and evaluation relates to the use of co-crystal according to the invention as with EVAV.12.0. described above for the manufacture of a medicament or O140 FIG.3: pharmaceutical composition for the treatment of pain, pref I0141 'H-NMR of (S)-duloxetine-(S)-naproxene (2:3) co erably acute pain, chronic pain, neuropathic pain, hyperalge crystal. sia, allodynia or cancer pain, including diabetic neuropathy or I0142 FIG. 3 is depicting a H-NMR analysis of the co osteoarthritis or fibromyalgia. crystral of (S)-duloxetine and (S)-naproxene showing a 2:3 0132) Another object of the current invention is a method of treatment of pain, preferably acute pain, chronic pain, ratio. neuropathic pain, hyperalgesia, allodynia or cancer pain, 0.143 Proton nuclear magnetic resonance analyses were including diabetic neuropathy or osteoarthritis or fibromyal recorded in deuterated methanol (MeOH-d4) in a Bruker gia, by providing to a patient in need thereof a sufficient Avance 400 Ultrashield NMR spectrometer, equipped with a amount of a co-crystal according to the invention as described Z-gradient 5 mm BBO (Broadband Observe) probe. Spectra above (or in preferred aspects as will be described below). were acquired solving 2-10 mg of sample in 0.6 mL of deu Preferably the co-crystal according to the invention is pro terated solvent. vided in physiologically suitable form like e.g. in form of a 014.4 FIG. 4: medicament or a pharmaceutical composition according to 0145 FT-IR spectrum of (S)-duloxetine-(S)-naproxene the invention as described above. (2:3) co-crystal. 0133. The present invention is illustrated below with the 0146 FIG. 4 shows the Infra-red spectrum of the co-crys help of the following figures and examples. These illustra tal obtained. tions are given solely by way of example and do not limit the 0147 The FTIR spectra were recorded using a Bruker invention. Tensor 27, equipped with a MKII golden gate single reflec tion ATR system, a mid-infrared source as the excitation BRIEF DESCRIPTION OF THE FIGURES source and a DTGS detector. The spectra were acquired in 32 scans at a resolution of 4 cm. 0134 FIG. 1: 0148 FIG. 5: 0135 Structure of the (S)-duloxetine-(S)-naproxene (2:3) 0149 DSC analysis of (S)-duloxetine-(S)-naproxene co-crystal obtained by SCXRD analysis. Hydrogen atoms (2:3) co-crystal. US 2011/O160273 A1 Jun. 30, 2011

0150 FIG. 5 shows the thermal analysis with a melting EXAMPLES point at 124°C. on the DSC. Example 1 a 0151. DSC analyses were recorded in a Mettler Toledo DSC822e. Samples of 1-2 mg were weighted into 40 uL Procedure to Obtain (S)-duloxetine-(S)-naproxene aluminium crucibles with a pinhole lid, and were heated, (2:3) Co-Crystal under nitrogen (50 mL/min), at 10°C./min from 30 to 300° C. 0172 A solution of (S)-duloxetine (472 mg, 1.59 mmol) in 0152 FIG. 6: 0.4 mL of ethanol was added to a stirred suspension of (S)- 0153. TG analysis of (S)-duloxetine-(S)-naproxene (2:3) naproxene (707 mg, 3.07 mmol. 1.9 eq.) in 0.8 mL of ethanol co-crystal. at 70° C. The resulting solution was left standing at room temperature and a white Solid crystallized. The Suspension 0154 FIG. 6 shows the thermogravimetric analysis with was filtered off and the obtained solid was washed with etha no weight-loss at temperatures below decomposition. nol and dried under vacuum (10 mm Hg) at 60° C. for 18 0155 Thermogravimetric analyses were recorded in a hours to give the co-crystal (S)-duloxetine-(S)-naproxene in a Mettler Toledo SDTA851e. Samples of 3-4 mg were 2:3 ratio, as a white crystalline solid (710 mg, 69% yield). weighted into 40 uL aluminium crucibles with a pinhole lid, and heated at 10°C/min from 30 to 500° C., under nitrogen Example 1b (80 mL/min). Procedure to Obtain (S)-duloxetine-(S)-naproxene 0156 FIG. 7 (2:3) Co-Crystal (O157 Stability study of (S)-duloxetine.HCl as described (0173 A solution of (S)-duloxetine (26.8 g., 0.09 mol) in 30 in Example 1 d) mL of ethanol was added to a stirred suspension of (S) 0158 FIG. 7 shows the HPLC chromatogram obtained of naproxene (31.1 g, 0.135 mol, 1.5 eq.) in 50 mL of ethanol at the (S)-duloxetine hydrochloride at initial time (dotted line) 70° C. The resulting solution was left standing at room tem and after 5 days (solid line). perature and a white solid crystallized. The Suspension was 0159 FIG. 8: filtered off and the obtained solid was washed with ethanol and dried under vacuum (10 mm Hg) at 50° C. for 7 hours to 0160 Stability study of (S)-duloxetine-(S)-naproxen give the co-crystal (S)-duloxetine-(S)-naproxene in a 2:3 (2:3) co-crystal as described in Example 1 d) ratio, as a white crystalline solid (55.6 g. 96% yield). The (0161 FIG. 8 shows the HPLC chromatogram obtained of co-crystal was the same as the one obtained in example la. the (S)-duloxetine-(S)-naproxen (2:3) co-crystal at initial time (dotted line) and after 5 days (solid line). Example 1c (0162 FIG.9: 0.174 (S)-duloxetine-(S)-naproxene co-crystal according 0163 DSC analysis of (S)-duloxetine-tolimetin (1:2) co to examples 1a and 1b has been obtained starting from mix crystal. tures of dulloxetine (S)-duloxetine) and (S)-naproxene from 0164 FIG. 9 shows the thermal analysis with a melting 1:1 to 1:2. In addition to the exemplification of examples 1 a point at 111° C. on the DSC. and 1b different solvents were screened in order to determine (0165 DSC analyses were recorded in a Mettler Toledo the most effective ones to obtain a co-crystal. The following DSC822e. Samples of 1-2 mg were weighted into 40 uL Solvents resulted in a co-crystal with duloxetine: acetone, aluminium crucibles with a pinhole lid, and were heated, isobutyl acetate, acetonitrile, ethyl acetate, 2-butanol, dim under nitrogen (50 mL/min), at 10°C./min from 30 to 300° C. ethylcarbonate, chlorobenzene, butylether, diisopropylether, ethanol, water, hexane, isopropanol, methyl ethyl ketone, 0166 TG analysis of (S)-duloxetine-tolmetin (1:2) methanol, methyl-isobutyl ketone, methyl t-butyl ether, co-crystal. 3-pentanone, toluene, DMF, cyclohexane and 1,1,1-trichlo 0167 FIG. 9 shows the thermogravimetric analysis with roethane. The co-crystal formed in each case was the same as no weight-loss at temperatures below decomposition. that found in examples 1a and 1b. 0168 Thermogravimetric analyses were recorded in a Mettler Toledo SDTA851e. Samples of 3-4 mg were Characterisation of the Co-Crystal: weighted into 40 uL aluminium crucibles with a pinhole lid, 0.175 (S)-duloxetine-(S)-naproxene (2:3) co-crystal and heated at 10°C/min from 30 to 500° C., under nitrogen obtained according to example 1 was fully characterised by (80 mL/min). 'H-NMR, FTIR, X-Ray diffraction, DSC and TG (see FIGS. (0169 FIG.10: 1 to 6). 0170 Powder X-Ray diffraction pattern of an (S)-dulox (0176) The optical rotation value is of C°, +74.5° (c=1. etine-tolmetin (1:2) co-crystal. 00, MeOH) 0171 Approximately 20 mg of the samples were prepared 0177. The structure was completely determined by single in standard sample holders using two foils of polyacetate. crystal X-ray diffraction (SCXRD) analysis: in FIG. 1 the Powder diffraction patterns were acquired on a D8 Advance structure formed by 3 molecules of (S)-naproxene and 2 Series 2Theta/Theta powder diffraction system using Cus, molecules of (S)-duloxetine is shown. Hydrogen atoms (ex radiation in transmission geometry. The system is equipped cept attached to heteroatoms) were omitted in the sake of with a VANTEC-1 single photon counting PSD, a Germa clarity. nium monochromator, a ninety positions auto changer sample (0178 FIG. 2 shows the Powder X-ray diffraction (PXRD) stage, fixed divergence slits and radial Soller. Programs used: pattern of the co-crystal of (S)-duloxetine and (S)-naproxen. Data collection with DIFFRAC plus XRD Commander V.2. The peaks expressed in d-value are described in detail in 4.1 and evaluation with EVAV.12.0. table 2: US 2011/O160273 A1 Jun. 30, 2011

TABLE 1. TABLE 1-continued PXRD of a co-crystal of (S)-duloxetine and (S)-naproxen PXRD of a co-crystal of (S)-duloxetine and (S)-naproxen d-Value Relative Intensity d-Value Relative Intensity Angle 20' (A) % Angle 20' (A) % 6.852 12.88.933 43.1 22.867 3.88582 12.9 8.231 10.73330 9.4 23.422 3.79497 24.2 8.392 10.52725 7.8 23.585 3.76910 39.0 9.612 9.19432 O.O 23.807 3.73455 39.0 O349 8.54082 2.5 23.935 3.71479 2O.S 1.644 7.59375 1.O 24427 3.64119 2O.S 1902 7.42988 1.O 24.871 3.57708 21.9 3.291 6.65638 9.8 25.187 3.53293 9.3 3.730 6.44449 5.9 4.SS1 6.08.241 45.3 The 20 values were obtained using copper radiation (Cuk, 1.54060 A) 4.815 5.97467 20.4 5.387 5.75386 6.2 (0179 FIG. 3 is depicting a H-NMR analysis of the co 6.294 5.43552 21.2 crystal of (S)-duloxetine and (S)-naproxene showing a 2:3 6.568 S.34631 1OO.O 6.845 S.25900 73.6 ratio. 7.099 S.18151 S.O 0180 "H NMR (400 MHz, d4-methanol) 8: 1.50 (d. J=7 7.269 5.13078 2.4 Hz, 9H), 2.38 (m, 2H), 2.56 (m, 2H), 2.66 (s, 6H), 3.13 (m, 7.894 4.95297 1.4 7.979 4.92982 9.3 2H), 3.23 (m, 2H), 3.75 (q, J–7 Hz, 3H), 3.88 (s, 9H), 5.88 8.405 4.81673 2.4 (dd, J–5 Hz, J=8 Hz, 2H), 6.92 (d. J=8 Hz, 2H), 6.94 (dd, J-3 8.601 4.76623 9.6 Hz, J=5 Hz, 2H), 7.07 (dd, J=3 Hz, J=9 Hz, 3H), 7.12 (d. J=3 8.708 4.73939 7.4 8.907 4.68.987 27.7 Hz, 2H), 7.16 (d. J=3 Hz, 3H), 7.27 (t, J=8 Hz, 2H), 7.32 (dd, 9.053 4.6542O 49.6 J=1 Hz, J=5 Hz, 2H), 7.41 (d. J=8 Hz, 2H), 7.44-7.51 (m, 7H), 9.120 4.63815 SO.6 7.67 (m, 9H), 7.79 (m, 2H), 8.28 (m, 2H). 9.291 4.59746 9.5 20.009 4.43406 O.2 0181 FIG. 4 shows the Infra-red spectrum of the co-crys 20.671 4.29348 99.6 tal thus obtained. 20.807 4.26574 5.8 0182. Thermal analysis shows a melting point at 124°C. 21.269 4.17406 410 on the DSC (FIG.5) and no weight loss is detected in the TGA 21.831 4.06785 4.5 22-18O 4.OO458 4.4 attemperatures below decomposition (FIG. 6). 22.294 3.984.42 3.0 0183 Crystal data and resolve of the structure refinement 22.549 3.940O2 43.7 for (S)-duloxetine-(S)-naproxene (2:3) co-crystal are given in the following table 3:

TABLE 2

Crystal data and resolve of the structure refinement for (S)-duloxetine-(S)-naproxene (2:3) co-crystal.

Identification code p0121 Onapeoh Om Empirical formula C78 H8ON2O11 S2 Formula weight 1285.56 Temperature 100(2) K Wavelength 0.71073 A Crystal system Triclinic Space group P1 Unit cell dimensions a = 10.9284(4) A C = 107.477(3). b = 12.1480(6) A B = 99.792(3). c = 13.5613(7) A Y = 95.382(2). Volume 1672.03(13) A Z. 1 Density (calculated) 1.277 Mg/m Absorption coefficient 0.144 mm F(000) 682 Crystal size 0.50 x 0.40 x 0.40 mm Theta range for data collection 2.71 to 39.67. Index ranges -19 s h a 19, -20 a ka 10, -24 a a 23 Reflections collected 39877 Independent reflections 23908 R(int) = 0.0303 Completeness to theta = 39.67 83.2% US 2011/O160273 A1 Jun. 30, 2011

TABLE 2-continued

Crystal data and resolve of the structure refinement for (S)-duloxetine-(S)-naproxene (2:3) co-crystal. Absorption correction SADABS (Bruker-Nonius) Max. and min. transmission 0.9446 and 0.9315 Refinement method Full-matrix least-squares on F. Data restraints, parameters 23908, 3,847 Goodness-of-fit on F. 1.028 Final Rindices I 2sigma(I) R1 = 0.0465, wR2 = 0.1115 Rindices (all data) R1 = 0.0650, wR2 = 0.1245 Absolute structure parameter 0.04(4) Largest diff. peak and hole 0.583 and -0.427 e.A

Example 1d 2.5), 28.8% methanol, 8.2% THF. B) 20% (0.02M KHPO, a Determination of the Stability of the Co-Crystals pH of 2.5), 80% CAN. Gradient: 100% A) 10 min: 100% A) According to the Invention to 25% A) 40 min. Solvent: HO/ACN, V/v. Concentration: 0.5 mg/ml. 0184 The objective was to measure the stability of the co-crystals of the present invention, and comparing it with the Preparation of Standards one of the dulloxetine HC1. In the literature is described (WO 0187 Between 5-5.5 mg of (S)-duloxetine-(S)-naproxene 2007 105021) that during stability testing of tablets contain (2:3) co-crystal and (S)-duloxetine.HCl standards, respec ing dulloxetine, a degradation product is produced in a rear tively, were weighed with accuracy and dissolved with water, rangement process of the molecule. This process is increased levelling to 10 ml with HO/ACN, V/v. with the presence of strong mineral acids like HCl and HBr. The purpose of the study is perform a comparative stress Preparation of Test Samples testing of (S)-duloxetine-(S)-naproxene (2:3) co-crystal at 0188 Between 5-5.5 mg of (S)-duloxetine-(S)-naproxene 600 CF75% RH. (2:3) co-crystal and (S)-duloxetine.HCl test samples, respec tively, were weighed with accuracy and dissolved with water, Exposure Conditions levelling to 10 ml with HO/ACN, V/v. 0185. Samples of 25 mg of each product are prepared and 0189 Solutions are injected by duplicate in above chro spread homogeneously on a 5 cm petri dish and stored closed matographic conditions. with perforated paper film, inside a climatic chamber Heraeus 0.190 Assay of each product was calculated by follows: HCO33, during 5 days. % assay=(area sample concentration standard*100), (area standard concentration sample) Degradation Products by HPLC (0191 Results: The results obtained are shown in the FIGS. 0186 Chromatographic conditions: Column: Sunfire 7 and 8 where the HPLC profiles of each sample at the initial C18, 3.5 um, 100*4.6 mm; Detection: UV 230 nm, Flow: 1 and after 5 days. The results obtainen are summarized in the mL/min. Mobile phase: A) 63% (0.02M KHPO at pH of following table 3:

TABLE 3

Impurities and degradation products

% assay Rt. 5 min Rt. 8 min Rt. 12.5 min Rt. 23 min

Duloxetine HCI O.01% O.01% O.15% O.O.3% test sample (initial control) Duloxetine HCI 100.9 O.05% O.05% O.15% O.07% test sample (5 days control) (S)-duloxetine-(S)-naproxene O.O.3% (2:3) co-crystal test sample (initial control) (S)-duloxetine-(S)-naproxene 98.2 O.O.3% (2:3) co-crystal test sample (5 days control) US 2011/O160273 A1 Jun. 30, 2011

Conclusions 0203 The results are summarized in the following table 4: 0.192 (S)-duloxetine-(S)-naproxene (2:3) co-crystal is more stable than (S)-duloxetine.HCl in the studied condi TABLE 4 tions. As it can be observed in the HPLC chromatogram in % of variation of the weight and Karl Fischer value FIGS. 7 and 8, whereas the (S)-duloxetine-(S)-naproxene (2:3) co-crystal profile does not change after 5 days, in the KF A% weigth A% weigth A% weigth (S)-duloxetine HCl profile some of the impurities increase. Sample (t=0) 24h 48 h. 6 days Sample 1 O.36 O O.09 O.13 Example le Sample 2 O.33 O.19 O.26 O.18 Sample 3 1.04 1439 1439 14.3 Determination of the Hygroscopicity of the Co-Crys tals According to the Invention 0204 According to the above mentioned scale, whereas 0193 The objective was to measure the hygroscopicity of the Sodium naproxen is hygroscopic, the duloxetine hydro the salts of the present invention, and comparing it with the chloride and the (S)-duloxetine-(S)-naproxene (2:3) co-crys one of the known salt of each counter part of the salts. The tal salt of example 1 is not hygroscopic. increasing of the weight will be measured in order to evaluate the incorporation of water in the samples, together with the Example 2a Karl Fischer factor. 0194 According to “Technical guide for the elaboration of Procedure to Obtain (S)-duloxetine-tolmetin (1:2) monographs” special issue PharmaEuropa,3" ed., December Co-Crystal 1999, the hygroscopicity is defined based on the augmenta 0205 Diisopropyl ether was added drop wise to a solution tion of weight after 24 hours of exposition to 80% of relative of (S)-duloxetine (289 mg, 0.97 mmol) and tolmetin (500 mg. humidity at 25°C. The scale is the following: 1.94 mmol. 2 eq) in ethyl acetate (1 mL) at reflux until precipitation started. Following, the minimum amount of ethyl acetate was added drop wise to reach complete disso lution again. The solution was then cooled to room tempera % incorporation of water ture, and slowly stirred during 48 h. The resulting Suspension A < 0.2% No hygroscopic was filtered off, washed with cold ethyl acetate and dried 0.2%

4. The co-crystal according to claim 1, wherein the co TABLE 5-continued crystal former or one of the co-crystal formers is selected from List of selected peaks obtained by powder X-Ray diffraction Acetylsalicylic acid, Diflunisal, Ethenzamide, Salicyla of (S)-duloxetine-toinetin co-crystal. mide, Triflusal, Fosfosal, Benorylate, Paracetamol, Pro Angle 20' d-value Relative intensity pacetamol, Phenidine, Etofenamate, Flufenamic acid, (°) (A) % Meclofenamic acid, Mefenamic acid, Niflumic acid, 9.662 9.14644 20.9 Tolfenamic acid, Acemetacin, Oxametacin, Glucameta 9.920 8.90904 27.5 cin, Proglumetacin, BufeXamac, Diclofenac, Alcofenac, 10.446 8.4615S 29.0 Aceclofenac, Indomethacin, Lonazolac, Sulindac, Tol 11.539 7.66249 11.8 12.903 6.85573 34.9 metin, Amtolimetin guacil, MofeZolac, Bromfenac, 13.750 6.43484 10.7 Nabumetone, Fentiazac, Felbinac, Flurbiprofen, Flurbi 13.982 6.32866 20.8 profen axetil, Ibuprofen, Ketoprofen, Naproxen, Tiapro 14.706 6.O1875 28.8 fenic acid, Zaltoprofen, Pirprofen, Fenoprofen, 1S.OS1 5.88147 22.O Vedaprofen, Nepafenac, Amfenac, Clidanac, Metami 15.493 5.71495 47.8 15.896 5.57085 31.6 Zol, Propylphenazone, KebuZone, , 16.844 5.25933 10.1 OxyphenbutaZone, PhenylbutaZone, ApaZone, Isoxi 17.689 S.O1008 24.7 cam, Lornoxicam, PiroXicam, Tenoxicam, Ketorolac, 17.987 4.92752 88.7 ProquaZone, Oxaprozine, Ditazole, Etodolac, Meloxi 18.133 4.888.18 94.3 19.410 4.56939 25.4 cam, Nimesulide, Celecoxib, Etoricoxib, Lumiracoxib, 19.96S 4.44359 15.8 Parecoxib, Rofecoxib, Valdecoxib, Cimicoxib; Bermo 20.766 4.274OO 26.O profen; Pelubiprofen; Tenosal; Aceneuramic acid; Pira 21.054 4.21622 1OO.O Zolac; Xinoprofen; Flobufen; Anirolac; Zoliprofen; Bro 21467 4.13607 12.4 22.029 4.03169 13.8 mfenac: Pemedolac; Dexpemedolac. Bindarit; 22.486 3.95085 18.1 Romazarit; Tiaprofenic acid; Ketorolac; Fenbufen; 22.805 3.89635 34.3 Fenoprofen; Flobufen: Oxaprozin; or their stereoiso 23.2O7 3.82974 47.1 mers, salts or metabolites. 23.664 3.75672 18.1 5. The co-crystal according to claim 1, wherein the co The 20 values were obtained using copper radiation (Cukoil 1,54060A) crystal former is naproxen, its enantiomers or salts thereof; preferably wherein the co-crystal former is (S)-naproxen, or 1. A co-crystal comprising duloxetine either as a free base salts thereof. or as its physiologically acceptable salt and at least one co 6. A co-crystal according to claim 5, wherein the molecular crystal former selected from COX-INHIBITORs. ratio between dulloxetine and (S)-naproxen is 2:3. 2. A co-crystal according to claim 1, wherein the co-crystal former or at least one of the co-crystal formers has at least one 7. A co-crystal according to claim 6, characterized in that functional group from the group consisting of ether, thioether, the endothermic sharp peak corresponding to the melting alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester, point has an onset at 124°C. phosphate ester, thiophosphate ester, ester, thioester, Sulfate 8. Co-crystal according to claim 6, characterized in that it ester, carboxylic acid, phosphonic acid, phosphinic acid, Sul shows a X-Ray powder diffraction pattern with peaks fonic acid, amide, primary amine, secondary amine, ammo expressed in d-Value in A at 12.889, 10.733, 10.527, 9.194, nia, tertiary amine, thiocyanate, cyanamide, oxime, nitrile, 8.541, 7.594, 7.430, 6.656, 6.444, 6.082, 5.975, 5.754, 5,436, diazo, organohalide, nitro, S-heterocyclic ring, thiophene, 5.346, 5.259, 5.182, 5.131, 4.953, 4.930, 4.817, 4.766, 4.739, n-heterocyclic ring, pyrrole, o-heterocyclic ring, furan, 4.690, 4.654, 4.638, 4.597, 4.434, 4.293, 4.266, 4.174, 4.068, epoxide, peroxide, hydroxamic acid, imidazole, and pyridine; 4.005, 3.984, 3.940, 3.886, 3.795, 3.769, 3.735, 3.715, 3.641, preferably wherein the co-crystal former or at least one of 3.577, and 3.533. the co-crystal formers has at least one functional group 9. Co-crystal according to claim 6, characterized in that it from the group consisting of alcohol, thiol, ester, car has a triclinic unit cell with the following dimensions boxylic acid, primary amine, secondary amine, tertiary a=10.9284(4) A amine; most preferably wherein the co-crystal former or at least b=12.1480(6) A one of the co-crystal formers has at least one functional c=13.5613(7) A group being a carboxylic acid c=107.477(3) 3. A co-crystal according to claim 1, wherein the co-crystal B=99.792(3) former or at least one of the co-crystal formers is chosen in y=95.382(2) Such a way that if compared to either dulloxetine alone or to a 10. The co-crystal according to claim 1, wherein the co mixture of dulloxetine and the corresponding active agent/s crystal former is tolmetin or its salts thereof. a) the solubility of the co-crystal is increased; and/or 11. A co-crystal according to claim 10, wherein the b) the dose response of the co-crystal is increased; and/or molecular ratio between dulloxetine and tolmetin is 1:2. c) the efficacy of the co-crystal is increased; and/or 12. A co-crystal according to claim 11, characterized in d) the dissolution of the co-crystal is increased; and/or that the endothermic sharp peak corresponding to the melting e) the bioavailability of the co-crystal is increased; and/or point has an onset at 111° C. f) the stability of the co-crystal is increased; and/or 13. Co-crystal according to claim 11, characterized in that g) the hygroscopicity of the co-crystal is decreased; and/or it shows a X-Ray powder diffraction pattern with peaks h) the form diversity of the co-crystal is decreased; and/or expressed in d-Value in A at 13.774, 12.845, 11.510, 9.146, i) the morphology of the co-crystal is modulated. 8.909, 8.462, 7.662, 6.856, 6.435, 6.329, 6.019, 5.881, 5.715, US 2011/O160273 A1 Jun. 30, 2011 12

5.571, 5.259, 5.010, 4.928, 4.888, 4.569, 4.443, 4.274, 4.216, the efficacy of the co-crystal is increased; and/or 4.136, 4,032, 3.951, 3.896, 3.830 and 3.757. the dissolution of the co-crystal is increased; and/or 14. Process for the production of a co-crystal according to the bioavailability of the co-crystal is increased; and/or claim 1 comprising the steps of the stability of the co-crystal is increased; and/or either (Alternative I): (a) dissolving or Suspending a co-crystal former in a sol the hygroscopicity of the co-crystal is decreased; and/or vent; and the form diversity of the co-crystal is decreased; and/or (b) heating the solution or dispersion to a temperature 18. The co-crystal according to claim 3, wherein the co above ambient temperature and below the boiling point crystal former or one of the co-crystal formers is selected of the Solution or dispersion; from (c) dissolving together with, or after, or before step (a) Acetylsalicylic acid, Diflunisal, Ethenzamide, Salicyla dulloxetine either as a free base or as a salt in a solvent, mide, Triflusal, Fosfosal, Benorylate, Paracetamol, Pro (d) adding the solution of (c) to the heated solvent of (b) and pacetamol, Phenidine, Etofenamate, Flufenamic acid, mixing them; Meclofenamic acid, Mefenamic acid, Niflumic acid, or (Alternative II): Tolfenamic acid, Acemetacin, Oxametacin, Glucameta (a) dissolving or Suspending a co-crystal former and dulox- cin, Proglumetacin, BufeXamac, Diclofenac, Alcofenac, etine in a solvent; and Aceclofenac, Indomethacin, Lonazolac, Sulindac, Tol (b) heating the solution or dispersion to a temperature metin, Amtolimetin guacil, MofeZolac, Bromfenac, above ambient temperature and below the boiling point Nabumetone, Fentiazac, Felbinac, Flurbiprofen, Flurbi of the Solution or dispersion; profen axetil, Ibuprofen, Ketoprofen, Naproxen, Tiapro (d) adding a solvent to the heated solvent of (b) and mixing fenic acid, Zaltoprofen, Pirprofen, Fenoprofen, them; Vedaprofen, Nepafenac, Amfenac, Clidanac, Metami followed by (for both Alternatives I and II) Zol, Propylphenazone, KebuZone, Mofebutazone, (e) cooling the mixed solution/dispersion of step (d) to OxyphenbutaZone, PhenylbutaZone, ApaZone, Isoxi ambient temperature; cam, Lornoxicam, PiroXicam, Tenoxicam, Ketorolac, (f) filtering-off the resulting co-crystals. ProquaZone, Oxaprozine, Ditazole, Etodolac, Meloxi 15. Pharmaceutical composition characterized in that it cam, Nimesulide, Celecoxib, Etoricoxib, Lumiracoxib, comprises atherapeutically effective amount of the co-crystal Parecoxib, Rofecoxib, Valdecoxib, Cimicoxib; Bermo according to claim 1 in a physiologically acceptable medium. profen; Pelubiprofen; Tenosal; Aceneuramic acid; Pira 16. A method for the treatment of pain, preferably acute Zolac:Xinoprofen; Flobufen; Anirolac; Zoliprofen; Bro pain, chronic pain, neuropathic pain, hyperalgesia, allodynia mfenac: Pemedolac; Dexpemedolac. Bindarit; or cancer pain, including diabetic neuropathy or diabetic Romazarit; Tiaprofenic acid; Ketorolac; Fenbufen; peripheral neuropathy and osteoarthritis or fibromyalgia in a Fenoprofen; Flobufen: Oxaprozin; or their stereoiso Subject in need thereof which comprises administering to the mers, salts or metabolites. Subject the co-crystal according to claim 1. 19. The co-crystal according to claim 4, wherein the co 17. A co-crystal according to claim 2, wherein the co- crystal former is naproxen, its enantiomers or salts thereof. crystal former or at least one of the co-crystal formers is preferably wherein the co-crystal former is (S)-naproxen, or chosen in Such a way that if compared to either dulloxetine salts thereof. alone or to a mixture of duloxetine and the corresponding 20. The co-crystal according to claim 4, wherein the co active agent/s crystal former is tolmetin or its salts thereof. the solubility of the co-crystal is increased; and/or the dose response of the co-crystal is increased; and/or ck