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US 2005O181041A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0181041 A1 Goldman (43) Pub. Date: Aug. 18, 2005

(54) METHOD OF PREPARATION OF MIXED Related U.S. Application Data PHASE CO-CRYSTALS WITH ACTIVE AGENTS (60) Provisional application No. 60/528,232, filed on Dec. 9, 2003. Provisional application No. 60/559,862, filed (75) Inventor: David Goldman, Portland, CT (US) on Apr. 6, 2004. Correspondence Address: Publication Classification LEYDIG VOIT & MAYER, LTD (51) Int. Cl." ...... A61K 31156; A61K 38/00; TWO PRUDENTIAL PLAZA, SUITE 4900 A61K 9/64 180 NORTH STETSON AVENUE (52) U.S. Cl...... 424/456; 514/179; 514/2; CHICAGO, IL 60601-6780 (US) 514/221 (73) Assignee: MedCrystallForms, LLC, Hunt Valley, ABSTRACT MD (57) This invention pertains to a method of preparing mixed phase co-crystals of active agents with one or more materials (21) Appl. No.: 11/008,034 that allows the modification of the active agent to a new physical/crystal form with unique properties useful for the delivery of the active agent, as well as compositions com (22) Filed: Dec. 9, 2004 prising the mixed phase co-crystals. Patent Application Publication Aug. 18, 2005 Sheet 1 of 8 US 2005/0181041 A1 FIG. 1 a

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METHOD OF PREPARATION OF MIXED PHASE active agent, lack the high concentrations that the mixed CO-CRYSTALS WITH ACTIVE AGENTS phase co-crystals enable, and lack the multi-functional aspects that mixed phase co-crystals offer with respect to CROSS-REFERENCE TO RELATED PATENT improved delivery. APPLICATIONS 0006 Co-crystallization of chemically related materials 0001. This patent application claims the benefit of U.S. is illustrated by the preparation of co-crystallized Sugars Provisional Patent Application No. 60/559,862, filed Apr. 6, (U.S. Pat. Nos. 4,101,680 and 4,338,339), of acetylenic 2004 and U.S. Provisional Patent Application No. 60/528, compounds (U.S. Pat. No. 4,384,980), and Sugar 232, filed Dec. 9, 2003, which are incorporated by reference (U.S. Pat. Nos. 5,679,398; 5,958,471 and 6,083,438). The herein. Simple co-crystals therein described do not have the broad utility that mixed phase co-crystals have for the enhance FIELD OF THE INVENTION ment of properties of widely different Structures and 0002 This invention pertains to methods of preparing an physico-chemical properties. active agent as mixed phase co-crystals that have unique 0007 Incorporation of minor components by a process physical properties that differ from the active agent in pure described as “co-crystallization that yields a product of form, as well as compositions comprising mixed phase indeterminate crystalline structure is illustrated by U.S. Pat. co-crystals. The formulated mixed phase co-crystals are Nos. 6,376,481, and 6,267.963 (sterol ); U.S. Pat. No. heterogenous and contain crystalline regions within the 6.214,402 (dilution of sweetener); U.S. Pat. No. 4,751,294 particles/granules produced. Mixed phase co-crystals are (stabilization by a base); U.S. Pat. No. 5,910,523 (nanocom useful for Systemic delivery of the active agent as human and posites); U.S. Pat. No. 5,876,506 (mesomorphic Sugar), U.S. animal pharmaceuticals, dietary Supplements, and agro Pat. No. 5,075,291 (uniform dispersion of drug in sugar chemicals. Furthermore, mixed phase co-crystals have util ); and U.S. Pat. No. 5,451,416. These materials of ity in imparting desirable physical and Stability properties indeterminate Structure lack the ability of mixed phase otherwise not achievable for the pure active agent or in co-crystals to maintain primary crystalline characteristics of combination as a simple formulation with the materials the active agent while imparting amorphous-like properties incorporated with the active agent. along with designed functionalities to enhance Solubility, dissolution, and absorption. BACKGROUND OF THE INVENTION 0008 Complex mixtures of crystalline materials formed 0.003 Co-crystals occur in nature and form spontane by melt/congealing process are described in U.S. Pat. Nos. ously with closely related chemical Structures, Such as 6,267.963 (sterol-emulsion complexes); U.S. Pat. Nos. chemical isomers (racemates, diasteriomers, and the like). 4.855,326 and 5,853,762 (rapidly dissolving dosage unit); Co-crystals are also found for materials that complex and U.S. Pat. No. 5,075,291. The process for preparing together in Solution Such as protein-ligands, chelates, inclu co-crystals by evaporation or cooling from a Solvent System Sion complexes as with cyclodextrins, and ligands. In U.S. is described in U.S. Pat. No. 4,145,214 (photoconductors); Pat. Nos. 4,971,797; 6,312,723 and 6,312,712, complexes of U.S. Pat. Nos. 4,751,294; 4,971,797; and 6,214,402. Appli cyclodextrin and active agents are described as being co cations for which no active agent is incorporated are crystallized together from Solution. These complexes lack described in U.S. Pat. Nos. 4,145,214 and 4,384,980. These the flexibility to incorporate materials with broadly different materials of indeterminate Structure lack the ability of mixed chemical Structures and lack the multi-functional properties phase co-crystals to maintain primary crystalline character that mixed co-crystals can impart. istics of the active agent while imparting amorphous-like properties along with designed functionalities to enhance 0004. In certain cases, macromolecules (both polymers and biopolymers) are capable of forming co-crystals with Solubility, dissolution, and absorption. other macromolecules. These co-crystallized products have 0009. In the field of active agent delivery, inherent prob been used to isolate macromolecules Such as proteins for lems associated with the active agent exist, Such as particle Structural characterization. An example of this is found in size, Stability, Solubility, powder physical properties and the paper by Murphy et al. (Acta Crystallogr D Biol Crys release rates. New and improved methods to solve the tallog, 55(Pt 9), 1594-1597 (1999)). These simple co problems associated with active agent delivery are needed. crystals are not useful to enhance Solubility, dissolution or The invention provides Such a method, as well as mixed absorption of poorly absorbed active agents. phase co-crystal compositions comprising an active agent. 0005 Minor amounts of materials can be incorporated in These and other advantages of the invention, as well as a particle Sub-structure. These components co-exist with additional inventive features, will be apparent from the crystalline phases of the particle and produce co-crystalline description of the invention provided herein. regions within the particle. The resulting co-crystallized material has a high level of crystallinity and lacks significant BRIEF SUMMARY OF THE INVENTION amounts of amorphous phase. Examples of these applica 0010. The invention is directed to a method of preparing tions can be found in patents describing the dilution of mixed phase co-crystals comprising: (a) forming a first Sweetening agents in Sugar carriers as in U.S. Pat. NoS. Solution of a first active agent and at least one crystal lattice 6,214,402 and 6,365,216. Incorporation of Small amounts of modifier dissolved in a Solvent; (b) mixing an anti-Solvent Single constituents differs from mixed phase co-crystals with the first Solution to form a second Solution; and (c) Since the particles produced do not have a significant amount forming a mixed phase crystalline material, wherein the of amorphous phase as indicated by melting properties and active agent and crystal lattice modifier are contained within Solubility. In addition, these materials do not contain an the mixed phase crystalline material. US 2005/0181041 A1 Aug. 18, 2005

0.011 The invention also is directed to a mixed phase monotropic co-crystal materials. The enhanced properties of co-crystal composition comprising a mixed phase co-crystal the mixed phase co-crystal materials are obtained even when of an active agent and at least one crystal lattice modifier, the thermodynamically favored polymorph of the active wherein the content of the active agent ranges from about agent is present as a component of the mixed phase co 5% to 95% by weight of the total weight of the material, and crystal Structure. Mixed phase co-crystal materials enable wherein the crystal lattice modifier ranges from about 2% to formation of conglomerates of the active agent with modi 95% by weight for each individual modifier of the total fiers that facilitate drug absorption process through perme weight of the material. ability modification, inhibitors of gut wall metabolism, and Stabilization of SuperSaturated Solutions. Since these mate BRIEF DESCRIPTION OF THE DRAWINGS rials are linked through the conglomerated mixed phase co-crystal Structure, they act in concert with the dissolution 0012 FIG. 1A is a graph showing heat flow to tempera of the active agent and are resistant to premature dissolution ture of a pure form of active agent wherein the active agent of the modifier in the absence of the active agent. By this is hydrocortisone acetate. mechanism the modifier imparts a full effect. 0013 FIG. 1B is a graph showing heat flow to tempera 0024. The process herein described for the mixed phase ture of a mixed phase co-crystal wherein the active agent is co-crystals is well Suited for the direct formation and incor hydrocortisone acetate. poration of mixed phase co-crystals as part of the dosage 0014 FIG. 2A is a graph of an X-ray diffraction (XRD) form manufacturing process without the need to isolate or pattern of pure . purify the mixed phase co-crystal material. 0015 FIG. 2B is a graph of an XRD pattern of a mixed 0025. Accordingly, the present invention is directed to phase co-crystal of a crystal lattice modifier (Stearic acid) mixed phase co-crystal compositions and methods of mak and active agent (hydrocortisone). ing mixed phase co-crystal compositions. The inventive method of preparing mixed phase co-crystals comprises: (a) 0016 FIG. 2C is a graph of an XRD pattern of pure forming a first Solution of an active agent and at least one active agent (hydrocortisone). crystal lattice modifier dissolved in a Solvent; (b) mixing an 0017 FIG. 3A is a graph of an XRD pattern of a mixed anti-Solvent with the first Solution to form a Second Solution; phase co-crystal of hydrocortisone (HC) acetate, Methocel and (c) forming the mixed phase co-crystal composition, E4M (hydroxypropyl methylcellulose), and cetosteryl wherein the active agent and crystal lattice modifier are alchohol. contained within the mixed phase co-crystal composition. The inventive method can further comprise evaporating the 0018 FIG. 3B is a graph of an XRD pattern of pure HC Solvent(s), isolating the mixed phase co-crystal composition, acetate. Washing the mixed phase co-crystal composition, and/or 0.019 FIG. 4 is a graph comparing dissolution profiles drying the mixed phase co-crystal composition. (mcg/mL over time) of mixed phase co-crystals of 0026. A mixed phase co-crystal is a particle or granule cyclosporin prepared using the method described in composed of two or more crystalline or non-crystalline Example 4. phases that are distributed randomly throughout the particle 0020 FIG. 5 is a graph showing the intrinsic dissolution Structure. One or more of the mixed phase co-crystal com rate of itraconazole mixed phase co-crystals in a 3% Sodium ponents must be Solids at room temperature. lauryl Sulfate 20% isopropanol:0.1 NHCl (1:1) media. 0027. An active agent that is co-crystallized with one or 0021 FIG. 6 is a graph showing comparing the in vitro more materials (additives) forms a mixed phase co-crystal dissolution rate for four lots of mixed phase co-crystal line form of the active agent and additive(s) that behaves as formulations (F833-023c, -024A, -025A, and -025B) con conglomerated particles or granules that have unique physi taining the active ingredient as compared to cal properties that are distinguishable from the pure active commercial Prometrium 200 mg capsules from two batches. agent or pure additive(s). These formulated mixed phase co-crystals have crystalline, co-crystalline, and amorphous DETAILED DESCRIPTION OF THE regions within the particle matrix. The active agent's crys talline form is usually maintained except that the additive(s) INVENTION are co-crystallized as part of active agent's crystal lattice 0022. The mixed phase co-crystal materials produced by Structure, thus forming co-crystalline regions or amorphous this invention have unique and unexpected properties Such regions or Semi-crystalline regions with crystal defects. This as increased apparent Solubility, increased dissolution rate, results in a characteristic reduction in melting point and reduced melting point of the active agent, and decrease in crystallinity of the thermodynamically favored crystalline crystallinity of the active agent. In addition, the mixed phase form of the active agent. co-crystal materials produce SuperSaturated concentrations 0028. Although not wishing to be bound by any particular of active agent for prolonged periods of time when SuS theory, it is believed that the additive(s) are co-crystallized pended in water, which facilitates absorption in Vivo. These as minor non-Stoichiometric components in the active changes in properties of the active agent are particularly agent's crystalline matrix. This co-crystalline phase has advantageous for the delivery of the active agent, e.g., in an Semi-crystalline nature and contains a high incidence of oral dosage form. crystal defects. Any excess additive that is not co-crystal 0023. Furthermore, combinations of more than one crys lized with the active agent forms a separate phase (Additive tallattice modifier with the active agent can result in additive Phase) apart from the active agent, which results in the and Super-additive effects that cannot be obtained with mixed phase co-crystal composition. The Additive Phase US 2005/0181041 A1 Aug. 18, 2005 and the active agent crystals containing co-crystallized addi 0033 1. C.-Adrenergic agonists such as Adrafinil, Adre tive can be tightly agglomerated forming a mixed phase nolone, Amidephrine, Apraclonidine, Budralazine, Cloni co-crystal particle. The unique physical properties obtained dine, Cyclopentamine, , Dimetofrine, Dipiv by this process of preparation can include changes in appar efrin, Ephedrine, Epinephrine, Fenoxazoline, Guanabenz, ent Solubility, crystallinity, water Wetability, dissolution Guanfacine, Hydroxyamphetamine, Ibopamine, Indanazo rates, physical powder properties (e.g., bulk density, abso line, Isometheptene, Mephentermine, Metaraminol, Meth lute density, refractive indeX, X-ray diffraction, Spectral, oxamine Hydrochloride, Methylhexaneamine, Metizolene, flowability, hygroscopicity, adsorption, and compaction), Midodrine, Naphazoline, Norepinephrine, Norfenefrine, bioavailability, apparent permeability, apparent taste, and/or Octodrine, Octopamine, Oxymetazoline, Phenylephrine Stability. For example, the inventive method of preparation Hydrochloride, Phenylpropanolamine Hydrochloride, Phe of the composition provides (a) an increase in water Solu nylpropylmethylamine, Pholedrine, Propylhexedrine, Pseu bility, (b) a decrease in melting point, (c) decrease in melting doephedrine, Rilmenidine, Synephrine, Tetrahydrozoline, enthalpy, (d) an increase in dissolution rate, (e) a reduction Tiamenidine, TramaZoline, Tuaminoheptane, Tymazoline, in crystallinity, or (f) a combination of two or more of (a)-(e) Tyramine, and Xylometazoline. as compared to the active agent itself. 0034 2. B-Adrenergic agonists such as Albuterol, Bam 0029. The mixed phase co-crystal that forms from the buterol, Bitolterol, Carbuterol, Clenbuterol, Clorprenaline, active agent and additive(s) is not a pure form stiochiometric Denopamine, Dioxethedrine, Dopexamine, Ephedrine, Epi eutectic. The mixed phase co-crystal composition produced nephrine, Etafedrine, Ethylnorepinephrine, Fenoterol, For according to the invention are thermodynamically favored. moterol, HeXoprenaline, Ibopamine, Isoetharine, Isoproter That is, the crystals exist at a lower energy, Stable State. enal, Mabuterol, Metaproterenol, Methoxyphenamine, Oxyfedrine, Pirbuterol, Prenalterol, Procaterol, Protokylol, 0030) In another aspect of the invention, after step (b) a Reproterol, Rimiterol, Ritodrine, Soterenol, Terbuterol, and kinetically favored crystalline phase is formed in the Second Xamoterol. Solution. The kinetically favored crystalline phase is also characterized as kinetically derived, meta-stable and ther 0035 3. C.-Adrenergic blockers such as Amosulalol, Aro modynamically disfavored. The meta-stable (i.e., kinetically tinolol, Dapiprazole, Doxazosin, MeSylates, Fen favored) crystalline phase is typically formed as a precipiate Spiride, Indoramin, Labetalol, Nicergoline, PraZosin, Tera in the Second Solution. The meta-stable crystalline phase is Zosin, Tolazoline, Trimazosin and . then Subsequently transformed (i.e., converted) to the ther 0.036 4. B-Adrenergic blockers Such as Acebutolol, modynamically favored mixed-phase co-crystal comopsi Alprenolol, AmoSulalol, Arotinolol, Atenolol, Befunolol, tion. The mixed phase co-crystalline material of the inven Betaxolol, Bevantolol, Bisoprolol, Bopindolol, Bucumolol, tion are kinetically favored and form upon Standing and/or Befetolol, Bufuralol, Bunitrolol, Bupranolol, Butidrine mixing of the initial meta-stable crystalline phase. Hydrochloride, Butofilolol, Carazolol, Carteolol, 0031. The amount of time required to achieve transfor Carvedilol, Celiprolol, Cetamolol, Cloranolol, Dilevalol, mation (i.e., conversion) from a kinetically favored crystal Epanolol, Esmolol, Indenolol, Labetalol, Levobunolol, line phase to the mixed phase co-crystal composition Mepindolol, Metipranalol, Metoprolol, Moprolol, Nadox depends on the particular active agent and other additives olol, Nifenalol, Nipradillol, Oxprenolol, Penbutolol, Pin present in the Second Solution. The Second Solution contain dolol, Practolol, Pronethalol, Propranolol, Sotalol, Sulfi ing the initial meta-stable crystalline phase is generally malol, Talinolol, Tertatolol, Timolol, Toliprolol, and mixed or allowed to stand for a sufficient period of time to Xibenolol. permit complete conversion to the mixed phase co-crystal 0037) 5. Alcohol deterrents such as Calcium Cyanamide line material. This transformation Step may take occur for Citrated, Disulfiram, Nadide, and Nitrefazole. any Suitable amount of time (e.g., about 10 Seconds, about 30 seconds, about 1 minute, about 5 minutes, about 10 0038 6. Aldose reductase inhibitors such as Epalrestat, minutes, about 30 minutes, about 1 hour, about 2 hours, Ponalrestat, Sorbinil, and Tolrestat. about 10 hours, about 20 hours, about 30 hours, about 40 0039 7. Anabolics such as Androisoxazole, Androstene hours, about 50 hours, or more). One of ordinary skill in the diol, , Bolasterone, Clostebol, Ethylestrenol. art will recognize the amount of time required for conver Formyldienolone, 4-Hydroxy-19-nortestosterone, Meth sion of the kinetically favored crystalline material to the andriol, Methenolone, Methyltrienolone, , Nan thermodynamically favored mixed phase co-crystal compo drolone Decanoate, Nandrolone p-HeXyloxyphenylpropi Sition. Incomplete conversion will result in problems filter onate, Nandrolone Phenpropionate, Norbolethone, ing the crystalline material, and therefore, more incubation Oxymesterone, Pizotyline, Quinbolone, Stenbolone, and time is required. Trenbolone. 0.032 The active agent for use in the composition and 0040) 8. Analgesics (narcotic) such as Alfentanil, Allyl method of the invention include any Suitable active agent. prodine, Alphaprodine, Anileridine, Benzylmorphine, Bez The active agent is preferably a Small chemical entity that is itramide, Buprenorphine, Butorphanol, ClonitaZene, approximately less than 10,000 daltons (e.g., less than about Codeine, Codeine Methyl , Codeine Phosphate, 9,000 daltons, less than about 8,000 daltons, less than about Codeine Sulfate, Desomorphine, Dextromoramide, Dezo 7,000 daltons, less than about 6,000 daltons, less than about cine, Diampromide, Dihydrocodeine, Dihydrocodeinone 5,000 daltons), Such as a pharmacologically active Substance Enol Acetate, Dihydromorphine, Dimenoxadol, Dimephep (drug), Vitamin, insecticide, fungicide, antibacterial agent, tanol, Dimethylthiambutene, Dioxaphetyl Butyrate, Dipi antiviral agent, antiparasitic agent or hormone. Exemplary panone, Eptazocine, Ethoheptazine, Ethylmethlythiam of active agents include, but are not limited to the following: , Ethylmorphine, EtonitaZene, Fentanyl, US 2005/0181041 A1 Aug. 18, 2005

Hydrocodone, Hydromorphone, Hydroxypethidine, Diperadon Hydrochloride, Dyclonine, Ecgonidine, Ecgo Isomethadone, Ketobemidone, Levorphanol, Lofentanil, nine, Ethyl Aminobenzoate, Ethyl Chloride, Etidocaine, Meperidine, Meptazinol, Metazocine, Methadone Hydro Etoxadrol, B-Eucaine, Euprocin, Fenalcomine, Fomocaine, chloride, Metopon, , Morphine Derivatives, Myro , Hexylcaine Hydrochloride, phine, Nalbuphine, Narceline, Nicomorphine, Norlevorpha Sodium, Hydroxyprocaine, Hydroxytetracaine, Isobutyl nol, Normethadone, Normorphine, Norpipanone, Opium, p-Aminobenzoate, Kentamine, Leucinocaine MeSylate, Oxycodone, Oxymorphone, Papaveretum, Pentazocine, LeVOXadrol, Lidocaine, Mepivacaine, Meprylcaine Hydro Phenadoxone, Phenazocine, Pheoperidine, Piminodine, Pir chloride, Metabutoxycaine Hydrochloride, itramide, Proheptazine, Promedol, Properidine, Propiram, Sodium, Methyl Chloride, , Myrtecaine, Nae Propoxyphene, Sufentanil, and Tilidine. paine, Octacaine, Orthocaine, Oxethazaine, Parethoxycaine, 0041) 9. Analgesics (non-narcotic) such as Acetami Phenacaine Hydrochloride, Phencyclidine, , Piper nophen, AcetaminoSalol, Acetanilide, Acetylsalicylsalicylic ocaine, Piridocaine, Polidocanol, Pramoxine, Prilocaine, Acid, Alclofenac, Alminoprofen, Aloxiprin, Aluminum Procaine, , Propanocaine, Proparacaine, Propi Bis(acetylsalicylate), Aminochlorthenoxazin, 2-Amino-4- pocaine, , Propoxycaine Hydrochloride, Pseudoco picoline, Aminopropylon, Aminopyrine, Ammonium Sali caine, Pyrrocaine, Quinine Hydochloride, Risocaine, cylate, Antipyrine, Antipyrine Salicylate, Antrafenine, Apa Salicyl Alcohol, Tetracaine Hydrochloride, , Zone, Aspirin, Benorylate, Benoxaprofen, BenZpiperylon, Thimylal, , Thiopental Sodium, Tolycaine, BenZydamine, p-Bromoacetanilide, 5-Bromosalicylic Acid Trimecaine, and Zolamine. Acetate, Bucetin, BufeXamac, Bumadizon, Butacetin, Cal 0044) 12. Anorectics such as Aminorex, Amphecloral, cium Acetylsalicylate, , Carbetidine, Carbi , BenZaphetamine, Chlorphentermine, phene, CarSalam, Chloralantipyrine, Chlorthenoxazin(e), Clobenzorex, Cloforex, Clortermine, Cyclexedrine, Destro Choline Salicylate, Cinchophen, Ciramadol, Clometacin, amphetamine Sulfate, Diethylpropion, Diphemethoxidine, Cropropamide, Crotethamide, DeXOXadrol, Difenamizole, N-Ethylamphetamine, Fenbutrazate, Fenfluramine, Fenpro Diflunisal, Dihydroxyaluminum Acetylsalicylate, Dipyro porex, Furfuirylmethylamphetamine, Levophacetoperate, cetyl, Dipyrone, EmorfaZone, Enfenamic Acid, Epirizole, Mazindol, Mefenorex, Metamfeproamone, Methamphet EterSalate, EthenZamide, Ethoxazene, Etodolac, Felbinac, amine, Norpseudoephedrine, Phendimetrazine, Phenmetra Fenoprofen, Floctafenine, , Fluoresone, zine, Phenpentermine, Phenylpropanolamine Hydrochlo , FluproduaZone, Flurbiprofen, Fosfosal, Gentisic ride, and Picilorex. Acid, Glafenine, Ibufenac, Salicylate, Indometha cin, Indoprofen, IsofeZolac, Isoladol, Isonixin, Ketoprofen, 0045 13. Anthelmintics (Cestodes) such as Arecoline, Ketorolac, p-Lactophenetide, Lefetamine, Loxoprofen, Aspidin, Aspidinol, Dichlorophen(e), Embelin, Kosin, Lysine Acetylsalicylate, Magnesium Acetylsalicylate, Meth Napthalene, Niclosamide, Pellertierine, Pellertierine Tan otrimeprazine, Metofoline, Miroprofen, Morazone, Mor nate, and Quinacrine. pholine Salicylate, Naproxen, Nefopam, Nifenazone, 5' 0046) 14. Anthelmintics (Nematodes) such as Alantolac Nitro-2' propoxyacetanilide, Parsalmide, Perisoxal, Phen tone, AmoScanate, AScaridole, Bephenium, Bitoscanate, acetin, Phenazopyridine Hydrochloride, Phenocoll, Phe Tetrachloride, Carvacrol, Cyclobendazole, Diethyl nopyrazone, Phenyl Acetylsalicylate, Phenyl Salicylate, carbamazine, Diphenane, Dithiazanine Iodide, Dymanthine, Phenyramidol, Pipebuzone, Piperylone, Prodilidine, Propac Gentian Violet, 4-Hexylresorcinol, Kainic Acid, Mebenda etamol, PropyphenaZone, Proxazole, Quinine Salicylate, Zole, 2-Napthol, Oxantel, Papain, Piperazine, Piperazine RamifenaZone, Rimazolium Metilsulfate, Salacetamide, Adipate, Piperazine Citrate, Piperazine Edetate Calcium, Salicin, Salicylamide, Salicylamide O-, Salicyl Piperazine Tartrate, Pyrantel, Pyrvinium Pamoate, C.-Santo , Salsalte, Salverine, Simetride, Sodium Sali nin, Stilbazium Iodide, Tetrachloroethylene, Tetramisole, cylate, Sulfamipyrine, Suprofen, Talniflumate, Tenoxicam, thiabendazole, , Thymyl N-Isoamylcarbamate, Tri Terofenamate, Tetradrine, Tinoridine, , Tol clofenol Piperazine, and Urea Stibamine. pronine, Tramadol, Viminol, Xenbucin, and Zomepirac. 0047 15. Anthelmintics (Onchocerca) such as 0.042 10. such as Boldenone, Fluoxymester and Suramin Sodium. one, Mestanolone, Mesterolone, Methandrostenolone, 17-, Methyltestosterone, 17C.-Methyltes 0048 16. Anthelmintics (Schistosoma) such as Amoscan tosterone 3-Cyclopentyl Enol Ether, Norethandrolone, ate, Amphotalide, Antimony Potassium Tartrate, Antimony Normethandrone, , Oxymesterone, Sodium Gluconate, Antimony Sodium Tartrate, Antimony Oxymetholone, , Stanlolone, Stanozolol, Test Sodium Thioglycollate, Antimony Thioglycollamide, osterone, 17- Hemiacetal, Testosterone Becanthone, Hycanthone, Lucanthone Hydrochloride, Niri 17 B-Cypionate, Testosterone Enanthate, Testosterone Nico dazole, Oxamniquine, Praziquantel, Stibocaptate, Sti tinate, Testosterone Pheynylacetate, Testosterone Propi bophen, and Urea Stibamine. onate, and Tiomesterone. 0049 17. Anthelmintic (Trematodes) such as Anthi 0043) 11. Anesthetics (intravenous) such as Acetami olimine and Tetrachloroethylene. doeugenol, Acetate, , Amucaine, 0050 18. Antiacne such as Algestone Amolanone, Amylocaine Hydrochloride, BenoXinate, Acetophenide, AZelaic Acid, Benzoyl Peroxide, Cyoctol, Betoxycaine, Biphenamine, Bupivacaine, Butacaine, Buta Cyproterone, Motretinide, Resorcinol, Retinoic Acid, and ben, Butanilicaine, Burethamine, Sodium, Butox Tetroquinone. ycaine, Carticaine, 2-Chloroprocaine Hydrochloride, Coca , Cocaine, Cyclomethycaine, 0051) 19. Antiallergics such as Amlexanox, Astemizole, DibucaineHydrochloride, Dimethisoquin, Dimethocaine, AZelastine, Cromolyn, Fenpiprane, Histamine, Ibudilast, US 2005/0181041 A1 Aug. 18, 2005

Nedocromil, Oxatomide, Pentigetide, Poison Ivy Extract, rfenicol, and Thiamphenicol; Ansamycins Such as Rifamide, Poison Oak Extract, Poison Sumac Extract, Repirinast, Rifampin, Rifamycin, and Rifaximin; B-Lactams, including: Tranilast, TraxanoX, and Urushiol. Carbapenems. Such as Imipenem; Cephalosporins Such as 0.052 20. Antiamebics such as Arsthinol, Bialamnicol, Cefactor, Cefadroxil, Cefamandole, Cefatrizine, Cefaze CarbarSone, Cephaeline, Chlorbetamide, Chloroquine, done, Cefazolin, Cefixime, CefinenoXime, Cefodizime, Chlorphenoxamide, Chlortetracycline, Dehydroemetine, Cefonicid, CefoperaZone, Ceforanide, CefotaXime, Cefo Dibromopropamidine, Diloxanide, DephetarSone, Emetine, tiam, Cefpimizole, Ce?pirimide, Cefpodoxime Proxetil, Fumagillin, Glaucarubin, Glycobiarsol, 8-Hydroxy-7-iodo Cefroxadine, Cefsulodin, Ceftazidime, Cefteram, Ceftezole, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefuroxime, Cefu 5-quinolineSulfonic Acid, Iodochlorhydroxyquin, Zonam, Cephacetrile Sodium, Cephalexin, Cephaloglycin, Iodoquinol, Paromomycin, Phanquinone, PhearSone Sul Cephaloridie, Cephalosporin, Cephalothin, Cephapirin foxylate, Polybenzarsol, Propamidine, Quinfamide, Sec Sodium, Cephradine and Piveefalexin; Cephamycins Such as nidazole, Sulfarside, Teclozan, Tetracycline, Thiocarbam CefbuperaZone, Cefnmetazole, Cefninox, Cefetan and izine, ThiocarbarSone, and Tinidazole. CefoXitin; Monobactams Such as Aztreonam, Carumonam 0.053 21. such as , Cyoctol, and Tigemonam, Oxacephems. Such as Flomoxef and Mox Cyproterone, Delmadinone Acetate, Flutimide, Nilutamide, olactam, Penicillins Such as Amidinocillin, Amdinocillin and Oxendolone. Pivoxil, Amoxicillin, Ampicillan, Apalcillin, ASpoxicillin, 0.054 22. Antianginals such as Acebutolol, Alprenolol, AZidocillan, AZlocillan, Bacampicillin, Benzylpenicillinic Amiodarone, Amlodipine, Arotinolol, Atenolol, Bepridil, Acid, Benzylpenicillin Sodium, Carbenicillin, Carfecillin Bevantolol, Bucumolol, Bufetolol, Bufuralol, Bunitrolol, Sodium, Carindacillin, Clometocillin, Cloxacillin, Cyclacil Bupranolol, Carozolol, Carteolol, Carvedilol, Celiprolol, lin, Dicloxacillin, Diphenicillin Sodium, Epicillin, Fenbeni CinepaZet Maleate, Diltiazem, Epanolol, Felodipine, Gallo cillin, Floxicillin, Hetacillin, Lenampicillin, Metampicillin, pamil, Imolamine, Indenolol, ISOSorbide Dinitrate, Israd Methicillin Sodium, Mezlocillin, Nafcillin Sodium, Oxacil ipine, Limaprost, Mepindolol, Metoprolol, Molsidomine, lin, Penamecillin, Penethamate Hydriodide, Penicillin G Nadolol, Nicardipine, Nifedipine, Nifenalol, Nilvadipine, Benethamine, Penicillin G BenZathine, Penicillin G Ben Nipradillol, Nisoldipine, Nitroglycerin, Oxprenolol, Oxy Zhydrylamine, Penicillin G Calcium, Penicillin G Hydrab amine, Penicillin G Potassium, Penicillin G Procaine, Peni fedrine, OZagrel, Penbutolol, Pentaerythritol Tetranitrate, cillen N, Penicillin O, Penicillin V, Penicillin V BenZathine, Pindolol, Pronethalol, Propranolol, Sotaiol, Terodiline, Penicillin V Hydrabamine, Penimepicycline, Phenethicillin Timolol, Toliprolol, and Verapamil. Potassium, Piperacillin, Pivapicillin, Propicillin, Quinacil 0.055 23. Antiarrhythmics such as Acebutol, Acecaine, lin, Sulbenicillin, Talampicillin, Temocillin and Ticarcillin; Adenosine, Ajmaline, Alprenolol, Amiodarone, Amoproxan, Lincosamides Such as Clindamycin and Lincomycin; Mac Aprindine, Arotinolol, Atenolol, Bevantolol, Bretylium rollides Such as Azithromycin, Carbomycin, Clarithromycin, Tosylate, Bubumolol, Bufetolol, Bunaftine, Bunitrolol, Erythromycin, Erythromycin Acistrate, Erythromycin Esto Bupranolol, Butidrine Hydrochloride, Butobendine, late, Erythromycin Glucoheptonate, Erythromycin Lacto Capobenic Acid, Carazolol, Carteolol, Cifenline, Clo bionate, Erythromycin Propionate, Erythromycin Stearate, ranolol, Disopyramide, Encainide, Esmolol, Flecainide, JoSamycin, Leucomycins, Midecamycins, Miokamycin, Gallopamil, Hydroquinidine, Indecainide, Indenolol, Iprat Oleandomycin, Primycin, Rokitamycin, Rosaramicin, ropium Bromide, Lidocaine, Lorajmine, Lorcainide, ROXithromycin, Spiramycin and Troleandomycin; Polypep Meobentine, Metipranolol, Mexiletine, Moricizine, Nadox tides Such as Amphomycin, Bacitracin, Capreomycin, Colis olol, Nifenalol, Oxprenolol, Penbutolol, Pindolol, Pirmenol, tin, Enduracidin, Enviomycin, Fusafumgine, Gramicidin(S), Practolol, Prajmaline, Procainamide Hydrochloride, Prone Gramicidin S, Mikamycin, Polymyxin, Polymyxin B-Meth thalol, Propafenone, Propranolol, Pyrinoline, Quinidine Sul aneSulfonic Acid, Pristinamycin, Ristocetin, Teicoplanin, fate, Quinidine, Sotalol, Talinolol, Timolol, Tocainide, Vera Thiostrepton, Tuberactinomycin, Tyrocidine, Tyrothricin, pamil, Vicquidil, and Xibenolol. Vancomycin, Viomycin, Viomycin Pantothenate, Virginia mycin and Zinc Bacitracin; Tetracyclines Such as Apicy 0056 24. Antiarteriosclerotics such as Pyridinol Carbam cline, Chlortetracycline, Clomocycline, Demeclocycline, ate. Doxycycline, Guamecycline, Lymecycline, Meclocycline, 0057 25. Antiarthritic/Antirheumatics such as Allocupre Methacycline, Minocycline, Oxytetracycline, Penimepicy ide Sodium, Auranofin, Aurothioglucose, Aurothiogly cline, Pipacycline, Rolitetracycline, Sancycline, Senociclin canide, AZathioprine, Calcium 3-Aurothio-2-propanol-1- and Tetracycline, and other antibioticS Such as CycloSerine, Sulfonate, Chloroquine, Clobu Zarit, CuproXoline, Diacerein, Mupirocin and Tuberin. Glucosamine, Gold Sodium Thiomalate, Gold Sodium Thio 0059 27. Antibacterial drugs (synthetic), including: 2,4- sulfate, Hydroxychloroquine, Kebuzone, Lobenzarit, Melit Diaminopyrimidines Such as Brodimoprim, TetroXoprim tin, Methotrexate, Myoral, and Penicillamine. and Trimethoprim; Nitrofurans such as Furaltadone, Fura 0.058 26. Antibacterial (antibiotic) drugs including Ami Zolium Chloride, Nifuradene, Nifuratel, Nifurfoline, noglycosides Such as Amikacin, Apramyclin, Arbekacin, Nifurpirinol, Nifurprazine, Nifurtoinol and Nitrofurantoin; Bambermycins, Butirosin, Dibekacin, Dihdrostreptomycin, Quinolones and Analogs Such as Amifloxacin, Cinoxacin, Fortimicin(s), Gentamicin, Ispamicin, Kanamycin, Micro Ciprofloxacin, Difloxacin, Enoxacin, Fleroxacin, Flume nomicin, Neomycin, Neomycin Undecylenate, Netilmicin, quine, nomefloxacin, Miloxacin, Nalidixic Acid, Norfloxa Paromomycin, Ribostamycin, Sisomicin, Spectinomycin, cin, Ofloxacin, Oxolinic Acid, Pefloxacin, Pipemidic Acid, Streptomycin, Streptonicozid, and Tobramycin; Ampheni Piromidic Acid, RoSoxacin, Temafloxacin and ToSufloxacin; colS Such as AZidamfenicol, Chloramphenicol, Chloram Sulfonamides Such as Acetyl Sulfamethoxypyrazine, Acetyl phenicol Palmitate, Chloramphenicol Pantothenate, Flo Sulfisoxazole, AZOsulfamide, Benzylsulfamide, Chloram US 2005/0181041 A1 Aug. 18, 2005

ine-B, Chloramine-T, Dichloramine T, Formosulfathiazole, droxybutyric Acid, Atrolactamide, Beclamide, Buramate, N.Sup.2 Formylsulfisomidine, N.Sup.2-f-D-Glucosylsulfa Calcium Bromide, Carbamazepine, Cinromide, Clomethia nilamide, Mafenide, 4'-(Methylsulfamoyl) sulfanilanilide, Zole, , Decimenide, Diethadione, Dimethadi p-Nitrosulfathiazole, Noprylsulfamide, Phthalylsulfaceta one, Doxenitoin, , Ethadione, Ethosuximide, Etho mide, Phthalylsulfathiazole, Salazosulfadimidine, Succinyl toin, Fluoresone, 5-Hydroxytryptophan, Lamotrigine, Sulfathiazole, Sulfabenzamide, Sulfacetamide, Sulfachlo Magnesium Bromide, Magnesium Sulfate, Mephenytoin, rpyridazine, Sulfachrysoidine, Sulfacytine, Sulfadiazine, Mephobarbital, , Methetoin, MethSuximide, Sulfadicramide, Sulfadimethoxine, Sulfadoxine, Sulfaethi 5-Methyl-5-(3-phenanthryl)hydantoin, 3-Methyl-5-phenyl dole, Sulfaguanidine, Sulfaguanol, Sulfalene, Sulfaloxic hydantoin, , , , Acid, Sulfamerazine, Sulfameter, Sulfamethazine, Sulfame Paramethadione, Phenacemide, Phenetharbital, Pheneturide, thizole, Sulfamethomidine, Sulfamethoxazole, Sul , Phenobarbital Sodium, Phensuximide, Phe famethoxypyridazine, Sulfametrole, Sulfamidochrysoidine. nylmethylbarbituric Acid, , Phethenylate Sodium, Sulfamoxole, Sulfanilamide, Sulfanilamidomethanesulfonic , , Progabide, Sodium Bro Acid Triethanolamine Salt, 4-Sulfanilamidosalicylic Acid, mide, Solanum, Strontium Bromide, Suclofenide, Sulthi N.Sup.4-Sulfanilylsulfanilamide, Sulfanily lurea, N-Sulfa ame, Tetrantoin, Trimethadione, Valproic Acid, Valpromide, nillyl-3,4-Xylamide, Sulfanitran, Sulfaperine, Sul Vigabatrin and Zonisamide. faphenazole. Sulfaproxyline, Sulfapyrazine, Sulfapyridine, 0062. 30. , including: Bicyclics such as Sulfasomizole, Sulfasymazine, Sulfathiazole, Sulfathiourea, Binedaline, CaroXaZone, Citalopram, Dimethazan, Indal Sulfatolamide, Sulfisomidine and Sulfisoxazole, Sulfones pine, Fencamine, Indeloxazine Hydrochcloride, Nefopam, Such as AcedapSone, AcediaSulfone, Acetosulfone Sodium, Nomifensine, Oxitriptan, Oxypertine, Paroxetine, Sertraline, Dapsone, Diathymosulfone, Glucosulfone Sodium, Solasul Thiazesim, and ; Hydrazides/Hydra fone, Succisulfone, Sulfanilic Acid, p-Sulfanilylbenzy Zines Such as Benmoxine, proclozide, Iproniazid, ISOcar lamine, pp'-Sulfonyldianiline-N,N' digalactoside, Sulfox boxazid, Nialamide, Octamoxin and Phenelzine; Pyrroli one Sodium and Thiazolsulfone, and otherS Such as dones Such as Cotinine, Rolicyprine and Rolipram; Clofoctol, Hexedine, Methenamine, Methenamine Anhy Tetracyclics such as Maprotiline, Metralindole, dromethylene-citrate, Methenamine Hippurate, Meth and Oxaprotiline. TricyclicS Such as , Amitrip enamine Mandelate, Methenamine Sulfosalicylate, Nitroxo tyline, Amitriptylinoxide, Amoxapine, Butriptyline, Clomi line and Xibomol. pramine, Demexiptiline, Desipramine, Dibenzepin, Dime 0060) 28. Anticholinergics such as Adiphenine Hydro tracrine, Dothiepin, , Fluacizine, Imipramine, chloride, Alverine, Ambutonomium Bromide, Aminopenta Imipramine N-Oxide, Iprindole, Lofepramine, Melitracen, mide, Amixetrine, Amprotropine Phosphate, Anisotropine Metapramine, Nortriptyline, Noxiptilin, Opipramol, Pizoty Methylbromide, Apoatropine, Atropine, Atropine N-Oxide, line, Propizepine, Protriptyline, Quinupramine, Tianeptine Benactyzine, BenapryZine, BenZetimide, BenZilonium Bro and ; and otherS Such as Adrafinil, Benac mide, Benztropine Mesylate, Bevonium Methyl Sulfate, ty Zine. , Butacetin, Deanol, Deanol Aceglumate, Biperiden, Butropium Bromide, N-Butylscopolammonium Deanol Acetamidobenzoate, Dioxadrol, , Febar Bromide, Buzepide, Camylofine, Caramiphen Hydrochlo bamate, Femoxetine, , , Fluvoxam ride, Chlorbenzoxamine, Chlorphenoxamine, Cimetropium ine, Hematoporphyrin, Hypercinin, Levophacetoperane, Bromide, Clidinium Bromide, Cyclodrine, Cyclonium Medifoxamine, Minaprine, Moclobemide, Oxaflozane, Pib Iodide, Cycrimine Hydrochloride, Deptropine, Dexetimide, eraline, Prolintane, Pyrisuccideanol, Rubidium Chloride, Dibutoline Sulfate, Dicyclomine Hydrochloride, Diethaz , Sultopride, Teniloxazine, ThoZalinone, Tofenacin, ine, Difemerine, Dihexyverine, Diphemanil Methylsulfate, Toloxatone, Tranylcypromine, L-Tryptophan, Viloxazine N-(1,2-Diphenylethyl) , Dipiproverine, Dipo and Zimeldine. nium Bromide, Emepronium Bromide, Endobenzyline Bro 0063. 31. Antidiabetics, including: Biguanides such as mide, Ethopropazine, Ethybenztropine, Ethylbenzhy , Metformin and Phenformin; Hormones such as dramine, Etomidoline, Eucatropine, Fenpiverinium Glucagon, Insulin, Insulin Injection, Insulin Zinc Suspen Bromide, Fentonium Bromide, Flutropium Bromide, Gly Sion, Isophane Insulin Suspension, Protamine Zinc Insulin copyrrolate, Heteronium Bromide, Hexocyclium Methyl Suspension and Zinc Insulin Crystals; Sulfonylurea deriva Sulfate, Homatropine, Hyoscyamine, pratropium Bromide, tives Such as Acetohexamide, 1-Butyl-3-metanily lurea, Isopropamide, Levomepate, Mecloxamine, MepenZolate Carbutamide, Chlorpropamide, Glibornuride, Gliclazide, Bromide, Metcaraphen, Methantheline Bromide, Methix Glipizide, Gliquidone, Glisoxepid, Glyburide, Glybuthiaz ene, Methscopolamine Bromide, Octamylamine, Oxybuty ol(e), Glybuzole, Glyhexamide, Glymidine, Glypinamide, nin Chloride, Oxyphencyclimine, Oxyphenonium Bromide, Phenbutamide, Tolazamide, Tolbutamide and Tolcyclamide; Pentapiperide, Penthienate Bromide, Phencarbamide, Phen and otherS Such as Acarbose, Calcium MeSoxalate and , Pipenzolate Bromide, Piperidolate, Piperilate, Miglitol. Poldine Methysulfate, Pridinol, Prifinium Bromide, Procy clidine, Propanthel ine Bromide, Propenzolate, Propyro 0064. 32. Antidiarrheal drugs such as Acetyltannic Acid, mazine, , Scopolamine N-Oxide, Stilonium Albumin Tannate, Alkofanone, Aluminum Salicylates-Ba Iodide, Stramonium, Sultroponium, Thihexinol, Thiphe Sic, , DilfenoXin, Diphenoxylate, Lidamidine, Lop namil, Tiemonium Iodide, Timepidium Bromide, Tiquizium eramide, Mebiquine, Trillium and Uzarin. Bromide, Tridihexethyl Iodide, Trihexyphenidyl Hydrochlo 0065 33. Antidiuretics such as Desmopressin, Fely ride, Tropacine, Tropenzile, Tropicamide, TroSpium Chlo pressin, Lypressin, Ornipressin, Oxycinchophen, Pituitary ride, Valethamate Bromide and Xeny tropium Bromide. Posterior, Terlipressin and Vasopressin. 0061 29. such as Acetylpheneturide, 0066 34. such as Delmadinone Acetate, Albutoin, Aloxidone, , 4-Amino-3-hy , and . US 2005/0181041 A1 Aug. 18, 2005

0067 35. Antifungal drugs (antibiotics), including: Poly Nicofibrate, Pirifibrate, Ronifibrate, Simfibrate and Theofi enes Such as Amphotericin-B, Candicidin, Dermostatin, brate; Bile acid Sequesterants Such as Cholestyramine Resin, Filipin, Fungichromin, Hachimycin, Hamycin, Lucensomy Colestipol and Polidexide; HMG CoA reductase inhibitors cin, Mepartricin, Natamycin, Nystatin, Pecilocin and Peri Such as Lovastatin, Pravastatin Sodium and Simvastatin; mycin; and otherS Such as AZaserine, Griseofulvin, Oligo Nicotinic acid derivatives Aluminum Nicotinate, Acipimox, mycins, Neomycin Undecylenate, Pyrrolnitrin, Siccanin, Niceritrol, Nicoclonate, Nicomol and Oxiniacic Acid; Thy Tubercidin and Viridin. roid hormones and analogS Such as EtiroXate, Thyropropic Acid and ThyroXine, and otherS Such as Acifran, AZacos 0068. 36. Antifungal drugs (synthetic), including: Ally terol, Benfluorex, B-Benzalbutyramide, Camitine, Chon lamines Such as Naftifine and Terbinafine; Such droitin Sulfate, Clomestone, DetaXtran, Dextran Sulfate as Bifonazole, Butoconazole, Chlordantoin, Chlormidazole, Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Cloconazole, Clotrimazole, Econazole, Enilconazole, Fen Furazbol, Meglutol, Melinamide, Mytatrienediol, Omithine, ticonazole, Isoconazole, Ketoconazole, Miconazole, Omo Y-Oryzanol, Pantethine, Penataerythritol Tetraacetate, conazole, Oxiconazole, Nitrate, Sulconazole and Tiocona C.-Phenylbutyramide, Pirozadil, Probucol, C.-Sitosterol, Sul Zole, Triazoles Such as Fluconazole, Itraconazole and tosilic Acid, Piperazine Salt, Tiadenol, Triparanol and Xen Terconazole; and otherS Such as Acrisorcin, Amorolfine, Biphenamine, Bromosalicylchloranilide, Buclosamide, Cal bucin. cium Propionate, Chlophenesin, Ciclopirox, Cloxyquin, 0074 42. Antihypertensive drugs, including: Arylethano Coparaffinate, Diamthazole, Dihydrochloride, Exalamide, lamine derivatives such as Amosulalol, Bufuralol, Dilevalol, Flucytosine, Halethazole, Hexetidine, Loflucarban, Nifura Labetalol, Pronethalol, Sotalol and Sulfinalol; Aryloxypro tel, Potassium Iodide, , Pyrithione, Salicyla panolamine derivatives Such as Acebutolol, Alprenolol, Aro nilide, Sodium Propionate, Sulbentine, Tenonitrozole, Tol tinolol, Atenolol, Betaxolol, Bevantolol, Bisoprolol, Bopin ciclate, Tolindate, Tolnaftate, Tricetin, Ujothion, dolol, Bunitrolol, Bupranolol, Butofilolol, Carazolol, Undecylenic Acid and Zinc Propionate. Cartezolol, Carvedilol, Celiprolol, Cetamolol, Epanolol, Indenolol, Mepindolol, Metipranolol, Metoprolol, 0069. 37. Antiglaucoma drugs such as Acetazolamide, Moprolol, Nadolol, Nipradillol, Oxprenolol, Penbutolol, Pin Beflnolol, Betaxolol, Bupranolol, Carteolol, Dapiprazoke, dolol, Propranolol, Talinolol, Tetraolol, Timolol and Tolip Dichlorphenamide, Dipivefrin, Epinephrine, Levobunolol, rolol, Benzothiadiazine derivatives Such as Althiazide, Ben Methazolamide, Metipranolol, Pilocarpine, Pindolol and droflumethiazide, Benzthiazide, Timolol. Benzylhydrochlorothiazide, Buthiazide, Chlorothiazide, Chlorthalidone, Cyclopenthiazide, Cyclothiazide, Diazox 0070 38. such as , ide, Epithiazide, Ethiazide, Fenguizone, Hydrochlorothiaz and . ide, Hydroflumethiazide, Methyclothiazide, Meticrane, 0071 39. Antigout drugs such as Allopurinol, Carprofen, Metolazone, Paraflutizide, Polythiazide, Tetrachlormethiaz Colchicine, Probenecid and Sulfinpyrazone. ide and Trichlormethiazide; N-Carboxyalkyl (petide/lactam) derivatives Such as Alacepril, Captopril, CilaZapril, Delapril, 0.072 40. , including: Alkylamine deriva Enalapril, Enalaprilat, Fosinopril, Lisinopril, Moveltipril, tives Such as Acrivastine, Bamipine, Brompheniramine, Perindopril, Quinapril and Ramipril; Dihydropyridine Chlorpheniramine, Dimethindene, Metton S., , derivatives Such as Amlodipine, Felodipine, Isradipine, Pyrrobutamine, Thenaldine, Tolpropamine and Triprolidine; Nicardipine, Nifedipine, Nilvadipine, Nisoldipine and Aminoalkyl etherS Such as Bietanautine, Bromodiphenhy Nitrendipine; dramine, Carbinoxamine, Clemastine, Diphenlypyraline, , Embrammine, Medrylamine, Mephenphy 0075 43. Guanidine derivatives such as Bethanidine, dramine, p-Methyldiphenhydramine, Orphenadrine, Phenyl Debrisoquin, Guanabenz, Guanacline, Guanadrel, GuanaZo toloxamine, Piprinhydrinate and Setasine; Ethylenediamine dine, Guanethidine, Guanfacine, Guanochlor, GuanoXabenz derivatives Such as Alloclamide, p-Brom tripelennamine, and GuanoXan; Hydrazines and phthalazines Such as Chloropyramine, Chlorothen, Histapyrrodine, Methafu Budralazine, Cadralazine, Dihydralazine, Endralazine, Hyd rylene, , , Phenbenzamine, racarbazine, Hydralazine, Pheniprazine, Pildralazine and Pyrilamine, Talastine, Thenyldiamine, Thonzylamine Todralazine, Imidazole derivatives Such as , Hydrochloride, Tripelennamine and Zolamine; Piperazines , , Tiamenidine and Tolonidine; Such as Cetirizine, Chlorcyclizine, Cinnarizine, Clocinizine Quaternary ammonium compounds AZamethonium Bro and Hydroxy Zine, Tricyclics, including: Phenothiazines mide, Chlorisondamine Chloride, Hexamethonium, Penta Such as Ahistan, Etymemazine,Hydroxyazine, N-Hydroxy cynium Bis(methyl sulfate), Pentamethonium Bromide, ethylpromethazine Chloride, Isopromethazine, Mequitazine, Pentolinium Tartate, Phenactopinium Chloride and Trime , Pyrathiazine and Thiazinamium Methyl Sul thidiunumMethoSulfate; Quinazoline derivatives Such as fate; and otherS Such as AZatadine, Clobenzepam, Cypro AlfuZosin, BunaZosin, Doxazosin, Prasosin, TeraZOsin and heptadine, Deptropine, Isothipendyl, Loratadine and Pro TrimaZOsin; Reserpine derivatives Such as Bietaserpine, thipendyl; and other antihistamines Such as Antazoline, DeSerpidine, Rescinnamine, Reserpine and Syrosingopine; Astemizole, AZelastine, Cetoxime, Clemizole, Clobenz Sulfonamide derivatives Such as AmbuSide, Clopamide, tropine, Diphenazoline, , Mebhydroline, Furosemide, Indapamide, QuinethaZone, Tripamide and Xipamide; and otherS Such as Ajmaline, Y-AminobutYric Phenindamine, Terfenadine and Tritoqualine. Acid, Bufeniode, Chlorthalidone, Cicletaine, Ciclosidom 0.073 41. Antihyperlipoproteinemics, including: Ary ine, Cryptenamine Tannates, Fenoldopam, FloSequinan, loxyalkanoic acid derivatives Such as Beclorbrate, Bazafi Indoramin, Ketanserin, Metbutamate, Mecamylamine, brate, Binifibrate, Ciprofibrate, Clinofibrate, Clofibrate, Methyldopa, Methyl 4-Pyridyl Ketone Thiosemicarbarzone, Clofibric Acid, Etonfibrate, Fenofibrate, Gemfibrozil, Metolazone, Minoxidil, Muzolimine, Pargyline, Pempidine, US 2005/0181041 A1 Aug. 18, 2005

Pinacidil, Piperoxan, Primaperone, Protoveratrines, crine, Quinine, Quinine Bisulfate, Quinine Carbonate, Raubasine, Rescimetol, Rilmenidene, Saralasin, Sodium Quinine Dihydrobromide, Quinine Dihydrochloride, Qui Nitroprusside, Ticrynafen, Trimethaphan Camsylate, Tyro nine Ethylcarbonate, Quinine Formate, Quinine Gluconate, Sinase and Urapidil. Quinine Hydriodide, Quinine Hydrochloride, Quinine Sali 0.076 44. Antihyperthyroids such as 2-Amino-4-meth cylate, Quinine Sulfate, Quinine Tannate, Quinine Urea ylthiazole, 2-Aminothiazole, Carbimazole, 3,5-Dibromo-L- Hydrochloride, Quinocide, Quinoline and Sodium Arsenate tyrosine, 3,5-Diiodotyrosine, Hinderin, Iodine, Iothiouracil, Diabasic. Methimazole, Methylthiouracil, propylthiouracil, Sodium 0081) 49. Antimigraine drugs such as Alpiropride, Dihy Perchlorate, Thibenzazoline, and 2-Thiouracil. droergotamine, Ergocomine, Ergocominine, Ergocryptine, 0.077 45. Antihypotensive drugs such as Amezinium Ergot, Ergotamine, FlumedroXone acetate, Fonazine, Methyl Sulfate, Angiotensin Amide, Dimetofrine, Dopam Lisuride, Methysergid(e), Oxetorone, Pizotyline and ine, Etifelmin, Etilefrin, Gepefrine, Metaraminol, Mido Sumatriptan. drine, Norepinephrine, Pholedrinead and Synephrine. 0082 50. Antinauseant drugs such as Acetylleucine 0078 46. Antihypothyroid drugs such as Levothyroxine Monoethanolamine, Alizapride, BenZquinamide, Bietanau Sodium, Liothyronine, Thyroid, Thyroidin, Thyroxine, tine, Bromopride, Buclizine, , Clebopride, Tiratricol and TSH. Cyclizine, , Dipheniodol, , 0079 47. Anti-Inflammatory (non-steroidal) drugs, Granisetron, Meclizine, Methalltal, , including: Aminoarylcarboxylic acid derivatives Such as Metopimazine, Nabilone, Ondansteron, Oxypendyl, Pipam Enfenamic Acid, Etofenamate, Flufenamic Acid, ISOnixin, azine, Piprinhydrinate, Prochlorperazine, Scopolamine, Tet , Mefanamic Acid, , Talni rahydrocannabinols, Thiethylperazine, ThioproperZaine and flumate, Terofenamate and Tolfenamic Acid, Arylacetic acid Trimethobenzamide. derivatives Such as Acemetacin, Alclofenac, Amfenac, BufeXamac, Cinmetacin, Clopirac, Diclofenac Sodium, 0083) 51. Antineoplastic drugs, including: Alkylating Etodolac, Felbinac, Fenclofenac, Fenclorac, Fenclozic Acid, agents, including: Alkyl Sulfonates Such as BuSulfan, Impro Fentiazac, Glucametacin, Ibufenac, Indomethacin, Isof Sulfan and PipOSulfan, AZiridines Such as BenZOdepa, Car eZolac, ISOXepac, Lonazolac, Metiazinic Acid, Oxametacine, boguone, Meturedepa and Uredepa; Ethylenimines and Proglumetacin, Sulindac, Tiaramide, Tolimetin and Zomepi methylmelamines Such as Altretamine, Triethylen rac, Arylbutyric acid derivatives Such as Bumadizon, Buti emelamine, Triethylenephosphoramide, Triethylenethio bufen, Fenbufen and Xenbucin; Arylcarboxylic acids such phosphoramide and Trimethylolomelamine, mus as Clidanac, Ketorolac and Tinoridine, Arylpropionic acid tards Such S Chlorambucil, Chlomaphazine, derivatives Such as Alminoprofen, Benoxaprofen, Bucloxic Chclophosphamide, , Ifosfamide, Mechlore Acid, Carprofen, Fenoprofen, Flunoxaprofen, Flurbiprofen, thamine, Mechlorethamine Oxide Hydrochloride, Mel Ibuprofen, Ibuproxam, Indoprofen, Ketoprofen, Loxopro phalan, Novembichin, Phenesterine, Prednimustine, Trofos fen, Miroprofen, Naproxen, Oxaprozin, Piketoprofen, Pir famide and Uracil Mustard; Nitrosoureas Such as profen, Pranoprofen, Protizinic Acid, Suprofen and Tiapro Carmustine, Chlorozotocin, Foremustine, Lomustine, fenic Acid, Pyrazoles Such as Difenamizole and Epirizole; Nimustine and Ranimustine, and otherS Such as Dacarba Pyrazolones Such as Apazone, BenZpiperylon, Feprazone, zine, Mannomustine, Mitobronitol, Mitolactol and Pipobro Mofebutazone, Morazone, Oxyphenbutazone, Phenylbuta man; Antibiotics Such as Aclacinomycins, Actinomycin Fl, Zone, PipebuZone, PropyphenaZone, RamifenaZone, Suxi , AZaSerine, Bleomycins, Cactinomycin, Caru buzone and Thiazolinobutazone; Salicylic acid derivatives bicin, Carzinophilin, Chromomycins, Dactinomycin, Such as AcetaminoSalol, Aspirin, Benorylate, Bromosalige Daunorubicin, 6-Diazo-5-oxo-L-norleucine, Doxorubicin, nin, Calcium Acetylsalicylate, Diflunisal, EterSalate, Fen Epirubicin, Mitomycins, Mycophenolic Acid, Nogalamycin, dosal, Gentisic Acid, Glycol Salicylate, Imidazole Salicy Olivomycins, Peplomycin, Plicamycin, Porfiromycin, Puro late, Lysine Acetylsalicylate, MeSalamine, Morpholine mycin, Streptonigrin, Streptozocin, Tubercidin, Ubenimex, Salicylate, I -Naphthyl Salicylate, Olsalazine, Parsalmide, Zinostatin and Zorubicin; Antimetabolites, including: Folic Phenyl Acetylsalicylate, Phenyl Salicylate, Salacetamide, acid analogs Such as Denopterin, Methotrexate, Pteropterin Salicylamine O-Acetic Acid, Salicylsulfuric Acid, Salsalate and Trimetrexate; Purine analogs Such as Fludarabine, and SulfaSalazine; Thiazinecarboxamides Such as Droxicam, 6-Mercaptopurine, Thiamiprine and Thioguanaine; and ISOXicam, PiroXicam and Tenoxicam, and otherS Such as Pyrimidine analogs Such as Ancitabine, AZacitidine, epsilon.-Acetamidocaproic Acid, S-Adenosylmethionine, 6-AZauridine, Carmofur, Cytarabine, Doxifluridine, Enocit abine, Floxuridine, Fluroouracil and Tegafur, Enzymes Such 3-Amino-4-hydroxybutyric Acid, Amixetrine, Bendazac, as L-ASparaginase; and otherS Such as Aceglatone, Amsa Benzydamine, Bucolome, Difenpiramide, Ditazol, Emorfa crine, BeStrabucil, Bisantrene, Carboplatin, Cisplatin, Defo Zone, GuaiaZulene, Nabumetone, NimeSulide, Orgotein, famide, Demecolcine, Diaziquone, Elfomithine, Elliptinium Oxaceprol, Paranyline, Perisoxal, Pifoxime, ProquaZone, Acetate, Etoglucid, Etoposide, Gallium Nitrate, Hydrox Proxazole and Tenidap. yurea, Interferon-C, Interferon-B, Interferon-Y, Interleukine 0080 48. Antimalarial drugs such as Acedapsone, Amo 2, Lentinan, Lonidamine, MitoguaZone, Mitoxantrone, diacquin, Arteether, Artemether, Artemisinin, ArteSunate, Mopidamol, Nitracrine, Pentostatin, Phenarnet, Pirarubicin, Bebeerine, Berberine, Chirata, Chlorguanide, Chloroquine, Podophyllinicc Acid, 2-Ethythydrazide, Procarbazine, Chlorproguanil, Cinchona, Cinchonidine, Cinchonine, PSKCR, Razoxane, Sizofiran, Spirogermanium, Taxol, Teni Cycloguanil, Gentiopicrin, Halofantrine, Hydroxychloro poside, TenuaZonic Acid, Triaziquone, 2,2,2"Trichlorotri quine, Mefloquine Hydrochloride, 3-Methylarsacetin, Pam ethylamine, Urethan, Vinblastine, Vincristine and Vin aquine, Plasmocid, Primaquine, Pyrimethamine, Quina desine; US 2005/0181041 A1 Aug. 18, 2005

008.4 52. Antineoplastic (hormonal) drugs, including: Clocapramine, Clomacran, Clothiapine, Clozapine, Androgens Such as Calusterone, DromoStanolone Propi Opipramol, Prothipendyl, Tetrabenazine, and Zotepine; and onate, , and , Antia otherS Such as Alizapride, Amisulpride, Buramate, Fluspir drenals. Such as Aminoglutethimide, Mitotane and Trilos ilene, Molindone, Penfluridol, Pimozide, Spirilene and tane, Antiandrogens Such as Flutamide and Nilutamide, and Sulpiride. Antiestrogens Such as Tamoxifen and Toremifene. 0096) 64. Antipyretics such as Acetaminophen, Acetami 0085 53. Antineoplastic adjuncts including folic acid noSalol, Acetanilide, Aconine, Aconite, Aconitine, replenisherS Such as Frolinic Acid. Alclofenac, Aluminum Bis(acetylsalicylate), Aminochlorth 0.086 54. Antiparkinsonian drugs such as Amantadine, enoxazin, Aminopyrine, Aspirin, Benorylate, BenZydamine, BenSerazide, Bietanautine, Biperiden, Bromocriptine, Berberine, p-Bromoacetanilide, BufeXamac, Bumadizon, Budipine, Carbidopa, Deprenyl, DeXetimide, Diethazine, Calcium Acetysalicylate, Chlorthenoxazin(e), Choline Sali Droxidopa, Ethopropazine, Ethylbenzhydramine, cylate, Clidanac, Dihydroxyaluminum Acetylsalicylate, Levodopa, Naxagolide, Pergolide, Piroheptine, Pridinol, Dipyrocetyl, Dipyrone, Epirizole, EterSalate, Imidazole Prodipine, Terguride, Tigloidine and Trihexyphenidyl Salicylate, Indomethacin, ISOfeZolac, p-Lactophenetide, Hydrochloride. Lysine Acetylsalicylate, Magnesium Acetylsalicylate, Meclofenamic Acid, Morazone, Morpholine Salicylate, 0.087 55. Antipheochromocytoma drugs such as Mety Naproxen, NifenaZone, 5'-Nitro-2'propoxyacetanilide, pro rosine, Phenoxybenzamine and Phentolamine. poxyacetanilide, Phenacetin, Phenicarbazide, Phenocol, 0088 56. Antipneumocystis drugs such as Effomithine, Phenopyrazone, PhenylAcetylsalicylate, Phenyl Salicylate, Pentamidine and Sulfamethoxazole. PipebuZone, Propacetamol, PropyphenaZone, Ramifena Zone, Salacetamide, Salicylamide 0-Acetic Acid, Sodium 0089. 57. Antiprostatic hypertrophy drugs such as Gesto Salicylate, Sulfamipyrine, Tetrandrine and Tinoridine. norone Caproate, Mepartricin, Oxendolone and Finasteride (Proscaro). 0097 65. Antirickettsial drugs such as p-Aminobenzoic Acid, Chloramphenicol, Chloramphenicol Palmitate, 0090) 58. Antiprotozoal drugs (Leshmania) such as Anti Chloramphenicol Pantothenate and Tetracycline. mony Sodium Gluconate, Ethylstibamine, HydroxyStilbami dine, N-Methylglucamine, Pentamidine, Stilbamidine and 0098 66. Antiseborrheic drugs such as Chloroxine, 3-O- Urea Stibamine. Lauroylpyridoxol Diacetate, Piroctone, Pyrithione, Resorci 0.091 59. Antiprotozoal drugs (Trichomonas) such as nol, Selenium Sulfides and Tioxolone. AcetarSone, Aminitrozole, Anisomycin, AZanidazole, Form 0099 67. Antiseptics, including: Guanidines such as initrazole, Furazolidone, Hachimycin, Lauroguadine, Alexidine, Ambazone, Chlorhexidine and Picloxydine; Mepartricin, Metronidazole, Nifuratel, Nifuroxime, Halogens and halogen compounds Such as Bismuth Iodide Nimorazole, Secnidazole, Silver Picrate, Tenonitrozole and Oxide, Bismuth Iodosubgallate, Bismuth Tribromophenate, Tinidazole. Bomyl Chloride, Calcium Iodate, Chlorinated Lime, Clof 0092) 60. Antiprotozoal drugs (Trypanosma) such as lucarban, Flurosalan, Iodic Acid, Iodine, Iodine Monochlo Benznidazole, Eflomithine, Melarsoprol, Nifurtimox, ride, Iodine Trichloride, Iodoform, Methenamine Tetraiod Oxophenarsine, Hydrochloride, Pentamidine, Propamidine, ine, Oxychlorosene, Povidone-lodine, Sodium Puromycin, Quinapyramine, Stilbamidine, Suramin Hypochlorite, Sodium Iodate, Symclosene, Thymol Iodide, Sodium, Trypan Red and Tryparasmide. , and Troclosene Potassium; Mercu rial compounds Such as Hydragaphen, Meralein Sodium, 0.093 61. Antipuritics such as Camphor, , Merbromin, Mercuric Chloride, Mercuric Chloride, Ammo Dichlorisone, Glycine, HalometaSone, 3-Hydroxycamphor, niated, Mercuric Sodium p-Phenolsulfonate, Mercuric Suc , Mesulphen, Methdilazine, Phenol, Polidocanol, cinimide, Mercuric Sulfide, Red, Mercurophen, Mercurous Risocaine, Spirit of Camphor, Thenaldine, Tolpropamine Acetate, Mercurous Chloride, Mercurous Iodide, Nitromer and Trimeprazine. sol, Potassium Tetraiodomercurate(II), Potassium Tri 0094) 62. Antipsoriatic drugs such as Acitretin, Ammo iodomercurate(II) Solution, Thimerfonate Sodium and nium Salicylate, Anthralin, 6-AZauridine, Bergapten(e), Thimerosal; Nitrofurans such as Furazolidone, 2-(Meth Chrysarobin, Etretinate and Pyrogallol. oxymethyl)-5-nitrofuran, Nidroxy Zone, Nifuroxime, Nifurz ide and Nitrofurazone; such as Acetomeroctol, 0.095 63. drugs, including: Butyrophe Bithionol, Salicylate, Carvacrol, Chloroxylenol, nones such as Benperidol, Bromperidol, Droperidol, Flu Clorophene, CreSote, Cresol(s), p-CreSol, Fenticlom, anisone, , Melperone, Moperone, Pipamperone, Hexachlorophene, 1-Napthyl Salicylate, 2-Napthyl Salicy Sniperone, Timiperone and Trifluperidol; Phenothiazines late, 2,4,6-Tribromo-m-cresol, and 3',4',5-Trichlorosalicyla Such as Acetophenazine, Butaperazine, Carphenazine, Chlo nilide, Quinolines Such as Aminoquinuride, BenZOXiquine, rproethazine, Chlorpromazine, CloSpirazine, Cyamemazine, Broxyquinoline, Chloroxine, Chlorquinaldol, Cloxyquin, Dixyrazine, Fluphenazine, Imiclopazine, Mepazine, Ethylhydrocupreine, Euprocin, Halquinol, Hydrastine, Mesoridazine, Methoxypromazine, Metofenazate, Oxaflu 8-Hydroxquinoline, 8-Hydroxquinoline Sulfate and Iodoch mazine, Perazine, Pericyazine, Perimethazine, Perphena lorhydroxyquin; and otherS Such as Aluminum Acetate Solu Zine, Piperacetazine, Pipotiazine, Prochlorperazine, Pro tion, Aluminum Subacetate Solution, Aluminum Sulfate, mazine, Sulforidazine, Thiopropazate, , 3-Amino-4-hydroxybutyric Acid, Boric Acid, Chlorhexi Trifluoperazine and Triflupromazine; Such as dine, ChloroaZOdin, m-Cresyl Acetate, Cupric Sulfate, Chlorprothixene, Clopenthixol, Flupentixol and Thiothix Dibromopropamidine, Ichthammol, Negatolg, Noxytiolin, ene; other tricyclicS Such as BenZquinamide, Carpipramine, Omidazole, B-Propiolactone, C-Terpineol. US 2005/0181041 A1 Aug. 18, 2005

0100 68. Antispasmodic drugs such as Alibendol, Ambu Lysozyme, Methisazone, Moroxydine, Podophyllotoxin, cetamide, Aminopromazine, Apoatropine, Bevonium Ribavirin, Rimantadine, Stallimycin, Statolon, Tromanta Methyl Sulfate, Bietamiverine, Butaverine, Butropium Bro dine and Xenazoic Acid. mide, N-Butylscopolammonium Bromide, Caroverine, 0106 74. drugs, including: Arylpiperaz ines Cimetropium Bromide, Cinnamedrine, Clebopride, Coniine Such as , Gepirone and Ipsapirone, BenZodiaz Hydrobromide, Coniine Hydrochloride, Cyclonium Iodide, epine derivatives Such as , Bromazepaam, Difemerine, Diisopromine, Dioxaphetyl Butyrate, Dipo , , , , nium Bromide, Drofenine, Emepronium Bromide, Ethaver Chotiazepam, , , , ine, Feclemine, Fenalamide, Fenoverine, Fenpiprane, Fen , Fluidazepam, , , piverinium Bromide, Fentonium Bromide, Flavoxate, , , , Loxapine, Flopropione, Gluconic Acid, Guaiactamine, Hydramitra , , , , Zine, Hymecromone, Leiopyrrole, Mebeverine, Moxaverine, , , , and Tofiso Nafiverine, Octamylamine, Octaverine, Pentapiperide, Phe pam; Such as , , namacide Hydrochloride, Phloroglucinol, Pinaverium Bro , , and mide, Piperilate, PipoxolanHydrochloride, Pramiverin, Pri finium Bromide, Properidine, Propivane, Propyromazine, ; and otherS Such as , BenZOctamine, Prozapine, Racefemine, Rociverine, Spasmolytol, Stilonium Captodiamine, , , Fluoresone, Iodide, Sultroponium, Tiemonium Iodide, Tiquizium Bro Glutamic Acid, Hydroxy Zine, Mecloralurea, Mephenoxa mide, Tiropramide, Trepibutone, Tricromyl, Trifolium, Tri lone, , , . mebutine, N,N-1Trimethyl-3,3-diphenyl-propylamine, Tro 0107 75. antagonists such as Flumaze penzile, Trospium Chloride and Xeny tropium Bromide. nil. 0101 69. Antithrombotic drugs such as Anagrelide, 0108) 76. Bronchodilators, including: Ephedrine deriva Argatroban, Cilostazol, Daltroban, Defibrotide, Enoxaparin, tives such as Albuterol, Bambuterol, Bitolterol, Carbuterol, Fraxiparine(R), Indobufen, Lamoparan, OZagrel, Picotamide, Clenbuterol, Clorprenaline, Dioxethedrine, Ephedrine, Plafibride, Tedelparin, Ticlopidine and Triflusal. Epiniphrine, EproZinol, Etafedrine, Ethylnorepinephrine, Fenoterol, Hexoprenaline, Isoetharine, Isoproterenol, 0102 70. Antitussive drugs such as Allocamide, Amici Mabuterol, Metaproterenol, N-Methylephedrine, Pirbuterol, bone, Benproperine, BenZonatate, Bibenzonium Bromide, Procaterol, Protokylol, Reproterol, Rimiterol, Soterenol, Bromoform, Butamirate, Butethamate, Caramiphen Terbutaline and Tulobuterol; Quaternary ammonium com Ethanedisulfonate, Carbetapentane, Chlophedianol, Clobu pounds such as Bevonium Methyl Sulfate, Clutropium Bro tinol, Cloperastine, Codeine, Codeine Methyl Bromide, mide, Ipratropium Bromide and OXitropium Bromide; Xan Codeine N-Oxide, Codeine Phosphate, Codeine Sulfate, thine derivatives Such as Acefylline, Acefylline Piperazine, Cyclexanone, Dextromethorphan, Dibunate Sodium, Dihy Ambuphylline, Aminophylline, Bamifylline, choline Theo drocodeine, Dihydrocodeinone Enol Acetate, Dimemorfan, phyllinate, Doxofylline, Dyphylline, Enprofylline, Etami Dimethoxanate, C.C.-Diphenyl-2-piperidinepropanol, Dro phyllin, Eto?ylline, Guaithylline, Proxyphylline, Theobro propizine, Drotebanol, Eprazinone, Ethyl Dibunate, Ethyl mine, 1-Theobromineacetic Acid and Theophylline; and morphine, , Guiaiapate, Hydrocodone, Isoami others such as Fenspiride, Medibazine, Methoxyphenanime nile, Levopropoxyphene, Morclofone, Narceline, and Tretoquinol. Normethadone, NoScapine, Oxeladin, Oxolamine, Pholcod 0109) 77. Calcium channel blockers, including: Arylalky ine, Picoperine, PipaZethate, , PrenoXdiazine lamines Such as Bepridil, Ditiazem, Fendiline, Gallopanil, Hydrochloride, Racemethorphan, Taziprinone Hydrochlo Prenylamine, Terodiline and Verapamil; Dihydropyridine ride, Tipepidine and Zipeprol. derivatives Such as Felodipine, Isradipine, Nicardipine, 0103) 71. Antiulcerative drugs such as Aceglutamide Nifedipine, Nilvadipine, Nimodipine, Nisoldipine and Aluminum Complex, epsilon.-Acetamidocaproic Acid Zinc Nitrendipine, Piperazine derivatives Such as Cinnarizine, Salt, Acetoxolone, Arbaprostil, BenexateHydrochloride, Flunarisine and Lidoflazine, and otherS Such as Bencyclane, Bismuth Subcitrate Sol (Dried), Carbenoxolone, Cetraxate, Etafenone and Perhexiline. Cimetidine, EnproStil, Esaprazole, Famotidine, Ftaxilide, 0.110) 78. Calcium regulators such as Calcifediol, Calci Gefarnate, GuaiaZulene, IrSogladine, Misoprostol, Nizati tonin, Calcitriol, Clodronic Acid, Dihydrotachysterol, Elca dine, Omeprazole, Ornoprostil, Y-Oryzanol, Pifarnine, tonin, Etidronic Acid, priflavone, Pamidronic Acid, Par Pirenzepine, Plaunotol, Ranitidine, RioproStil, Rosaprostol, athyroid Hormone and Teriparatide Acetate. Rotraxate, Roxatidine Acetate, Sofalicone, Spizofurone, Sucralfate, Teprenone, Trimoprostil, Thrithiozine, Troxipide 0111 79. Cardiotonics such as Acefylline, Acetyldigiti and Zolimidine. toxins, 2-Amino-4-picoline, Amrinone, Benfurodil Hemisuccinate, Buclasdesine, Cerberoside, Camphotamide, 0104 72. Antiurolithic drugs such as Acetohydroxamic Convallatoxin, Cymarin, Denopamine, Deslanoside, Ditalin, Acid, Allopurinol, Potassium Citrate and Succinimide. Digitalis, , , Digoxin, Dobutamine, Dopamine, 0105. 73. Antiviral drugs, including: Purines and pyrimi Dopexamine, EnoXimone, Erythrophleine, Fenalcomine, dinones Such as Acyclovir, Cytarabine, Dideoxyadenosine, Gitalin, Gitoxin, Glycocyamine, Heptaminol, Hydrastinine, Dideoxycytidine, Dideoxyinosine, Edoxudine, FloXuridine, Ibopamine, Lanotodises, Metamivam, Milrinone, Neriifolin, Ganciclovir, Idoxuridine, Inosine Pranobex, MADU, Triflu Oleandrin, Ouabain, Oxyfedrine, Prenalterol, Proscillaridin, ridine, Vidrarbine and Zidovudine; and others such as ReSibufogenin, Scillaren, Scillarenin, Strophanthin, Sulma Acetylleucine Monoethanolamine, Amantadine, Amidino Zole, Theobromine and Xamoterol. mycin, Cuminaldehyde ThiosemicarbZone, FoScarnet 0112 80. Chelating agents such as Deferozmine, Ditio Sodium, Interferon-C, Interferon-B, Interferon-Y, Kethoxal, carb Sodium, Edetate Calcium Disodium, Edetate Diso US 2005/0181041 A1 Aug. 18, 2005

dium, Edeate Sodium, Edetate Trisodium, Penicillamine, and Theobromine; Such as Canrenone, Oleandrin Pentetate Calcium Trisodium, Pentectic Acid, Succimer and and , Sulfonamide derivatives Such as Aceta Trientine. Zolmide, AmbuSide, AZOSemide, Bumetanide, Butazola mide, Chloraminophenamide, Clofenamide, Clopamide, 0113 81. Cholecystokinin antagonists such as Proglu Clorexolene, Diphenylmethane-4,4'-disulfonamide, Disulfa mide. mide, EthoXZolamide, Furosemide, Indapamide, Mefruside, 0114 82. Cholelitholytic agents such as Chenodiol, Methazolamide, Piretanide, Quinethazone, Torasemide, Tri Methyl tert-Butyl Ether, Monooctanoin and Ursodiol pamide and Xipamide, Uracils. Such as Aminometradine and 0115 83. Choleretics such as Alibendol, Amisometradine; otherS Such as Amanozine, Amiloride, Trithion, AZintamide, Cholic Acid, Cicrotoic Acid, Clanobu Arbutin, Chlorazanil, Ethacrynic Acid, EtoZolin, Hydracar tin, Cyclobutyrol, Cyclovalone, Cynarin(e), Dehydrocholic bazine, Isosorbide, Mannitol, Metochalcone, Muzolimine, Acid, Deoxycholic Acid, Dimecrotic Acid, O.-Ethylbenzyl Perhexiline, Ticrynafen and Urea. Alcohol, Exiproben, Feguprol, Fencibutirol, Fenipentol, 0.124 92. Dopamine receptor agonists such as Bro Florantyrone, Hymecromone, Menbutone, 3-(o-Methox mocriptine, Dopexamine, Fenoldopam, Ibopamine, yphenyl)-2-phenylacrylic Acid, Metochalcone, Moquizone, Lisuride, Naxagolide and Pergolide. Osalmid, Ox Bile Extract, 4.4'-Oxydi-2-butanol, Piprozolin, 0.125 93. Ectoparasiticides such as Amitraz, Benzyl Ben Prozapine, 4-Salicyloylmorpholine, Sincalide, Taurocholic Zoate, Carbaryl, Crotamiton, DDT, Dixanthogen, isobomyl Acid, Timonacic, Tocamphyl, Trepibutone and Vanitiolide. Thiocyanoacetate-Technical, Lime Sulfurated Solution, LIn 0116 84. Cholinergic agents such as Aceclidine, Acetyl dane, Malathion, Mercuric Oleate, Mesulphen and Sul choline Bromide, Acetylcholide Chloride, Aclatonium phur-Pharmaceutical, and Mucolytic enzymes Such as Napadisilate, BenZpyrinium Bromide, Bethanechol chlo Lysozyme. ride, Carbachol, Carpronium chloride, Demecarium Bro mide, Dexpanthenol, Diisopropyl Paraoxon, Echothiophate 0126 94. Enzyme inducers (hepatic) such as Flumecinol. Iodide, Edrophomium chloride, Eseridine, Furtrethonium, 0127 95. , including: Nonsteroidal estrogens Isoflurophate, Methacholine chloride, Muscarine, Neostig Such as , Broparoestrol, , Dienes mine, Oxapropanium Iodide, PhySoStigmine and PyridoStig trol, , Diethylstilbestrol Diproprionate, mine Bromide. , , , and Meth estrol; and Steroidal estrogens Such as Colpormon, Conju 0117 85. Cholinesterase inhibitors such as Ambenonium gated Estrogenic Hormones, , , , Chloride, Distigmine Bromide and Galanthamine. , Estradiol 17(3-Cypionate, , 0118 86. Cholinesterase reactivators such as Obidox , Ethinyl Estradiol, , , imine Chloride and Pralidoxime Chloride. Mytatrienediol, Quinestradiol and . 0119 87. Central nervous system stimulants and agents 0128 96. Gastric secretion inhibitors such as Enterogas Such as Amineptine, Amphetimine, Amphetaminil, Beme trone and Octreotide. gride, BenZphetamine, Brucine, Caffeine, Chlorphenter mine, Clofenciclan, Clortermine, Coca, Demanyl Phos 0.129 97. Glucocorticoids such as 21-Acetox phate, Dexoxadrol, Dextroamphetamine Sulfate, yprefnenolone, Aalclometasone, AlgeStone, Amicinonide, Diethlpropion, N-Ethytlamphetamine, Ethamivan, Etife Beclomethasone, Betamethasone, BudeSonide, Chloropred lmin, Etryptamine, Fencamfamine, Fenethylline, FenoSo nisone, ClobetaSol, Blovetasone, Clocortolone, Cloprednol, lone, Flurothyl, Hexacyclonate Sodium, Homocamfin, Corticosterone, Cortisone, CortivaZol, Deflazacort, DeS Mazindol, Megexamide, , Methylpheni onide, DeSoximetasone, Dexamethasone, Diflorasone, Diflucortolone, Difluprednate, Enoxolone, Fluazacort, Flu date, Nikethamide, Pemoline, Pentylenetetrazole, Pheni cloronide, Flumehtasone, Flunisolide, Fluocinolone dimetrazine, Phenmetrazine, Phenternine, Picrotoxin, Acetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone, Pipradrol, Prolintane and Pyrovalerone. Fluorometholone, Fluperolone Acetate, Fluprednidene 0120) 88. Decongestants such as Amidephrine, Cafami Acetate, Fluprednisolone, Flurandrenolide, Formocortal, nol, Cyclopentamine, Ephedrine, Epinephrine, Fenoxazo Halcinonide, Halometasone, Halopredone Acetate, Hydro line, Indanazoline, Metizoline, Naphazoline, Nordefrin cortamate, Hydrocortisone, Hydrocortisone Acetate, yaro Hydrochloride, Octodrine, Oxymetazoline, Phenylephrine cortisone Phosphate, Hydrocortisone 21-Sodium Succinate, Hydrochloride, Phenylpropanolamine Hydrochloride, Phe Hydrocortisone Tebutate, Mazipredone, Medrysone, Mepre nylpropylmethylamine, Propylhexedrine, Pseudoephedrine, dnisone, Methyolprednisolone, Mometasone Furoate, Tetrahydrozoline, Tymazoline and Xylometazoline. Paramethasone, Prednicarbate, Prednisolone, Prednisolone 21-Diethylaminoacetate, Prednisone Sodium Phosphate, 0121 89. Dental carries prophylactics such as Sodium Prednisolone Sodium Succinate, Prednisolone Sodium Fluoride. 21-m-Sulfobenzoate, Prednisolone 21-Stearoylglycolate, 0.122 90. Depigmentors such as Hydroquinine, Hydro Prednisolone Tebutate, Prednisolone 21-Trimethylacetate, quinone and Monobenzone. Prednisone, Prednival, Prednylidene, Prednylidene 21-Di 0123 92. Diuretics, including: Organomercurials such as ethylaminoacetate, Tixocortal, Triamcinolone, Triamcino Chlormerodrin, Meralluride, Mercamphamide, Mercaptom lone Acetonide, Triamcinolone Benetonide and Triamcino erin Sodium, Mercumallylic Acid, Mercumatilin Sodium, lone Hexacetonide. Mercurous Chloride and Mersalyl; Pteridines such as Fur 0.130 98. Gonad-Stimulating principles such as Buser terene and Triamterene; Purines such as Acefylline, 7-Mor elin, Clomiphene, , , FSH, HCG and pholinomethyltheophylline, Pamabrom, Protheobromine LH-RH. US 2005/0181041 A1 Aug. 18, 2005

0131 99. Gonadotropic hormones such as LH and Gallamine Triethiodide, Hexacarbacholine Bromide, PMSG. Hexafluorenium Bromide, Idrocilamide, Lauexium Methyl Sulfate, Leptodactyline, Memantine, Mephenes in, Mephe 0132) 100. Growth hormone inhibitors such as Octreotide noxalone, , , Metocurine Iodide, and Somatostatin. Nimetazepam, Orphenadrine, Pancuronium Bromide, Phen 0.133 101. Growth hormone releasing factors such as probamate, Phenyramidol, Pipecurium Bromide, Promox Semorelin. olane, Quinine Sulfate, , Succinylcholine Bro mide, Succinylcholine Chloride, Succinylcholine Iodine, 0134) 102. Growth stimulants such as Somatotropin. Suxethonium Bromide, , Thiocolchicoside, Tiza 0135 103. Hemolytic agents such as Phenylhydrazine nidine, Tolperisone, Tubocurarine Chloride, Vecuronium and Phenylhydrazine Hydrochloride. Bromide and Zoxolamine. 0.136) 104. Heparin antagonists such as Hexadimethrine 0150 118: Narcotic antagonists such as Amiphenazole, Bromide and Protamines. Cyclazocine, Levallorphan, Nadide, Nalmfene, Nalorphine, 0.137 105. Hepatoprotectants such as S-Adenosylme Nalorphine Dinicotinate, Naloxone and Naltrexone. thionine, Betaine, Catechin, Citolone, Malotilate, Oraza 0151 119. Neuroprotective agents such as Dizocilpine. mide, Phosphorylcholine, Protoporphyrin IX, Silymarin Group, Thiotic Acid and Tiopronin. 0152 120. Nootropic agents such as Aceglutamide, Ace tylcarnitine, Aniracetam, Bifematlane, Exifone, Fipexide, 0138 106. Immunomodulators such as Amiprilose, Buci Idebenone, Indeloxazune Hydrochloride, Nizofenone, llamine, Ditiocarb Sodium, Inosine Pranobex, Interferon-y, Oxiracetam, Piracetam, Propentofylline, Pyritinol and Interleukin-2, Lentinan, Muroctasin, Platonin, Procodazole, Tetramisole, Thymomodulin, Thymopentin and Ubenimex. Tacrine. 0139 107. Immunosuppressants such as Azathioprine, 0153. 121. Ophthalmic agents such as 15-ketoprostaglan Cyclosporins and Mizoribine. dins. 0140 108. Ion exchange resins such as Carbacrylic Res 0154) 122. Ovarian hormone such as relaxin. ins, Cholestyramine Resin, Colestipol, Polidexide, Resodec O155 123. Oxytocic drugs such as Carboprost, Carguto and Sodium Polystyrene Sulfonate. cin, Deaminooxytocin, Ergonovine, Gemeprost, Methyler 0141 109. Lactation stimulating hormone such as Pro gonovine, Oxytocin, Pituitary (Posterior), E2, lactin. Prostaglandin F2C. and Sparteine. 0142) 110. LH-RH agonists such as Buserelin, , 0156 124. Pepsin inhibitors such as Sodium Amylosul Leuprolide, Nafarelin, and Triptorelin. fate. 0143) 111. Lipotropic agents such as N-Acetylmethion O157 125. Peristaltic stimulants such as Cisapride. ine, Choline Chloride, Choline Dehydrocholate, Choline 0158 126. such as Allylestrenol, Anage Dihydrogen Citrate, Inositol, Lecithin and Methionine. Stone, , Delmadinone Acetate, 0144) 112. Lupus erythematosus Suppressants Such as Demegestone, DeSogeStrel, Dimethisterone, Dydrogester Bismuth Sodium Triglycollamate, Bismuth Subsalicylate, one, Ethisterone, Ethynodiol, Flurogestone Acetate, Chloroquine and Hydroxychloroquine. Gestodene, , Haloprogesterone, 17-Hydroxy-16-methylene-progesterone, 17C.-Hydrox 0.145) 113. Mineralcorticoids such as , yprogesterone, 17C.-Hydroxygesterone Caproate, LyneStre Deoxycorticosterone, Deoxycorticosterone Acetate and nol, Medrogestone, Medroxyprogesterone, Megestrol Fludrocortisone. Acetate, Melengestrol, Norethindrone, Norethynodrel, 0146 114. Miotic drugs such as Carbachol, Physostig Norgesterone, Norgestimate, Norgestrel, Norgestrienone, mine, Pilocarpine and Pilocarpus. Norvinisterone, Pentagestrone, Progesterone, Promege Stone, Quingestrone and Trengestone. 0147 115: Monoamine oxidase inhibitors such as Depre nyl, Iproclozide, Iproniazid, ISOcarboxazid, Moclobemide, 0159) 127. inhibitors such as Metergoline. Octomoxin, Pargyline, PhenelZine, Phenoxypropazine, Pivalylbenzhydrazine, Prodipine, Toloxatone and Tranyl 0160 128. and prostaglandin analogs cypromine. Such as Arbaprostil, Carboprost, Enprostil, Bemeprost, Limaprost, Misoprostol, Omoprostil, ProStacyclin, ProStag 0148 116. Mucolytic agents such as Acetylcysteine, Bro landin E1, Prostaglandin E2, Prostagland in F2C, Rioprostil, mheXine, Carbocysteine, Domiodol, Letosteine, Lysozyme, Rosaprostol, Sulprostone and Trimoprostil. Mecysteine Hydrochloride, Mesna, Sobrerol, Stepronin, Tiopronin and Tyloxapol. 0.161 129. Protease inhibitors such as Aprotinin, Camo Stat, GabeXate and NafamoStat. 0149) 117. Muscle relaxants (skeletal) such as Afloqua lone, Alcuronium, Atracurium BeSylate, , BenZOc 0162) 130. Respiratory stimulants such as Almitrine, tamine, Benzoquinonium Chloride, C-Calebassine, Cariso Bemegride, Carbon Dioxide, Cropropamide, Crotethamide, prodol, ChlormeZanone, Chlorphenesin , Dimefline, Dimorpholamine, Doxapram, Ethamivan, Fomi Chlorproethazine, ChloZOXaZ one, Curare, Cyclarbamate, noben, Lobeline, Mepixanox, Metamivam, Nikethamide, Cyclobenzaprine, Dantrolene, Decamethonium Bromide, Picrotoxin, Pimeclone, Pyridofylline, Sodium Succinate and Diazepam, Eperisone, Fazadinium Bromide, Flumetramide, Tacrine. US 2005/0181041 A1 Aug. 18, 2005

0163 131. Sclerosing agents such as Ethanolamine, cizine, Chromonar, Clobenfurol, Clonitrate, DilaZep, Dipy Ethylamine, 2-Hexyldecanoic Acid, Polidocanol, Quinine ridamole, Droprenilamine, Efloxate, Erythritol, Erythrityl Bisulfate, Quinine Urea Hydrochloride, Sodium Ricino Tetranitrate, Etafenone, Fendiline, Floredil, Ganglefene, leate, Sodium Tetradecyl Sulfate and Tribenoside. Hexestrol Bis(B-diethylaminoethyl ether), Hexobendine, 0164. 132. and , including: Acyclic Itramin Tosylate, Khellin, Lidoflazine, Mannitol Hexani ureides Such as , Apronalide, BomisoValum, trate, Medibazine, Nicorandil, Nitroglycerin, Pentaerythritol Capuride, and Ectylurea; Alcohols Such as Chlo Tetranitrate, Pentrinitrol, Perhexiline, Pimefylline, Preny rhexadol, , Meparfynol, 4-Methyl-5-thiaz lamine, Propatyl Nitrate, Pyridofylline, Trapidil, Tricromyl, oleethanol, tert-Pentyl Alcohol and 2,2,2-Trichloroethanol; Trimetazidine, Trolnitrate Phosphate and Visnadine. Amides Such as Butoctamide, Diethylbromoacetamide, 0170 138. Vasodilators (peripheral) such as Aluminum Ibrotamide, Isovaleryl Diethylamide, , Triceta Nicotinate, Bamethan, Bencyclane, Betahistine, Bradykinin, mide, , and ; Barbituric acid Brovincamine, Bufoniode, Buflomedil, Butalamine, derivatives such as , , , Cetiedil, Ciclonicate, Cinepazide, Cinnarizine, Cyclande , Brallabarbital, Sodium, , late, Diisopropylamine Dichloracetate, Eledoisin, Fenoxidil, , Butethal, , , Cyclopen Flunarisine, Heronicate, Ifenprodil, InoSitol Niacinate, ISOX tobarbital, Enallylpropymal, 5-Ethyl-5-(1-piperidyl) barbi Suprine, Kallidin, Kallikrein, , Nafronyl, Nica turic Acid, 5-Furfuryl-5-isopropylbarbituric Acid, Heptabar metate, Nicergoline, Nicofuranose, Nicotinyl Alcohol, bital, Sodium, Hexobarbital, Mephobarbital, Nylidrin, Pentifylline, Pentoxifylline, Piribedil, Protaglan , Narcobarbital, , din E, Suloctidil and Xanthinal Niacinate. Sodium, Phenallymal, Phenobarbital, Phenobarbital Sodium, Phenylmethylbarbituric Acid, , Propal 0171 139. Vasoprotectants such as Benzarone, Biofla lylonal, ProXibarbal, , Sodium, Talb vonoids, Chromocarb, Clobeoside, Diosmin, Dobesilate utal, , Sodium and ; Ben Calcium, Escin, Rolescutol, Leucocyanidin, Metescufylline, Zodiazepine derivatives Such as , , , Rutin and Troxerutin. , , , , 0172 140. Vitamins, vitamin sources, and vitamin , , Nitrazepam, , extracts Such as Vitamins A, B, C, D, E, and K and Temasepam and ; Such as Ammonium derivatives thereof, Calciferols, Glycyrrhiza and Mecobal Bromide, Calcium Bromide, Calcium Bromolactobionate, amin. , Magnesium Bromide, Potassium Bro mide and ; Carbamates such as Amyl 0173 141. Vulnerary agents such as Acetylcysteine, Carbamate-Tertiary, , Hexaprpymate, Allantoin, Asiaticoside, CadeXomer Iodine, Chitin, Dextra Meparfynol Carbamate, Novonal and Tricholorourethan; nomer and Oxaceprol. Chloral derivatives Such as Carbocloral, , Chloral Formamide, , Chloralantipyrine, 0.174. The initial crystallization phase of the process , Pentaerythritol Chloral and ; requires use of a Solvent and anti-Solvent, wherein the Piperidinediones such as Glutehimide, , Pip Solvent and anti-Solvent System consists of one or more eridione, , Taglutimide and Thalidomide; pharmaceutically acceptable Solvents (here defined as Class Quinazolone derivatives Such as , 3 Solvents as designated in the European Pharmacopea, and ; and otherS Such as Acetal, Acetophe 2002, 4th edition or appear as monographs in European none, Aldol, Ammonium Valerate, Amphenidone, d-Bomyl Pharmacopea or in the United States Pharmacopea). C-Bromoisovalerate, d-Bomyl Isovalerate, Bromoform, 0.175 Examples of solvents and anti-solvents include Calcium 2-Ethylbutanoate, Carfinate, C.-Chlorolose, Clom aprotic solvents (DMSO, N-methylpyrrollidone, and ethers), ethiazole, Cypripedium, Doxylamine, , Etomi alcohols (ethanol, , benzyl alcohol and isopro date, , Homofenazine, Hydrobromic Acid, panol), hydrocarbons (hexane, cyclo-hexane and heptane), Mecloxamine, Menthyl Valerate, Opium, , Per and other protic Solvents (water and acetic acid). Examples lapine, , , , Sul of Solvent (e.g., common Solvents and anti-Solvents) for use fonethylmethane and . in the inventive compositions and methods of the invention 0165) 133. Thrombolytic agents such as APSAC, Plas include, but are not limited to, transesterfied vegetable oils, min, Pro-Urokinase, Streptokinase, Tissue Plasminogen 1-pentanol, 1-propanol, 1-butanol, 2-butanol, 2-methyl-1- Activator and Urokinase. propanol, 2-piperidone, 2-pyrrolidone, 3-methyl-1-butanol, , acetyl tributyl citrate, acetyl triethylcitrate, acety 0166 134. Thyrotropic hormones such as TRH and TSH. lated glycerol esters, acetylated monoglycerides 0167 135. Uricosurics such as Benzbromarone, Ethe and Sterols, benzyl alcohol, butanediol and isomers thereof, benecid, Orotic Acid, Oxycinchophen, Probenecid, Sulfin butanol, butyl acetate, Co fatty acids, Cs and Co mono and pyrazone, Ticrynafen and Zoxazolamine. diglycerides and mixtures thereof, Cs and Co triglycerides, cumene, dimethyl isosorbide, dimethyl Sulphoxide, ethanol, 0168 136. Vasodilators (cerebral) such as Bencyclane, ethyl acetate, ethyl butyrate, ethyl caprylate, ethyl ether, Cinnarizine, Citicoline, Cyclandelate, Ciclonicate, Diiso ethyl formate, ethyl oleate, ethyl propionate, fatty acids, propylamine Dichloractetate, Ebumrinamonine, Fenoxedil, glycerol, glycerol fatty acid esters, glyceryl dicaprate, glyc Flunarizine, Ibudilast, Ifenprodil, Nafronyl, Nicametate, eryl dicaprylate, glyceryl dilaurate, glyceryl dioleate, glyc Nicergoline, Nimodipine, , Pentifylline, eryl monocaprate, glyceryl monocaprylate, glyceryl mono Tinofedrine, Vincamine, Vinpocetine and Vicquidil. laurate, glyceryl monooleate, glycofurol, heptane, 0169 137. Vasodilators (coronary) such as Amotriphene, hydrogenated vegetable oils, isobutyl acetate, isopropanol, Bendazol, Benfurodil Hemisuccinate, BenZiodarone, Chloa isopropyl acetate, lactic acid conjugates of mono- and dig US 2005/0181041 A1 Aug. 18, 2005

lycerides, lauric acid, lower alcohol fatty acid esters, meth Preferably, the isolated mixed phase co-crystals are dried oxy PEG, methyl acetate, methylethylketone, methylisobu under vacuum at ambient or elevated temperature. The dried tylketone, N-hydroxyalkylpyrrolidone, powder is then deaggregated using a milling or Sieving N-methylpyrrolidone, oleic acid, PEG 2-4 oleate, PEG 3-16 proceSS. castor oil, PEG 5-10 hydrogenated castor oil, PEG 6-20 0182 The additive(s) for use in the inventive methods almond oil, PEG 6-20 corn oil, PEG-20 almond oil, PEG-20 and compositions include any Suitable additives. corn oil, PEG-4 dilaurate, PEG-4 dioleate, PEG-4 distearate, PEG-6 corn oil, PEG-6 dioleate, PEG-6 distearate, PEG-6 0183) Additives, such as crystal lattice modifiers, can be olive oil, PEG-6 palm kernel oil, PEG-6 peanut oil, PEG-8 added to the first solution. These modifiers must be accept dioleate, pentaerythritol, pentane, polyethylene glycol, poly able for pharmaceutical or the intended use and usually are ethylene glycol 200-600, polyethylene glycol glycerol fatty Solids at room temperature. Examples of crystal lattice acid esters, polyglyceryl fatty acid esters, polyglyceryl-3 modifiers include, but are not limited to, fatty acids, fatty oleate, polyglyceryl-6 dioleate, polyoxyethylene glycerides, alcohols, PEG esters, PEG ethers, cellulose derivatives, polyoxyethylene Sorbitan fatty acid esters, polyoxyethylene pectins, glycerides, fatty esters, waxes, ethers, polyols, vegetable oils, polyoxyethylene-polyoxypropylene block cyclodextrins (alpha, beta and gamma), hydroxpropyl-beta copolymers, polypropylene glycol, polypropylene glycol cyclodextrin, Sorbitan esters, propylene glycol esters, acety fatty acid esters, propyl acetate, propylene glycol, propylene lated proteins, Stearols, polyesters, polyvinylpyrrolidones, glycol diacetate, propylene glycol esters of C8, propylene polyethylene glycols, triglycerides, cellulose acetates and glycol esters of unsaturated fatty acids, propylene glycol Sugar esters. Preferably, the crystal lattice modifier is laurate, propylene glycol oleate, Sorbitan fatty acid esters, Selected from the group consisting of acetylated glycerol Sorbitan monolaurate, Sorbitan monooleate, t-butylmethyl fatty acid esters, acetylated monoglycerides, acetylated ether, tetrahydofuran, transcutol, triacetin, tributylcitrate, monoglycerides of C to Co fatty acids, alkylgluceosides, triethylcitrate, vegetable oils, water, and acetic acid. alkylmaltosides, bile Salts, , corn oil, diglycerides of C to Co fatty acids, ethyl linoleate, ethyl oleate, fatty 0176) The solvent system selected is able to dissolve the acid Salts, Saturated fatty acids, unsaturated fatty acids, fatty active agent and additives at Sufficient concentration at alcohols, fractionated cocoanut oil, glycerol fatty acid esters, ambient or elevated temperatures to enable efficient proceSS glyceryl dicaprate, glyceryl dicaprylate, glyceryl dilaurate, ing. The anti-Solvent System consists of one or more Sol glyceryl dioleate, glyceryl monocaprate, glyceryl monoca vents, preferably water along with modifierS Such as coSol prylate, glyceryl monolaurate, glyceryl monooleate, isopro vents, suspending agents, and/or pH modifiers. Other pyllinoleate, isopropyl myristate, isopropyl palmitate, lactic examples of anti-Solvents include alcohols, ethers, acids and acid conjugates of diglycerides, lactic acid conjugates of hydrocarbons. It is preferable that the solvent and anti mono- and diglycerides, lactic acid conjugates of monoglyc solvent system is miscible to allow mixing of the two. The erides, lauric acid, lauryl macrogolglycenides, lower alcohol Solvent System must have adequate affinity for the Solutes So fatty acids esters, monoglycerides of a C to Co fatty acids, that a uniform Suspension forms. myristic acid, oleic acid, palmitic acid, PEG 10-100 lionyl phenol series, PEG 1-4 stearate, PEG 15-100 octyl phenol 0177. The initial crystallization phase of the process series, PEG 20 dilaurate, PEG 20 glyceryl Stearate, PEG 2-4 involves the mixing of the Solvent containing the active oleate, PEG 2-5 oleyl ether, PEG 3-16 castor oil, PEG 5-10 agent and additive(s) with the anti-Solvent. It is of impor hydrogenated castor oil, PEG 5-20 soya sterol, PEG 6-20 tance to Select a System that enables formation of a uniform almond oil, PEG 6-20 corn oil, PEG-10 laurate, PEG-100 Suspension to allow the formation of uniform mixed phase Stearate, PEG-12 laurate, PEG-12 oleate, PEG-15 Stearate, co-crystals. PEG-2 cetyl ether, PEG-2 stearyl ether, PEG-20 almond oil, 0.178 The anti-solvent may be mixed with the first solu PEG-20 corn oil, PEG-20 dioleate, PEG-20 glyceryl laurate, tion containing the active agent and additives by any Suitable PEG-20 glycidyl oleate, PEG-20 laurate, PEG-20 oleate, method. The anti-solvent may be added to the first solution PEG-20 trioleate, PEG-200 oleate, PEG-24 cholesterol, to form a Second Solution. Alternatively, the first Solution PEG-25 glyceryl trioleate, PEG-25 phyto sterol, PEG-30 may be added to the anti-Solvent to form a Second Solution. cholesterol, PEG-30 glyceryl laurate, PEG-30 glyceryl ole The mixing of the Second Solution may optionally involve ate, PEG-30 soya sterol, PEG-32 dilaurate, PEG-32 dioleate, Stirring including, for example, through using a magnetic PEG-32 distearate, PEG-32 laurate, PEG-32 oleate, PEG-35 Stirrer or other mechanical Stirrer. castor oil, PEG-4 capric/caprylic triglyceride, mono, di, tri, tetra esters of vegetable oil and Sorbitol, PEG-4 dilaurate, 0179 The solvent is important for the successful incor PEG-4 dioleate, PEG-4 distearate, PEG-40 castor oil, PEG poration of the Solutes and formation of the transient meta 40 glyceryl laurate, PEG-40 hydrogenated castor oil, PEG Stable fraction. The Solvent is also important in determining 40 palm kernel oil, PEG-40 stearate, PEG-400 oleate, PEG the loading concentrations achieved for the active agent and 50 hydrogenated castor oil, PEG-6 caprate/caprylate additives. glycerides, PEG-6 corn oil, PEG-6 dioleate, PEG-6 distear 0180. The anti-solvent is important to allow successful ate, PEG-6 hydrogenated palm kernel oil, PEG-6 olive oil, initial crystallization of the active agent and additive(s) and PEG-6 palm kernel oil, PEG-6 peanut oil, PEG-6 sorbitan in determining the physical properties of the resulting mixed tetra, hexastearate, PEG-6 Sorbitan tetraoleate, PEG-60 cas tor oil, PEG-60 corn oil, PEG-60 hydrogenated castor oil, phase co-crystalline Suspension and powder. PEG-8 caprate/caprylate glycerides, PEG-8 caprate/capry 0181. The mixed phase co-crystals can be isolated by late glycerides, PEG-8 dioleate, PEG-80 sorbitan laurate, conventional filtration methods, centrifugation or Sedimen pentaerythritol di, tetra Stearate, isoStearate, oleate, capry tation. Removal of bulk Solvent and anti-Solvent compo latc, or caprate, phospholipids, polyoxym nents can be performed by Washing the isolated Solid. ethylene alkylethers, , Pluronic F68, Pluronics, US 2005/0181041 A1 Aug. 18, 2005 poloxamers, polyethylene glycol fatty acids esters, polyeth 0186 Modifiers, such as stabilizers, generally are incor ylene glycol glycerol fatty acid esters, polyglyceryl 2-4 porated into the mixed phase co-crystal at relatively low oleate, Stearate, or isoStearate, polyglyceryl 4-10 penta levels relative to the major component, with typical concen oleate, polyglyceryl fatty acid esters, polyglyceryl fatty acid trations less than about 10% (e.g., about 9%, about 8%, esters, fatty acids, polyglyceryl-10 laurate, polyglyceryl-10 about 7%, about 6%, about 5%, about 4%, about 3%, about trioleate, polyglyceryl-3 dioleate, polyglyceryl-3 distearate, 2%, about 1%) of the mixed phase co-crystal composition. polyglyceryl-3 oleate, polyglyceryl-6 dioleate, polyglyc Modifiers, Such as Stabilizers, are preferably crystalline eryl-6 dioleate, polyoxyethylene alkyl ethers, polyoxyeth solids soluble in the solvent system and insoluble in the ylene alkylphenols, polyoxyethylene glycerides, polyoxy anti-Solvent System. Chemically these modifiers function as ethylene hydrogenated vegetable oils, polyoxyethylene acids, bases, antioxidants, light protectants, Viscosity modi Sorbitan fatty acid esters, polyoxyethylene Sterols, polyoxy fiers, and/or Surfactants. ethylene vegetable oils, polyoxyethylene vegetable oils, 0187 Examples of acid modifiers for use in the invention polyoxyethylene hydrogenated vegetable oils, polyoxyeth include, but are not limited to, acetic acid, acrylic acid, ylene-polyoxypropylene block copolymers, polyoxyethyl adipic acid, alginic acid, alkaneSulfonic acid, an amino acid, ene-polyoxypropylene block copolymers, polypropylene ascorbic acid, , boric acid, , car glycol fatty acid esters, polySorbate 20, polySorbate 80, bonic acid, citric acid, a fatty acid, formic acid, fumaric acid, propylene glycol diglycerides, propylene glycol laurate, gluconic acid, hydroquinoSulfonic acid, hydrochloric acid, propylene glycol mono- or diesters of a C to Co fatty acids isoascorbic acid, lactic acid, maleic acid, methaneSulfonic fatty acids, propylene glycol oleate, reaction mixtures of acid, Oxalic acid, para-bromophenylsulfonic acid, phospho polyols and at least one member Selected from the group ric acid, propionic acid, p-toluenesulfonic acid, Salicylic consisting of fatty acids, glycerides, vegetable oils, hydro acid, Stearic acid, Succinic acid, tannic acid, tartaric acid, genated vegetable oils, and Sterols, Sesame Seed oil, Sorbitan thioglycolic acid, toluenesulfonic acid, uric acid, and mix fatty acid esters, Sorbitan mono, trioleate, Sorbitan mono, tures thereof. triStearate, Sorbitan monoisoStearate, Sorbitan monolaurate, Sorbitan monooleate, Sorbitan monopalmitate, Sorbitan 0188 Examples of base modifiers for use in the invention monoStearate, Sorbitan Sesquioleate, Sorbitan Sesquistearate, include, but are not limited to, ammonia, ethanolamine, Soybean oil, Stearic acid, Sterols, Sucroglycerides, Sucrose diethanolamine, glucosamine, trolamine, Sodium bicarbon dipalmitate, Sucrose distearate, Sucrose monolaurate, ate, potassium bicarbonate, Sodium hydroxide, potassium Sucrose monopalmitate, Sucrose monostearate, Sugar esters, hydroxide, TRIS, arginine, lysine, magnesium hydroxide, Sugar ethers, tocopheryl PEG-100 Succinate, tocopheryl calcium hydroxide, Sodium carbonate, potassium carbonate, PEG-1000 succinate, transesteriefied vegetable oils, Tween ammonium bicarbonate, and mixtures thereof. 40, Tween 60, and mixtures thereof. 0189 Examples of antioxidant modifiers for use in the 0184 The crystal lattice modifiers are crystalline, semi invention include, but are not limited to, C-tocopherol, crystalline, amorphous, or ligands in form. The crystal ascorbic acid, ascorbyl palmitate, BHT, BHA, malic acid, lattice modifiers are not closely related to the active agent in propyl gallate, and mixtures thereof. chemical Structure. They are typically Soluble in the Solvent 0190. Examples of viscosity modifiers for use in the System and insoluble in the anti-Solvent System. These invention include, but are not limited to, methylcellulose, materials can be incorporated into the mixed phase co ethylcellulose, acetylated gelatin, hydroxypropyl cellulose, crystal and will either decrease or increase the melting point hydroxypropyl methylcellulose, hydroxyethyl cellulose, of the mixed phase co-crystal relative to the active agent, but hydroxypropyl methyl , polyvinyl acetate phtha preferably reduce the melting point. Crystalline active late, Sodium carboxymethylcellulose, agar, acacia, traga agents will experience a reduction in melting point and canth, carrageen, pectins, polyvinylpyrrollidone, polyvinyl broadening of the endotherm when observed with a differ alcohol, polyvinyl acetate, Xanthane gum, and mixtures ential Scanning calorimeter (DSC). Depending on the appli thereof cation and the relative hydrophobicity of the active agent, the additive may increase or decrease the water Solubility 0191 Examples of Surfactant modifiers for use in the and wetability of the mixed phase co-crystal relative to the invention include, but are not limited to, acetylated glycerol active agent. Depending on the application and the desired fatty acid esters, acetylated monoglycerides, acetylated properties, the combined amount of crystal lattice modifiers monoglycerides of C to Co fatty acids, alkylgluceosides, may range widely in composition. It is desirable to co alkylmaltosides, bile Salts, cholesterol, corn oil, diglycerides crystallize more than one crystal lattice modifier with one or of C to Co fatty acids, ethyl linoleate, ethyl oleate, fatty more active agents. Accordingly, the methods of the inven acid Salts, Saturated fatty acids, unsaturated fatty acids, fatty alcohols, fractionated cocoanut oil, glycerol fatty acid esters, tion can comprise one or more crystal lattice modifiers. glyceryl dicaprate, glyceryl dicaprylate, glyceryl dilaurate, 0185. It is possible to crystallize minor or low concen glyceryl dioleate, glyceryl monocaprate, glyceryl monoca tration additives along with the active agent(s) and crystal prylate, glyceryl monolaurate, glyceryl monooleate, isopro lattice modifier(s) of the mixed phase co-crystal composi pyllinoleate, isopropyl myristate, isopropyl palmitate, lactic tion. These additional additives can contribute to the forma acid conjugates of diglycerides, lactic acid conjugates of tion of the mixed phase co-crystal particle and the addition mono- and diglycerides, lactic acid conjugates of monoglyc of these additives then becomes integral to the particle erides, lauric acid, lauryl macrogolglycenides, lower alcohol Structure. Examples of additional additives for use in the fatty acids esters, monoglycerides of a C to Co fatty acids, mixed phase co-crystal composition include modifiers, Such myristic acid, oleic acid, palmitic acid, PEG 10-100 lionyl as Stabilizers and additives that impart specialized proper phenol series, PEG 1-4 stearate, PEG 15-100 octyl phenol ties. series, PEG 20 dilaurate, PEG 20 glyceryl Stearate, PEG 2-4 US 2005/0181041 A1 Aug. 18, 2005

oleate, PEG 2-5 oleyl ether, PEG 3-16 castor oil, PEG 5-10 0.192 Other additives can be incorporated in the mixed hydrogenated castor oil, PEG 5-20 soya sterol, PEG 6-20 phase co-crystal particle to impart Specialized properties, almond oil, PEG 6-20 corn oil, PEG-10 laurate, PEG-100 Such as improved intestinal membrane permeability, resis Stearate, PEG-12 laurate, PEG-12 oleate, PEG-15 Stearate, tance toward enzymatic bioconversion, bioadhesion, etc. PEG-2 cetyl ether, PEG-2 stearyl ether, PEG-20 almond oil, Examples of these include caprylic acid, oleic acid, bile PEG-20 corn oil, PEG-20 dioleate, PEG-20 glyceryl laurate, Salts, PEG ethers, grapefruit extract, , cellulose deriva PEG-20 glycidyl oleate, PEG-20 laurate, PEG-20 oleate, tives, Silicon dioxide, Starch and the like. PEG-20 trioleate, PEG-200 oleate, PEG-24 cholesterol, 0193 Distinguishing properties of the mixed phase co PEG-25 glyceryl trioleate, PEG-25 phyto sterol, PEG-30 crystal include the preservation of the crystal form of the cholesterol, PEG-30 glyceryl laurate, PEG-30 glyceryl ole active agent(s), reduced crystallinity of the active agent, ate, PEG-30 soya sterol, PEG-32 dilaurate, PEG-32 dioleate, preservation of the crystalline form of the additive and PEG-32 distearate, PEG-32 laurate, PEG-32 oleate, PEG-35 enhanced physical properties of the mixed phase co-crystal castor oil, PEG-4 capric/caprylic triglyceride, mono, di, tri, powder. For instance, in the case of reduced crystallinity of tetra esters of vegetable oil and Sorbitol, PEG-4 dilaurate, the active agent, the active agent shows a Small reduction in PEG-4 dioleate, PEG-4 distearate, PEG-40 castor oil, PEG melting point and broadening of the endotherm (FIGS. 1A 40 glyceryl laurate, PEG-40 hydrogenated castor oil, PEG and 1B). This is brought about by the co-crystallization of 40 palm kernel oil, PEG-40 stearate, PEG-400 oleate, PEG the crystal lattice modifier in the active crystal lattice, hence 50 hydrogenated castor oil, PEG-6 caprate/caprylate an apparent reduction of crystallinity. The presence of the glycerides, PEG-6 corn oil, PEG-6 dioleate, PEG-6 distear Additive Phase is shown by the presence of a characteristic ate, PEG-6 hydrogenated palm kernel oil, PEG-6 olive oil, melting point or endotherm in the DSC. The existence of PEG-6 palm kernel oil, PEG-6 peanut oil, PEG-6 sorbitan both active and Additive Phases is also evident in the X-ray tetra, hexastearate, PEG-6 Sorbitan tetraoleate, PEG-60 cas diffraction (XRD) pattern of the mixed phase co-crystal tor oil, PEG-60 corn oil, PEG-60 hydrogenated castor oil, powder (FIG. 2). A reduction in the signal to noise ratio in PEG-8 caprate/caprylate glycerides, PEG-8 caprate/capry the XRD pattern is another indicator of reduced crystallinity late glycerides, PEG-8 dioleate, PEG-80 sorbitan laurate, of the active agent in mixed phase co-crystal powders (FIG. pentaerythritol di, tetra Stearate, isoStearate, oleate, capry 3). latc, or caprate, phospholipids, phosphoric acid polyoxym ethylene alkylethers, phytosterol, Pluronic F68, Pluronics, 0194 In Tables 1, 2, 4, 6, and 7, a reduction in melting poloxamers, polyethylene glycol fatty acids esters, polyeth point of the mixed phase co-crystal composition as com ylene glycol glycerol fatty acid esters, polyglyceryl 2-4 pared with the pure active agent (API) is observed. This is oleate, Stearate, or isoStearate, polyglyceryl 4-10 penta an indication of reduced crystallinity of the active agent oleate, polyglyceryl fatty acid esters, polyglyceryl fatty acid brought about by the co-crystallization of the modifiers with esters, fatty acids, polyglyceryl-10 laurate, polyglyceryl-10 the active agent. trioleate, polyglyceryl-3 dioleate, polyglyceryl-3 distearate, 0.195. In Tables 2, 6, and 7, a reduction in enthalpy in the polyglyceryl-3 oleate, polyglyceryl-6 dioleate, polyglyc mixed phase co-crystal composition as compared to the pure eryl-6 dioleate, polyoxyethylene alkyl ethers, polyoxyeth active agent is observed. This is also an indication of ylene alkylphenols, polyoxyethylene glycerides, polyoxy reduced crystallinity of the active agent brought about by the ethylene hydrogenated vegetable oils, polyoxyethylene co-crystallization of the modifiers with the active agent. Sorbitan fatty acid esters, polyoxyethylene Sterols, polyoxy ethylene vegetable oils, polyoxyethylene vegetable oils, 0196. In Tables 1, 2, 3, 4, 6, and 7, an increase of water polyoxyethylene hydrogenated vegetable oils, polyoxyeth Solubility as compared to the active agent is obtained for the ylene-polyoxypropylene block copolymers, polyoxyethyl mixed phase co-crystalline materials shown in these tables. ene-polyoxypropylene block copolymers, polypropylene This illustrates the distinguishing property for improvement glycol fatty acid esters, polySorbate 20, polySorbate 80, of water Solubility of the mixed phase co-crystal composi propylene glycol diglycerides, propylene glycol laurate, tion of the invention. Another distinguishing property is propylene glycol mono- or diesters of a C to Cofatty acids improvement of dissolution of the active agent as shown in fatty acids, propylene glycol oleate, reaction mixtures of Table 5 and FIGS. 4, 5, and 6. polyols and at least one member Selected from the group 0197) The formulated mixed phase co-crystalline mate consisting of fatty acids, glycerides, vegetable oils, hydro rial can be directly incorporated in a pharmaceutically genated vegetable oils, and Sterols, Sesame Seed oil, Sorbitan acceptable dosage form as part of the formulation process fatty acid esters, Sorbitan mono, trioleate, Sorbitan mono, without prior isolation of the mixed phase co-crystalline triStearate, Sorbitan monoisoStearate, Sorbitan monolaurate, particles. This requires that all the Solvents, anti-Solvents Sorbitan monooleate, Sorbitan monopalmitate, Sorbitan and crystal modifiers are GRAS materials, listed in major monoStearate, Sorbitan Sesquioleate, Sorbitan Sesquistearate, pharmacopeas or are found as inactive ingredients in phar Soybean oil, Stearic acid, Sterols, Sucroglycerides, Sucrose maceutical dosage forms. The Solvent and anti-Solvents dipalmitate, Sucrose distearate, Sucrose monolaurate, must be volatile or can remain as a component of the dosage Sucrose monopalmitate, Sucrose monoStearate, Sugar esters, form. Should the Solvent/anti-Solvents remain in the dosage Sugar ethers, tocopheryl PEG-100 Succinate, tocopheryl form they must be pharmaceutically acceptable and have PEG-1000 succinate, transesteriefied vegetable oils, Tween prior use in pharmaceutical dosage forms found in com 40, Tween 60, and mixtures thereof. Examples of stabilizers include BHA, BHT, , Vitamin C, titanium oxide, merce (references: USP, EP, PDR and FDA Inactive Ingre acetic acid, benzoic acid, glycine, arginine, monoethanola dient List). mine, N-glucosamine, methySulfonic acid, maleic acid and 0198 Alternatively, mixed phase co-crystals can be iso UV blockers. lated by filtration, Sedimentation or centrifugation. The US 2005/0181041 A1 Aug. 18, 2005

isolated material can then be washed with water and dried glycerides (Gelucires, Labrasol and Labrafils), PEG esters, with the aid of heat or vacuum. polySorbates, glycerin, polyol Solutions (Sorbitol, mannitol, 0199 The process used in preparation of the mixed phase maltose, etc), water, and other pharmaceutically acceptable co-crystalline material utilizes one or more volatile Solvents/ oils. In this case, the Volatile Solvent/anti-Solvents are anti-Solvents that are removed during a drying Step of the removed partially or completely after crystallization of the process. This can be accomplished by Several methods mixed phase co-crystalline particles with the aid of a carrier commonly used for processing pharmaceutical dosage gas, Vacuum, and/or application of heat. Sparging of the forms. These can include combining the crystallized mixed resulting Suspension with a carrier gas Such as nitrogen or phase co-crystalline material Suspended in the Solvent/anti compressed air is the preferred method when a carrier gas is Solvent System with a pharmaceutically acceptable bulking used. The mixed phase co-crystal preparation results in a agent. The volatile solvent/anti-solvent is removed by dry Suitable Suspension for encapsulation as anoil based or ing the resulting granulation containing the formulated hydrophilic based fill formulation as Soft gelatin or hard mixed phase co-crystal and bulking agent(s). Alternatively, gelatin capsules. the Solvent System can be combined with the bulking agent 0204. The present invention provides methods for for and the volatile Solvents removed through evaporation with mulation of mixed phase co-crystals that include initial out prior crystallization of the mixed phase co-crystalline crystallization of the active agent along with additive(s) and material. Subsequent transformation to the mixed phase co-crystal 0200 Any suitable bulking agent can be used. Preferably, form(s) or by evaporation of volatile Solvents containing the the bulking agent is a pharmaceutically acceptable bulking co-crystalline components. The ratio or composition of the agent. Examples of Suitable bulking agents include, but are components can be varied and produced in a wide range. The not limited to, microcrystalline cellulose, lactose anhydrous, composition of the mixed phase co-crystal form and the lactose monohydrate, Sucrose, mannitol, maltitol, Sorbitol, extent of co-crystallization achieved will determine the calcium phosphate, calcium Sulfate, Starch, pregelatinized Specific physical properties. Thus, it is possible to formulate Starch, Silica, powdered cellulose, croScarmollose, bento a mixed phase co-crystal with the desired properties based nite, kaolin, magnesium aluminum Silicate, dextrins, amy on the nature of the additive(s) and the composition of the lose, glucose, ethylcellulose, hydroxyethyl cellulose, additive(s) incorporated. It has been discovered that the hydroxymethyl cellulose, hydroxypropylmethyl cellulose, desired properties can be optimized through the use of maltodextrin, povidone, calcium carbonate, compressible carefully balanced components that are co-crystallized with Sugar, cyclodextrins, dextran, talc, Sodium Starch glycolate, the active agent(s). gelatin, magnesium carbonate, magnesium oxide, maltitol, 0205. In a preferred embodiment of the invention, the methylcellulose, Xylitol, and carbomer. solvent and anti-solvent are substantially removed from the 0201 Preferred examples of the bulking excipient mixed phase crystalline material, Such that the mixed phase include pharmaceutically acceptable powders that are gen crystalline material is a dry powder Suitable for direct erally recognized as safe (GRAS) or listed in major Phar encapsulation or tableting. macopeas. Examples of powders include cellulosic materials 0206. The inventor discovered that mixed phase co (microcrystalline cellulose and hydroxypropylcellulose), crystals can improve the inherent properties of active agents polyvinylpyrrolidones (PVP and crospovidone), Sugars (lac that enable the Successful development of delivery Systems tose and Sucrose), Starches (pregelatined Starch and corn for the active agents. These mixed phase co-crystalline Starch), inorganic Salts (dicalcium phosphate and calcium materials can be incorporated in a formulation while being Sulfate) and reduced Sugars (mannitol and Sorbitol). formed as part of the dosage form processing Steps. 0202 Preferred methods for removing the volatile sol 0207. In a preferred embodiment, the mixed phase co vents utilize a fluid bed Spray granulation, Spray drying, or crystal composition comprises a mixed phase co-crystal of Vacuum granulating/drying processes. The resulting powder an active agent and at least one crystal lattice modifier, or granulation is sized to an average particle size in the range wherein the content of the active agent ranges from about of 50 to 300 microns in size (e.g., about 75 microns, about 5% to 95% (e.g., about 10%, about 15%, about 20%, about 100 microns, about 125 microns, about 150 microns, about 25%, about 30%, about 35%, about 40%, about 45%, about 175 microns, about 200 microns, about 225 microns, about 50%, about 55%, about 60%, about 65%, about 70%, about 250 microns, about 275 microns, or ranges thereof) which is 75%, about 80%, about 85%, or ranges thereof) by weight Suitable for further powder blending and Subsequent dosage of the total weight of the material, and wherein the crystal form manufacture by encapsulation into hard gelatin cap lattice modifier ranges from 2% to 95% (e.g., about 5%, Sules, tablets, or other dosage forms. about 10%, about 15%, about 20%, about 25%, about 30%, 0203) A second alternative process for mixed phase co about 35%, about 40%, about 45%, about 50%, about 55%, crystal formation utilizes a volatile Solvent System that has about 60%, about 65%, about 70%, about 75%, about 80%, Sufficient Solvent capacity to dissolve the active agent and about 85%, about 90%, or ranges thereof). Preferably, the modifiers. The mixed phase co-crystals are formed by pre crystal lattice modifier ranges from 10% to 40% by weight cipitation with a non-Solvent System using materials that are for each individual modifier of the total weight of the ingestable (GRAS) and can be formulated as a fill for soft material. gelatin and 2-piece hard gelatin capsules. Examples of these 0208. The following examples further illustrate the liquids include triglycerides (Sesame oil, Soybean oil and invention but, of course, should not be construed as in any fractioned cocoanut oil), propylene glycol esters, fatty acids way limiting its Scope. The examples do not constitute the (oleic acid, caprylic acid and myristic acid), polyethylene entire range of active agents or crystal lattice modifiers that glycols (PEG 400, PEG 600, PEG 3350, etc.), mixed phase may be used. US 2005/0181041 A1 Aug. 18, 2005

EXAMPLE 1. 0209. This example demonstrates a method to prepare mixed phase co-crystals of hydrocortisone. Ingredients Amount 1. Hydrocortisone acetate 320 mg 2 Methocel E4M (as 2% solution in 200 mg Ingredients Amount DMSO) 3 Sorbitan monostearate 4 mg 1. Hydrocortisone (Pharmacia-Upjohn) 300 mg 4 Stearic acid 4 mg 2 Sorbitan monopalmitate (ICI) 100 mg 5 Cetostearyl alcohol 4 mg 3 Dimethyl sulfoxide 1.6 mL. 6 Lanolin 4 mg 4 Deionized water 8.0 mL. 7 Dimethyl sulfoxide 1.6 mL. 8 Deionized water 8.0 mL. *Removed *Removed 0210. The mixed phase co-crystals of hydrocortisone were prepared by dissolving the active gent (hydrocortisone; 0214) To prepare the mixed phase co-crystals, hydrocor Pharmacia-Upjohn) and a crystal lattice modifier (Sorbitan tisone acetate (Pharmacia-Upjohn), Sorbitan monostearate monopalmitate; ICI) in dimethylsulfoxide (DMSO, Fisher) (ICI), Stearic acid (Croda), cetostearyl alcohol (Croda), with the application of heat (ca. 60° C.) and vortex mixing. lanolin (Croda) were dissolved in dimethyl sulfoxide with The resulting Solution was added gradually over a period of the application of heat (ca. 60° C.) and vortex mixing. 200 5 minutes to deoinoized water at 30 to 40 C. while being mg of a 2% solution of Methocel E4M (methylcellulose) in vortex mixed or stirred with a magnetic stir bar. The DMSO was added and mixed with the previous ingredients precipitation that forms was mixed for 1 to 2 hours at 30 to 40° C. The reactive mixture was allowed to cool to room until dissolved. The resulting Solution was added gradually temperature and gently mixed for an additional 12 to 48 over a period of 5 minutes to the water at room temperature hours. The resulting mixed phase co-crystal product was while being Vortex mixed or Stirred with a magnetic Stir bar. collected with a Buchner funnel using a Whatman paper The precipitation that formed was gently mixed for an filter. The filter cake was repeatedly washed with additional additional 12 to 48 hours. The resulting mixed phase co water and dried under vacuum at 25 C. for 1 or more days. crystal product was collected with a Buchner funnel using Whatman paper filter. The filter cake was repeatedly washed EXAMPLE 2 with additional water and dried under vacuum at 25 C. for 0211 This example demonstrates a method of preparing 1 or more days. mixed phase co-crystals of hydrocortisone. EXAMPLE 4 0215. This example demonstrates a method of preparing Ingredients Amount mixed phase co-crystals of cycloSporin. 1. Hydrocortisone 300 mg 2 Cetostearyl alcohol 84 mg 3 Methocel E4M (as 2% solution in 800 mg DMSO) Ingredients Amount 4 N-methylpyrrollidone 1.6 ml 5 Deionized water 8.0 mL. 1. Cyclosporin (Gallipot) 40 mg 2 Crotein ADW (10% in ethanol) 100 uL *Removed 3 Sorbitan monostearate 1 mg 4 Lanolin 1 mg 0212 To prepare the mixed phase co-crystals, hydrocor 5 Stearic acid 1 mg 6 Compritol 888 ATO 1 mg tisone (Pharmacia Upjohn) and cetostearyl alcohol (Croda) 7 N-methylpyrrollidone O.2 mL. were dissolved in N-methylpyrrollidone (ISP Technologies) 8 Deionized water 1.0 mL. with the application of heat (ca. 60° C.) and vortex mixing. These ingredients were added to 800 mg of a 2% solution of *Removed Methocel E4M (methylcellulose) in DMSO and mixed with until dissolved. The resulting Solution was added gradually 0216) To prepare the mixed phase co-crystals, over a period of 5 minutes to 8.0 mL of deionized water at cyclosporin (Gallipot), Crotein ADW (AMP-Isostearoyl 30 to 40 C. while being vortex mixed or stirred with a Hydrolyzed Wheat Protein; 10% in ethanol), Sorbitan magnetic Stir bar. The precipitation that formed was mixed monostearate, lanolin (Croda), Stearic acid, and Compritol for 1 to 2 hours at 30 to 40 C. The reaction mixture was 888 ATO (glycerol behenate; Gattefosse) were dissolved in allowed to cool to room temperature and gently mixed for an N-methylpyrrollidone (ISP) with the application of heat (ca. additional 12 to 48 hours. The resulting mixed phase co 60° C.) and vortex mixing. 1.0 mL of deionized water was crystal product was collected with a Buchner fimnel using a added to this Solution was added and the resulting reaction Whatman paper filter. The filter cake was repeatedly washed mixture was Vortexed at room temperature. The reaction with additional water and dried under vacuum at 25 C. for mixture was agitated at room temperature for 18 to 48 hours. 1 or more dayS. The resulting mixed phase co-crystal product was collected EXAMPLE 3 with a Buchner funnel using Whatman paper filter. The filter 0213 This example demonstrates a method of preparing cake was repeatedly washed with additional water and dried mixed phase co-crystals of hydrocortisone acetate. under vacuum at 25 C. for 1 or more days. US 2005/0181041 A1 Aug. 18, 2005 19

EXAMPLE 5 0217. This example demonstrates a method of preparing mixed phase co-crystals of itraconazole. Ingredients Amount 1. Nimodipine (Lusochimica) 300 mg 2 Capmul GMS (Croda) 5 mg Ingredients Amount 3 Compritol 888 ATO (Croda) 5 mg 4 Crodacid B (Croda) 5 mg Part A: 5 Solutol HS 15 (BASF) 5 mg 6 Dimethyl sulfoxide 1.0 mL. 1. Itraconazole (Spectrum) 300 mg 7 N-methylpyrrollidone 800 mg 2 Crodesta F160 (Croda) 50 mg 8 Deionized water 1.0 mL. 3 Crodacid (Croda) 50 mg 4 DMSO* 900 mg *Removed 5 Urea 200 mg 6 N-methylpyrrollidone 800 mg Part B: 0223) To prepare the mixed phase co-crystals, nimo dipine, Capmul GMS (glycerol momoStearate), Compritol 7 Urea 4000 mg 888 ATO (glycerol behenate), Crodacid B (behenic acid), 8 Deionized water 4000 mg and Solutol HS 15 (PEG 660 hydroxystearate) were dis *Removed solved in N-methylpyrrolidone and DMSO with the appli cation of heat (ca. 60° C) and vortex mixing. The resulting 0218. To prepare the mixed phase co-crystals, Crodesta Solution was added gradually over a period of 5 minutes to F160 (sucrose stearate) and Crodacid (behenic acid) were deionized water at room temperature, while being Vortex dissolved in DMSO. Urea was dissolved in N-methylpyr mixed or Stirred with a magnetic Stir bar. The precipitation rolidone with heating. The resulting Solutions were com that formed was gently mixed for an additional 12 to 48 bined, and itraconazole (Spectrum) was added and dissolved hours. The resulting mixed phase co-crystal product was with heat, completing Part A Solution. collected with a Buchner funnel using Whatman paper filter. 0219 Part B solution was prepared by dissolving urea in The filter cake was repeatedly washed with additional water water with heating, then allowing the Solution to cool to and dried under vacuum at 25 C. for 1 or more days. room temperature. The Part A Solution was then added to Part B by Slow addition with mixing, forming a precipitate. EXAMPLE 8 The resulting Suspension was gently Vortexed at room temperature for 2 days. The mixed phase co-crystals were 0224. This example demonstrates a method of preparing isolated by filtration, washed with a Small aliquot of water, mixed phase co-crystals (Batch No. F833-025B of FIG. 6) and dried at 40 C. in an oven. of progesterone. EXAMPLE 6 0220. This example demonstrates a method of preparing mixed phase co-crystals of itraconazole. Ingredients Amount 1. Progesterone (Pharmacia-Upjohn) 2000 mg 2 Pluronic F68 (BASF) 600 mg 3 Methocel E15 300 mg Ingredients Amount 4 Ethanol 2.0 mL. 1. Itraconazole 5000 mg 5 Soybean oil 3.0 mL. 2 Stearth-20 (Croda) 2500 mg 6 Miglyol 810 3.0 mL. 3 Pluronic F-68 2500 mg 4 Ethanol: 200 mL. *Removed 5 Refined soybean oil 100 mL. *Removed 0225. To prepare the mixed phase co-crystals, progester one, Pluronic F68 (Poloxamer 188) and Methocel E15 0221) To prepare the mixed phase co-crystals, itracona (hydroxypropylmethyl cellulose) were dissolved in ethanol zole, Stearth-20, and Pluronic F-68 (Poloxamer 188) were (>70° C.). Soybean oil and Miglyol 810 (glycerol tri dissolved in hot ethanol (>70° C.) with mixing and main caprylate/caprate) were mixed at 5 C., and then the warm tained at this temperature. The hot ethanol Solution was ethanol Solution was added and mixed. The resulting Sus added gradually to the Soybean oil that was kept cool (0 to pension is mixed at 5 C. for 2 hours. Compressed air was 10 C.) with vigorous mixing. The resulting Suspension of Sparged through the oil Suspension at room temperature to the mixed phase co-crystals was stirred while compressed evaporate the ethanol for approximately 18 hours. The air was bubbled through the Suspension at room temperature resulting Suspension was ground or Sieved to a Smooth until the residual alcohol was reduced to less than 10% by consistency and encapsulated in hard gelatin capsules. A weight as determined by loss on drying at 105 C. This Scaled up version of the same formulation was encapsulated prepared Suspension was then encapsulated into hard gelatin in Soft gelatin capsules. and Soft gelatin capsules. EXAMPLE 7 EXAMPLE 9 0222. This example demonstrates a method of preparing 0226. This example demonstrates a method of preparing mixed phase co-crystals of nimodipine. mixed phase co-crystals of progestrone. US 2005/0181041 A1 Aug. 18, 2005

increased rate of dissolution as compared to the commercial progesterone capsules (FIG. 6). Ingredients Amount 0231. Thus, mixed phase co-crystal formulations pre Part A pared by the methods of the invention demonstrate improved properties, Such as dissolution rate. 1. Progesterone (Pharmacia-Upjohn) 40.0 g 2 Sucrose monostearate 12.0 g 3 Pharmacoat 603 6.0 g EXAMPLE 11 4 Ethanol (200 proof)* 50 g 5 Purified water* 200 g 0232 This method demonstrates a method of preparing Part B mixed phase co-crystals of progesterone. 6 Part A suspension 308 g 7 Lactose, hydrous 400 g *Removed Ingredients Amount 1. Progesterone (Pharmacia-Upjohn) 20.0 g 0227 To prepare the mixed phase co-crystals, progester 2 Pluronic F68 (Poloxamer 188) 6.0 g 3 Methocel E15 (Hydroxypropyl 3.0 g one, Sucrose monostearate, and Pharmacoat 603 (hydrox Methylcellulose) ypropylmethyl cellulose) were dissolved in ethanol (>70 4 Ethanol (200 proof)* 80 g C.). The hot ethanol solution was gradually added to the 5 Purified water* 150 g purified water (5 C.) and mixed. The resulting Suspension was mixed at room temperature for 2 hours. The Suspension *Removed then was passed through a 30-mesh Screen and Sprayed onto the lactose in a fluid bed drier. The final dried granulation 0233. To prepare the mixed phase co-crystals, progester was then encapsulated into a two-piece hard gelatin capsule. one, Pluronic F68 (Poloxamer 188), and Methocel E15 (hydroxypropyl methylcellulose) were dissolved in hot etha EXAMPLE 10 nol (boiling temperature). This Solution was gradually added over a period of 20 minutes to water at 5 C. while mixing. 0228. This example demonstrates that mixed phase co After the initial crystallization of the mixed phase co-crystal crystals prepared by the methods of the invention have material, mixing was continued for an additional 2 hours at beneficial properties. 5 C. The suspension was allowed to remain at room 0229. Four lots of mixed phase co-crystal formulations temperature for 24 hours. The mixed phase co-crystals were were prepared by the method described in Example 8 using isolated by filtration, washed with additional water, and the following compositions: dried at 40 C.

Amount Batch No.

Ingredients F-833-O2SB F-833-O23C F-833-024A F-833-O25A 1 Progesterone (Pharmacia- 2000 mg 1000 mg 1000 mg 2000 mg Upjohn) 2 Pluronic F68 (Poloxamer 600 mg 300 mg 300 mg 600 mg 188) Methocel E15 3 (Hydroxypropylmethyl 300 mg Cellulose) 4 Stearth 20 300 mg 5 Ethanol: 2.0 mL. 1.0 mL. 1.0 mL. 2.0 mL. PVP K30 6 (Polyvinylpyrrollidone) 300 mg 7 Soybean oil 3.0 mL. 1.5 mL. 1.5 mL. 3.0 mL. 8 Miglyol 810 (Glycerol Tri- 3.0 mL. 1.5 mL. 1.5 mL. 3.0 mL. caprylate/Caprate)

*Removed

0230 FIG. 6 illustrates a comparison of in vitro disso 0234 Photomicrographs were taken with a polarizing lution results for the four lots of mixed phase co-crystal microScope at 100x magnification after different time points formulations (F833-023c, -024A, -025A and -025B) con in the manufacture of the mixed phase co-crystals. An image taining progesterone as the active ingredient as compared to taken immediately after the addition of the alcohol solution commercial Prometrium 200 mg softgel capsules from two illustrated that large needle-like crystals and large plate-like batches. The dissolution method used USP apparatus I, crystals had formed. These crystal forms were transient and, paddles at 50 rpm, 27 C., and media of therefore, were kinetically favored products. These crystal :water (1:1). Progesterone was analyzed via HPLC. Each of forms gradually converted with time to the thermodynami the mixed phase co-crystal formulations showed an cally favored mixed phase co-crystals that were Smaller in US 2005/0181041 A1 Aug. 18, 2005

Size and of uniform morphology, as observed in photomi pyrrolidone or a blend of the two with gentle heating (60° crographs taken 1 hour and 2 hours after mixing at 5 C. C.) and Vortex mixing. The resulting Solution was combined with water to intiate the crystallization of the mixed phase EXAMPLE 12 co-crystals and vortexed for 18 to 48 hours at room tem 0235. This example demonstrates the physical properties perature. The mixed phase co-crystals were isolated by of various mixed phase co-crystal materials produced by the filtration, washed with water, and dried. methods of the invention. 0236 Tables 1 and 2 demonstrate the physical properties 0237 Gelucire 44/14 refers to lauroyl macrogol-32 glyc of mixed phase co-crystals of hydrocortisone and hydrocor erides; Ethocel refers to ethylcellulose resin; Emucire refers tisone acetate, respectively. To prepare the mixed phase to cetyl alcohol (and) ceteth-20 (and) steareth-20; Methocel co-crystals of Tables 1 and 2, the active agent and crystal E3 refers to hydoxypropyl methylcellulose; and Suppiircire lattice modifiers were dissolved in DMSO or n-methyl refers to a blend of mono-, di-, and tri-glycerides.

TABLE 1. Physical Properties of Hydrocortisone Mixed Phase Co-Crystals Co-crystal Melting Point(s)* Water Solubility Assay Lot No. Description ( C.) (meg/mL) (% w/w) Control (Intact API) Hydrocortisone (HC) 240-242 3O2 1OO DG-5B 20% Stearic Acid 180-188 318 87 DG-27 20% Cetostearyl Alcohol 185-195 319 8O DG-45A 10% Sorbitan Monopalmitate 186-191 376 87 DG-45C 30% Sorbitan Monopalmitate 179-187 375 77 DG-6Oa 25% Sorbitan Monopalmitate 174-182 530 81 dg-60b 21% Sorbitan Monopalmitate, 4% Methocel E4M 170-18O 660 81 dg-60c 21% Sorbitan Monopalmitate, 4% Gelucire 44/14 168-182 530 82 dg-60d 21% Sorbitan Monopalmitate, 4% Ethocel 168-18O 440 76 dg-60e 25% Cetostearyl Alcohol 183-190 390 79 dg-60f 21% Cetostearyl Alcohol, 4% Methocel E4M 180-188 590 76 dg-60g 21% Cetostearyl Alcohol, 4% Gelucire 44/14 175-185 490 76 dg-60h. 21% Cetostearyl Alcohol, 4% Ethocel 178-190 430 77 dg-61f 21% Cetostearyl Alcohol, 4% Methocel E4M 171-18O 481 8O *For each mixed phase co-crystal, only the highest melting point is specified

0238)

TABLE 2 Physical Properties of Hydrocortisone Acetate Mixed Phase Co-Crystals Assay Solubility Peak Mp Enthalpy Lot No. (% w/w) (mcg/mL) (C.) ((-) J/g) Ingredients Control N/A 4.5 219.92 119.05 Hydrocortisone Acetate (Intact API) 47A N/A 7.0 215.84 8051 Cetostearyl Alcohol, NF 47D N/A 6.9 212.14 72.59 Stearic Acid 57A N/A 5.1 222.17 90.81 Compritol 888 ATO 57B N/A 2.6 N/A N/A Cetostearyl Alcohol, NF Emulcire 57C N/A 6.1 217.31 84.84 Cetostearyl Alcohol, NF Gelucire 44/14 57D N/A 6.7 216.09 88.7O Cetostearyl Alcohol, NF Povidone 57E N/A 6.9 N/A N/A Cetostearyl Alcohol, NF PVA 57F N/A 15.4 217.26 92.77 Cetostearyl Alcohol, NF Methocel E4M 61A 78.5 6.5 N/A N/A Cetostearyl Alcohol, NF Ethocel 61C 78.5 6.O N/A N/A Stearic Acid Ethocel 61D 76.9 6.9 212.84 89.71 Stearic Acid Methocel E4M 63B 92.1 6.9 221.82 98.36 Sucrose 63C 82.1 7.4 218.02 82.10 Monosterol 63H 91.5 6.9 N/A N/A Emulcire 69B 86.4 24.8 217.22 90.22 Cetostearyl Alcohol, NF Methocel E4M 69C 89.8 13.1 216.93 88.49 Cetostearyl Alcohol, NF Methocel E3 69D 89.3 12.5 218.90 87.84 Monosterol Methocel E4M 69E 87.4 12.9 221.02 82.46 Cetostearyl Alcohol, NF Methocel E4M 69F 95.5 12.5 219.33 92.57 Monosterol Methocel E3 69G 89.8 12.7 223.88 96.32 Suppercire Methocel E4M 91.7 11.2 222.39 92.77 Suppercire Methocel E3 US 2005/0181041 A1 Aug. 18, 2005 22

0239 Tables 3 and 4 demonstrate the physical properties Lanolin Protalan MOD; SPAN 60 refers to Sorbitan of mixed phase co-crystals of cycloSporin. The materials monoStearate; Crodafos CES refers to dicetyl phosphate, were prepared by the method described in Example 4. cetearyl alcohol, ceteth-10 phosphate; Polychol 5 refers to Phospholipon refers to a refined soy derived lecithin. laneth-5; Methocel K4M refers to hydoxypropyl methylcel lulose; Volpo S-10 refers to steareth-10; and Crodesta F110 TABLE 3 refers to Sucrose Stearate (and) Sucrose distearate. The Relative Water Solubility of a Series of Cyclosporin Mixed phase Co-Crystal Powders TABLE 5 Sample Code No. Solubility Factor Intrinsic Dissolution of Itraconazole in 3% Sodium Lauryl Sulfate 20%. Isopropanol:0.1 NHCl (1:1 93c 66 93e 23 Sample Intrinsic Dissolution Rate 93. 15 Code (meg/min/cm) 94c 12 76a 8 745-4-8 6.4 94e 5 745-7-8 7.45 93f 4 745-48g 9.15 Control 11.1 *Solubility ratio in water at room temperature compared to the amorphous 745-71C 11.4 powder solubility. 745-71A 12.4 745-7-6 12.2 0240

TABLE 4 Physical Properties of Cyclosporin Mixed Phase Co-Crystals Mixed Phase Co- Melting Point(s) or Water Solubility Assay Crystal Lot No. Description Glass Transition Point (mcg/mL) (% w/w) 66c 25%. Ethocel 90-100 3.8 85.5 66d 50%. Ethocel 100–110, 89-104f 4.0 61 66e 25% Compritol 888 ATO 80-86 4.5 69 66f 25%. Sucrose Ester 1670 92-102 4.1 101 66g 25%, Stearic Acid 58-65, 51–61 3.6 85.7 7Ob 25% Sucrose Ester 1670, 25% Methocel E4M 85-123 3.9 93.8 7Od 50% Stearic Acid 57-59 3.2 59.5 7Oe 25% Stearic Acid, 25% Ethocel 55-73 3.4 57.3 7Of 25% Cetosterol Alcohol 46-71 3.5 813 70g 25% Phospholipon 118-139 3.7 95.4 7Oh 25% Emulcire 42-80 3.5 87.3 71c 50%. Phospholipon 120-165 2.7 43.2 71d 66%. Sucrose Ester 1670 90-110 3.5 36.8 71e 25% Phospholipon, 25% Methocel E4M 104-130 3.2 54.5 71f 33% Powidone 120-140 3.9 80.1 71g 50% Compritol 888 ATO 60-65 4.1 45.8 *For each mixed phase co-crystal, only the highest melting point is specified Data from duplicate experiments

0241 Tables 5 and 6 demonstrate the physical properties of mixed phase co-crystals of itraconazole (see also FIG. 5). TABLE 5-continued To prepare the mixed co-crystals, itraconazole and crystal lattice. modifiers were dissolved in DMSO or n-methyl- Intrinsic Dissolution of Itraconazole in 3% Sodium pyrrolidone or a blend of the two with gentle heating (60° Lauryl Sulfate 20% Isopropanol:0.1 NHCl (1:1) C.) and Vortex mixing. The resulting Solution was combined with water to intiate the crystallization of the mixed phase Sample Intrinsic Dissolution Rate co-crystals and vortexed for 18 to 48 hours at room tem- C :- 1-2 perature. The mixed phase co-crystals were isolated by Ode (mcg/min/cm) filtration, washed with water, and dried. 745-71H 14.4 0242. In the case of 833-2A, -2B, -2C, and -2D, a solution 833-2A 55.3 of urea in water (50%) was combined with the solvent phase 833-2B 17.7 to initiate crystallization. The resulting Suspensions were 833-2C 19.3 allowed to mix for 18 to 48 hours at room temperature, 833-1A 19.9 collected by filtration, washed with water, and dried. 833-1B 18.5 0243 Capmul MCM C10 refrs to glyceryl monocaprate; 833-1C 15.4 SPAN 40 refers to sorbitan palmitate; Pharmalan USP refers 833-1D 8.5 to lanolin; Crodesta F10 refers to Sucrose distearate; Cro dacol C-95 refers to cetyl alcohol; Acylan refrs to Acetylated US 2005/0181041 A1 Aug. 18, 2005 23

0244)

TABLE 6 Physical Properties of Itraconazole Mixed Phase Co-Crystals Assay Peak Yield (% Solubility Mp Enthalpy Lot No. (%) w/w) (meg/mL) (C.) ((-) J/g) Ingredients Control N/A N/A <.01 67.11 78.31 - (Intact API) 745-4-1 90.3 65.3 O.12 56.96 53.00 Capmul SPAN 40 Stearic Pharmalan, MCM C10 Acid USP 745-4-2 70.5 69.8 O.O2 58.21 57.87 Stearic Acid Crodesta F10 Pluronic Crodacol C-95, F68 NF 745-4-3 83.O N/A O.OO 56.88 52.31 Crodacol C- SPAN 40 Crodacid B Capmul GMS 95, NF 745-4-4 85.O N/A O.OO 56.90 56.28 Acylan Crodacol C-95, SPAN 60 Crodacid B NF 745-4-5 78.8 N/A O.O2 56.82 52.10 Crodafos SPAN 60 Crodacid B Stearic Acid CES 745-4-6 77.0 749 O.47 61.82 65.32 Crodacid B Capmul GMS Crodafos Polychol 5 CES 745-4-7 63.9 70.8 O.28 58.23 59.34 Solutol HS Stearic Acid Crodacol Capmul MCM 15 C-95, NF C10 745-4-8 84.5 70.7 O.43 61.16 62.00 Capmul SPAN 60 Crodacid B Gelucire 44f14 MCM C10 745-7-1 103.O N/A O.04 55.71 48.97 Campul SPAN 40 Stearic Pharmalan, Methocel MCM C10 Acid USP K4M 745-7-2 112.O 59.3 O.78 53.56 45.62 Stearic Acid Crodesta F10 Pluronic Crodacol C-95, Methocel F68 NF K4M 745-7-3 N/A N/A O.O3 52.76 46.14 Crodacol C- SPAN 40 Crodacid B Capmul GMS Methocel 95, NF K4M 745-7-4 N/A N/A 0.27 55.67 48.28 Acylan Crodacol C-95, SPAN 60 Crodacid B Methocel NF K4M 745-7-5 N/A 53.7 1.OO 49.88 41.93 Crodafos SPAN 60 Crodacid B Stearic Acid Methocel CES K4M 745-7-6 N/A 49.6 O.94 53.37 43.65 Crodacid B Capmul GMS Cradafos polychol 5 Methocel CES K4M 745-7-7 N/A 71.7 O.90 58.69 56.56 Solutol HS Stearic Acid Crodacol Capmul MCM Methocael 15 C-95, NF C10 K4M 745-7-8 90.0 73.O O31 61.12 58.00 Capmul SPAN 60 Crodacid B Gelucire 44f14 Methocel MCM C10 K4M 745-11-1 813 N/A O.OO 52.88 54.60 Cholesterol, Dehydrocholic Crodacid B SPAN 60 NF Acid 745-11-2 87.8 N/A O.32 58.54 57.56 Choles-terol, Capmul MCM Gelucire Stearic Acid NF C10 44f14 745-11-3 94.3 N/A O.OO 55.77 28.69 Choles-terol, Dehydrocholic Compritol Solutol HS 15 NF Acid 888 ATO 745-11-4 72.O 713 O.93 60.06 61.21 Monosteol Crodacid B Solutol HS Capmul MCM 15 C10 745-11-5 91.3 55.7 3.94 57.60 55.19 Ceto-stearyl Cholesterol, Monosteol Solutol HS 15 Alcohol, NF NF 745-11-6 87.O 65.4 O.58 59.42 56.36 Capmul GMS Solutol HS 15 Crodacid B Monosteol 745-11-7 93.3 N/A O.05 57.30 56.36 CrOdesta F10 Stearic Acid Crodacol Capmul MCM C-95, NF C10 745-11-8 8O.S N/A 1.28 54.66 N/A Solutol HS Stearic Acid Crodacol Dehydrocholic 15 C-95, NF Acid 745-14-1 78.1 N/A 2.22 58.64 59.88 Cetostearyl Cholesterol, Monosteol Solutol HS 15 Alcohol, NF NF 745-14-2 87.1 N/A O.OO 55.06 63.46 Cetostearyl Cholesterol, Monosteol Dehydrocholic Alcohol, NF NF Acid 745-14-3 84.2 N/A O.O2 58.52 60.15 Cetostearyl Cholesterol, Monosteol Gelucire 44f14 Alcohol, NF NF 745-14-4 85.3 N/A O.OO 58.13 64.86 Cetostearyl Cholesterol, Monosteol Pluronic F68 Alcohol, NF NF 745-14-5 82.9 N/A O.OO 6O.O2 64.20 Cetostearyl Cholesterol, Monosteol Crodesta F10 Alcohol, NF NF 745-14-6 79.3 N/A O.78 58.87 62.33 Cetostearyl Cholesterol, Monosteol Volpo S-10 Alcohol, NF NF 745-14-7 69.8 N/A O16 58.64 58.10 Cetostearyl Cholesterol, Monosteol Crodesta F10 Alcohol, NF NF 745-14-8 77.5 N/A O.OO 59.67 69.06 Cetostearyl Cholesterol, Monosteol Capmul MCM Alcohol, NF NF C10 745-40-A 60.8 N/A 2.22 N/A N/A Solutol HS Stearic Acid Crodacol Capmul MCM 15 C-95, NF C10 US 2005/0181041 A1 Aug. 18, 2005 24

TABLE 6-continued Physical Properties of Itraconazole Mixed Phase Co-Crystals Assay Peak Yield (% Solubility Mp Enthalpy Lot No. (%) w/w) (meg/mL) (C.) ((-) J/g) Ingredients 745-4O-B 86.5 N/A O.OO N/A N/A Cetostearyl Cholesterol, Monosteol Solutol HS 15 Alcohol, NF

0245) 95 Sition of glyceryl Stearate, behenyl alcohol, palmitic acid, 0246 Table 7 demonstrates the physical properties of Stearic acid, lecithin, lauryl alcohol, myristyl alcohol, and mixed phase co-crystals of intraconazole. To prepare the cetyl alcohol; Liposorb S-4 refers to polysorbate 61; Ganex mixed phase co-crystals, itraconazole and crystal lattice WP-660 and Ganex V-220 refer to PVP/eicosene copoly modifiers were dissolved in DMSO or n-methyl-pyrrolidone mers; and Methocel A4K refers to methylcellulose.

TABLE 7 Physical Properties of Itraconazole Mixed Phase Co-Crystals Assay Peak Yield (% Solubility Mp Enthalpy Lot No. (%) w/w) (meg/mL) (C.) ((-) J/g) Ingredients Control N/A N/A <.01 67.11 78.31 - (Intact API) 745-16-1 84.1 66.O 3.78 12.63 79.17 Capmul Compritol 888 Crodacid B Solutol HS 15 GMS ATO 745-16-2 94.6 N/A O.2O 10.87 84.38 Cetostearyl SPAN 60 Volpo S-2 Crodacid B Alcohol, NF 745-16-3 98.3 76.2 1.70 2O.92 75.28 Cholesterol, Compritol 888 Dehydrocholic Volpo S-10 NF ATO Acid 745-16-4 92.1 N/A 0.72 10.21 83.49 Cholesterol, Dehydrocholic Monosteol Volpo S-2 NF Acid 745-16-5 N/A N/A O.43 O4.46 72.55 Volpo S-2 Volpo S-10 Cetostearyl Crodacid B Alcohol, NF 745-16-6 92.7 86.8 3.11 13.23 92.44 SPAN 60 Stearic Acid Volpo S-2 Solutol HS 15 745-16-7 99.1 88.0 56 12.17 91.12 Cholesterol, Capmul GMS Cetostearyl Solutol HS 15 NF Alcohol, NF 745-16-8 94.8 N/A O.78 12.49 95.38 Syncrowax Stearic Acid SPAN 60 Solutol HS 15 AW1-C 745-44-A 58.3 .74 12.95 86.48 Crodacid B Compritol 888 Solutol HS 15 Volpo S-2 ATO 745-44-B 67.7 82 21.21 76.10 Cholesterol, Compritol 888 Solutol HS 15 Dehydrocholic NF ATO Acid 745-44-C 62.7 2.54 21.52 77.63 Crodesta Volpo S-2 Solutol HS 15 Prolipid 141 F160 745-44-D 68.0 .74 22.89 78.31 Capmul Compritol 888 Crodacid B Liposorb S-4 GMS ATO 745-44-E 53.5 2.33 23.66 82.42 Capmul Compritol 888 Crodacid B Solutol HS 15 Methocel GMS ATO E4M 745-44-F 72.6 15 1427 96.29 Capmul Compritol 888 Crodacid B Solutol HS 15 Ganex GMS ATO WP-660 745-44-G 723 84 23.37 81.92 Capmul Compritol 888 Crodacid B Solutol HS 15 Methocel GMS ATO A4K 745-44-H 69.6 19 14.15 87.68 Capmul Compritol 888 Crodacid B Solutol HS 15 Ganex GMS ATO V-22OF or a blend of the two with gentle heating (60°C.) and vortex 0248 All references, including publications, patent appli mixing. The resulting Solution was combined with water to cations, and patents, cited herein are hereby incorporated by intiate the crystallization of the mixed phase co-crystals and reference to the same extent as if each reference were vortexed for 18 to 48 hours at room temperature. The mixed individually and Specifically indicated to be incorporated by phase co-crystals were isolated by filtration, washed with reference and were Set forth in its entirety herein. water, and dried. 0249. The use of the terms “a” and “an” and “the” and 0247 Volpo S-2 refers to steareth-2; Syncrowax AW1-C Similar referents in the context of describing the invention refers to a hard acid wax; Prolipid 141 refers to a compo (especially in the context of the following claims) are to be US 2005/0181041 A1 Aug. 18, 2005 25 construed to cover both the Singular and the plural, unless carbomer and the Second Solution is (b) evaporated, forming otherwise indicated herein or clearly contradicted by con a mixed phase co-crystal composition. text. The terms “comprising,”“having,”“including,” and 4. The method of claim 1, wherein the solvent is selected “containing” are to be construed as open-ended terms (i.e., from the group consisting of transesterfied vegetable oils, meaning “including, but not limited to,”) unless otherwise 1-pentanol, 1-propanol, 1-butanol, 2-butanol, 2-methyl-1- noted. Recitation of ranges of values herein are merely propanol, 2-piperidone, 2-pyrrolidone, 3-methyl-1-butanol, intended to Serve as a shorthand method of referring indi acetone, acetyl tributyl citrate, acetyl triethylcitrate, acety vidually to each Separate value falling within the range, lated glycerol fatty acid esters, acetylated monoglycerides unless otherwise indicated herein, and each Separate value is and Sterols, benzyl alcohol, butanediol and isomers thereof, incorporated into the Specification as if it were individually butanol, butyl acetate, Co fatty acids, C and Co mono and recited herein. All methods described herein can be per diglycerides and mixtures thereof, Cs and Co triglycerides, formed in any Suitable order unless otherwise indicated cumene, dimethyl isosorbide, dimethyl Sulphoxide, ethanol, herein or otherwise clearly contradicted by context. The use ethyl acetate, ethyl butyrate, ethyl caprylate, ethyl ether, of any and all examples, or exemplary language (e.g., "Such ethyl formate, ethyl oleate, ethyl propionate, fatty acids, as”) provided herein, is intended merely to better illuminate glycerol, glycerol fatty acid esters, glyceryl dicaprate, glyc the invention and does not pose a limitation on the Scope of eryl dicaprylate, glyceryl dilaurate, glyceryl dioleate, glyc the invention unless otherwise claimed. No language in the eryl monocaprate, glyceryl monocaprylate, glyceryl mono Specification should be construed as indicating any non laurate, glyceryl monooleate, glycofurol, heptane, claimed element as essential to the practice of the invention. hydrogenated vegetable oils, isobutyl acetate, isopropanol, 0250 Preferred embodiments of this invention are isopropyl acetate, lactic acid conjugates of mono- and dig described herein, including the best mode known to the lycerides, lauric acid, lower alcohol fatty acid esters, meth inventors for carrying out the invention. Variations of those oxy PEG, methyl acetate, methylethylketone, methylisobu preferred embodiments may become apparent to those of tylketone, N-hydroxyalkpyrrolidone, N-methylpyrrolidone, ordinary skill in the art upon reading the foregoing descrip oleic acid, PEG 2-4 oleate, PEG 3-16 castor oil. PEG 5-10 tion. The inventors expect skilled artisans to employ Such hydrogenated castor oil, PEG 6-20 almond oil, PEG 6-20 variations as appropriate, and the inventors intend for the corn oil, PEG-20 almond oil, PEG-20 corn oil, PEG-4 invention to be practiced otherwise than as Specifically dilaurate, PEG-4 dioleate, PEG-4 distearate, PEG-6 corn oil, described herein. Accordingly, this invention includes all PEG-6 dioleate, PEG-6 distearate, PEG-6 olive oil, PEG-6 modifications and equivalents of the Subject matter recited in palm kernel oil, PEG-6 peanut oil, PEG-8 dioleate, pen the claims appended hereto as permitted by applicable law. taerythritol, pentane, polyethylene glycol, polyethylene gly Moreover, any combination of the above-described elements col 200-600, polyethylene glycol glycerol fatty acid esters, in all possible variations thereof is encompassed by the polyglyceryl fatty acid esters, polyglyceryl-3 oleate, polyg invention unless otherwise indicated herein or otherwise lyceryl-6 dioleate, polyoxyethylene glycerides, polyoxyeth clearly contradicted by context. ylene Sorbitan fatty acid esters, polyoxyethylene vegetable oils, polyoxyethylene-polyoxypropylene block copolymers, What is claimed is: polypropylene glycol, polypropylene glycol fatty acid 1. A method of preparing mixed phase co-crystal compo esters, propyl acetate, propylene glycol, propylene glycol Sition comprising: diacetate, propylene glycol esters of Cs, propylene glycol esters of unsaturated fatty acids, propylene glycol laurate, (a) forming a first Solution of a first active agent and at propylene glycol oleate, Sorbitan fatty acid esters, Sorbitan least one crystal lattice modifier dissolved in a Solvent; monolaurate, Sorbitan monooleate, t-butylmethyl ether, tet (b) mixing an anti-solvent with the first solution to form rahydofuran, transcutol, triacetin, tributylcitrate, triethylci a Second Solution; and trate, vegetable oils, water, and acetic acid. (c) forming the mixed phase co-crystal composition, 5. The method of claim 1, wherein the anti-solvent is Selected from the group consisting transesterfied vegetable wherein the active agent and crystal lattice modifier are oils, 1-pentanol, 1-propanol, 1-butanol, 2-butanol, 2-methyl contained within the mixed phase co-crystal composi 1-propanol, 2-piperidone, 2-pyrrolidone, 3-methyl-1-bu tion. tanol, acetone, acetyl tributyl citrate, acetyl triethylcitrate, 2. The method of claim 1, wherein after step (b) an initial acetylated glycerol fatty acid esters, acetylated monoglyc meta-stable cyrstalline phase is formed in the Second Solu erides and Sterols, benzyl alcohol, butanediol and isomers tion. thereof, butanol, butyl acetate, Co fatty acids, Cs and Co 3. The method of claim 1, wherein the first solution is (a) mono and diglycerides and mixtures thereof, C and Co mixed with a pharmaceutically acceptable bulking agent triglycerides, cumene, dimethyl isosorbide, dimethyl Sul Selected from the group consisting of microcrystalline cel phoxide, ethanol, ethyl acetate, ethylbutyrate, ethyl capry lulose, lactose anhydrous, lactose monohydrate, Sucrose, late, ethyl ether, ethyl forminate, ethyl oleate, ethyl propi mannitol, maltitol, Sorbitol, calcium phosphate, calcium onate, fatty acids, glycerol, glycerol fatty acid esters, Sulfate, Starch, pregelatinized Starch, Silica, powdered cel glyceryl dicaprate, glyceryl dicaprylate, glyceryl dilaurate, lulose, croScarmollose, bentonite, kaolin, magnesium alu glyceryl dioleate, glyceryl monocaprate, glyceryl monoca minum Silicate, dextrins, amylose, glucose, ethylcellulose, prylate, glyceryl monolaurate, glyceryl monooleate, glyco hydroxyethyl cellulose, hydroxymethyl cellulose, hydrox furol, heptane, hydrogenated vegetable oils, isobutyl acetate, ypropylmethyl cellulose, maltodextrin, povidone, calcium isopropanol, isopropyl acetate, lactic acid conjugates of carbonate, compressible Sugar, cyclodextrins, dextran, talc, mono- and diglycerides, lauric acid, lower alcohol fatty acid Sodium Starch glycolate, gelatin, magnesium carbonate, esters, methoxy PEG, methyl acetate, methylethylketone, magnesium oxide, maltitol, methylcellulose, Xylitol, and methylisobutylketone, N-hydroxyalkylpyrrolidone, N-me US 2005/0181041 A1 Aug. 18, 2005 26 thylpyrrollidone, oleic acid, PEG 2-4 oleate, PEG 3-16 castor Sedatives and hypnotics, thrombolytic agents, thyrotropic oil. PEG 5-10 hydrogenated castor oil, PEG 6-20 almond oil, hormones, uricoSurics, vasodilators, Vasoprotectants, Vita PEG 6-20 corn oil, PEG-20 almond oil, PEG-20 corn oil, mins, Vitamin Sources, Vitamin extracts, and Vulnerary PEG-4 dilaurate, PEG-4 dioleate, PEG-4 distearate, PEG-6 agents. corn oil, PEG-6 dioleate, PEG-6 distearate, PEG-6 olive oil, 7. The method of claim 1, wherein the crystal lattice PEG-6 palm kernel oil, PEG-6 peanut oil, PEG-8 dioleate, modifier is Selected from the group consisting of acetylated pentaerythritol, pentane, polyethylene glycol, polyethylene glycerol fatty acid esters, acetylated monoglycerides, acety glycol 200-600, polyethylene glycol glycerol fatty acid lated monoglycerides of C to Co fatty acids, alkylgluceo esters, polyglyceryl fatty acid esters, polyglyceryl-3 oleate, Sides, alkylmaltosides, bile Salts, cholesterol, corn oil, dig polyglyceryl-6 dioleate, polyoxyethylene glycerides, poly lycerides of C to Co fatty acids, ethyl linoleate, ethyl oxyethylene Sorbitan fatty acid esters, polyoxyethylene Veg oleate, fatty acid Salts, Saturated fatty acids, unsaturated fatty etable oils, polyoxyethylene-polyoxypropylene block acids, fatty alcohols, fractionated cocoanut oil, glycerol fatty copolymers, polypropylene glycol, polypropylene glycol acid esters, glyceryl dicaprate, glyceryl dicaprylate, glyceryl fatty acid esters, propyl acetate, propylene glycol, propylene dilaurate, glyceryl dioleate, glyceryl monocaprate, glyceryl glycol diacetate, propylene glycol esters of Cs, propylene monocaprylate, glyceryl monolaurate, glyceryl monooleate, glycol esters of unsaturated fatty acids, propylene glycol isopropyllinoleate, isopropyl myristate, isopropyl palmitate, laurate, propylene glycol oleate, Sorbitan fatty acid esters, lactic acid conjugates of diglycerides, lactic acid conjugates Sorbitan monolaurate, Sorbitan monooleate, t-butylmethyl of mono- and diglycerides, lactic acid conjugates of ether, tetrahydofuran, transcutol, triacetin, tributylcitrate, monoglycerides, lauric acid, lauryl macrogolglycenides, triethylcitrate, vegetable oils, water, and acetic acid. lower alcohol fatty acids esters, monoglycerides of a C to 6. The method of claim 1, wherein the active agent is Co fatty acids, myristic acid, oleic acid, palmitic acid, PEG elected from the group consisting of adrenergic agonists, 10-100 lionyl phenol series, PEG 1-4 stearate, PEG 15-100 B-adrenergic agonists, C.-adrenergic blockers, B-adrenergic octyl phenol series, PEG 20 dilaurate, PEG 20 glyceryl blockers, alcohol deterrents, aldose reductase inhibitors, stearate, PEG 2-4 oleate, PEG 2-5 oleyl ether, PEG 3-16 anabolics, analgesics, androgens, anesthetics, anorectics, castor oil, PEG 5-10 hydrogenated castor oil, PEG 5-20 soya anthelmintics, anti-acne drugs, antiallergics, antiamebics, sterol, PEG 6-20 almond oil, PEG 6-20 corn oil, PEG-10 antiandrogens, antianginals, antiarrhythmics, antiarterio laurate, PEG-100 stearate, PEG-12 laurate, PEG-12 oleate, Sclerotics, antiarthritic/antirheumatics, antibacterial drugs, PEG-15 stearate, PEG-2 cetyl ether, PEG-2 stearyl ether, anticholinergics, anticonvulsants, antidepressants, antidia PEG-20 almond oil, PEG-20 corn oil, PEG-20 dioleate, betics, antidiarrheal drugs, antidiuretics, antiestrogens anti PEG-20 glyceryl laurate, PEG-20 glycidyl oleate, PEG-20 fungal drugs, antiglaucoma drugs, antigonadotropins, anti laurate, PEG-20 oleate, PEG-20 trioleate, PEG-200 oleate, gout drugs, antihistamines, antihyperlipoproteinemics, PEG-24 cholesterol, PEG-25 glyceryl trioleate, PEG-25 antihypertensive drugs, antihyperthyroids, antihypotensive phytosterol, PEG-30 cholesterol, PEG-30 glyceryl laurate, drugs, antihypothyroid drugs, anti-inflammatory drugs, anti PEG-30 glyceryl oleate, PEG-30 soya sterol, PEG-32 dilau malarial drugs, antimigraine drugs, antinauseant drugs, anti rate, PEG-32 dioleate, PEG-32 distearate, PEG-32 laurate, neoplastic drugs, antineoplastic adjuncts, antiparkinsonian PEG-32 oleate, PEG-35 castor oil, PEG-4 capric/caprylic drugs, antipheochromocytoma drugs, antipneumocystis triglyceride, mono, di, tri, tetra esters of vegetable oil and drugs, antiprostatic hypertrophy drugs, antiprotozoal drugs, Sorbitol, PEG-4 dilaurate, PEG-4 dioleate, PEG-4 distearate, antipuritics, antipsoriatic drugs, antipsychotic drugs, anti PEG-40 castor oil, PEG-40 glyceryl laurate, PEG-40 hydro pyretics, antirickettsial drugs, antiseborrheic drugs, antisep genated castor oil, PEG-40 palm kernel oil, PEG-40 stearate, tics, antispasmodic drugs, antithrombotic drugs, antituSSive PEG-400 oleate, PEG-50 hydrogenated castor oil, PEG-6 drugs, antiulcerative drugs, antiurolithic drugs, antiviral caprate/caprylate glycerides, PEG-6 corn oil, PEG-6 drugs, anxiolytic drugs, benzodiazepine antagonists, bron dioleate, PEG-6 distearate, PEG-6 hydrogenated palm ker chodilators, calcium channel blockers, calcium regulators, nel oil, PEG-6 olive oil, PEG-6 palm kernel oil, PEG-6 cardiotonics, chelating agents, cholecystokinin antagonists, peanut oil, PEG-6 sorbitan tetra, hexastearate, PEG-6 sor cholelitholytic agents, choleretics, cholinergic agents, cho bitan tetraoleate, PEG-60 castor oil, PEG-60 corn oil, PEG linesterase inhibitors, cholinesterase reactivators, central 60 hydrogenated castor oil, PEG-8 caprate/caprylate glyc nervous System Stimulants and agents, decongestants, dental erides, PEG-8 caprate/caprylate glycerides, PEG-8 dioleate, carrier prophylactics, depigmentors, diuretics, dopamine PEG-80 Sorbitan laurate, pentaerythritol di, tetra stearate, receptor agonists, ectoparasiticides, enzyme inducers, estro isoStearate, oleate, caprylatc, or caprate, phospholipids, gens, gastric Secretion inhibitors, glucocorticoids, gonad phosphoric acid polyoxymethylene alkylethers, phytosterol, Stimulating principles, gonadotropic hormones, growth hor Pluronic F68, Pluronics, poloxamers, polyethylene glycol mone inhibitors, growth hormone releasing factors, growth fatty acids esters, polyethylene glycol glycerol fatty acid Stimulants, hemolytic agents, heparin antagonists, hepato esters, polyglyceryl 2-4 oleate, Stearate, or isoStearate, protectants, immunomodulators, immunosuppreSSants, ion polyglyceryl 4-10 pentaoleate, polyglyceryl fatty acid esters, eXchange resins, lactation Stimulating hormone, LH-RH polyglyceryl fatty acid esters, fatty acids, polyglyceryl-10 agonists, lipotropic agents, lupus erythematoSuS Suppres laurate, polyglyceryl-10 trioleate, polyglyceryl-3 dioleate, Sants, mineralcorticoids, miotic drugs, monoamine oxidase polyglyceryl-3 distearate, polyglyceryl-3 oleate, polyglyc inhibitors, mucolytic agents, muscle relaxants, narcotic eryl-6 dioleate, polyglyceryl-6 dioleate, polyoxyethylene antagonists, neuroprotective agents, nootropic agents, oph alkyl ethers, polyoxyethylene alkylphenols, polyoxyethyl thalmic agents, ovarian hormones, oxytocic drugs, pepsin ene glycerides, polyoxyethylene hydrogenated vegetable inhibitors, peristaltic Stimulants, progestogens, prolactin oils, polyoxyethylene Sorbitan fatty acid esters, polyoxyeth inhibitors, prostaglandins and prostaglandin analogs, pro ylene Sterols, polyoxyethylene vegetable oils, polyoxyeth tease inhibitors, respiratory Stimulants, Sclerosing agents, ylene vegetable oils, polyoxyethylene hydrogenated Veg US 2005/0181041 A1 Aug. 18, 2005 27 etable oils, polyoxyethylene-polyoxypropylene block 2-5 oleyl ether, PEG 3-16 castor oil, PEG 5-10 hydrogenated copolymers, polyoxyethylene-polyoxypropylene block castor oil, PEG 5-20 soya sterol, PEG 6-20 almond oil, PEG copolymers, polypropylene glycol fatty acid esters, polySor 6-20 corn oil, PEG-10 laurate, PEG-100 stearate, PEG-12 bate 20, polySorbate 80, propylene glycol diglycerides, laurate, PEG-12 oleate, PEG-15 stearate, PEG-2 cetyl ether, propylene glycol laurate, propylene glycol mono- or diesters PEG-2 stearyl ether, PEG-20 almond oil, PEG-20 corn oil, of a C to Cofatty acids fatty acids, propylene glycol oleate, PEG-20 dioleate, PEG-20 glyceryl laurate, PEG-20 glycidyl reaction mixtures of polyols and at least one member oleate, PEG-20 laurate, PEG-20 oleate, PEG-20 trioleate, Selected from the group consisting of fatty acids, glycerides, PEG-200 oleate, PEG-24 cholesterol, PEG-25 glyceryl tri vegetable oils, hydrogenated vegetable oils, and Sterols, oleate, PEG-25 phytosterol, PEG-30 cholesterol, PEG-30 Sesame Seed oil, Sorbitan fatty acid esters, Sorbitan mono, glyceryl laurate, PEG-30 glyceryl oleate, PEG-30 Soya trioleate, Sorbitan mono, tristearate, Sorbitan monoisoStear sterol, PEG-32 dilaurate, PEG-32 dioleate, PEG-32 distear ate, Sorbitan monolaurate, Sorbitan monooleate, Sorbitan ate, PEG-32 laurate, PEG-32 oleate, PEG-35 castor oil, monopalmitate, Sorbitan monoStearate, Sorbitan Sesqui PEG-4 capric/caprylic triglyceride, mono, di, tri, tetra esters oleate, Sorbitan Sesquistearate, Soybean oil, Stearic acid, of vegetable oil and Sorbitol, PEG-4 dilaurate, PEG-4 Sterols, Sucroglycerides, Sucrose dipalmitate, Sucrose dis dioleate, PEG-4 distearate, PEG-40 castor oil, PEG-40 glyc tearate, Sucrose monolaurate, Sucrose monopalmitate, eryl laurate, PEG-40 hydrogenated castor oil, PEG-40 palm Sucrose monoStearate, Sugar esters, Sugar ethers, tocopheryl kernel oil, PEG-40 stearate, PEG-400 oleate, PEG-50 hydro PEG-100 succinate, tocopheryl PEG-1000 succinate, trans genated castor oil, PEG-6 caprate/caprylate glycerides, esteriefied vegetable oils, Tween 40, Tween 60, and mixtures PEG-6 corn oil, PEG-6 dioleate, PEG-6 distearate, PEG-6 thereof. hydrogenated palm kernel oil, PEG-6 olive oil, PEG-6 palm 8. The method of claim 1, further comprising adding an kernel oil, PEG-6 peanut oil, PEG-6 sorbitan tetra, hexas acid modifier Selected from the group consisting of acetic tearate, PEG-6 Sorbitan tetraoleate, PEG-60 castor oil, PEG acid, acrylic acid, adipic acid, alginic acid, alkaneSulfonic 60 corn oil, PEG-60 hydrogenated castor oil, PEG-8 caprate/ acid, an amino acid, ascorbic acid, benzoic acid, boric acid, caprylate glycerides, PEG-8 caprate/caprylate glycerides, butyric acid, carbonic acid, citric acid, a fatty acid, formic PEG-8 dioleate, PEG-80 Sorbitan laurate, pentaerythritol di, acid, fuimaric acid, gluconic acid, hydroquinoSulfonic acid, tetra Stearate, isoStearate, oleate, caprylatc, or caprate, phos hydrochloric acid, isoascorbic acid, lactic acid, maleic acid, pholipids, phosphoric acid polyoxymethylene alkylethers, methaneSulfonic acid, oxalic acid, para-bromophenylsul phytosterol, Pluronic F68, Pluronics, poloxamers, polyeth fonic acid, phosphoric acid, propionic acid, p- ylene glycol fatty acids esters, polyethylene glycol glycerol Sulfonic acid, Salicylic acid, Stearic acid, Succinic acid, fatty acid esters, polyglyceryl 2-4 oleate, Stearate, or isOS tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic tearate, polyglyceryl 4-10 pentaoleate, polyglyceryl fatty acid, uric acid, and mixtures thereof. acid esters, polyglyceryl fatty acid esters, fatty acids, polyg 9. The method of claim 1, further comprising adding a lyceryl-10 laurate, polyglyceryl-10 trioleate, polyglyceryl-3 base modifier Selected from the group consisting of ammo dioleate, polyglyceryl-3 distearate, polyglyceryl-3 oleate, nia, ethanolamine, diethanolamine, glucosamine, trolamine, polyglyceryl-6 dioleate, polyglyceryl-6 dioleate, polyoxy Sodium bicarbonate, potassium bicarbonate, Sodium hydrox ethylene alkyl ethers, polyoxyethylene alkylphenols, poly ide, potassium hydroxide, TRIS, arginine, lysine, magne oxyethylene glycerides, polyoxyethylene hydrogenated Veg sium hydroxide, calcium hydroxide, Sodium carbonate, etable oils, polyoxyethylene Sorbitan fatty acid esters, potassium carbonate, ammonium bicarbonate, and mixtures polyoxyethylene Sterols, polyoxyethylene vegetable oils, thereof. polyoxyethylene vegetable oils, polyoxyethylene hydroge 10. The method of claim 1, further comprising adding an nated vegetable oils, polyoxyethylene-polyoxypropylene antioxidant modifier Selected from the group consisting of block copolymers, polyoxyethylene-polyoxypropylene C-tocopherol, ascorbic acid, ascorbyl palmitate, BHT, BHA, block copolymers, polypropylene glycol fatty acid esters, malic acid, propyl gallate, and mixtures thereof. polySorbate 20, polySorbate 80, propylene glycol diglycer 11. The method of claim 1, further comprising adding a ides, propylene glycol laurate, propylene glycol mono- or Surfactant modifier Selected from the group consisting of diesters of a C to Co fatty acids fatty acids, propylene acetylated glycerol fatty acid esters, acetylated monoglyc glycol oleate, reaction mixtures of polyols and at least one erides, acetylated monoglycerides of C to Co fatty acids, member Selected from the group consisting of fatty acids, alkylgluceosides, alkylmaltosides., bile Salts, cholesterol, glycerides, vegetable oils, hydrogenated vegetable oils, and corn oil, diglycerides of C to Cofatty acids, ethyllinoleate, Sterols, Sesame Seed oil, Sorbitan fatty acid esters, Sorbitan ethyl oleate, fatty acid Salts, Saturated fatty acids, unsatur mono, trioleate, Sorbitan mono, tristearate, Sorbitan monoi ated fatty acids, fatty alcohols, fractionated cocoanut oil, SOStearate, Sorbitan monolaurate, Sorbitan monooleate, Sor glycerol fatty acid esters, glyceryl dicaprate, glyceryl dica bitan monopalmitate, Sorbitan monoStearate, Sorbitan Ses prylate, glyceryl dilaurate, glyceryl dioleate, glyceryl mono quioleate, Sorbitan Sesquistearate, Soybean oil, Stearic acid, caprate, glyceryl monocaprylate, glyceryl monolaurate, Sterols, Sucroglycerides, Sucrose dipalmitate, Sucrose dis glyceryl monooleate, isopropyl linoleate, isopropyl tearate, Sucrose monolaurate, Sucrose monopalmitate, myristate, isopropyl palmitate, lactic acid conjugates of Sucrose monoStearate, Sugar esters, Sugar ethers, tocopheryl diglycerides, lactic acid conjugates of mono- and diglycer PEG-100 Succinate, tocopheryl PEG-1000 succinate, trans ides, lactic acid conjugates of monoglycerides, lauric acid, esteriefied vegetable oils, Tween 40, Tween 60, and mixtures lauryl macrogolglycenides, lower alcohol fatty acids esters, thereof. monoglycerides of a C to Co fatty acids, myristic acid, 12. The method of claim 1, further comprising adding at oleic acid, palmitic acid, PEG 10-100 lionyl phenol series, least one additional crystal lattice modifier Selected from the PEG 1-4 stearate, PEG 15-100 octyl phenol series, PEG 20 group consisting of acetylated glycerol fatty acid esters, dilaurate, PEG 20 glyceryl Stearate, PEG 2-4 oleate, PEG acetylated monoglycerides, acetylated monoglycerides of US 2005/0181041 A1 Aug. 18, 2005 28

C to Co fatty acids, alkylgluceosides, alkylmaltosides, bile polyoxyethylene hydrogenated vegetable oils, polyoxyeth Salts, cholesterol, corn oil, diglycerides of C to Co fatty ylene-polyoxypropylene block copolymers, polyoxyethyl acids, ethyl linoleate, ethyl oleate, fatty acid Salts, Saturated ene-polyoxypropylene block copolymers, polypropylene fatty acids, unsaturated fatty acids, fatty alcohols, fraction glycol fatty acid esters, polySorbate 20, polySorbate 80, ated cocoanut oil, glycerol fatty acid esters, glyceryl dica propylene glycol diglycerides, propylene glycol laurate, prate, glyceryl dicaprylate, glyceryl dilaurate, glyceryl propylene glycol mono- or diesters of a C to Cofatty acids dioleate, glyceryl monocaprate, glyceryl monocaprylate, fatty acids, propylene glycol oleate, reaction mixtures of glyceryl monolaurate, glyceryl monooleate, isopropyl polyols and at least one member Selected from the group linoleate, isopropyl myristate, isopropyl palmitate, lactic consisting of fatty acids, glycerides, vegetable oils, hydro acid conjugates of diglycerides, lactic acid conjugates of genated vegetable oils, and Sterols, Sesame Seed oil, Sorbitan mono- and diglycerides, lactic acid conjugates of monoglyc fatty acid esters, Sorbitan mono, trioleate, Sorbitan mono, erides, lauric acid, lauryl macrogolglycenides, lower alcohol triStearate, Sorbitan monoisoStearate, Sorbitan monolaurate, fatty acids esters, monoglycerides of a C to Co fatty acids, Sorbitan monooleate, Sorbitan monopalmitate, Sorbitan myristic acid, oleic acid, palmitic acid, PEG 10-100 lionyl monoStearate, Sorbitan Sesquioleate, Sorbitan Sesquistearate, phenol series, PEG 1-4 stearate, PEG 15-100 octyl phenol Soybean oil, Stearic acid, Sterols, Sucroglycerides, Sucrose series, PEG 20 dilaurate, PEG 20 glyceryl Stearate, PEG 2-4 dipalmitate, Sucrose distearate, Sucrose monolaurate, oleate, PEG 2-5 oleyl ether, PEG 3-16 castor oil, PEG 5-10 Sucrose monopalmitate, Sucrose monoStearate, Sugar esters, hydrogenated castor oil, PEG 5-20 soya sterol, PEG 6-20 Sugar ethers, tocopheryl PEG-100 Succinate, tocopheryl almond oil, PEG 6-20 corn oil, PEG-10 laurate, PEG-100 PEG-1000 Succinate, transesteriefied vegetable oils, Tween Stearate, PEG-12 laurate, PEG-12 oleate, PEG-15 Stearate, 40, Tween 60, and mixtures thereof. PEG-2 cetyl ether, PEG-2 stearyl ether, PEG-20 almond oil, 13. The method of claim 1, wherein the active agent is less PEG-20 corn oil, PEG-20 dioleate, PEG-20 glyceryl laurate, than about 10,000 daltons in molecular weight. PEG-20 glycidyl oleate, PEG-20 laurate, PEG-20 oleate, 14. The method of claim 1, further comprising isolating PEG-20 trioleate, PEG-200 oleate, PEG-24 cholesterol, the mixed phase co-crystal composition. PEG-25 glyceryl trioleate, PEG-25 phyto sterol, PEG-30 15. The method of claim 1, further comprising washing cholesterol, PEG-30 glyceryl laurate, PEG-30 glyceryl ole the mixed phase co-crystal composition. ate, PEG-30 soya sterol, PEG-32 dilaurate, PEG-32 dioleate, 16. The method of claim 1, further comprising drying the PEG-32 distearate, PEG-32 laurate, PEG-32 oleate, PEG-35 mixed phase co-crystal composition. castor oil, PEG-4 capric/caprylic triglyceride, mono, di, tri, 17. The method of claim 1, wherein the solvent is miscible tetra esters of vegetable oil and Sorbitol, PEG-4 dilaurate, with the anti-solvent. PEG-4 dioleate, PEG-4 distearate, PEG-40 castor oil, PEG 18. The method of claim 1, wherein the anti-solvent is a 40 glyceryl laurate, PEG-40 hydrogenated castor oil, PEG compatible fill System for Soft gelatin capsules. 40 palm kernel oil, PEG-40 stearate, PEG-400 oleate, PEG 19. The method of claim 1, wherein the anti-solvent is a 50 hydrogenated castor oil, PEG-6 caprate/caprylate compatible fill System for liquid filled hard gelatin capsules. glycerides, PEG-6 corn oil, PEG-6 dioleate, PEG-6 distear 20. The method of claim 1, wherein the Solvent and ate, PEG-6 hydrogenated palm kernel oil, PEG-6 olive oil, anti-Solvent are Substantially removed from the mixed phase PEG-6 palm kernel oil, PEG-6 peanut oil, PEG-6 sorbitan crystalline material, Such that the mixed phase crystalline tetra, hexastearate, PEG-6 Sorbitan tetraoleate, PEG-60 cas material is a dry powder Suitable for direct encapsulation or tor oil, PEG-60 corn oil, PEG-60 hydrogenated castor oil, tableting. PEG-8 caprate/caprylate glycerides, PEG-8 caprate/capry 21. A mixed phase co-crystal composition prepared by the late glycerides, PEG-8 dioleate, PEG-80 sorbitan laurate, method of claim 1. pentaerythritol di, tetra Stearate, isoStearate, oleate, capry 22. A mixed phase co-crystal composition comprising a latc, or caprate, phospholipids, phosphoric acid polyoxym mixed phase co-crystal of an active agent and at least one ethylene alkylethers, phytosterol, Pluronic F68, Pluronics, crystal lattice modifier, wherein the content of the active poloxamers, polyethylene glycol fatty acids esters, polyeth agent ranges from about 5% to 95% by weight of the total ylene glycol glycerol fatty acid esters, polyglyceryl 2-4 weight of the material and wherein the crystal lattice modi oleate, Stearate, or isoStearate, polyglyceryl 4-10 penta fier ranges from 2% to 95% by weight for each individual oleate, polyglyceryl fatty acid esters, polyglyceryl fatty acid modifier of the total weight of the material. esters, fatty acids, polyglyceryl-10 laurate, polyglyceryl-10 23. The composition of claim 22, wherein the composi trioleate, polyglyceryl-3 dioleate, polyglyceryl-3 distearate, tion provides (a) an increase in water Solubility, (b) a polyglyceryl-3 oleate, polyglyceryl-6 dioleate, polyglyc decrease in melting point, (c) decrease in melting enthalpy, eryl-6 dioleate, polyoxyethylene alkyl ethers, polyoxyeth (d) an increase in dissolution rate, (e) a reduction in crys ylene alkylphenols, polyoxyethylene glycerides, polyoxy tallinity, or (f) a combination of two or more of (a)-(e) as ethylene hydrogenated vegetable oils, polyoxyethylene compared to the active agent alone. Sorbitan fatty acid esters, polyoxyethylene Sterols, polyoxy ethylene vegetable oils, polyoxyethylene vegetable oils, k k k k k