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(12) United States Patent (10) Patent No.: US 9,682,043 B2 Goldman (45) Date of Patent: Jun. 20, 2017

(54) METHOD OF PREPARATION OF MIXED FOREIGN PATENT DOCUMENTS PHASE CO-CRYSTALS WITH ACTIVE AGENTS JP 63-240936 A 10, 1988 JP 2003-522097 A 8, 1999 JP 20O2506876 A 3, 2002 (75) Inventor: David Goldman, Portland, CT (US) JP 2002356419 A 12/2002 WO WO99/47543 A2 9, 1999 (73) Assignee: MedCrystallForms, LLC, Hunt Valley, WO WO O2/O55,059 A2 T 2002 MD (US) WO WO O3/101392 A2 12/2003 WO WO 2004/043358 5, 2004 (*) Notice: Subject to any disclaimer, the term of this WO WO 2004/078161 A1 9, 2004 patent is extended or adjusted under 35 WO WO 2004/082666 9, 2004 U.S.C. 154(b) by 537 days. OTHER PUBLICATIONS (21) Appl. No.: 11/008,034 Lide CRC Handbook of Chemistry and Physics 2003 p. 3-246 and 3-480. (22) Filed: Dec. 9, 2004 Meyerson et al. “Crystals, Crystal Growth, and Nucleation' Hand book of Industrial Crystallization Ed. Meyerson. Woburn: But (65) Prior Publication Data terworth-Heinemann 2002 p. 33, and 38-39.* US 2005/0181041 A1 Aug. 18, 2005 Payne et al. International Journal of Pharmaceutics 1999 177:231 245-k Zhang et al. Journal of Pharmaceutical Sciences 2007 96(5):990 Related U.S. Application Data 995.* (60) Provisional application No. 60/528.232, filed on Dec. Reutzel-Edens et al. Solid-state pharmaceutical development: 9, 2003, provisional application No. 60/559,862, filed Ensuring stability through salt and polymorph screening. Pharma ceutical Stress Testing. Ed. Baertschi et al. New York:Informa on Apr. 6, 2004. Healthcare 2011 p. 254 and 266-267.* Drenth Principles of Protein X-ray Crystallography 1999 New (51) Int. Cl. York:Springer Science+Business Media p. 19.* A6 IK 9/14 (2006.01) International Search Report for PCT/US2004/041500 (Oct. 6, A6 IK 8/63 (2006.01) 2006). A6 IK 9/48 (2006.01) Khan et al. "Stability characterization of controlled release A6 IK 9/10 (2006.01) coprecipitates and Solid dispersions,” Journal of Controlled Release, (52) U.S. Cl. Elsevier Science Publishers B.V., vol. 63, No. 1-2, Jan. 2000. Japanese Patent Office, Office Action in connection with Japanese CPC ...... A61K 9/145 (2013.01); A61K 8/63 Patent Application No. 1495.02/2011 (May 7, 2013). (2013.01); A61K 9/146 (2013.01); A61K 9/148 Japanese Patent Office, Office Action in connection with Japanese (2013.01); A61 K 9/10 (2013.01); A61 K9/4858 Patent Application No. 182177/2014 (May 24, 2016). (2013.01) Japanese Patent Office, Office Action in connection with Japanese (58) Field of Classification Search Patent Application No. 182177/2014 (Aug. 18, 2015). None See application file for complete search history. * cited by examiner (56) References Cited Primary Examiner — Robert A Wax Assistant Examiner — Caralynne Helm U.S. PATENT DOCUMENTS (74) Attorney, Agent, or Firm — Leydig, Voit & Mayer, 4,384,980 A 5, 1983 Patel et al. Ltd. 4,606.909 A * 8/1986 Bechgaard et al...... 424/469 5,118,528 A 6, 1992 Fessi et al. (57) ABSTRACT 5,266,712 A * 11/1993 Lanquetin ...... 552,574 5,665,331 A 9/1997 Bagchi et al. This invention pertains to a method of preparing mixed 2002/0142049 A1 * 10, 2002 Lee ...... 424/499 phase co-crystals of active agents with one or more materials 2003/0003155 A1* 1/2003 Kipp et al...... 424/489 that allows the modification of the active agent to a new 2003/0031721 A1 2/2003 Bogue physical/crystal form with unique properties useful for the 2003/0049323 A1 3f2003 Hitt et al...... 424/489 2003.0068384 A1 4/2003 Brocchini et al. delivery of the active agent, as well as compositions com 2003/0077297 A1* 4, 2003 Chen et al...... 424/400 prising the mixed phase co-crystals. 2003/0077329 A1 * 4/2003 Kipp et al...... 424/489 2003. O166509 A1 9, 2003 Edwards et al. 1 Claim, 8 Drawing Sheets U.S. Patent Jun. 20, 2017 Sheet 1 of 8 US 9,682,043 B2

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peNIOSSIO % US 9,682,043 B2 1. 2 METHOD OF PREPARATION OF MIXED phase co-crystals enable, and lack the multi-functional PHASE CO-CRYSTALS WITH ACTIVE aspects that mixed phase co-crystals offer with respect to AGENTS improved drug delivery. Co-crystallization of chemically related materials is illus CROSS-REFERENCE TO RELATED PATENT 5 trated by the preparation of co-crystallized sugars (U.S. Pat. APPLICATIONS Nos. 4,101,680 and 4.338,339), of acetylenic compounds (U.S. Pat. No. 4,384,980), and sugar alcohols (U.S. Pat. Nos. This patent application claims the benefit of U.S. Provi 5,679,398; 5,958,471 and 6,083,438). The simple co-crys sional Patent Application No. 60/559,862, filed Apr. 6, 2004 tals therein described do not have the broad utility that and U.S. Provisional Patent Application No. 60/528.232, 10 mixed phase co-crystals have for the enhancement of prop filed Dec. 9, 2003, which are incorporated by reference erties of widely different structures and physico-chemical herein. properties. Incorporation of minor components by a process FIELD OF THE INVENTION described as co-crystallization that yields a product of 15 indeterminate crystalline structure is illustrated by U.S. Pat. This invention pertains to methods of preparing an active Nos. 6,376,481, and 6,267.963 (sterol esters); U.S. Pat. No. agent as mixed phase co-crystals that have unique physical 6.214,402 (dilution of sweetener); U.S. Pat. No. 4,751,294 properties that differ from the active agent in pure form, as (stabilization by a base); U.S. Pat. No. 5,910.523 (nanocom well as compositions comprising mixed phase co-crystals. posites); U.S. Pat. No. 5,876,506 (mesomorphic sugar), U.S. The formulated mixed phase co-crystals are heterogenous Pat. No. 5,075,291 (uniform dispersion of drug in sugar and contain crystalline regions within the particles/granules alcohol); and U.S. Pat. No. 5,451,416. These materials of produced. Mixed phase co-crystals are useful for systemic indeterminate structure lack the ability of mixed phase delivery of the active agent as human and animal pharma co-crystals to maintain primary crystalline characteristics of ceuticals, dietary Supplements, and agrochemicals. Further the active agent while imparting amorphous-like properties more, mixed phase co-crystals have utility in imparting 25 along with designed functionalities to enhance solubility, desirable physical and stability properties otherwise not dissolution, and absorption. achievable for the pure active agent or in combination as a Complex mixtures of crystalline materials formed by simple formulation with the materials incorporated with the melt/congealing process are described in U.S. Pat. No. active agent. 6.267.963 (sterol-emulsion complexes); U.S. Pat. Nos. 30 4.855,326 and 5,853.762 (rapidly dissolving dosage unit); BACKGROUND OF THE INVENTION and U.S. Pat. No. 5,075,291. The process for preparing co-crystals by evaporation or cooling from a solvent system Co-crystals occur in nature and form spontaneously with is described in U.S. Pat. No. 4,145,214 (photoconductors); closely related chemical structures, such as chemical iso U.S. Pat. Nos. 4,751.294; 4,971,797; and 6,214,402. Appli mers (racemates, diasteriomers, and the like). Co-crystals 35 cations for which no active agent is incorporated are are also found for materials that complex together in Solu described in U.S. Pat. Nos. 4,145,214 and 4,384,980. These tion Such as protein-ligands, chelates, inclusion complexes materials of indeterminate structure lack the ability of mixed as with cyclodextrins, and ligands. In U.S. Pat. Nos. 4,971, phase co-crystals to maintain primary crystalline character 797; 6,312,723 and 6.312,712, complexes of cyclodextrin istics of the active agent while imparting amorphous-like and active agents are described as being co-crystallized 40 properties along with designed functionalities to enhance together from solution. These complexes lack the flexibility solubility, dissolution, and absorption. to incorporate materials with broadly different chemical In the field of active agent delivery, inherent problems structures and lack the multi-functional properties that associated with the active agent exist, Such as particle size, mixed co-crystals can impart. stability, solubility, powder physical properties and release In certain cases, macromolecules (both polymers and 45 rates. New and improved methods to solve the problems biopolymers) are capable of forming co-crystals with other associated with active agent delivery are needed. The inven macromolecules. These co-crystallized products have been tion provides such a method, as well as mixed phase used to isolate macromolecules such as proteins for struc co-crystal compositions comprising an active agent. These tural characterization. An example of this is found in the and other advantages of the invention, as well as additional paper by Murphy et al. (Acta Crystallogr D Biol Crystallogr. 50 inventive features, will be apparent from the description of 55(Pt 9), 1594-1597 (1999)). These simple co-crystals are the invention provided herein. not useful to enhance solubility, dissolution or absorption of poorly absorbed active agents. BRIEF SUMMARY OF THE INVENTION Minor amounts of materials can be incorporated in a particle Sub-structure. These components co-exist with crys 55 The invention is directed to a method of preparing mixed talline phases of the particle and produce co-crystalline phase co-crystals comprising: (a) forming a first solution of regions within the particle. The resulting co-crystallized a first active agent and at least one crystal lattice modifier material has a high level of crystallinity and lacks significant dissolved in a solvent; (b) mixing an anti-solvent with the amounts of amorphous phase. Examples of these applica first solution to form a second solution; and (c) forming a tions can be found in patents describing the dilution of 60 mixed phase crystalline material, wherein the active agent Sweetening agents in Sugar carriers as in U.S. Pat. Nos. and crystal lattice modifier are contained within the mixed 6.214,402 and 6.365,216. Incorporation of small amounts of phase crystalline material. single constituents differs from mixed phase co-crystals The invention also is directed to a mixed phase co-crystal since the particles produced do not have a significant amount composition comprising a mixed phase co-crystal of an of amorphous phase as indicated by melting properties and 65 active agent and at least one crystal lattice modifier, wherein solubility. In addition, these materials do not contain an the content of the active agent ranges from about 5% to 95% active agent, lack the high concentrations that the mixed by weight of the total weight of the material, and wherein the US 9,682,043 B2 3 4 crystal lattice modifier ranges from about 2% to 95% by The process herein described for the mixed phase co weight for each individual modifier of the total weight of the crystals is well suited for the direct formation and incorpo material. ration of mixed phase co-crystals as part of the dosage form manufacturing process without the need to isolate or purify BRIEF DESCRIPTION OF THE DRAWINGS the mixed phase co-crystal material. Accordingly, the present invention is directed to mixed FIG. 1A is a graph showing heat flow to temperature of a phase co-crystal compositions and methods of making pure form of active agent wherein the active agent is mixed phase co-crystal compositions. The inventive method hydrocortisone acetate. of preparing mixed phase co-crystals comprises: (a) forming FIG. 1B is a graph showing heat flow to temperature of a 10 a first solution of an active agent and at least one crystal mixed phase co-crystal wherein the active agent is hydro lattice modifier dissolved in a solvent; (b) mixing an anti cortisone acetate. solvent with the first solution to form a second solution; and FIG. 2A is a graph of an x-ray diffraction (XRD) pattern (c) forming the mixed phase co-crystal composition, of pure Stearic acid. wherein the active agent and crystal lattice modifier are FIG. 2B is a graph of an XRD pattern of a mixed phase 15 contained within the mixed phase co-crystal composition. co-crystal of a crystal lattice modifier (Stearic acid) and The inventive method can further comprise evaporating the active agent (hydrocortisone). Solvent(s), isolating the mixed phase co-crystal composition, FIG. 2C is a graph of an XRD pattern of pure active agent washing the mixed phase co-crystal composition, and/or (hydrocortisone). drying the mixed phase co-crystal composition. FIG. 3A is a graph of an XRD pattern of a mixed phase A mixed phase co-crystal is a particle or granule com co-crystal of hydrocortisone (HC) acetate, Methocel E4M posed of two or more crystalline or non-crystalline phases (hydroxypropyl methylcellulose), and cetosteryl alchohol. that are distributed randomly throughout the particle struc FIG. 3B is a graph of an XRD pattern of pure HC acetate. ture. One or more of the mixed phase co-crystal components FIG. 4 is a graph comparing dissolution profiles (mcg/mL 25 must be solids at room temperature. over time) of mixed phase co-crystals of cyclosporin pre An active agent that is co-crystallized with one or more pared using the method described in Example 4. materials (additives) forms a mixed phase co-crystalline FIG. 5 is a graph showing the intrinsic dissolution rate of form of the active agent and additive(s) that behaves as itraconazole mixed phase co-crystals in a 3% sodium lauryl conglomerated particles or granules that have unique physi sulfate 20% isopropanol:0.1 NHCl (1:1) media. 30 cal properties that are distinguishable from the pure active FIG. 6 is a graph showing comparing the in vitro disso agent or pure additive(s). These formulated mixed phase lution rate for four lots of mixed phase co-crystal formula co-crystals have crystalline, co-crystalline, and amorphous tions (F833-023c, -024A, -025A, and -025B) containing the regions within the particle matrix. The active agent's crys active ingredient progesterone as compared to commercial talline form is usually maintained except that the additive(s) Prometrium 200 mg capsules from two batches. 35 are co-crystallized as part of active agent's crystal lattice structure, thus forming co-crystalline regions or amorphous DETAILED DESCRIPTION OF THE regions or semi-crystalline regions with crystal defects. This INVENTION results in a characteristic reduction in melting point and crystallinity of the thermodynamically favored crystalline The mixed phase co-crystal materials produced by this 40 form of the active agent. invention have unique and unexpected properties such as Although not wishing to be bound by any particular increased apparent solubility, increased dissolution rate, theory, it is believed that the additive(s) are co-crystallized reduced melting point of the active agent, and decrease in as minor non-stoichiometric components in the active crystallinity of the active agent. In addition, the mixed phase agent's crystalline matrix. This co-crystalline phase has co-crystal materials produce Supersaturated concentrations 45 semi-crystalline nature and contains a high incidence of of active agent for prolonged periods of time when Sus crystal defects. Any excess additive that is not co-crystal pended in water, which facilitates absorption in vivo. These lized with the active agent forms a separate phase (Additive changes in properties of the active agent are particularly Phase) apart from the active agent, which results in the advantageous for the delivery of the active agent, e.g., in an mixed phase co-crystal composition. The Additive Phase oral dosage form. 50 and the active agent crystals containing co-crystallized addi Furthermore, combinations of more than one crystal lat tive can be tightly agglomerated forming a mixed phase tice modifier with the active agent can result in additive and co-crystal particle. The unique physical properties obtained super-additive effects that cannot be obtained with mono by this process of preparation can include changes in appar tropic co-crystal materials. The enhanced properties of the ent solubility, crystallinity, water wetability, dissolution mixed phase co-crystal materials are obtained even when the 55 rates, physical powder properties (e.g., bulk density, abso thermodynamically favored polymorph of the active agent is lute density, refractive index, X-ray diffraction, spectral, present as a component of the mixed phase co-crystal flowability, hygroscopicity, adsorption, and compaction), structure. Mixed phase co-crystal materials enable formation bioavailability, apparent permeability, apparent taste, and/or of conglomerates of the active agent with modifiers that stability. For example, the inventive method of preparation facilitate drug absorption process through permeability 60 of the composition provides (a) an increase in water solu modification, inhibitors of gut wall metabolism, and Stabi bility, (b) a decrease in melting point, (c) decrease in melting lization of Supersaturated Solutions. Since these materials enthalpy, (d) an increase in dissolution rate, (e) a reduction are linked through the conglomerated mixed phase co in crystallinity, or (f) a combination of two or more of (a)-(e) crystal structure, they act in concert with the dissolution of as compared to the active agent itself. the active agent and are resistant to premature dissolution of 65 The mixed phase co-crystal that forms from the active the modifier in the absence of the active agent. By this agent and additive(s) is not a pure form stiochiometric mechanism the modifier imparts a full effect. eutectic. The mixed phase co-crystal composition produced US 9,682,043 B2 5 6 according to the invention are thermodynamically favored. 3. C.-Adrenergic blockers such as Amosulalol, Arotinolol. That is, the crystals exist at a lower energy, stable state. Dapiprazole, Doxazosin, Ergoloid Mesylates, Fenspiride, In another aspect of the invention, after step (b) a kineti Indoramin, Labetalol, Nicergoline, PraZosin, Terazosin, cally favored crystalline phase is formed in the second Tolazoline, Trimazosin and Yohimbine. solution. The kinetically favored crystalline phase is also 5 4. B-Adrenergic blockers such as Acebutolol, Alprenolol. characterized as kinetically derived, meta-stable and ther Amosulalol, Arotinolol, Atenolol, Befunolol, Betaxolol, modynamically disfavored. The meta-stable (i.e., kinetically Bevantolol, Bisoprolol, Bopindolol, Bucumolol. Befetolol, favored) crystalline phase is typically formed as a precipiate Bufuralol, Bunitrolol, Bupranolol. Butidrine Hydrochloride, in the second Solution. The meta-stable crystalline phase is Butofilolol, Carazolol, Carteolol, Carvedilol, Celiprolol, 10 Cetamolol, Cloranolol, Dilevalol, Epanolol, Esmolol, Inde then Subsequently transformed (i.e., converted) to the ther nolol, Labetalol, Levobunolol, Mepindolol, Metipranalol, modynamically favored mixed-phase co-crystal comopsi Metoprolol, Moprolol, Nadoxolol, Nifenalol, Nipradillol, tion. The mixed phase co-crystalline material of the inven Oxprenolol, Penbutolol, Pindolol, Practolol, Pronethalol, tion are kinetically favored and form upon standing and/or Propranolol, Sotalol, Sulfinalol, Talinolol, Tertatolol, mixing of the initial meta-stable crystalline phase. 15 Timolol, Toliprolol, and Xibenolol. The amount of time required to achieve transformation 5. Alcohol deterrents such as Calcium Cyanamide Cit (i.e., conversion) from a kinetically favored crystalline rated, Disulfiram, Nadide, and Nitrefazole. phase to the mixed phase co-crystal composition depends on 6. Aldose reductase inhibitors such as Epalrestat, Ponal the particular active agent and other additives present in the restat, Sorbinil, and Tolrestat. second solution. The second solution containing the initial 7. Anabolics Such as Androisoxazole, Androstenediol, meta-stable crystalline phase is generally mixed or allowed Bolandiol, Bolasterone, Clostebol, Ethylestrenol. Formyl to stand for a sufficient period of time to permit complete dienolone, 4-Hydroxy-19-nortestosterone, Methandriol, conversion to the mixed phase co-crystalline material. This Methenolone, Methyltrienolone, Nandrolone, Nandrolone transformation step may take occur for any suitable amount Decanoate, Nandrolone p-Hexyloxyphenylpropionate, Nan of time (e.g., about 10 seconds, about 30 seconds, about 1 25 drolone Phenpropionate, Norbolethone, Oxymesterone, minute, about 5 minutes, about 10 minutes, about 30 min Pizotyline, Quinbolone, Stenbolone, and Trenbolone. utes, about 1 hour, about 2 hours, about 10 hours, about 20 8. Analgesics (narcotic) Such as Alfentanil, Allylprodine, hours, about 30 hours, about 40 hours, about 50 hours, or Alphaprodine, Anileridine, Benzylmorphine, Bezitramide, more). One of ordinary skill in the art will recognize the Buprenorphine. Butorphanol, Clonitazene, Codeine, amount of time required for conversion of the kinetically 30 Codeine Methyl Bromide, Codeine Phosphate, Codeine Sul favored crystalline material to the thermodynamically fate, Desomorphine, Dextromoramide, DeZocine, Diampro favored mixed phase co-crystal composition. Incomplete mide, Dihydrocodeine, Dihydrocodeinone Enol Acetate, conversion will result in problems filtering the crystalline Dihydromorphine, Dimenoxadol, Dimepheptanol, Dimeth material, and therefore, more incubation time is required. ylthiambutene, Dioxaphetyl Butyrate, Dipipanone, Eptazo The active agent for use in the composition and method of 35 cine, Ethoheptazine, Ethylmethlythiambutene, Ethylmor the invention include any suitable active agent. The active phine, EtonitaZene, Fentanyl, Hydrocodone, agent is preferably a small chemical entity that is approxi Hydromorphone, Hydroxypethidine, Isomethadone, mately less than 10,000 daltons (e.g., less than about 9,000 Ketobemidone, Levorphanol, Lofentanil, Meperidine, daltons, less than about 8,000 daltons, less than about 7,000 Meptazinol, Metazocine, Methadone Hydrochloride, Meto daltons, less than about 6,000 daltons, less than about 5,000 40 pon, Morphine, Morphine Derivatives, Myrophine, Nalbu daltons). Such as a pharmacologically active Substance phine, Narceline, Nicomorphine, Norlevorphanol, (drug), vitamin, insecticide, fungicide, antibacterial agent, Normethadone, Normorphine, Norpipanone, Opium, Oxy antiviral agent, antiparasitic agent or hormone. Exemplary codone, Oxymorphone, Papaveretum, Pentazocine, Phen of active agents include, but are not limited to the following: adoxone, Phenazocine, Pheoperidine, Piminodine, Piritr 1. C.-Adrenergic agonists such as Adrafinil, Adrenolone, 45 amide, Proheptazine, Promedol, Properidine, Propiram, Amidephrine, Apraclonidine, Budralazine, Clonidine, Propoxyphene, Sufentanil, and Tilidine. Cyclopentamine, Detomidine, Dimetofrine, Dipivefrin, 9. Analgesics (non-narcotic) such as Acetaminophen, Ephedrine, Epinephrine, Fenoxazoline, GuanabenZ, Guan Acetaminosalol, Acetanilide, Acetylsalicylsalicylic Acid, facine, Hydroxyamphetamine, Ibopamine, Indanazoline, Alclofenac. Alminoprofen, Aloxiprin, Aluminum Bis(ace Isometheptene, Mephentermine, Metaraminol, Methoxam 50 tylsalicylate), Aminochlorthenoxazin, 2-Amino-4-picoline, ine Hydrochloride, Methylhexaneamine, Metizolene, Mido Aminopropylon, Aminopyrine, Ammonium Salicylate, Anti drine, Naphazoline, Norepinephrine, Norfenefrine, Octo pyrine, Antipyrine Salicylate, Antrafenine, ApaZone, Aspi drine, Octopamine, Oxymetazoline, Phenylephrine rin, Benorylate, Benoxaprofen, BenZpiperylon, Benzy Hydrochloride, Phenylpropanolamine Hydrochloride, Phe damine, p-Bromoacetanilide, 5-Bromosalicylic Acid nylpropylmethylamine, Pholedrine, Propylhexedrine, Pseu 55 Acetate, Bucetin, Bufexamac, Bumadizon, Butacetin, Cal doephedrine, Rilmenidine, Synephrine, Tetrahydrozoline, cium Acetylsalicylate, Carbamazepine, Carbetidine, Carbi Tiamenidine, TramaZoline, Tuaminoheptane, Tymazoline, phene, Carsalam, Chloralantipyrine, Chlorthenoxazin(e). Tyramine, and Xylometazoline. Choline Salicylate, Cinchophen, Ciramadol, Clometacin, 2. B-Adrenergic agonists such as Albuterol, Bambuterol, Cropropamide, Crotethamide, Dexoxadrol, Difenamizole, Bitolterol, Carbuterol, Clenbuterol, Clorprenaline, Deno 60 Diflunisal, Dihydroxyaluminum Acetylsalicylate, Dipyro pamine, Dioxethedrine, Dopexamine, Ephedrine, Epineph cetyl, Dipyrone, EmorfaZone, Enfenamic Acid, Epirizole, rine, Etafedrine, Ethylnorepinephrine, Fenoterol, For Etersalate, Ethenzamide, Ethoxazene, Etodolac, Felbinac, moterol, Hexoprenaline, Ibopamine, Isoetharine, Fenoprofen, Floctafenine, Flufenamic Acid, Fluoresone, Isoproterenal, Mabuterol, Metaproterenol, Methoxyphe Flupirtine, FluproduaZone, Flurbiprofen, Fosfosal, Gentisic namine, Oxyfedrine, Pirbuterol, Prenalterol, Procaterol, 65 Acid, Glafenine, Ibufenac, Imidazole Salicylate, Indometha Protokylol, Reproterol, Rimiterol, Ritodrine, Soterenol, Ter cin, Indoprofen, IsofeZolac, Isoladol, Isonixin, Ketoprofen, buterol, and Xamoterol. Ketorolac, p-Lactophenetide, Lefetamine, Loxoprofen, US 9,682,043 B2 7 8 Lysine Acetylsalicylate, Magnesium Acetylsalicylate, tian Violet, 4-Hexylresorcinol, Kainic Acid, Mebendazole, Methotrimeprazine, Metofoline, Miroprofen, Morazone, 2-Napthol, Oxantel, Papain, Piperazine, Piperazine Adipate, Morpholine Salicylate, Naproxen, Nefopam, Nifenazone, 5' Piperazine Citrate, Piperazine Edetate Calcium, Piperazine Nitro-2' propoxyacetanilide, Parsalmide, Perisoxal, Phen Tartrate, Pyrantel, Pyrvinium Pamoate, C.-Santonin, Stilba acetin, Phenazopyridine Hydrochloride, Phenocol, Phen Zium Iodide, Tetrachloroethylene, Tetramisole, thiabenda opyrazone, PhenylAcetylsalicylate, Phenyl Salicylate, Phe Zole, Thymol, Thymyl N-Isoamylcarbamate, Triclofenol nyramidol, PipebuZone, Piperylone, Prodilidine, Piperazine, and Urea Stibamine. Propacetamol, Propyphenazone, Proxazole, Quinine Salicy 15. Anthelmintics (Onchocerca) such as Ivermectin and late, RamifenaZone, Rimazolium Metilsulfate, Salacet Suramin Sodium. amide, Salicin, Salicylamide, Salicylamide O-Acetic Acid, 10 Salicylsulfuric Acid, Salsalte, Salverine, Simetride, Sodium 16. Anthelmintics (Schistosoma) Such as Amoscanate, Salicylate, Sulfamipyrine, Suprofen, Talniflumate, Tenoxi Amphotalide, Antimony Potassium Tartrate, Antimony cam, Terofenamate, Tetradrine, Tinoridine, Tolfenamic Sodium Gluconate, Antimony Sodium Tartrate, Antimony Acid, Tolpronine, Tramadol, Viminol, Xenbucin, and Sodium Thioglycollate, Antimony Thioglycollamide, Zomepirac. 15 Becanthone, Hycanthone, Lucanthone Hydrochloride, 10. Androgens such as Boldenone, Fluoxymesterone, Niridazole, Oxamniquine, Praziquantel, Stibocaptate, Stibo Mestanolone, Mesterolone, Methandrostenolone, 17-Meth phen, and Urea Stibamine. yltestosterone, Methyltestosterone, 17C.-Methyltestosterone 17. Anthelmintic (Trematodes) such as Anthiolimine and 3-Cyclopenty1 Enol Ether, Norethandrolone, Normethan Tetrachloroethylene. drone, Oxandrolone, Oxymesterone, Oxymetholone, Pras 18. Antiacne drugs such as Algestone Acetophenide, terone, Stanlolone, Stanozolol, Testosterone, Testosterone Azelaic Acid, Benzoyl Peroxide, Cyoctol, Cyproterone, 17-Chloral Hemiacetal, Testosterone 17 B-Cypionate, Tes Motretinide, Resorcinol, Retinoic Acid, and Tetroquinone. tosterone Enanthate, Testosterone Nicotinate, Testosterone 19. Antiallergics such as Amlexanox, Astemizole, AZelas Pheynylacetate, Testosterone Propionate, and Tiomesterone. tine, Cromolyn, Fenpiprane. Histamine, Ibudilast, Nedocro 11. Anesthetics (intravenous) such as Acetamidoeugenol, 25 mil, Oxatomide, Pentigetide, Poison Ivy Extract, Poison Alfadolone Acetate, Alfaxalone, Amucaine, Amolanone, Oak Extract, Poison Sumac Extract, Repirinast, Tranilast, Amylocaine Hydrochloride, Benoximate, Betoxycaine, Traxanox, and Urushiol. Biphenamine, Bupivacaine, Butacaine. Butaben, Butanilic 20. Antiamebics such as Arsthinol, Bialamnicol, Carbar aine, Burethamine. Buthalital Sodium, Butoxycaine, Cartic sone, Cephaeline, Chlorbetamide, Chloroquine, Chlorphe aine, 2-Chloroprocaine Hydrochloride, Cocaethylene, 30 noxamide, Chlortetracycline, Dehydroemetime, Dibro Cocaine, Cyclomethycaine, DibucaineHydrochloride, mopropamidine, Diloxanide, DephetarSone, Emetine, Dimethisoquin, Dimethocaine, Diperadon Hydrochloride, Fumagillin, Glaucarubin, Glycobiarsol, 8-Hydroxy-7-iodo Dyclonine, Ecgonidine, Ecgonine, Ethyl Aminobenzoate, 5-quinolinesulfonic Acid, Iodochlorhydroxyquin, Iodoqui Ethyl Chloride, Etidocaine, Etoxadrol, B-Eucaine, Euprocin, nol, Paromomycin, Phanquinone, Phearsone Sulfoxylate, Fenalcomine, Fomocaine, Hexobarbital, Hexylcaine Hydro 35 Polybenzarsol, Propamidine, Quinfamide, Secnidazole, Sul chloride, Hydroxydione Sodium, Hydroxyprocaine, farside, Teclozan, Tetracycline. Thiocarbamizine. Thiocar Hydroxytetracaine, Isobutyl p-Aminobenzoate, Kentamine, barsone, and Tinidazole. Leucinocaine Mesylate, Levoxadrol, Lidocaine, Mepiva 21. Antiandrogens such as Bifluranol, Cyoctol, Cyproter caine, Meprylcaine Hydrochloride, Metabutoxycaine one, Delmadinone Acetate, Flutimide, Nilutamide, and Hydrochloride, Methohexital Sodium, Methyl Chloride, 40 Oxendolone. Midazolam, Myrtecaine, Naepaine, Octacaine, Orthocaine, 22. Antianginals such as Acebutolol, Alprenolol, Amio Oxethazaine, Parethoxycaine, Phenacaine Hydrochloride, darone, Amlodipine, Arotinolol, Atenolol, Bepridil, Bevan Phencyclidine, Phenol, Piperocaine, Piridocaine, Polidoca tolol, Bucumolol, Bufetolol, Bufuralol, Bunitrolol, Bupra nol, Pramoxine, Prilocaine, Procaine, Propanidid, Propano nolol, Carozolol, Carteolol, Carvedilol, Celiprolol, caine, Proparacaine, Propipocaine, Propofol, Propoxycaine 45 Cinepazet Maleate, Diltiazem, Epanolol, Felodipine, Gallo Hydrochloride, Pseudococaine, Pyrrocaine, Quinine Urea pamil, Imolamine, Indenolol. Isosorbide Dinitrate, Israd Hydochloride, Risocaine, Salicyl Alcohol, Tetracaine ipine, Limaprost, Mepindolol, Metoprolol, Molsidomine, Hydrochloride. Thialbarbital. Thimylal. Thiobutabarbital, Nadolol, Nicardipine, Nifedipine, Nifenalol, Nilvadipine, Thiopental Sodium, Tolycaine, Trimecaine, and Zolamine. Nipradillol, Nisoldipine, Nitroglycerin, Oxprenolol, Oxyfe 12. Anorectics such as Aminorex, Amphecloral, Amphet 50 drine, OZagrel, Penbutolol, Pentaerythritol Tetranitrate, Pin amine, BenZaphetamine, Chlorphentermine, Clobenzorex, dolol, Pronethalol, Propranolol, Sotaiol, Terodiline, Timolol, Cloforex, Clortermine, Cyclexedrine. Destroamphetamine Toliprolol, and Verapamil. Sulfate, Diethylpropion, Diphemethoxidine. N-Ethylam 23. Antiarrhythmics such as Acebutol, Acecaine, Adenos phetamine, Fenbutrazate, Fenfluramine, Fenproporex. Fur ine, Ajmaline, Alprenolol. Amiodarone, Amoproxan, Aprin fuirylmethylamphetamine, Levophacetoperate, Mazindol, 55 dine, Arotinolol, Atenolol, Bevantolol, Bretylium Tosylate, Mefenorex, Metamfeproamone, Methamphetamine, Norp Bulbumolol, Bufetolol, Bunaftine, Bunitrolol, Bupranolol, seudoephedrine, Phendimetrazine, Phenmetrazine, Phen Butidrine Hydrochloride, Butobendine, Capobenic Acid, pentermine, Phenylpropanolamine Hydrochloride, and Carazolol, Carteolol, Cifenline, Cloranolol, Disopyramide, Picilorex. Encainide, Esmolol, Flecainide, Gallopamil, Hydroquini 13. Anthelmintics (Cestodes) such as Arecoline, Aspidin, 60 dine, Indecainide, Indenolol, pratropium Bromide, Lido Aspidinol, Dichlorophen(e). Embelin, Kosin, Napthalene, caine, Lorajmine, Lorcainide, Meobentine, Metipranolol. Niclosamide, Pellertierine, Pellertierine Tannate, and Qui Mexiletine, Moricizine, Nadoxolol, Nifenalol, Oxprenolol, nacrine. Penbutolol, Pindolol, Pirmenol, Practolol, Prajmaline, Pro 14. Anthelmintics (Nematodes) Such as Alantolactone, cainamide Hydrochloride, Pronethalol, Propafenone, Pro Amoscanate, Ascaridole, Bephenium, Bitoscanate, Carbon 65 pranolol, Pyrinoline, Quinidine Sulfate, Quinidine, Sotalol, Tetrachloride, Carvacrol, Cyclobendazole, Diethylcarbam Talinolol, Timolol, Tocainide, Verapamil, Vicquidil, and azine, Diphenane, Dithiazanine Iodide, Dymanthine, Gen Xibenolol. US 9,682,043 B2 9 10 24. Antiarteriosclerotics such as Pyridinol Carbamate. cline, Rolitetracycline, Sancycline, Senociclin and Tetracy 25. Antiarthritic/Antirheumatics such as Allocupreide cline; and other antibiotics such as Cycloserine, Mupirocin Sodium, Auranofin, Aurothioglucose, Aurothioglycanide, and Tuberin. Azathioprine, Calcium 3-Aurothio-2-propanol-1-sulfonate, 27. Antibacterial drugs (synthetic), including: 2,4-Di Chloroquine, Clobuzarit, Cuproxoline, Diacerein, Glu aminopyrimidines Such as Brodimoprim, TetroXoprim and cosamine, Gold Sodium Thiomalate, Gold Sodium Thiosul Trimethoprim; Nitrofurans such as Furaltadone. Furazolium fate, Hydroxychloroquine, KebuZone, Lobenzarit, Melittin, Chloride, Nifuradene, Nifuratel, Nifurfoline, Nifurpirinol, Methotrexate, Myoral, and Penicillamine. Nifurprazine, Nifurtoinol and Nitrofurantoin: Quinolones 26. Antibacterial (antibiotic) drugs including Aminogly and Analogs such as Amifloxacin, Cinoxacin, Ciprofloxacin, 10 Difloxacin, Enoxacin, Fleroxacin, Flumequine, nomefloxa cosides such as Amikacin, Apramyclin, Arbekacin, Bamber cin, Miloxacin, Nalidixic Acid, Norfloxacin, Ofloxacin, mycins, Butirosin, Dibekacin, Dihdrostreptomycin, Fortimi Oxolinic Acid, Pefloxacin, Pipemidic Acid, Piromidic Acid, cin(s), Gentamicin, Ispamicin, Kanamycin, Micronomicin, Rosoxacin, Temafloxacin and ToSufloxacin; Sulfonamides Neomycin, Neomycin Undecylenate, Netilmicin, Paromo such as Acetyl Sulfamethoxypyrazine, Acetyl Sulfisoxazole, mycin, Ribostamycin, Sisomicin, Spectinomycin, Strepto 15 AZosulfamide, Benzylsulfamide, Chloramine-B, Chloram mycin, Streptonicozid, and Tobramycin; Amphenicols such ine-T, Dichloramine T. Formosulfathiazole, N.sup.2 Form as AZidamfenicol, Chloramphenicol, Chloramphenicol ylsulfisomidine, N.sup.2-3-D-Glucosylsulfanilamide, Palmitate, Chloramphenicol Pantothenate, Florfenicol, and Mafenide, 4'-(Methylsulfamoyl) sulfanilanilide, p-Nitrosul Thiamphenicol; Ansamycins such as Rifamide, Rifampin, fathiazole, Noprylsulfamide, Phthalylsulfacetamide, Phth Rifamycin, and Rifaximin; B-Lactams, including: Carbapen alylsulfathiazole, Salazosulfadimidine, Succinylsulfathiaz ems such as Imipenem; Cephalosporins such as Cefactor, ole, Sulfabenzamide, Sulfacetamide, Sulfachlorpyridazine, Cefadroxil, Cefamandole, Cefatrizine, Cefazedone, Cefazo Sulfachrysoidine, Sulfacytine, Sulfadiazine, Sulfadicr lin, Cefixime, Cefinenoxime, Cefodizime, Cefonicid, Cefop amide, Sulfadimethoxine, Sulfadoxine, Sulfaethidole, Sulfa eraZone, Ceforanide, Cefotaxime, Cefotiam, Ce?pimizole, guanidine, Sulfaguanol, Sulfalene, Sulfaloxic Acid, Sulfam Ce?pirimide, Cefpodoxime Proxetil, Cefroxadine, Cefsulo 25 erazine, Sulfameter, Sulfamethazine, Sulfamethizole, din, Ceftazidime, Cefteram, Ceftezole, Ceftibuten, Ceftizox Sulfamethomidine, Sulfamethoxazole, Sulfamethoxy ime, Ceftriaxone, Cefuroxime, CefuZonam, Cephacetrile pyridazine, Sulfametrole, Sulfamidochrysoidine. Sulfamox Sodium, Cephalexin, Cephaloglycin, Cephaloridie, Cepha ole, Sulfanilamide, Sulfanilamidomethanesulfonic Acid Tri losporin, Cephalothin, Cephapirin Sodium, Cephradine and ethanolamine Salt, 4-Sulfanilamidosalicylic Acid, N. Sup.4- Pivcefalexin; Cephamycins such as Cefbuperazone, Cef 30 Sulfanilylsulfanilamide, Sulfanily lurea, N-Sulfanilyl-3,4- metazole, Cefninox, Cefetan and Cefoxitin; Monobactams xylamide, Sulfanitran, Sulfaperine, Sulfaphenazole. Such as Aztreonam, Carumonam and Tigemonam; Sulfaproxyline, Sulfapyrazine, Sulfapyridine, Sulfa Oxacephems such as Flomoxefand Moxolactam; Penicillins somizole, Sulfasymazine, Sulfathiazole, Sulfathiourea, such as Amidinocillin, Amdinocillin Pivoxil, Amoxicillin, Sulfatolamide, Sulfisomidine and Sulfisoxazole; Sulfones Ampicillan, Apalcillin, Aspoxicillin, AZidocillan, AZlocil 35 Such as Acedapsone, Acediasulfone, Acetosulfone Sodium, lan, Bacampicillin, Benzylpenicillinic Acid, Benzylpenicil Dapsone, Diathymosulfone, Glucosulfone Sodium, Solasul lin Sodium, Carbenicillin, Carfecillin Sodium, Carindacillin, fone, Succisulfone, Sulfanilic Acid, p-Sulfanilylbenzylam Clometocillin, Cloxacillin, Cyclacillin, Dicloxacillin, ine, p.p'-Sulfonyldianiline-N,N' digalactoside, Sulfoxone Diphenicillin Sodium, Epicillin, Fenbenicillin, Floxicillin, Sodium and Thiazolsulfone; and others such as Clofoctol, Hetacillin, Lenampicillin, Metampicillin, Methicillin 40 Hexedine, Methenamine, Methenamine Anhydromethylene Sodium, Mezlocillin, Nafcillin Sodium, Oxacillin, Pename citrate, Methenamine Hippurate, Methenamine Mandelate, cillin, Penethamate Hydriodide, Penicillin G Benethamine, Methenamine Sulfosalicylate, Nitroxoline and Xibomol. Penicillin G BenZathine, Penicillin G Benzhydrylamine, 28. Anticholinergics such as Adiphenine Hydrochloride, Penicillin G Calcium, Penicillin G Hydrabamine, Penicillin Alverine, Ambutonomium Bromide, Aminopentamide, G Potassium, Penicillin G Procaine, Penicillen N, Penicillin 45 Amixetrine, Amprotropine Phosphate, Anisotropine Meth O, Penicillin V. Penicillin V Benzathine, Penicillin V Hydra ylbromide, Apoatropine, Atropine, Atropine N-Oxide, Ben bamine, Penimepicycline, Phenethicillin Potassium, Pipera actyzine, Benapryzine, Benzetimide, Benzilonium Bromide, cillin, Pivapicillin, Propicillin, Quinacillin, Sulbenicillin, Benztropine Mesylate, Bevonium Methyl Sulfate, Biper Talampicillin, Temocillin and Ticarcillin; Lincosamides iden, Butropium Bromide, N-Butylscopolammonium Bro Such as Clindamycin and Lincomycin; Macrollides such as 50 mide, Buzepide, Camylofine, Caramiphen Hydrochloride, Azithromycin, Carbomycin, Clarithromycin, Erythromycin, Chlorbenzoxamine, Chlorphenoxamine, Cimetropium Bro Erythromycin Acistrate, Erythromycin Estolate, Erythromy mide, Clidinium Bromide, Cyclodrine, Cyclonium Iodide, cin Glucoheptonate, Erythromycin Lactobionate, Erythro Cycrimine Hydrochloride, Deptropine, Dexetimide, Dibu mycin Propionate, Erythromycin Stearate, Josamycin, Leu toline Sulfate, Dicyclomine Hydrochloride, Diethazine, comycins, Midecamycins, Miokamycin, Oleandomycin, 55 Difemerine, Dihexyverine, Diphemanil Methylsulfate, N-(1, Primycin, Rokitamycin, Rosaramicin, Roxithromycin, Spi 2-Diphenylethyl) nicotinamide, Dipiproverine, Diponium ramycin and Troleandomycin; Polypeptides such as Ampho Bromide, Emepronium Bromide, Endobenzyline Bromide, mycin, Bacitracin, Capreomycin, Colistin, Enduracidin, Ethopropazine, Ethybenztropine, Ethylbenzhydramine, Eto Enviomycin, Fusafumgine, Gramicidin(s), Gramicidin S. midoline, Eucatropine, Fenpiverinium Bromide, Fentonium Mikamycin, Polymyxin, Polymyxin B-Methanesulfonic 60 Bromide, Flutropium Bromide, Glycopyrrolate, Heteronium Acid, Pristinamycin, Ristocetin, Teicoplanin, Thiostrepton, Bromide, Hexocyclium Methyl Sulfate, Homatropine, Tuberactinomycin, Tyrocidine, Tyrothricin, Vancomycin, Hyoscyamine, Ipratropium Bromide, Isopropamide, Viomycin, Viomycin Pantothenate, Virginiamycin and Zinc Levomepate, Mecloxamine, Mepenzolate Bromide, Met Bacitracin; Tetracyclines Such as Apicycline, Chlortetracy caraphen, Methantheline Bromide, Methixene, Methscopol cline, Clomocycline, Demeclocycline, Doxycycline, 65 amine Bromide, Octamylamine, Oxybutynin Chloride, Oxy Guamecycline, Lymecycline, Meclocycline, Methacycline, phencyclimine, Oxyphenonium Bromide, Pentapiperide, Minocycline, Oxytetracycline, Penimepicycline, Pipacy Penthienate Bromide, Phencarbamide, Phenglutarimide, US 9,682,043 B2 11 12 Pipenzolate Bromide, Piperidolate, Piperilate, Poldine echin, Dilfenoxin, Diphenoxylate, Lidamidine, Loperamide, Methysulfate, Pridinol, Prifinium Bromide, Procyclidine, Mebiquine, Trillium and Uzarin. Propantheline Bromide, Propenzolate, Propyromazine, Sco 33. Antidiuretics Such as Desmopressin, Fely pressin, polamine, Scopolamine N-Oxide, Stilonium Iodide, Stramo Lypressin, Ornipressin, Oxycinchophen, Pituitary-Posterior, nium, Sultroponium, Thihexinol, Thiphenamil, Tiemonium Terlipressin and Vasopressin. Iodide, Timepidium Bromide, Tiquizium Bromide, Tridi 34. Antiestrogens such as Delmadinone Acetate, hexethyl Iodide, Trihexyphenidyl Hydrochloride, Tropacine, Ethamoxytriphetol, Tamoxifen and Toremifene. Tropenzile, Tropicamide, Trospium Chloride, Valethamate 35. Antifungal drugs (antibiotics), including: Polyenes Bromide and Xeny tropium Bromide. Such as Amphotericin-B, Candicidin, Dermostatin, Filipin, 29. Anticonvulsants such as Acetylpheneturide, Albutoin, 10 Fungichromin, Hachimycin, Hamycin, Lucensomycin, Aloxidone, Aminoglutethimide, 4-Amino-3-hydroxybutyric Mepartricin, Natamycin, Nystatin, Pecilocin and Perimycin; Acid, Atrolactamide, Beclamide, Buramate, Calcium Bro and others such as AZaserine, Griseofulvin, Oligomycins, mide, Carbamazepine, Cinromide, Clomethiazole, Clonaze Neomycin Undecylenate, Pyrrolnitrin, Siccanin, Tubercidin pam, Decimemide, Diethadione, Dimethadione, Doxenitoin, and Viridin. Eterobarb, Ethadione, Ethosuximide, Ethotoin, Fluoresone, 15 36. Antifungal drugs (synthetic), including: Allylamines 5-Hydroxytryptophan, Lamotrigine, Magnesium Bromide, such as Naftifine and Terbinafine: Imidazoles such as Bifon Magnesium Sulfate, Mephenytoin, Mephobarbital, Methar azole, Butoconazole, Chlordantoin, Chlormidazole, Clocon bital, Methetoin, MethSuximide, 5-Methyl-5-(3-phenan azole, Clotrimazole, Econazole, Enilconazole, Fenticon thryl)hydantoin, 3-Methyl-5-phenylhydantoin, Narcobarbi azole, Isoconazole, Ketoconazole, Miconazole, tal, Nimetazepam, Nitrazepam, Paramethadione, Omoconazole, Oxiconazole, Nitrate, Sulconazole and Tio Phenacemide, Phenetharbital, Pheneturide, Phenobarbital, conazole; Triazoles such as Fluconazole, Itraconazole and Phenobarbital Sodium, Phensuximide, Phenylmethylbarbi Terconazole; and others such as Acrisorcin, Amorolfine, turic Acid, Phenytoin, Phethenylate Sodium, Potassium Bro Biphenamine, Bromosalicylchloranilide, Buclosamide, Cal mide, Primidone, Progabide, Sodium Bromide, Solanum, cium Propionate, Chlophenesin, Ciclopirox, Cloxyquin, Strontium Bromide, Suclofenide, Sulthiame, Tetrantoin, 25 Coparaffinate, Diamthazole, Dihydrochloride. Exalamide, Trimethadione, Valproic Acid, Valpromide, Vigabatrin and Flucytosine, Halethazole, Hexetidine, Loflucarban, Nifura Zonisamide. tel, Potassium Iodide, Propionic Acid, Pyrithione, Salicy 30. Antidepressants, including: Bicyclics Such as Bineda lanilide, Sodium Propionate, Sulbentine, Tenonitrozole, Tol line, CaroXaZone, Citalopram, Dimethazan, Indalpine, Fen ciclate, Tolindate, Tolnaftate, Tricetin, Ujothion, camine, Indeloxazine Hydrochcloride, Nefopam, 30 Undecylenic Acid and Zinc Propionate. Nomifensine, Oxitriptan, Oxypertine, Paroxetine, Sertraline, 37. Antiglaucoma drugs such as Acetazolamide. Befl Thiazesim, Trazodone and Zometapine: Hydrazides/Hydra nolol, Betaxolol, Bupranolol, Carteolol, Dapiprazoke. Zines such as Benmoxine, proclozide, Iproniazid, Isocar Dichlorphenamide, Dipivefrin, Epinephrine, Levobunolol, boxazid, Nialamide, Octamoxin and Phenelzine: Pyrroli Methazolamide, Metipranolol, Pilocarpine, Pindolol and dones such as Cotinine, Rolicyprine and Rolipram; 35 Timolol. Tetracyclics such as Maprotiline, Metralindole, Mianserin 38. Antigonadotropins such as DanaZol, Gestrinone and and Oxaprotiline. Tricyclics such as Adinazolam, Amitrip Paroxypropione. tyline, Amitriptylinoxide, Amoxapine, Butriptyline, Clo 39. Antigout drugs such as Allopurinol, Carprofen, mipramine, Demexiptiline, Desipramine, Dibenzepin, Colchicine, Probenecid and Sulfinpyrazone. Dimetracrine, Dothiepin, Doxepin, Fluacizine, Imipramine, 40 40. Antihistamines, including: Alkylamine derivatives Imipramine N-Oxide, Iprindole, Lofepramine, Melitracen, Such as Acrivastine, Bamipine, Brompheniramine, Chlo Metapramine, Nortriptyline, Noxiptilin, Opipramol, Pizoty rpheniramine, Dimethindene, Metton S. Pheniramine, Pyr line, Propizepine, Protriptyline, Quinupramine, Tianeptine robutamine. Thenaldine, Tolpropamine and Triprolidine: and Trimipramine; and others such as Adrafinil, Benac Aminoalkyl ethers such as Bietanautine, Bromodiphenhy tyZine. Bupropion, Butacetin, Deanol, Deanol Aceglumate, 45 dramine, Carbinoxamine, Clemastine, Diphenlypyraline, Deanol Acetamidobenzoate, Dioxadrol, Etoperidone, Febar Doxylamine, Embrammine, Medrylamine, Mephenphy bamate, Femoxetine, Fenpentadiol, Fluoxetine, Fluvoxam dramine, p-Methyldiphenhydramine, Orphenadrine, Phenyl ine, Hematoporphyrin, Hypercinin, Levophacetoperane, toloxamine, Piprinhydrinate and Setasine; Ethylenediamine Medifoxamine, Minaprine, Moclobemide, Oxaflozane, Pib derivatives such as Alloclamide, p-Bromtripelennamine, eraline, Prolintane, Pyrisuccideanol, Rubidium Chloride, 50 Chloropyramine, Chlorothen, Histapyrrodine, Methafu Sulpiride, Sultopride, Teniloxazine, Thozalinone, Tofenacin, rylene, Methaphenilene, Methapyrilene, Phenbenzamine, Toloxatone, Tranylcypromine, L-Tryptophan, Viloxazine Pyrilamine, Talastine, Thenyldiamine, Thonzylamine and Zimeldine. Hydrochloride, Tripelennamine and Zolamine; Piperazines 31. Antidiabetics, including: Biguanides such as such as Cetirizine, Chlorcyclizine, Cinnarizine, Clocinizine Buformin, Metformin and Phenformin; Hormones such as 55 and Hydroxyzine; Tricyclics, including: Phenothiazines Glucagon, Insulin, Insulin Injection, Insulin Zinc Suspen Such as Ahistan, Etymemazine, Hydroxyazine, N-Hydroxy Sion, Isophane Insulin Suspension, Protamine Zinc Insulin ethylpromethazine Chloride, Isopromethazine, Mequitazine, Suspension and Zinc Insulin Crystals; Sulfonylurea deriva Promethazine, Pyrathiazine and Thiazinamium Methyl Sul tives Such as Acetohexamide, 1-Butyl-3-metanily lurea, fate; and others such as AZatadine, Clobenzepam, Cypro Carbutamide, Chlorpropamide, Glibornuride, Gliclazide, 60 heptadine, Deptropine, Isothipendyl, Loratadine and Proth Glipizide, Gliquidone, Glisoxepid, Glyburide, Glybuthiazol ipendyl; and other antihistamines Such as Antazoline, (e), Glybuzole, Glyhexamide, Glymidine, Glypinamide, Astemizole, AZelastine, Cetoxime, Clemizole, Clobenz Phenbutamide, Tolazamide, Tolbutamide and Tolcyclamide: tropine, Diphenazoline, Diphenhydramine, Mebhydroline, and others such as Acarbose, Calcium Mesoxalate and Phenindamine, Terfenadine and Tritoqualine. Miglitol. 65 41. Antihyperlipoproteinemics, including: Aryloxyal 32. Antidiarrheal drugs such as Acetyltannic Acid, Albu kanoic acid derivatives such as Beclorbrate, Bazafibrate, min Tannate, Alkofanone, Aluminum Salicylates-Basic, Cat Binifibrate, Ciprofibrate, Clinofibrate, Clofibrate, Clofibric US 9,682,043 B2 13 14 Acid, Etonfibrate, Fenofibrate, Gemfibrozil, Nicofibrate, 44. Antihyperthyroids such as 2-Amino-4-methylthiazole, Pirifibrate, Ronifibrate, Simfibrate and Theofibrate; Bile 2-Aminothiazole, Carbimazole, 3,5-Dibromo-L-tyrosine, acid sequesterants such as Cholestyramine Resin, Colestipol 3,5-Diiodotyrosine, Hinderin, Iodine, Iothiouracil, Methi and Polidexide; HMG CoA reductase inhibitors such as mazole, Methylthiouracil, propylthiouracil, Sodium Per Lovastatin, Pravastatin Sodium and Simvastatin; Nicotinic chlorate. Thibenzazoline. Thiobarbital and 2-Thiouracil. acid derivatives Aluminum Nicotinate, Acipimox, Nicer 45. Antihypotensive drugs such as Amezinium Methyl itrol, Nicoclonate, Nicomol and Oxiniacic Acid; Thyroid Sulfate, Angiotensin Amide, Dimetofrine, Dopamine, hormones and analogs such as EtiroXate, Thyropropic Acid Etifelmin, Etilefrin, Gepefrine, Metaraminol, Midodrine, and Thyroxine; and others such as Acifran, AZacosterol, Norepinephrine, Pholedrinead and Synephrine. Benfluorex, B-Benzalbutyramide, Camitine, Chondroitin 10 46. Antihypothyroid drugs such as Levothyroxine Sulfate, Clomestone, Detaxtran, Dextran Sulfate Sodium, 5,8,11,14, 17-Eicosapentaenoic Acid, Eritadenine, Furazbol, Sodium, Liothyronine, Thyroid, Thyroidin, Thyroxine, Meglutol, Melinamide, Mytatrienediol, Omithine, Y-Oryza Tiratricol and TSH. nol, Pantethine, Penataerythritol Tetraacetate, C.-Phenylbu 47. Anti-Inflammatory (non-steroidal) drugs, including: tyramide, Pirozadil, Probucol, C.-Sitosterol, Sultosilic Acid, 15 Aminoarylcarboxylic acid derivatives such as Enfenamic Piperazine Salt, Tiadenol, Triparanol and Xenbucin. Acid, Etofenamate, Flufenamic Acid, Isonixin, Meclofe 42. Antihypertensive drugs, including: Arylethanolamine namic Acid, Mefanamic Acid, Niflumic Acid, Talniflumate, derivatives such as Amosulalol, Bufuralol, Dilevalol, Terofenamate and Tolfenamic Acid; Arylacetic acid deriva Labetalol, Pronethalol, Sotalol and Sulfinalol; Aryloxypro tives such as Acemetacin, Alclofenac, Amfenac, Bufexamac, panolamine derivatives Such as Acebutolol, Alprenolol. Aro Cinmetacin, Clopirac, Diclofenac Sodium, Etodolac, Felbi tinolol, Atenolol, Betaxolol, Bevantolol, Bisoprolol, Bopin nac, Fenclofenac, Fenclorac, Fenclozic Acid, Fentiazac, dolol, Bunitrolol, Bupranolol, Butofilolol, Carazolol, Glucametacin, Ibufenac, Indomethacin, IsofeZolac, ISOX Cartezolol, Carvedilol, Celiprolol, Cetamolol, Epanolol, epac, Lonazolac, Metiazinic Acid, Oxametacine, Proglu Indenolol, Mepindolol, Metipranolol, Metoprolol, metacin, Sulindac, Tiaramide, Tolimetin and Zomepirac: Moprolol, Nadolol, Nipradilol, Oxprenolol, Penbutolol, Pin 25 Arylbutyric acid derivatives such as Bumadizon, Butibufen, dolol, Propranolol, Talinolol, Tetraolol, Timolol and Tolip Fenbufen and Xenbucin; Arylcarboxylic acids such as Cli rolol, Benzothiadiazine derivatives such as Althiazide, Ben danac, Ketorolac and Tinoridine; Arylpropionic acid deriva droflumethiazide, Benzthiazide, tives Such as Alminoprofen, Benoxaprofen, Bucloxic Acid, Benzylhydrochlorothiazide. Buthiazide, Chlorothiazide, Carprofen, Fenoprofen, Flunoxaprofen, Flurbiprofen, Ibu Chlorthalidone, Cyclopenthiazide, Cyclothiazide, Diazox 30 profen, Ibuproxam, Indoprofen, Ketoprofen, Loxoprofen, ide, Epithiazide, Ethiazide, Fenguizone, Hydrochlorothiaz Miroprofen, Naproxen, Oxaprozin, Piketoprofen, Pirprofen, ide, Hydroflumethiazide, Methyclothiazide, Meticrane, Pranoprofen, Protizinic Acid, Suprofen and Tiaprofenic Metolazone, Paraflutizide, Polythiazide, Tetrachlormethiaz Acid; Pyrazoles such as Difenamizole and Epirizole; Pyra ide and Trichlormethiazide, N-Carboxyalkyl (petide/lactam) Zolones such as Apazone, BenZpiperylon, Feprazone, derivatives such as Alacepril, Captopril, Cilazapril, Delapril, 35 Mofebutazone, Morazone, Oxyphenbutazone, Phenylbuta Enalapril, Enalaprilat, Fosinopril, Lisinopril, Moveltipril, Zone, PipebuZone, PropyphenaZone, RamifenaZone, Suxi Perindopril, Quinapril and Ramipril; Dihydropyridine buZone and Thiazolinobutazone; Salicylic acid derivatives derivatives such as Amlodipine, Felodipine, Isradipine, Such as Acetaminosalol, Aspirin, Benorylate, Bromosali Nicardipine, Nifedipine, Nilvadipine, Nisoldipine and genin, Calcium Acetylsalicylate, Diflunisal, Etersalate, Fen Nitrendipine; 40 dosal, Gentisic Acid, Glycol Salicylate. Imidazole Salicy 43. Guanidine derivatives such as Bethanidine, Debriso late, Lysine Acetylsalicylate, Mesalamine, Morpholine quin, Guanabenz, Guanacline, Guanadrel, GuanaZodine, Salicylate, 1-Naphthyl Salicylate, Olsalazine, Parsalmide, Guanethidine, Guanfacine, Guanochlor, Guanoxabenz, and Phenyl Acetylsalicylate, Phenyl Salicylate, Salacetamide, Guanoxan; Hydrazines and phthalazines such as Budrala Salicylamine O-Acetic Acid, Salicylsulfuric Acid, Salsalate zine, Cadralazine, Dihydralazine, Endralazine, Hydracarba 45 and SulfaSalazine; Thiazinecarboxamides such as Droxicam, zine, Hydralazine, Pheniprazine, Pildralazine and Todrala Isoxicam, PiroXicam and Tenoxicam, and others such Zine: Imidazole derivatives such as Clonidine, Lofexidine, as .epsilon.-Acetamidocaproic Acid, S-Adenosylmethio Phentolamine, Tiamenidine and Tolonidine; Quaternary nine, 3-Amino-4-hydroxybutyric Acid, Amixetrine, Ben ammonium compounds AZamethonium Bromide, Chlor dazac, BenZydamine, Bucolome, Dilfenpiramide, DitaZol. isondamine Chloride, Hexamethonium, Pentacynium Bis 50 EmorfaZone, GuaiaZulene, Nabumetone, Nimesulide, (methyl sulfate), Pentamethonium Bromide, Pentolinium Orgotein, Oxaceprol, Paranyline, Perisoxal, Pifoxime, Pro Tartate, Phenactopinium Chloride and Trimethidiunum quaZone, Proxazole and Tenidap. Methosulfate; Quinazoline derivatives such as Alfuzosin, 48. Antimalarial drugs such as Acedapsone, Amodiaquin, BunaZosin, Doxazosin, Prasosin, Terazosin and TrimaZosin; Arteether, Artemether, Artemisinin, Artesunate, Bebeerine, Reserpine derivatives such as Bietaserpine, Deserpidine, 55 Berberine, Chirata, Chlorguanide, Chloroquine, Chlo Rescinnamine, Reserpine and Syrosingopine; Sulfonamide rproguanil, Cinchona, Cinchonidine, Cinchonine, Cyclogua derivatives such as Ambuside, Clopamide, Furosemide, nil, Gentiopicrin, Halofantrine, Hydroxychloroquine, Indapamide, QuinethaZone, Tripamide and Xipamide; and Mefloquine Hydrochloride, 3-Methylarsacetin, Pamaquine, others such as Ajmaline, Y-Aminobutyric Acid, Bufeniode, Plasmocid, Primaquine, Pyrimethamine, Quinacrine, Qui Chlorthalidone, Cicletaine, Ciclosidomine, Cryptenamine 60 nine, Quinine Bisulfate, Quinine Carbonate, Quinine Dihy Tannates, Fenoldopam, Flosequinan, Indoramin, Ketanserin, drobromide, Quinine Dihydrochloride, Quinine Ethylcar Metbutamate, Mecamylamine, Methyldopa, Methyl bonate, Quinine Formate, Quinine Gluconate, Quinine 4-Pyridyl Ketone Thiosemicarbarzone, Metolazone, Hydriodide, Quinine Hydrochloride, Quinine Salicylate, Minoxidil, Muzolimine, Pargyline, Pempidine, Pinacidil, Quinine Sulfate, Quinine Tannate, Quinine Urea Hydrochlo Piperoxan, Primaperone, Protoveratrines, Raubasine, Resci 65 ride, Quinocide, Quinoline and Sodium Arsenate Diabasic. metol, Rilmenidene, Saralasin, Sodium Nitroprusside, Tic 49. Antimigraine drugs such as Alpiropride, Dihydroer rynafen, Trimethaphan Camsylate, Tyrosinase and Urapidil. gotamine, Ergocomine, Ergocominine, Ergocryptine, Ergot, US 9,682,043 B2 15 16 Ergotamine, FlumedroXone acetate, Fonazine, Lisuride, 56. Antipneumocystis drugs such as Effomithine, Pent Methysergid(e), Oxetorone, Pizotyline and Sumatriptan. amidine and Sulfamethoxazole. 50. Antinauseant drugs such as Acetylleucine Monoetha 57. Antiprostatic hypertrophy drugs such as Gestonorone nolamine, Alizapride, BenZquinamide, Bietanautine, Bro Caproate, Mepartricin, Oxendolone and Finasteride (Pros mopride, Buclizine, Chlorpromazine, Clebopride, Cyclizine, carO). Dimenhydrinate, Dipheniodol, Domperidone, Granisetron, 58. Antiprotozoal drugs (Leshmania) Such as Antimony Meclizine, Methalltal, Metoclopramide, Metopimazine, Sodium Gluconate, Ethylstibamine, Hydroxy stilbamidine, Nabilone, Ondansteron, Oxypendyl, Pipamazine, Piprinhy N-Methylglucamine, Pentamidine, Stilbamidine and Urea drinate, Prochlorperazine, Scopolamine, Tetrahydrocannab Stibamine. inols. Thiethylperazine. Thioproperzaine and Trimethoben 10 Zamide. 59. Antiprotozoal drugs (Trichomonas) such as Acetar 51. Antineoplastic drugs, including: Alkylating agents, Sone, AminitroZole, Anisomycin, AZanidazole, Forminitra including: Alkyl Sulfonates such as BuSulfan, ImproSulfan Zole, Furazolidone, Hachimycin, Lauroguadine, Mepartri and Piposulfan, AZiridines such as BenZodepa, Carboquone, cin, Metronidazole, Nifuratel, Nifuroxime, Nimorazole, Meturedepa and Uredepa; Ethylenimines and methyl 15 Secnidazole, Silver Picrate, Tenonitrozole and Tinidazole. melamines Such as Altretamine, Triethylenemelamine, Tri 60. Antiprotozoal drugs (Trypanosma) Such as BenZnida ethylenephosphoramide, Triethylenethiophosphoramide and Zole, Eflomithine, Melarsoprol, Nifurtimox, Oxophenarsine, Trimethylolomelamine; Nitrogen mustards such as Hydrochloride, Pentamidine, Propamidine, Puromycin, Qui Chlorambucil, Chlomaphazine, Chclophosphamide, Estra napyramine, Stilbamidine, Suramin Sodium, Trypan Red mustine, Ifosfamide, Mechlorethamine, Mechlorethamine and Tryparasmide. Oxide Hydrochloride, Melphalan, Novembichin, Phenester 61. Antipuritics such as Camphor, Cyproheptadine, ine, Prednimustine, Trofosfamide and Uracil Mustard; Dichlorisone, Glycine, Halometasone, 3-Hydroxycamphor, Nitrosoureas such as Carmustine, Chlorozotocin, Foremus Menthol, Mesulphen, Methdilazine, Phenol, Polidocanol, tine, Lomustine, Nimustine and Ranimustine; and others Risocaine, Spirit of Camphor, Thenaldine, Tolpropamine such as Dacarbazine, Mannomustine, Mitobronitol, Mito 25 and Trimeprazine. lactol and Pipobroman; Antibiotics such as Aclacinomycins, 62. Antipsoriatic drugs such as Acitretin, Ammonium Actinomycin F, Anthramycin, AZaserine, Bleomycins, Cac Salicylate, Anthralin, 6-AZauridine, Bergapten(e), Chrysar tinomycin, Carubicin, Carzinophilin, Chromomycins, Dac obin, Etretinate and Pyrogallol. tinomycin, Daunorubicin, 6-Diazo-5-oxo-L-norleucine, 63. Antipsychotic drugs, including: Butyrophenones such Doxorubicin, Epirubicin, Mitomycins, Mycophenolic Acid, 30 as Benperidol, Bromperidol, Droperidol, Fluanisone, Halo Nogalamycin, Olivomycins, Peplomycin, Plicamycin, peridol, Melperone, Moperone, Pipamperone, Sniperone, Porfiromycin, Puromycin, Streptonigrin, Streptozocin, Timiperone and Trifluperidol; Phenothiazines such as Aceto Tubercidin, Ubenimex, Zinostatin and Zorubicin; Antime phenazine, Butaperazine, Carphenazine, Chlorproethazine, tabolites, including: Folic acid analogs such as Denopterin, Chlorpromazine, Clospirazine, Cyamemazine, Dixyrazine, Methotrexate, Pteropterin and Trimetrexate; Purine analogs 35 such as Fludarabine, 6-Mercaptopurine. Thiamiprine and Fluphenazine, Imiclopazine, Mepazine, Mesoridazine, Thioguanaine; and Pyrimidine analogs such as Ancitabine, Methoxypromazine, Metofenazate, Oxaflumazine, Perazine, Azacitidine, 6-AZauridine, Carmofur, Cytarabine, Doxiflu Pericyazine, Perimethazine, Perphenazine, Piperacetazine, ridine, Enocitabine, Floxuridine, Fluroouracil and Tegafur, Pipotiazine, Prochlorperazine, Promazine, Sulforidazine, Enzymes such as L-Asparaginase; and others such as 40 Thiopropazate. Thioridazine, Trifluoperazine and Triflupro Aceglatone, Amsacrine, Bestrabucil, Bisantrene, Carbopla mazine; Thioxanthenes such as Chlorprothixene, Clopen tin, Cisplatin, Defofamide, Demecolcine, Diaziquone, thixol, Flupentixoland Thiothixene; other tricyclics such as Elfomithine, Elliptinium Acetate, Etoglucid, Etoposide, Gal BenZquinamide, Carpipramine, Clocapramine, Clomacran, lium Nitrate, Hydroxyurea, Interferon-C. Interferon-B, Inter Clothiapine, Clozapine, Opipramol, Prothipendyl, Tetra feron-Y, Interleukine-2, Lentinan, Lonidamine, Mitogua 45 benazine, and Zotepine; and others such as Alizapride, Zone, Mitoxantrone, Mopidamol, Nitracrine, Pentostatin, Amisulpride, Buramate, Fluspirilene, Molindone, Penfluri Phenarnet, Pirarubicin, Podophyllinicc Acid, 2-Ethythydraz dol, Pimozide, Spirilene and Sulpiride. ide, Procarbazine, PSKR), Razoxane, Sizofiran, Spirogerma 64. Antipyretics such as Acetaminophen, Acetaminosalol, nium, Taxol. Teniposide, TenuaZonic Acid, Triaziquone, Acetanilide, Aconine, Aconite, Aconitine, Alclofenac, Alu 2.2.2"Trichlorotriethylamine, Urethan, Vinblastine, Vincris 50 minum Bis(acetylsalicylate), Aminochlorthenoxazin, Amin tine and Vindesine; opyrine, Aspirin, Benorylate, BenZydamine, Berberine, 52. Antineoplastic (hormonal) drugs, including: Andro p-Bromoacetanilide, Bufexamac, Bumadizon, Calcium gens such as Calusterone, Dromostanolone Propionate, Epi Acetysalicylate, Chlorthenoxazin(e), Choline Salicylate, tiostanol, Mepitiostane and Testolactone; Antiadrenals such Clidanac, Dihydroxyaluminum Acetylsalicylate, Dipyro as Aminoglutethimide, Mitotane and TriloStane; Antiandro 55 cetyl, Dipyrone, Epirizole, Etersalate. Imidazole Salicylate, gens such as Flutamide and Nilutamide; and Antiestrogens Indomethacin, IsofeZolac, p-Lactophenetide, Lysine Acetyl Such as Tamoxifen and Toremifene. salicylate, Magnesium Acetylsalicylate, Meclofenamic 53. Antineoplastic adjuncts including folic acid replen Acid, Morazone, Morpholine Salicylate, Naproxen, Nifena ishers such as Frolinic Acid. Zone, 5'-Nitro-2'propoxyacetanilide, propoxyacetanilide, 54. Antiparkinsonian drugs such as Amantadine, Benser 60 Phenacetin, Phenicarbazide, Phenocol, Phenopyrazone, azide, Bietanautine, Biperiden, Bromocriptine, Budipine, Phenyl Acetylsalicylate, Phenyl Salicylate, PipebuZone, Carbidopa, Deprenyl, Dexetimide, Diethazine, Droxidopa, Propacetamol, PropyphenaZone, RamifenaZone, Salacet Ethopropazine, Ethylbenzhydramine, Levodopa, Nax amide, Salicylamide 0-Acetic Acid, Sodium Salicylate, Sul agolide, Pergolide, Piroheptine, Pridinol, Prodipine, Tergu famipyrine, Tetrandrine and Tinoridine. ride, Tigloidine and Trihexyphenidyl Hydrochloride. 65 65. Antirickettsial drugs such as p-Aminobenzoic Acid, 55. Antipheochromocytoma drugs such as Metyrosine, Chloramphenicol, Chloramphenicol Palmitate, Chloram Phenoxybenzamine and Phentolamine. phenicol Pantothenate and Tetracycline. US 9,682,043 B2 17 18 66. Antiseborrheic drugs such as Chloroxine, 3-O-Lau N-Oxide, Codeine Phosphate, Codeine Sulfate, Cyclex roylpyridoxol Diacetate, Piroctone, Pyrithione, Resorcinol, anone, Dextromethorphan, Dibunate Sodium, Dihydroco Selenium Sulfides and Tioxolone. deine, Dihydrocodeinone Enol Acetate, Dimemorfan, Dime 67. Antiseptics, including: Guanidines such as Alexidine, thoxanate, C.C.-Diphenyl-2-piperidinepropanol, Ambazone, Chlorhexidine and Picloxydine: Halogens and Dropropizine, Drotebanol, Eprazinone, Ethyl Dibunate, Eth halogen compounds such as Bismuth Iodide Oxide, Bismuth ylmorphine, Fominoben, Guiaiapate, Hydrocodone, Isoam Iodosubgallate, Bismuth Tribromophenate, Bomyl Chloride, inile, Levopropoxyphene, Morclofone, Narceline, Calcium Iodate, Chlorinated Lime, Cloflucarban, Fluro Normethadone, Noscapine, Oxeladin, Oxolamine, Pholco salan, Iodic Acid, Iodine, Iodine Monochloride, Iodine dine, Picoperine, Pipazethate, Piperidione, Prenoxdiazine Trichloride, Iodoform, Methenamine Tetraiodine, Oxychlo 10 Hydrochloride, Racemethorphan, Taziprinone Hydrochlo rosene, Povidone-lodine, Sodium Hypochlorite, Sodium Iodate, Symclosene, Thymol Iodide, Triclocarban, Triclosan ride, Tipepidine and Zipeprol. and Troclosene Potassium; Mercurial compounds such as 71. Antiulcerative drugs such as Aceglutamide Aluminum Hydragaphen, Meralein Sodium, Merbromin, Mercuric Complex, .epsilon.-Acetamidocaproic Acid Zinc Salt, Chloride, Mercuric Chloride, Ammoniated, Mercuric 15 Acetoxolone, Arbaprostil, BenexateHydrochloride, Bismuth Sodium p-Phenolsulfonate, Mercuric Succinimide, Mercu Subcitrate Sol (Dried), Carbenoxolone, Cetraxate, Cimeti ric Sulfide, Red, Mercurophen, Mercurous Acetate, Mercu dine, Enprostil, Esaprazole, Famotidine, Ftaxilide, Gefar rous Chloride, Mercurous Iodide, Nitromersol, Potassium nate, GuaiaZulene, Irsogladine, Misoprostol, Nizatidine, Tetraiodomercurate(II), Potassium Triiodomercurate(II) Omeprazole, Ornoprostil, Y-Oryzanol, Pifarnine, Solution, Thimerfonate Sodium and Thimerosal; Nitro Pirenzepine, Plaunotol, Ranitidine, Rioprostil, Rosaprostol, furans such as Furazolidone, 2-(Methoxymethyl)-5-nitro Rotraxate, Roxatidine Acetate, Sofalicone, Spizofurone, furan, Nidroxy Zone, Nifuroxime, Nifurzide and Nitrofura Sucralfate, Teprenone, Trimoprostil, Thrithiozine, Troxipide Zone; Phenols such as Acetomeroctol, Bithionol, Cadmium and Zolimidine. Salicylate, Carvacrol, Chloroxylenol, Clorophene, Cresote, 72. Antiurolithic drugs such as Acetohydroxamic Acid, Cresol(s), p-Cresol, Fenticlom, Hexachlorophene, 25 Allopurinol, Potassium Citrate and Succinimide. 1-Napthyl Salicylate, 2-Napthyl Salicylate, 2.4.6-Tribromo 73. Antiviral drugs, including: Purines and pyrimidinones m-cresol, and 3',4',5-Trichlorosalicylanilide; Quinolines Such as Acyclovir, Cytarabine, Dideoxyadenosine, Dideoxy Such as Aminoquinuride, BenZOXiquine, Broxyquinoline, cytidine, Dideoxyinosine, Edoxudine, Floxuridine, Ganci Chloroxine, Chlorquinaldol, Cloxyquin, Ethylhydrocu clovir, Idoxuridine, Inosine Pranobex, MADU, Trifluridine, preine, Euprocin, Halquinol, Hydrastine, 8-Hydroxquino 30 line, 8-Hydroxquinoline Sulfate and Iodochlorhydroxyquin; Vidrarbine and Zidovudiine; and others such as Acetylleu and others such as Aluminum Acetate Solution, Aluminum cine Monoethanolamine, Amantadine, Amidinomycin, Subacetate Solution, Aluminum Sulfate, 3-Amino-4-hy Cuminaldehyde Thiosemicarbzone, Foscarnet Sodium, droxybutyric Acid, Boric Acid, Chlorhexidine, Chloroazo Interferon-C. Interferon-B, Interferon-Y, Kethoxal, din, m-Cresyl Acetate, Cupric Sulfate, Dibromopropami 35 Lysozyme, Methisazone, Moroxydine, Podophyllotoxin, dine, Ichthammol. Negatolg, Noxytiolin, Omidazole, Ribavirin, Rimantadine, Stallimycin, Statolon, Tromanta B-Propiolactone, C-Terpineol. dine and Xenazoic Acid. 68. Antispasmodic drugs such as Alibendol, Ambucet 74. Anxiolytic drugs, including: Arylpiperaz ines Such as amide, Aminopromazine, Apoatropine, Bevonium Methyl Buspirone, Gepirone and Ipsapirone; BenZodiazepine Sulfate, Bietamiverine, Butaverine. Butropium Bromide, 40 derivatives Such as Alprazolam, Bromazepaam, Camaze N-Butylscopolammonium Bromide, Caroverine, Cimetro pam, Chlordiazepoxide, Clobazam, Clorazepate, Chotiaz pium Bromide, Cinnamedrine, Clebopride, Coniine Hydro epam, Cloxazolam, Diazepam, Ethyl Loflazepate, Etizolam, bromide, Coniine Hydrochloride, Cyclonium Iodide. Dife Fluidazepam, Flutazolam, Flutoprazepam, Halazepam, merine, Diisopromine, Dioxaphetyl Butyrate, Diponium Ketazolam, Lorazepam, Loxapine, Medazepam, Metaclaze Bromide, Drofenine, Emepronium Bromide, Ethaverine, 45 pam, Mexazolam, Nordazepam, Oxazepam, Oxazolam, Feclemine, Fenalamide, Fenoverine, Fenpiprane, Fenpiver Pinazepam, Prazepam and Tofisopam; Carbamates such as inium Bromide, Fentonium Bromide, Flavoxate, Flopropi Cyclarbamate, Emylcamate, Hydroxyphenamate, Mepro one, Gluconic Acid, Guaiactamine, Hydramitrazine, Hyme bamate, Phenprobamate and Tybamate; and others such as cromone, Leiopyrrole, Mebeverine, Moxaverine, Alpidem, BenZoctamine, Captodiamine, ChlormeZanone, Nafiverine, Octamylamine, Octaverine, Pentapiperide, Phe 50 Etifoxine, Fluoresone, Glutamic Acid, Hydroxyzine, Meclo namacide Hydrochloride, Phloroglucinol, Pinaverium Bro ralurea, Mephenoxalone, Oxanamide, Phenaglycodol, Suri mide, Piperilate, Pipoxolanhydrochloride, Pramiverin, Pri clone. finium Bromide, Properidine, Propivane, Propyromazine, 75. BenZodiazepine antagonists such as Flumazenil. Prozapine, Racefemine, Rociverine, Spasmolytol, Stilonium 76. Bronchodilators, including: Ephedrine derivatives Iodide, Sultroponium, Tiemonium Iodide, Tiquizium Bro 55 such as Albuterol, Bambuterol, Bitolterol, Carbuterol, Clen mide, Tiropramide, Trepibutone, Tricromyl, Trifolium, buterol, Clorprenaline, Dioxethedrine, Ephedrine, Epiniph Trimebutine, N.N-1Trimethyl-3,3-diphenyl-propylamine, rine, Eprozinol, Etafedrine, Ethylnorepinephrine, Fenoterol, Tropenzile, Trospium Chloride and Xeny tropium Bromide. Hexoprenaline, Isoetharine, Isoproterenol, Mabuterol, 69. Antithrombotic drugs such as Anagrelide, Argatroban, Metaproterenol, N-Methylephedrine, Pirbuterol, Procaterol, Cilostazol, Daltroban, Defibrotide, Enoxaparin, Fraxi 60 Protokylol, Reproterol, Rimiterol, Soterenol, Terbutaline parine R, Indobufen, Lamoparan, OZagrel, Picotamide, Pla and Tulobuterol; Quaternary ammonium compounds such as fibride, Tedelparin, Ticlopidine and Triflusal. Bevonium Methyl Sulfate, Clutropium Bromide, Ipratro 70. Antitussive drugs such as Allocamide, Amicibone, pium Bromide and Oxitropium Bromide; Xanthine deriva Benproperine, Benzonatate, Bibenzonium Bromide, Bromo tives such as Acefylline, Acefylline Piperazine, Ambuphyl form, Butamirate. Butethamate, Caramiphen Ethanedisul 65 line, Aminophylline, Bamifylline, choline Theophyllinate, fonate, Carbetapentane, Chlophedianol, Clobutinol, Clop Doxofylline, Dyphylline, Enprofylline, Etamiphyllin, Etof erastine, Codeine, Codeine Methyl Bromide, Codeine yline, Guaithylline, Proxyphylline. Theobromine, 1-Theo US 9,682,043 B2 19 20 bromineacetic Acid and Theophylline; and others such as 88. Decongestants such as Amidephrine, Cafaminol, Fenspiride, Medibazine, Methoxyphenanime and Tretoqui Cyclopentamine, Ephedrine, Epinephrine, Fenoxazoline, nol. Indanazoline, Metizoline, Naphazoline, Nordefrin Hydro 77. Calcium channel blockers, including: Arylalkylam chloride, Octodrine, Oxymetazoline, Phenylephrine Hydro ines such as Bepridil, Ditiazem, Fendiline, Gallopanil, Pre chloride, Phenylpropanolamine Hydrochloride, Phenylpro nylamine, Terodiline and Verapamil: Dihydropyridine pylmethylamine, Propylhexedrine, Pseudoephedrine, derivatives such as Felodipine, Isradipine, Nicardipine, Tetrahydrozoline, Tymazoline and Xylometazoline. Nifedipine, Nilvadipine, Nimodipine, Nisoldipine and 89. Dental carries prophylactics such as Sodium Fluoride. Nitrendipine; Piperazine derivatives such as Cinnarizine, 90. Depigmentors such as Hydroquinine, Hydroquinone Flunarisine and Lidoflazine; and others such as Bencyclane, 10 and Monobenzone. Etafenone and Perhexiline. 92. Diuretics, including: Organomercurials such as Chlo 78. Calcium regulators such as Calcifediol, Calcitonin, rmerodrin, Meralluride, Mercamphamide, Mercaptomerin Calcitriol, Clodronic Acid, Dihydrotachysterol, Elcatonin, Sodium, Mercumallylic Acid, Mercumatilin Sodium, Mer Etidronic Acid, priflavone, Pamidronic Acid, Parathyroid curous Chloride and Mersalyl; Pteridines such as Furterene Hormone and Teriparatide Acetate. 15 and Triamterene; Purines such as Acefylline, 7-Morpholi 79. Cardiotonics such as Acefylline, Acetyldigititoxins, nomethyltheophylline, Pamabrom, Protheobromine and 2-Amino-4-picoline, Amrinone, Benfurodil Hemisuccinate, Theobromine; Steroids such as Canrenone, Oleandrin and Buclasdesine, Cerberoside, Camphotamide, Convallatoxin, Spironolactone; Sulfonamide derivatives such as Acetazol Cymarin, Denopamine, Deslanoside, Ditalin, Digitalis, mide, Ambuside, AZOsemide, Bumetanide, Butazolamide, Digitoxin, Digoxin, Dobutamine, Dopamine, Dopexamine, Chloraminophenamide, Clofenamide, Clopamide, Clorex Enoximone, Erythrophleine, Fenalcomine, Gitalin, Gitoxin, olene, Diphenylmethane-4.4'-disulfonamide, Disulfamide, Glycocyamine, Heptaminol, Hydrastinine, Ibopamine, EthoXZolamide. Furosemide, Indapamide, Mefruside, Met Lanotodises, Metamivam, Milrinone, Neriifolin, Oleandrin, hazolamide, Piretanide, Quinethazone, Torasemide, Trip Ouabain, Oxyfedrine, Prenalterol, Proscillaridin, Resibufo amide and Xipamide; Uracils such as Aminometradine and genin, Scillaren, Scillarenin, Strophanthin, Sulmazole, 25 Amisometradine; others such as Amanozine, Amiloride, Theobromine and Xamoterol. Arbutin, Chlorazanil, Ethacrynic Acid, Etozolin, Hydracar 80. Chelating agents such as Deferozmine, Ditiocarb bazine, Isosorbide, Mannitol, Metochalcone, Muzolimine, Sodium, Edetate Calcium Disodium, Edetate Disodium, Perhexiline, Ticrynafen and Urea. Edeate Sodium, Edetate Trisodium, Penicillamine, Pentetate 92. Dopamine receptor agonists such as Bromocriptine, Calcium Trisodium, Pentectic Acid, Succimer and Trientine. 30 Dopexamine, Fenoldopam, Ibopamine, Lisuride, Nax 81. Cholecystokinin antagonists such as Proglumide. agolide and Pergolide. 82. Cholelitholytic agents such as Chenodiol, Methyl 93. Ectoparasiticides such as Amitraz, Benzyl Benzoate, tert-Butyl Ether, Monooctanoin and Ursodiol Carbaryl, Crotamiton, DDT. Dixanthogen, isobomyl Thio 83. Choleretics such as Alibendol, Anethole Trithion, cyanoacetate-Technical, Lime Sulfurated Solution, LIndane, AZintamide, Cholic Acid, Cicrotoic Acid, Clanobutin, 35 Malathion, Mercuric Oleate, Mesulphen and Sulphur— Cyclobutyrol, Cyclovalone, Cynarin(e), Dehydrocholic Pharmaceutical; and Mucolytic enzymes Such as Lysozyme. Acid, Deoxycholic Acid, Dimecrotic Acid, O.-Ethylbenzyl 94. Enzyme inducers (hepatic) such as Flumecinol. Alcohol, Exiproben, Feguprol, Fencibutirol, Fenipentol, 95. Estrogens, including: Nonsteroidal estrogens Such as Florantyrone, Hymecromone, Menbutone, 3-(o-Methoxy Benzestrol, Broparoestrol, Chlorotrianisene, Dienestrol, phenyl)-2-phenylacrylic Acid, Metochalcone, Moquizone, 40 Diethylstilbestrol, Diethylstilbestrol Diproprionate, Dime Osalmid, Ox Bile Extract, 4.4'-Oxydi-2-butanol, Piprozolin, strol, Fosfestrol, Hexestrol, Methallenestril and Methestrol; Prozapine, 4-Salicyloylmorpholine, Sincalide, Taurocholic and Steroidal estrogens such as Colpormon, Conjugated Acid, Timonacic, Tocamphyl, Trepibutone and Vanitiolide. Estrogenic Hormones, Equilenin, Equilin, Estradiol, Estra 84. Cholinergic agents such as Aceclidine, Acetylcholine diol Benzoate, Estradiol 17B-Cypionate, Estriol, Estrone, Bromide, Acetylcholide Chloride, Aclatonium Napadisilate, 45 Ethinyl Estradiol, Mestranol, Moxestrol, Mytatrienediol, Benzpyrinium Bromide, Bethanechol chloride, Carbachol, Quinestradiol and Quinestrol. Carpronium chloride, Demecarium Bromide, Dexpanthenol, 96. Gastric secretion inhibitors such as Enterogastrone Diisopropyl Paraoxon, Echothiophate Iodide, Edrophomium and Octreotide. chloride, Eseridine. Furtrethonium, Isoflurophate, Metha 97. Glucocorticoids such as 21-Acetoxyprefnenolone, choline chloride, Muscarine, Neostigmine, Oxapropanium 50 AalclometaSone, Algestone, Amicinonide, Beclomethasone, Iodide, Physostigmine and Pyridostigmine Bromide. Betamethasone, Budesonide, Chloroprednisone, Clobetasol, 85. Cholinesterase inhibitors such as Ambenonium Chlo Blovetasone, Clocortolone, Cloprednol, Corticosterone, ride, Distigmine Bromide and Galanthamine. Cortisone, Cortivazol, Deflazacort, Desonide, Desoximeta 86. Cholinesterase reactivators such as Obidoximine sone, Dexamethasone, Diflorasone, Diflucortolone, Diflu Chloride and Pralidoxime Chloride. 55 prednate, Enoxolone, Fluazacort, Flucloronide, Flumehta 87. Central nervous system stimulants and agents such as sone, Flunisolide, Fluocinolone Acetonide, Fluocinonide, Amineptine, Amphetimine, Amphetaminil, Bemegride, Fluocortin Butyl, Fluocortolone, Fluorometholone, Fluper Benzphetamine, Brucine, Caffeine, Chlorphentermine, olone Acetate, Fluprednidene Acetate, Fluprednisolone, Flu Clofenciclan, Clortermine, Coca, Demanyl Phosphate, Dex randrenolide, Formocortal, Halcinonide, HalometaSone, oxadrol, Dextroamphetamine Sulfate, Diethlpropion, 60 Halopredone Acetate, Hydrocortamate, Hydrocortisone, N-Ethytlamphetamine, Ethamivan, Etifelmin, Etryptamine, Hydrocortisone Acetate, ydrocortisone Phosphate, Hydro Fencamfamine, Fenethylline, Fenosolone, Flurothyl, cortisone 21-Sodium Succinate, Hydrocortisone Tebutate, Hexacyclonate Sodium, Homocamfin, Mazindol, Megexam Mazipredone, Medrysone, Meprednisone, Methyolpredni ide, Methamphetamine, Methylphenidate, Nikethamide, solone, Mometasone Furoate, Paramethasone, Prednicar Pemoline, Pentylenetetrazole, Phenidimetrazine, Phen 65 bate, Prednisolone, Prednisolone 21-Diethylaminoacetate, metrazine, Phenternine, Picrotoxin, Pipradrol, Prolintane Prednisone Sodium Phosphate, Prednisolone Sodium Suc and Pyrovalerone. cinate, Prednisolone Sodium 21-m-Sulfobenzoate, Predni US 9,682,043 B2 21 22 solone 21-Stearoylglycolate, Prednisolone Tebutate, Predni cinylcholine Chloride. Succinylcholine Iodine, Suxetho solone 21-Trimethylacetate, Prednisone, Prednival, nium Bromide, Tetrazepam, Thiocolchicoside, Tizanidine, Prednylidene, Prednylidene 21-Diethylaminoacetate, Tixo Tolperisone, Tubocurarine Chloride, Vecuronium Bromide cortal, Triamcinolone, Triamcinolone Acetonide, Triamci and Zoxolamine. nolone Benetonide and Triamcinolone Hexacetonide. 118: Narcotic antagonists such as Amiphenazole, Cycla 98. Gonad-Stimulating principles such as Buserelin, Clo Zocine, Levallorphan, Nadide, Nalmfene, Nalorphine, miphene, Cyclofenil, Epimestrol, FSH, HCG and LH-RH. Nalorphine Dinicotinate, Naloxone and Naltrexone. 99. Gonadotropic hormones such as LH and PMSG. 119. Neuroprotective agents such as Dizocilpine. 100. Growth hormone inhibitors such as Octreotide and 120. Nootropic agents such as Aceglutamide, Acetylcar Somatostatin. 10 nitine, Aniracetam, Bifematlane, Exifone, Fipexide, Ide 101. Growth hormone releasing factors such as Semo benone, Indeloxazune Hydrochloride, Nizofenone, Oxirac relin. etam, Piracetam, Propentofylline, Pyritinol and Tacrine. 102. Growth stimulants such as Somatotropin. 121. Ophthalmic agents such as 15-ketoprostaglandins. 103. Hemolytic agents such as Phenylhydrazine and Phe 122. Ovarian hormone Such as relaxin. nylhydrazine Hydrochloride. 15 123. Oxytocic drugs such as Carboprost, Cargutocin, 104. Heparin antagonists such as Hexadimethrine Bro Deaminooxytocin, Ergonovine, Gemeprost, Methylergon mide and Protamines. ovine, Oxytocin, Pituitary (Posterior), Prostaglandin E2. 105. Hepatoprotectants such as S-Adenosylmethionine, Prostaglandin F2C. and Sparteine. Betaine, Catechin, Citolone, Malotilate, Orazamide, Phos 124. Pepsin inhibitors such as Sodium Amylosulfate. phorylcholine, Protoporphyrin IX, Silymarin-Group. Thiotic 125. Peristaltic stimulants such as Cisapride. Acid and Tiopronin. 126. Progestogens such as Allylestrenol, Anagestone, 106. Immunomodulators such as Amiprilose, Bucil Chlormadinone Acetate, Delmadinone Acetate, Demege lamine, Ditiocarb Sodium, Inosine Pranobex, Interferon-y, stone, Desogestrel, Dimethisterone, Dydrogesterone, Ethis Interleukin-2, Lentinan, Muroctasin, Platonin, Procodazole, terone, Ethynodiol, Flurogestone Acetate, Gestodene, Tetramisole, Thymomodulin, Thymopentin and Ubenimex. 25 Gestonorone Caproate, Haloprogesterone, 17-Hydroxy-16 107. Immunosuppressants such as Azathioprine, methylene-progesterone, 17C-Hydroxyprogesterone, 17C.- Cyclosporins and Mizoribine. Hydroxygesterone Caproate, Lynestrenol, Medrogestone, 108. Ion exchange resins such as Carbacrylic Resins, Medroxyprogesterone, Megestrol Acetate, Melengestrol, Cholestyramine Resin, Colestipol, Polidexide, Resodec and Norethindrone, Norethynodrel, Norgesterone, Norgestimate, Sodium Polystyrene Sulfonate. 30 Norgestrel, Norgestrienone, Norvinisterone, Pentagestrone, 109. Lactation stimulating hormone such as Prolactin. Progesterone, Promegestone, Quingestrone and Trenge 110. LH-RH agonists such as Buserelin, Goserelin, Leu StOne. prolide, Nafarelin, and Triptorelin. 127. Prolactin inhibitors such as Metergoline. 111. Lipotropic agents such as N-Acetylmethionine, Cho 128. Prostaglandins and prostaglandin analogs such as line Chloride, Choline Dehydrocholate, Choline Dihydrogen 35 Arbaprostil, Carboprost, Enprostil, Bemeprost, Limaprost, Citrate, Inositol, Lecithin and Methionine. Misoprostol, Omoprostil, Prostacyclin, Prostaglandin E1. 112. Lupus erythematosus Suppressants such as Bismuth Prostaglandin E2. Prostagland in F2C, Rioprostil, Rosapro Sodium Triglycollamate, Bismuth Subsalicylate, Chloro stol, Sulprostone and Trimoprostil. quine and Hydroxychloroquine. 129. Protease inhibitors such as Aprotinin, Camostat, 113. Mineralcorticoids such as Aldosterone, Deoxycorti 40 Gabexate and Nafamo.stat. costerone, Deoxycorticosterone Acetate and Fludrocorti 130. Respiratory stimulants such as Almitrine, Beme SO. gride, Carbon Dioxide, Cropropamide, Crotethamide, Dime 114. Miotic drugs such as Carbachol, Physostigmine, fline, Dimorpholamine, Doxapram, Ethamivan, Fominoben, Pilocarpine and Pilocarpus. Lobeline, Mepixanox, Metamivam, Nikethamide, Picro 115: Monoamine oxidase inhibitors such as Deprenyl, 45 toxin, Pimeclone, Pyridofylline, Sodium Succinate and Iproclozide, Iproniazid, Isocarboxazid, Moclobemide, Octo Tacrine. moxin, Pargyline, Phenelzine, Phenoxypropazine, Pivalyl 131. Sclerosing agents such as Ethanolamine, Ethylam benzhydrazine, Prodipine, Toloxatone and Tranylcyprom ine, 2-Hexyldecanoic Acid, Polidocanol, Quinine Bisulfate, 1C. Quinine Urea Hydrochloride, Sodium Ricinoleate, Sodium 116. Mucolytic agents such as Acetylcysteine, Bromhex 50 Tetradecyl Sulfate and Tribenoside. ine, Carbocysteine, Domiodol, Letosteine, Lysozyme, 132. Sedatives and hypnotics, including: Acyclic ureides Mecysteine Hydrochloride, Mesna, Sobrerol, Stepronin, Such as Acecarbromal, Apronalide, Bomisovalum, Capuride, Tiopronin and Tyloxapol. Carbromal and Ectylurea; Alcohols such as Chlorhexadol, 117. Muscle relaxants (skeletal) such as Afloqualone, Ethchlorvynol, Meparfynol, 4-Methyl-5-thiazoleethanol, Alcuronium, Atracurium Besylate, Baclofen, BenZoctamine, 55 tert-Pentyl Alcohol and 2.2.2-Trichloroethanol; Amides Benzoquinonium Chloride, C-Calebassine, Carisoprodol, such as Butoctamide, Diethylbromoacetamide, Ibrotamide, Chlormezanone, Chlorphenesin Carbamate, Chlorproethaz Isovaleryl Diethylamide, Niaprazine, Tricetamide, Trime ine, ChloZOXaZ one, Curare, Cyclarbamate, Cyclobenzap tozine, Zolpidem and Zopiclone; Barbituric acid derivatives rine, Dantrolene, Decamethonium Bromide, Diazepam, such as Allobarbital. Amobarbital, Aprobarbital, Barbital, Eperisone, Fazadinium Bromide, Flumetramide, Gallamine 60 Brallabarbital, Butabarbital Sodium, Butalbital, Butally Triethiodide, Hexacarbacholine Bromide, Hexafluorenium lonal, Butethal, Carbubarb, Cyclobarbital, Cyclopentobarbi Bromide, Idrocilamide, Lauexium Methyl Sulfate, Lepto tal, Enallylpropymal, 5-Ethyl-5-(1-piperidyl) barbituric dactyline, Memantine, Mephenes in, Mephenoxalone, Acid, 5-Furfuryl-5-isopropylbarbituric Acid, Heptabarbital, Metaxalone, Methocarbamol, Metocurine Iodide, Nimetaze Hexethal Sodium, Hexobarbital, Mephobarbital, Methitural, pam, Orphenadrine, Pancuronium Bromide, Phenprobam 65 Narcobarbital, Nealbarbital, Pentobarbital Sodium, Phenal ate, Phenyramidol, Pipecurium Bromide, Promoxolane, lymal, Phenobarbital, Phenobarbital Sodium, Phenylmeth Quinine Sulfate, Styramate. Succinylcholine Bromide. Suc ylbarbituric Acid, Probarbital, Propallylonal, Proxibarbal, US 9,682,043 B2 23 24 Reposal, Secobarbital Sodium, Talbutal, Tetrabarbital, Vin 141. Vulnerary agents such as Acetylcysteine, Allantoin, barbital Sodium and Vinylbital; Benzodiazepine derivatives Asiaticoside, Cadexomer Iodine, Chitin, Dextranomer and Such as Brotizolam, Doxefazepam, Estazolam, Flunitraze Oxaceprol. pam, Flurazepam, Haloxazolam, Loprazolam, Lorimetaze The initial crystallization phase of the process requires pam, Nitrazepam, Quazepam, Temasepam and Triazolam; use of a solvent and anti-solvent, wherein the solvent and Bromides such as Ammonium Bromide, Calcium Bromide, anti-solvent system consists of one or more pharmaceuti Calcium Bromolactobionate, Lithium Bromide, Magnesium cally acceptable solvents (here defined as Class 3 solvents as Bromide, Potassium Bromide and Sodium Bromide; Car designated in the European Pharmacopea, 2002, 4th edition bamates such as Amyl Carbamate-Tertiary, Ethinamate, or appear as monographs in European Pharmacopea or in the Hexaprpymate, Meparfynol Carbamate, Novonal and Trich 10 United States Pharmacopea). olorourethan; Chloral derivatives such as Carbocloral, Chlo ral Betaine, Chloral Formamide, Chloral Hydrate, Chloral Examples of solvents and anti-solvents include aprotic antipyrine, Dichloralphenazone, Pentaerythritol Chloral and solvents (DMSO, N-methylpyrrolidone, and ethers), alco Triclofos; Piperidinediones such as Glutehimide, Methypry hols (ethanol, methanol, benzyl alcohol and isopropanol), lon, Piperidione, Pyrithyldione, Taglutimide and Thalido 15 hydrocarbons (hexane, cyclo-hexane and heptane), and mide; Quinazolone derivatives Such as Etaqualone, Meclo other protic solvents (water and acetic acid). Examples of qualone and Methaqualone; and others such as Acetal, Solvent (e.g., common solvents and anti-solvents) for use in Acetophenone, Aldol, Ammonium Valerate, Amphenidone, the inventive compositions and methods of the invention d-Bomyl C-Bromoisovalerate, d-Bomyl Isovalerate, Bromo include, but are not limited to, transesterfied vegetable oils, form, Calcium 2-Ethylbutanoate, Carfinate, C.-Chlorolose, 1-pentanol. 1-propanol, 1-butanol, 2-butanol, 2-methyl-1- Clomethiazole, Cypripedium, Doxylamine, Etodroxizine, propanol. 2-piperidone, 2-pyrrolidone, 3-methyl-1-butanol, Etomidate, Fenadiazole, Homofenazine, Hydrobromic Acid, acetone, acetyl tributyl citrate, acetyl triethylcitrate, acety Mecloxamine, Menthyl Valerate, Opium, Paraldehyde, Per lated glycerol fatty acid esters, acetylated monoglycerides lapine, Propiomazine, Rilmazafone, Sodium Oxybate, Sul and sterols, benzyl alcohol, butanediol and isomers thereof, fonethylmethane and Sulfonmethane. 25 butanol, butyl acetate, Co fatty acids, Cs and Co mono and 133. Thrombolytic agents such as APSAC, Plasmin, Pro diglycerides and mixtures thereof, C and Co triglycerides, Urokinase, Streptokinase, Tissue Plasminogen Activator and cumene, dimethyl isosorbide, dimethyl Sulphoxide, ethanol, Urokinase. ethyl acetate, ethyl butyrate, ethyl caprylate, ethyl ether, 134. Thyrotropic hormones such as TRH and TSH. ethyl formate, ethyl oleate, ethyl propionate, fatty acids, 135. Uricosurics such as Benzbromarone, Ethebenecid, 30 glycerol, glycerol fatty acid esters, glyceryl dicaprate, glyc Orotic Acid, Oxycinchophen, Probenecid, Sulfinpyrazone, eryl dicaprylate, glyceryl dilaurate, glyceryl dioleate, glyc Ticrynafen and Zoxazolamine. eryl monocaprate, glyceryl monocaprylate, glyceryl mono 136. Vasodilators (cerebral) such as Bencyclane, Cin laurate, glyceryl monooleate, glycofurol, heptane, narizine, Citicoline, Cyclandelate, Ciclonicate, Diisopro hydrogenated vegetable oils, isobutyl acetate, isopropanol, pylamine Dichloractetate, Ebumrinamonine, Fenoxedil, Flu 35 narizine, Ibudilast, Ifenprodil, Nafronyl, Nicametate, isopropyl acetate, lactic acid conjugates of mono- and Nicergoline, Nimodipine, Papaverine, Pentifylline, Tinofe diglycerides, lauric acid, lower alcohol fatty acid esters, drine, Vincamine, Vinpocetine and Vicquidil. methoxy PEG, methyl acetate, methylethylketone, methyl 137. Vasodilators (coronary) such as Amotriphene, Ben isobutylketone, N-hydroxyalkylpyrrolidone, N-methylpyr dazol, Benfurodil Hemisuccinate, BenZiodarone, Chlo 40 rolidone, oleic acid, PEG 2-4 oleate, PEG 3-16 castor oil, acizine, Chromonar, Clobenfurol, Clonitrate, Dilazep, PEG 5-10 hydrogenated castor oil, PEG 6-20 almond oil, Dipyridamole, Droprenilamine, Efloxate, Erythritol, Eryth PEG 6-20 corn oil, PEG-20 almond oil, PEG-20 corn oil, rity1 Tetranitrate, Etafenone, Fendiline, Floredil, Gangle PEG-4 dilaurate, PEG-4 dioleate, PEG-4 distearate, PEG-6 fene, Hexestrol Bis(B-diethylaminoethyl ether), Hexoben corn oil, PEG-6 dioleate, PEG-6 distearate, PEG-6 olive oil, dine, Itramin Tosylate, Khellin, Lidoflazine, Mannitol 45 PEG-6 palm kernel oil, PEG-6 peanut oil, PEG-8 dioleate, Hexanitrate, Medibazine, Nicorandil, Nitroglycerin, Pen pentaerythritol, pentane, polyethylene glycol, polyethylene taerythritol Tetranitrate, Pentrinitrol, Perhexiline, Pimefyl glycol 200-600, polyethylene glycol glycerol fatty acid line, Prenylamine, Propatyl Nitrate, Pyridofylline, Trapidil, esters, polyglyceryl fatty acid esters, polyglyceryl-3 oleate, Tricromyl, Trimetazidine, Trolnitrate Phosphate and Visna polyglyceryl-6 dioleate, polyoxyethylene glycerides, poly dine. 50 oxyethylene Sorbitan fatty acid esters, polyoxyethylene Veg 138. Vasodilators (peripheral) such as Aluminum Nicoti etable oils, polyoxyethylene-polyoxypropylene block copo nate, Bamethan, Bencyclane, Betahistine, Bradykinin, lymers, polypropylene glycol, polypropylene glycol fatty Brovincamine, Bufoniode, Buflomedil, Butalamine, acid esters, propyl acetate, propylene glycol, propylene Cetiedil, Ciclonicate, Cinepazide, Cinnarizine, Cyclande glycol diacetate, propylene glycol esters of C8, propylene late. Diisopropylamine Dichloracetate, Eledoisin, Fenoxidil, 55 glycol esters of unsaturated fatty acids, propylene glycol Flunarisine. Heronicate, Ifenprodil, Inositol Niacinate, Isox laurate, propylene glycol oleate, Sorbitan fatty acid esters, suprine, Kallidin, Kallikrein, Moxisylyte, Nafronyl, Nica Sorbitan monolaurate, Sorbitan monooleate, t-butylmethyl metate, Nicergoline, Nicofuranose, Nicotinyl Alcohol, ether, tetrahydofuran, transcutol, triacetin, tributylcitrate, Nylidrin, Pentifylline, Pentoxifylline, Piribedil, Protaglan triethylcitrate, vegetable oils, water, and acetic acid. din E, Suloctidil and Xanthinal Niacinate. 60 The solvent system selected is able to dissolve the active 139. Vasoprotectants such as Benzarone, Bioflavonoids, agent and additives at Sufficient concentration at ambient or Chromocarb, Clobeoside, Diosmin, Dobesilate Calcium, elevated temperatures to enable efficient processing. The Escin, Rolescutol, Leucocyanidin, Metescufylline, Querce anti-solvent system consists of one or more solvents, pref tin, Rutin and Troxerutin. erably water along with modifiers such as cosolvents, Sus 140. Vitamins, vitamin Sources, and vitamin extracts Such 65 pending agents, and/or pH modifiers. Other examples of as Vitamins A, B, C, D, E, and K and derivatives thereof, anti-solvents include alcohols, ethers, acids and hydrocar Calciferols, Glycyrrhiza and Mecobalamin. bons. It is preferable that the solvent and anti-solvent system US 9,682,043 B2 25 26 is miscible to allow mixing of the two. The solvent system stearate, PEG-12 laurate, PEG-12 oleate, PEG-15 stearate, must have adequate affinity for the solutes So that a uniform PEG-2 cetyl ether, PEG-2 stearyl ether, PEG-20 almond oil, Suspension forms. PEG-20 corn oil, PEG-20 dioleate, PEG-20 glyceryl laurate, The initial crystallization phase of the process involves PEG-20 glycidyl oleate, PEG-20 laurate, PEG-20 oleate, the mixing of the solvent containing the active agent and 5 PEG-20 trioleate, PEG-200 oleate, PEG-24 cholesterol, additive(s) with the anti-solvent. It is of importance to select PEG-25 glyceryl trioleate, PEG-25 phyto sterol, PEG-30 a system that enables formation of a uniform Suspension to cholesterol, PEG-30 glyceryl laurate, PEG-30 glyceryl allow the formation of uniform mixed phase co-crystals. oleate, PEG-30 soya sterol, PEG-32 dilaurate, PEG-32 The anti-solvent may be mixed with the first solution dioleate, PEG-32 distearate, PEG-32 laurate, PEG-32 oleate, containing the active agent and additives by any Suitable 10 PEG-35 castor oil, PEG-4 capric/caprylic triglyceride, method. The anti-solvent may be added to the first solution mono, di, tri, tetra esters of vegetable oil and sorbitol, PEG-4 to form a second solution. Alternatively, the first solution dilaurate, PEG-4 dioleate, PEG-4 distearate, PEG-40 castor may be added to the anti-solvent to form a second solution. oil, PEG-40 glyceryl laurate, PEG-40 hydrogenated castor The mixing of the second solution may optionally involve oil, PEG-40 palm kernel oil, PEG-40 stearate, PEG-400 stirring including, for example, through using a magnetic 15 oleate, PEG-50 hydrogenated castor oil, PEG-6 caprate/ stirrer or other mechanical stirrer. caprylate glycerides, PEG-6 corn oil, PEG-6 dioleate, The solvent is important for the successful incorporation PEG-6 distearate, PEG-6 hydrogenated palm kernel oil, of the solutes and formation of the transient meta-stable PEG-6 olive oil, PEG-6 palm kernel oil, PEG-6 peanut oil, fraction. The solvent is also important in determining the PEG-6 sorbitan tetra, hexastearate, PEG-6 sorbitan tet loading concentrations achieved for the active agent and raoleate, PEG-60 castor oil, PEG-60 corn oil, PEG-60 additives. hydrogenated castor oil, PEG-8 caprate/caprylate glycer The anti-solvent is important to allow successful initial ides, PEG-8 caprate/caprylate glycerides, PEG-8 dioleate, crystallization of the active agent and additive(s) and in PEG-80 sorbitan laurate, pentaerythritol di, tetra stearate, determining the physical properties of the resulting mixed isostearate, oleate, caprylate, or caprate, phospholipids, phase co-crystalline Suspension and powder. 25 phosphoric acid polyoxymethylene alkylethers, phytosterol, The mixed phase co-crystals can be isolated by conven poloxamer 188 (Pluronic R 68), poloxamers (Pluronics.(R), tional filtration methods, centrifugation or sedimentation. polyethylene glycol fatty acids esters, polyethylene glycol Removal of bulk solvent and anti-solvent components can glycerol fatty acid esters, polyglyceryl 2-4 oleate, Stearate, be performed by washing the isolated solid. Preferably, the or isoStearate, polyglyceryl 4-10 pentaoleate, polyglyceryl isolated mixed phase co-crystals are dried under vacuum at 30 fatty acid esters, polyglyceryl fatty acid esters, fatty acids, ambient or elevated temperature. The dried powder is then polyglyceryl-10 laurate, polyglyceryl-10 trioleate, polyglyc deaggregated using a milling or sieving process. eryl-3 dioleate, polyglyceryl-3 distearate, polyglyceryl-3 The additive(s) for use in the inventive methods and oleate, polyglyceryl-6 dioleate, polyglyceryl-6 dioleate, compositions include any suitable additives. polyoxyethylene alkyl ethers, polyoxyethylene alkylphe Additives, such as crystal lattice modifiers, can be added 35 nols, polyoxyethylene glycerides, polyoxyethylene hydro to the first solution. These modifiers must be acceptable for genated vegetable oils, polyoxyethylene Sorbitan fatty acid pharmaceutical or the intended use and usually are solids at esters, polyoxyethylene Sterols, polyoxyethylene vegetable room temperature. Examples of crystal lattice modifiers oils, polyoxyethylene vegetable oils, polyoxyethylene include, but are not limited to, fatty acids, fatty alcohols, hydrogenated vegetable oils, polyoxyethylene-polyoxypro PEG esters, PEG ethers, cellulose derivatives, pectins, glyc 40 pylene block copolymers, polyoxyethylene-polyoxypropyl erides, fatty esters, waxes, ethers, polyols, cyclodextrins ene block copolymers, polypropylene glycol fatty acid (alpha, beta and gamma), hydroxpropyl-beta-cyclodextrin, esters, polysorbate 20, polysorbate 80, propylene glycol Sorbitan esters, propylene glycol esters, acetylated proteins, diglycerides, propylene glycol laurate, propylene glycol Stearols, polyesters, polyvinylpyrrolidones, polyethylene mono- or diesters of a C to Co fatty acids fatty acids, glycols, triglycerides, cellulose acetates and Sugar esters. 45 propylene glycol oleate, reaction mixtures of polyols and at Preferably, the crystal lattice modifier is selected from the least one member selected from the group consisting offatty group consisting of acetylated glycerol fatty acid esters, acids, glycerides, vegetable oils, hydrogenated vegetable acetylated monoglycerides, acetylated monoglycerides of oils, and sterols, sesame seed oil, Sorbitan fatty acid esters, C to Co fatty acids, alkylgluceosides, alkylmaltosides, bile Sorbitan mono, trioleate, Sorbitan mono, tristearate, Sorbitan salts, cholesterol, corn oil, diglycerides of C to Co fatty 50 monoisoStearate, sorbitan monolaurate, sorbitan acids, ethyl linoleate, ethyl oleate, fatty acid salts, Saturated monooleate, Sorbitan monopalmitate, Sorbitan monostearate, fatty acids, unsaturated fatty acids, fatty alcohols, fraction Sorbitan sesquioleate, Sorbitan sesquistearate, soybean oil, ated cocoanut oil, glycerol fatty acid esters, glyceryl Stearic acid, sterols, sucroglycerides. Sucrose dipalmitate, dicaprate, glyceryl dicaprylate, glyceryl dilaurate, glyceryl Sucrose distearate. Sucrose monolaurate. Sucrose mono dioleate, glyceryl monocaprate, glyceryl monocaprylate, 55 palmitate. Sucrose monostearate, Sugar esters, Sugar ethers, glyceryl monolaurate, glyceryl monooleate, isopropyl tocopheryl PEG-100 succinate, tocopheryl PEG-1000 suc linoleate, isopropyl myristate, isopropyl palmitate, lactic cinate, transesteriefied vegetable oils, polysorbate 40 acid conjugates of diglycerides, lactic acid conjugates of (Tween R 40), polysorbate 60 (Tween R. 60) and mixtures mono- and diglycerides, lactic acid conjugates of monoglyc thereof. erides, lauric acid, lauryl macrogolglycenides, lower alcohol 60 The crystal lattice modifiers are crystalline, semi-crystal fatty acids esters, monoglycerides of a C to Co fatty acids, line, amorphous, or ligands in form. The crystal lattice myristic acid, oleic acid, palmitic acid, PEG 10-100 lionyl modifiers are not closely related to the active agent in phenol series, PEG 1-4 stearate, PEG 15-100 octyl phenol chemical structure. They are typically soluble in the solvent series, PEG 20 dilaurate, PEG 20 glyceryl stearate, PEG 2-4 system and insoluble in the anti-solvent system. These oleate, PEG 2-5 oleyl ether, PEG 3-16 castor oil, PEG 5-10 65 materials can be incorporated into the mixed phase co hydrogenated castor oil, PEG 5-20 soya sterol, PEG 6-20 crystal and will either decrease or increase the melting point almond oil, PEG 6-20 corn oil, PEG-10 laurate, PEG-100 of the mixed phase co-crystal relative to the active agent, but US 9,682,043 B2 27 28 preferably reduce the melting point. Crystalline active ides of C to Co fatty acids, alkylgluceosides, alkylmalto agents will experience a reduction in melting point and sides, bile salts, cholesterol, corn oil, diglycerides of C to broadening of the endotherm when observed with a differ Co fatty acids, ethyl linoleate, ethyl oleate, fatty acid salts, ential scanning calorimeter (DSC). Depending on the appli saturated fatty acids, unsaturated fatty acids, fatty alcohols, cation and the relative hydrophobicity of the active agent, fractionated cocoanut oil, glycerol fatty acid esters, glyceryl the additive may increase or decrease the water solubility dicaprate, glyceryl dicaprylate, glyceryl dilaurate, glyceryl and wetability of the mixed phase co-crystal relative to the dioleate, glyceryl monocaprate, glyceryl monocaprylate, active agent. Depending on the application and the desired glyceryl monolaurate, glyceryl monooleate, isopropyl properties, the combined amount of crystal lattice modifiers linoleate, isopropyl myristate, isopropyl palmitate, lactic may range widely in composition. It is desirable to co 10 acid conjugates of diglycerides, lactic acid conjugates of crystallize more than one crystal lattice modifier with one or mono- and diglycerides, lactic acid conjugates of monoglyc more active agents. Accordingly, the methods of the inven erides, lauric acid, lauryl macrogolglycenides, lower alcohol tion can comprise one or more crystal lattice modifiers. fatty acids esters, monoglycerides of a C to Co fatty acids, It is possible to crystallize minor or low concentration myristic acid, oleic acid, palmitic acid, PEG 10-100 lionyl additives along with the active agent(s) and crystal lattice 15 phenol series, PEG 1-4 stearate, PEG 15-100 octyl phenol modifier(s) of the mixed phase co-crystal composition. series, PEG 20 dilaurate, PEG 20 glyceryl stearate, PEG 2-4 These additional additives can contribute to the formation of oleate, PEG 2-5 oleyl ether, PEG 3-16 castor oil, PEG 5-10 the mixed phase co-crystal particle and the addition of these hydrogenated castor oil, PEG 5-20 soya sterol, PEG 6-20 additives then becomes integral to the particle structure. almond oil, PEG 6-20 corn oil, PEG-10 laurate, PEG-100 Examples of additional additives for use in the mixed phase stearate, PEG-12 laurate, PEG-12 oleate, PEG-15 stearate, co-crystal composition include modifiers, such as stabilizers PEG-2 cetyl ether, PEG-2 stearyl ether, PEG-20 almond oil, and additives that impart specialized properties. PEG-20 corn oil, PEG-20 dioleate, PEG-20 glyceryl laurate, Modifiers, such as stabilizers, generally are incorporated PEG-20 glycidyl oleate, PEG-20 laurate, PEG-20 oleate, into the mixed phase co-crystal at relatively low levels PEG-20 trioleate, PEG-200 oleate, PEG-24 cholesterol, relative to the major component, with typical concentrations 25 PEG-25 glyceryl trioleate, PEG-25 phyto sterol, PEG-30 less than about 10% (e.g., about 9%, about 8%, about 7%. cholesterol, PEG-30 glyceryl laurate, PEG-30 glyceryl about 6%, about 5%, about 4%, about 3%, about 2%, about oleate, PEG-30 soya sterol, PEG-32 dilaurate, PEG-32 1%) of the mixed phase co-crystal composition. Modifiers, dioleate, PEG-32 distearate, PEG-32 laurate, PEG-32 oleate, such as stabilizers, are preferably crystalline solids soluble PEG-35 castor oil, PEG-4 capric/caprylic triglyceride, in the solvent system and insoluble in the anti-solvent 30 mono, di, tri, tetra esters of vegetable oil and sorbitol, PEG-4 system. Chemically these modifiers function as acids, bases, dilaurate, PEG-4 dioleate, PEG-4 distearate, PEG-40 castor antioxidants, light protectants, viscosity modifiers, and/or oil, PEG-40 glyceryl laurate, PEG-40 hydrogenated castor Surfactants. oil, PEG-40 palm kernel oil, PEG-40 stearate, PEG-400 Examples of acid modifiers for use in the invention oleate, PEG-50 hydrogenated castor oil, PEG-6 caprate/ include, but are not limited to, acetic acid, acrylic acid, 35 caprylate glycerides, PEG-6 corn oil, PEG-6 dioleate, adipic acid, alginic acid, alkanesulfonic acid, an amino acid, PEG-6 distearate, PEG-6 hydrogenated palm kernel oil, ascorbic acid, benzoic acid, boric acid, butyric acid, car PEG-6 olive oil, PEG-6 palm kernel oil, PEG-6 peanut oil, bonic acid, citric acid, a fatty acid, formic acid, fumaric acid, PEG-6 sorbitan tetra, hexastearate, PEG-6 sorbitan tet gluconic acid, hydroquinosulfonic acid, hydrochloric acid, raoleate, PEG-60 castor oil, PEG-60 corn oil, PEG-60 isoascorbic acid, lactic acid, maleic acid, methanesulfonic 40 hydrogenated castor oil, PEG-8 caprate/caprylate glycer acid, oxalic acid, para-bromophenylsulfonic acid, phos ides, PEG-8 caprate/caprylate glycerides, PEG-8 dioleate, phoric acid, propionic acid, p-toluenesulfonic acid, Salicylic PEG-80 sorbitan laurate, pentaerythritol di, tetra stearate, acid, Stearic acid, Succinic acid, tannic acid, tartaric acid, isostearate, oleate, caprylate, or caprate, phospholipids, thioglycolic acid, toluenesulfonic acid, uric acid, and mix phosphoric acid polyoxymethylene alkylethers, phytosterol, tures thereof. 45 Pluronic F68, Pluronics, poloxamers, polyethylene glycol Examples of base modifiers for use in the invention fatty acids esters, polyethylene glycol glycerol fatty acid include, but are not limited to, ammonia, ethanolamine, esters, polyglyceryl 2-4 oleate, Stearate, or isostearate, diethanolamine, glucosamine, trolamine, sodium bicarbon polyglyceryl 4-10 pentaoleate, polyglyceryl fatty acid esters, ate, potassium bicarbonate, Sodium hydroxide, potassium polyglyceryl fatty acid esters, fatty acids, polyglyceryl-10 hydroxide, TRIS, arginine, lysine, magnesium hydroxide, 50 laurate, polyglyceryl-10 trioleate, polyglyceryl-3 dioleate, calcium hydroxide, sodium carbonate, potassium carbonate, polyglyceryl-3 distearate, polyglyceryl-3 oleate, polyglyc ammonium bicarbonate, and mixtures thereof. eryl-6 dioleate, polyglyceryl-6 dioleate, polyoxyethylene Examples of antioxidant modifiers for use in the invention alkyl ethers, polyoxyethylene alkylphenols, polyoxyethyl include, but are not limited to, C-tocopherol, ascorbic acid, ene glycerides, polyoxyethylene hydrogenated vegetable ascorbyl palmitate, BHT, BHA, malic acid, propyl gallate, 55 oils, polyoxyethylene Sorbitan fatty acid esters, polyoxyeth and mixtures thereof. ylene sterols, polyoxyethylene vegetable oils, polyoxyeth Examples of viscosity modifiers for use in the invention ylene vegetable oils, polyoxyethylene hydrogenated veg include, but are not limited to, methylcellulose, ethylcellu etable oils, polyoxyethylene-polyoxypropylene block lose, acetylated gelatin, hydroxypropyl cellulose, hydroxy copolymers, polyoxyethylene-polyoxypropylene block propyl methylcellulose, hydroxyethyl cellulose, hydroxy 60 copolymers, polypropylene glycol fatty acid esters, polysor propyl methyl phthalate, polyvinyl acetate phthalate, sodium bate 20, polysorbate 80, propylene glycol diglycerides, carboxymethylcellulose, agar, acacia, tragacanth, carrageen, propylene glycol laurate, propylene glycol mono- or diesters pectins, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl of a C to Cofatty acids fatty acids, propylene glycol oleate, acetate, Xanthane gum, and mixtures thereof. reaction mixtures of polyols and at least one member Examples of surfactant modifiers for use in the invention 65 selected from the group consisting offatty acids, glycerides, include, but are not limited to, acetylated glycerol fatty acid vegetable oils, hydrogenated vegetable oils, and sterols, esters, acetylated monoglycerides, acetylated monoglycer sesame seed oil, Sorbitan fatty acid esters, Sorbitan mono, US 9,682,043 B2 29 30 trioleate, Sorbitan mono, tristearate, Sorbitan monoisoStear ceutical dosage forms found in commerce (references: USP ate, Sorbitan monolaurate, Sorbitan monooleate, Sorbitan EP PDR and FDA Inactive Ingredient List). monopalmitate, Sorbitan monostearate, Sorbitan sesqui Alternatively, mixed phase co-crystals can be isolated by oleate, Sorbitan sesquistearate, soybean oil, Stearic acid, filtration, sedimentation or centrifugation. The isolated sterols. Sucroglycerides. Sucrose dipalmitate. Sucrose dis material can then be washed with water and dried with the tearate. Sucrose monolaurate, Sucrose monopalmitate, aid of heat or vacuum. Sucrose monostearate, Sugar esters, Sugar ethers, tocopheryl The process used in preparation of the mixed phase PEG-100 succinate, tocopheryl PEG-1000 succinate, trans co-crystalline material utilizes one or more volatile solvents/ esteriefied vegetable oils, Tween 40, Tween 60, and mixtures anti-solvents that are removed during a drying step of the thereof. Examples of stabilizers include BHA, BHT. Vitamin 10 process. This can be accomplished by several methods E. Vitamin C, titanium oxide, acetic acid, benzoic acid, commonly used for processing pharmaceutical dosage glycine, arginine, monoethanolamine, N-glucosamine, forms. These can include combining the crystallized mixed methysulfonic acid, maleic acid and UV blockers. phase co-crystalline material Suspended in the solvent/anti Other additives can be incorporated in the mixed phase Solvent system with a pharmaceutically acceptable bulking co-crystal particle to impart specialized properties, such as 15 agent. The volatile solvent/anti-solvent is removed by dry improved intestinal membrane permeability, resistance ing the resulting granulation containing the formulated toward enzymatic bioconversion, bioadhesion, etc. mixed phase co-crystal and bulking agent(s). Alternatively, Examples of these include caprylic acid, oleic acid, bile the solvent system can be combined with the bulking agent salts, PEG ethers, grapefruit extract, niacin, cellulose deriva and the volatile solvents removed through evaporation with tives, silicon dioxide, starch and the like. out prior crystallization of the mixed phase co-crystalline Distinguishing properties of the mixed phase co-crystal material. include the preservation of the crystal form of the active Any suitable bulking agent can be used. Preferably, the agent(s), reduced crystallinity of the active agent, preserva bulking agent is a pharmaceutically acceptable bulking tion of the crystalline form of the additive and enhanced agent. Examples of Suitable bulking agents include, but are physical properties of the mixed phase co-crystal powder. 25 not limited to, microcrystalline cellulose, lactose anhydrous, For instance, in the case of reduced crystallinity of the active lactose monohydrate. Sucrose, mannitol, maltitol, Sorbitol, agent, the active agent shows a small reduction in melting calcium phosphate, calcium sulfate, starch, pregelatinized point and broadening of the endotherm (FIGS. 1A and 1B). starch, silica, powdered cellulose, croScarmollose, benton This is brought about by the co-crystallization of the crystal ite, kaolin, magnesium aluminum silicate, dextrins, amylose, lattice modifier in the active crystal lattice, hence an appar 30 glucose, ethylcellulose, hydroxyethyl cellulose, hydroxym ent reduction of crystallinity. The presence of the Additive ethyl cellulose, hydroxypropylmethyl cellulose, maltodex Phase is shown by the presence of a characteristic melting trin, povidone, calcium carbonate, compressible sugar, point or endotherm in the DSC. The existence of both active cyclodextrins, dextran, talc, sodium starch glycolate, gelatin, and Additive Phases is also evident in the X-ray diffraction magnesium carbonate, magnesium oxide, maltitol, methyl (XRD) pattern of the mixed phase co-crystal powder (FIG. 35 cellulose, Xylitol, and carbomer. 2). A reduction in the signal to noise ratio in the XRD pattern Preferred examples of the bulking excipient include phar is another indicator of reduced crystallinity of the active maceutically acceptable powders that are generally recog agent in mixed phase co-crystal powders (FIG. 3). nized as safe (GRAS) or listed in major Pharmacopeas. In Tables 1, 2, 4, 6, and 7, a reduction in melting point of Examples of powders include cellulosic materials (microc the mixed phase co-crystal composition as compared with 40 rystalline cellulose and hydroxypropylcellulose), polyvi the pure active agent (API) is observed. This is an indication nylpyrrolidones (PVP and crospovidone), sugars (lactose of reduced crystallinity of the active agent brought about by and Sucrose), starches (pregelatined Starch and corn starch), the co-crystallization of the modifiers with the active agent. inorganic salts (dicalcium phosphate and calcium sulfate) In Tables 2, 6, and 7, a reduction in enthalpy in the mixed and reduced Sugars (mannitol and Sorbitol). phase co-crystal composition as compared to the pure active 45 Preferred methods for removing the volatile solvents agent is observed. This is also an indication of reduced utilize a fluid bed spray granulation, spray drying, or crystallinity of the active agent brought about by the co vacuum granulating/drying processes. The resulting powder crystallization of the modifiers with the active agent. or granulation is sized to an average particle size in the range In Tables 1, 2, 3, 4, 6, and 7, an increase of water solubility of 50 to 300 microns in size (e.g., about 75 microns, about as compared to the active agent is obtained for the mixed 50 100 microns, about 125 microns, about 150 microns, about phase co-crystalline materials shown in these tables. This 175 microns, about 200 microns, about 225 microns, about illustrates the distinguishing property for improvement of 250 microns, about 275 microns, or ranges thereof) which is water solubility of the mixed phase co-crystal composition Suitable for further powder blending and Subsequent dosage of the invention. Another distinguishing property is form manufacture by encapsulation into hard gelatin cap improvement of dissolution of the active agent as shown in 55 Sules, tablets, or other dosage forms. Table 5 and FIGS. 4, 5, and 6. A second alternative process for mixed phase co-crystal The formulated mixed phase co-crystalline material can formation utilizes a volatile solvent system that has suffi be directly incorporated in a pharmaceutically acceptable cient solvent capacity to dissolve the active agent and dosage form as part of the formulation process without prior modifiers. The mixed phase co-crystals are formed by pre isolation of the mixed phase co-crystalline particles. This 60 cipitation with a non-solvent system using materials that are requires that all the solvents, anti-solvents and crystal modi ingestable (GRAS) and can be formulated as a fill for soft fiers are GRAS materials, listed in major pharmacopeas or gelatin and 2-piece hard gelatin capsules. Examples of these are found as inactive ingredients in pharmaceutical dosage liquids include triglycerides (sesame oil, Soybean oil and forms. The solvent and anti-solvents must be volatile or can fractioned cocoanut oil), propylene glycol esters, fatty acids remain as a component of the dosage form. Should the 65 (oleic acid, caprylic acid and myristic acid), polyethylene Solvent/anti-solvents remain in the dosage form they must be glycols (PEG 400, PEG 600, PEG 3350, etc.), mixed phase pharmaceutically acceptable and have prior use in pharma glycerides (Gelucires, Labrasol and Labrafils), PEG esters, US 9,682,043 B2 31 32 polysorbates, glycerin, polyol solutions (Sorbitol, mannitol, Example 1 maltose, etc), water, and other pharmaceutically acceptable oils. In this case, the volatile solvent/anti-solvents are This example demonstrates a method to prepare mixed removed partially or completely after crystallization of the phase co-crystals of hydrocortisone. mixed phase co-crystalline particles with the aid of a carrier 5 gas, vacuum, and/or application of heat. Sparging of the resulting Suspension with a carrier gas Such as nitrogen or Ingredients Amount compressed air is the preferred method when a carrier gas is used. The mixed phase co-crystal preparation results in a Suitable Suspension for encapsulation as anoil based or 10 1 Hydrocortisone (Pharmacia-Upjohn) 300 mg hydrophilic based fill formulation as soft gelatin or hard 2 Sorbitan monopalmitate (ICI) 100 mg gelatin capsules. 3 Dimethyl sulfoxide 1.6 L The present invention provides methods for formulation 4 Deionized water 8.0 mL. of mixed phase co-crystals that include initial crystallization 15 of the active agent along with additive(s) and Subsequent Removed transformation to the mixed phase co-crystal form(s) or by The mixed phase co-crystals of hydrocortisone were evaporation of volatile solvents containing the co-crystalline prepared by dissolving the active gent (hydrocortisone; components. The ratio or composition of the components Pharmacia-Upjohn) and a crystal lattice modifier (sorbitan can be varied and produced in a wide range. The composi monopalmitate; ICI) in dimethyl sulfoxide (DMSO, Fisher) tion of the mixed phase co-crystal form and the extent of with the application of heat (ca. 60° C.) and vortex mixing. co-crystallization achieved will determine the specific The resulting solution was added gradually over a period of physical properties. Thus, it is possible to formulate a mixed 5 minutes to deoinoized water at 30 to 40°C. while being 25 vortex mixed or stirred with a magnetic stir bar. The phase co-crystal with the desired properties based on the precipitation that forms was mixed for 1 to 2 hours at 30 to nature of the additive(s) and the composition of the 40° C. The reactive mixture was allowed to cool to room additive(s) incorporated. It has been discovered that the temperature and gently mixed for an additional 12 to 48 desired properties can be optimized through the use of hours. The resulting mixed phase co-crystal product was carefully balanced components that are co-crystallized with 30 collected with a Buchner funnel using a Whatman paper the active agent(s). filter. The filter cake was repeatedly washed with additional In a preferred embodiment of the invention, the solvent water and dried under vacuum at 25°C. for 1 or more days. and anti-solvent are substantially removed from the mixed phase crystalline material. Such that the mixed phase crys 35 Example 2 talline material is a dry powder suitable for direct encapsu lation or tableting. This example demonstrates a method of preparing mixed The inventor discovered that mixed phase co-crystals can phase co-crystals of hydrocortisone. improve the inherent properties of active agents that enable the successful development of delivery systems for the 40 active agents. These mixed phase co-crystalline materials Ingredients Amount can be incorporated in a formulation while being formed as 1 Hydrocortisone 300 mg part of the dosage form processing steps. Cetostearyl alcohol 84 mg 3 Methocel E4M (as 2% solution in 800 mg In a preferred embodiment, the mixed phase co-crystal 45 DMSO) composition comprises a mixed phase co-crystal of an active 4 N-methylpyrrollidone 1.6 in agent and at least one crystal lattice modifier, wherein the 5 Deionized water 8.0 mL. content of the active agent ranges from about 5% to 95% Removed (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 50 To prepare the mixed phase co-crystals, hydrocortisone (Pharmacia Upjohn) and cetostearyl alcohol (Croda) were 55%, about 60%, about 65%, about 70%, about 75%, about dissolved in N-methylpyrrolidone (ISP Technologies) with 80%, about 85%, or ranges thereof) by weight of the total the application of heat (ca. 60°C.) and vortex mixing. These weight of the material, and wherein the crystal lattice ingredients were added to 800 mg of a 2% solution of modifier ranges from 2% to 95% (e.g., about 5%, about 55 Methocel E4M (methylcellulose) in DMSO and mixed with 10%, about 15%, about 20%, about 25%, about 30%, about until dissolved. The resulting solution was added gradually 35%, about 40%, about 45%, about 50%, about 55%, about over a period of 5 minutes to 8.0 mL of deionized water at 60%, about 65%, about 70%, about 75%, about 80%, about 30 to 40° C. while being vortex mixed or stirred with a 85%, about 90%, or ranges thereof). Preferably, the crystal 60 magnetic stir bar. The precipitation that formed was mixed lattice modifier ranges from 10% to 40% by weight for each for 1 to 2 hours at 30 to 40° C. The reaction mixture was individual modifier of the total weight of the material. allowed to cool to room temperature and gently mixed for an The following examples further illustrate the invention additional 12 to 48 hours. The resulting mixed phase co but, of course, should not be construed as in any way crystal product was collected with a Buchner funnel using a limiting its scope. The examples do not constitute the entire 65 Whatman paper filter. The filter cake was repeatedly washed range of active agents or crystal lattice modifiers that may be with additional water and dried under vacuum at 25° C. for used. 1 or more days. US 9,682,043 B2 33 34 Example 3 Example 5

This example demonstrates a method of preparing mixed This example demonstrates a method of preparing mixed phase co-crystals of hydrocortisone acetate. phase co-crystals of itraconazole. 5

Ingredients Amount Ingredients Amount 1 Hydrocortisone acetate 320 mg Part A: 2 Methocel E4M (as 2% solution in 200 mg 10 DMSO) 3 Sorbitan monostearate 4 mg 1 Itraconazole (Spectrum) 300 mg 4 Stearic acid 4 mg 5 Cetostearyl alcohol 4 mg 2 Crodesta F160 (Croda) 50 mg 6 Lanolin 4 mg 3 Crodacid (Croda) 50 mg 7 Dimethylsulfoxide 1.6 L 4 DMSO: 900 mg 8 Deionized water 8.0 mL. 15 5 Urea 200 mg 6 N-methylpyrrollidone 800 mg Removed Part B: To prepare the mixed phase co-crystals, hydrocortisone acetate (Pharmacia-Upjohn), Sorbitan monostearate (ICI), Urea 4000 mg Stearic acid (Croda), cetostearyl alcohol (Croda), lanolin 8 Deionized water 4000 mg (Croda) were dissolved in dimethyl sulfoxide with the application of heat (ca. 60° C.) and vortex mixing. 200 mg Removed of a 2% solution of Methocel E4M (methylcellulose) in To prepare the mixed phase co-crystals, Crodesta F160 DMSO was added and mixed with the previous ingredients 25 (sucrose Stearate) and Crodacid (behenic acid) were dis until dissolved. The resulting solution was added gradually solved in DMSO. Urea was dissolved in N-methylpyrroli over a period of 5 minutes to the water at room temperature done with heating. The resulting Solutions were combined, while being vortex mixed or stirred with a magnetic stir bar. and itraconazole (Spectrum) was added and dissolved with The precipitation that formed was gently mixed for an heat, completing Part A Solution. additional 12 to 48 hours. The resulting mixed phase co 30 crystal product was collected with a Buchner funnel using Part B solution was prepared by dissolving urea in water Whatman paper filter. The filter cake was repeatedly washed with heating, then allowing the solution to cool to room with additional water and dried under vacuum at 25° C. for temperature. The Part A solution was then added to Part B 1 or more days. by slow addition with mixing, forming a precipitate. The 35 resulting Suspension was gently Vortexed at room tempera ture for 2 days. The mixed phase co-crystals were isolated by Example 4 filtration, washed with a small aliquot of water, and dried at 40° C. in an oven.

This example demonstrates a method of preparing mixed 40 phase co-crystals of cyclosporin. Example 6

Ingredients Amount This example demonstrates a method of preparing mixed phase co-crystals of itraconazole. 1 Cyclosporin (Gallipot) 40 mg 45 2 Crotein ADW (10% in ethanol) 100 IL 3 Sorbitan monostearate 1 mg 4 Lanolin 1 mg Ingredients Amount 5 Stearic acid 1 mg 6 Compritol 888 ATO 1 mg 1 Itraconazole 5000 mg 2 Stearth-20 (Croda) 2500 mg 7 N-methylpyrrollidone O.2 mL. 50 8 Deionized water 1.0 L 3 Pluronic F-68 2500 mg 4 Ethanol 200 mL. Removed 5 Refined soybean oil 100 mL. To prepare the mixed phase co-crystals, cyclosporin (Gal Removed lipot), Crotein ADW (AMP-Isostearoyl Hydrolyzed Wheat 55 To prepare the mixed phase co-crystals, itraconazole, Protein; 10% in ethanol), sorbitan monostearate, lanolin (Croda), stearic acid, and Compritol 888 ATO (glycerol Stearth-20, and Pluronic F-68 (Poloxamer 188) were dis behenate: Gattefosse) were dissolved in N-methylpyrroli solved in hot ethanol (>70° C.) with mixing and maintained done (ISP) with the application of heat (ca. 60° C.) and at this temperature. The hot ethanol solution was added vortex mixing. 1.0 mL of deionized water was added to this 60 gradually to the soybean oil that was kept cool (0 to 10° C.) Solution was added and the resulting reaction mixture was with vigorous mixing. The resulting Suspension of the mixed Vortexed at room temperature. The reaction mixture was phase co-crystals was stirred while compressed air was agitated at room temperature for 18 to 48 hours. The bubbled through the suspension at room temperature until resulting mixed phase co-crystal product was collected with the residual alcohol was reduced to less than 10% by weight a Buchner funnel using Whatman paper filter. The filter cake 65 as determined by loss on drying at 105° C. This prepared was repeatedly washed with additional water and dried Suspension was then encapsulated into hard gelatin and soft under vacuum at 25°C. for 1 or more days. gelatin capsules. US 9,682,043 B2 35 36 Example 7 To prepare the mixed phase co-crystals, progesterone, Pluronic F68 (Poloxamer 188) and Methocel E15 (hydroxy This example demonstrates a method of preparing mixed propylmethyl cellulose) were dissolved in ethanol (>70° C.). phase co-crystals of nimodipine. Soybean oil and Miglyol 810 (glycerol tri-caprylate/caprate) were mixed at 5°C., and then the warm ethanol solution was added and mixed. The resulting Suspension is mixed at 5°C. for 2 hours. Compressed air was sparged through the oil Ingredients Amount Suspension at room temperature to evaporate the ethanol for 1 Nimodipine (Lusochimica) 300 mg approximately 18 hours. The resulting Suspension was 2 Capmul GMS (Croda) 5 mg ground or sieved to a smooth consistency and encapsulated 3 Compritol 888 ATO (Croda) 5 mg 10 4 Crodacid B (Croda) 5 mg in hard gelatin capsules. A scaled up version of the same 5 Solutol HS 15 (BASF) 5 mg formulation was encapsulated in Soft gelatin capsules. 6 Dimethylsulfoxide 1.0 L 7 N-methylpyrrollidone 800 mg Example 9 8 Deionized water 1.0 L 15 This example demonstrates a method of preparing mixed Removed phase co-crystals of progestrone. To prepare the mixed phase co-crystals, nimodipine, Capmul GMS (glycerol momostearate), Compritol 888 ATO Ingredients Amount (glycerol behenate), Crodacid B (behenic acid), and Solutol 2O HS 15 (PEG 660 hydroxystearate) were dissolved in N-methylpyrrolidone and DMSO with the application of Progesterone (Pharmacia-Upjohn) 40.0 g heat (ca. 60° C.) and vortex mixing. The resulting solution Sucrose monostearate 12.0 g Pharmacoat 603 6.0 g was added gradually over a period of 5 minutes to deionized Ethanol (200 proof)* 50 g water at room temperature, while being Vortex mixed or 25 Purified water 200 g stirred with a magnetic stir bar. The precipitation that formed was gently mixed for an additional 12 to 48 hours. The resulting mixed phase co-crystal product was collected with 6 Part A. Suspension 308 g a Buchner funnel using Whatman paper filter. The filter cake 7 Lactose, hydrous 400 g Removed was repeatedly washed with additional water and dried 30 under vacuum at 25°C. for 1 or more days. To prepare the mixed phase co-crystals, progesterone, Example 8 sucrose monostearate, and Pharmacoat 603 (hydroxypropy lmethyl cellulose) were dissolved in ethanol (>70° C.). The hot ethanol solution was gradually added to the purified This example demonstrates a method of preparing mixed 35 water (5° C.) and mixed. The resulting Suspension was phase co-crystals (Batch No. F833-025B of FIG. 6) of mixed at room temperature for 2 hours. The Suspension then progesterone. was passed through a 30-mesh screen and sprayed onto the lactose in a fluid bed drier. The final dried granulation was Ingredients Amount then encapsulated into a two-piece hard gelatin capsule. 40 Progesterone (Pharmacia-Upjohn) 2000 mg Example 10 Pluronic F68 (BASF) 600 mg Methocel E15 300 mg This example demonstrates that mixed phase co-crystals Ethanol 2.0 mL. prepared by the methods of the invention have beneficial Soybean oil 3.0 mL. properties. Miglyol 810 3.0 mL. 45 Four lots of mixed phase co-crystal formulations were Removed prepared by the method described in Example 8 using the following compositions:

Amount Batch No. Ingredients 1 Progesterone (Pharmacia 2000 mg 1000 mg 1000 mg 2000 mg Upjohn) Pluronic F68 (Poloxamer 600 mg 300 mg 300 mg 600 mg 188) Methocel E15 (Hydroxypropylmethyl 300 mg Cellulose) Stearth 20 300 mg 5 Ethanol 2.0 mL. 1.0 mL. 1.0 mL. 2.0 mL. PVP K30 (Polyvinylpyrrollidone) 300 mg Soybean oil 3.0 mL. 1.5 mL. 1.5 mL. 3.0 mL. Miglyol 810 (Glycerol Tri 3.0 mL. 1.5 mL. 1.5 mL. 3.0 mL. caprylate? Caprate)

Removed US 9,682,043 B2 37 38 FIG. 6 illustrates a comparison of in vitro dissolution 5° C. The suspension was allowed to remain at room results for the four lots of mixed phase co-crystal formula temperature for 24 hours. The mixed phase co-crystals were tions (F833-023c, -024A, -025A and -025B) containing isolated by filtration, washed with additional water, and progesterone as the active ingredient as compared to com dried at 40° C. mercial Prometrium 200 mg softgel capsules from two Photomicrographs were taken with a polarizing micro batches. The dissolution method used USP apparatus I, scope at 100x magnification after different time points in the paddles at 50 rpm, 27°C., and media of isopropyl alcohol: manufacture of the mixed phase co-crystals. An image taken water (1:1). Progesterone was analyzed via HPLC. Each of immediately after the addition of the alcohol solution illus the mixed phase co-crystal formulations showed an trated that large needle-like crystals and large plate-like increased rate of dissolution as compared to the commercial 10 crystals had formed. These crystal forms were transient and, progesterone capsules (FIG. 6). therefore, were kinetically favored products. These crystal Thus, mixed phase co-crystal formulations prepared by forms gradually converted with time to the thermodynami the methods of the invention demonstrate improved prop cally favored mixed phase co-crystals that were Smaller in erties, such as dissolution rate. size and of uniform morphology, as observed in photomi 15 crographs taken 1 hour and 2 hours after mixing at 5° C. Example 11 Example 12 This method demonstrates a method of preparing mixed phase co-crystals of progesterone. This example demonstrates the physical properties of various mixed phase co-crystal materials produced by the methods of the invention. Tables 1 and 2 demonstrate the physical properties of Ingredients Amount mixed phase co-crystals of hydrocortisone and hydrocorti 1 Progesterone (Pharmacia-Upjohn) 20.0 g Sone acetate, respectively. To prepare the mixed phase 2 Pluronic F68 (Poloxamer 188) 6.0 g 3 Methocel E15 (Hydroxypropyl 3.0 g 25 co-crystals of Tables 1 and 2, the active agent and crystal Methylcellulose) lattice modifiers were dissolved in DMSO or n-methyl 4 Ethanol (200 proof)* 80 g pyrrolidone or a blend of the two with gentle heating (60° 5 Purified water 150 g C.) and Vortex mixing. The resulting Solution was combined Removed with water to intiate the crystallization of the mixed phase 30 co-crystals and vortexed for 18 to 48 hours at room tem To prepare the mixed phase co-crystals, progesterone, perature. The mixed phase co-crystals were isolated by Pluronic F68 (Poloxamer 188), and Methocel E15 (hydroxy filtration, washed with water, and dried. propyl methylcellulose) were dissolved in hot ethanol (boil Gelucire 44/14 refers to lauroyl macrogol-32 glycerides: ing temperature). This solution was gradually added over a Ethocel refers to ethylcellulose resin; Emucire refers to cetyl period of 20 minutes to water at 5° C. while mixing. After alcohol (and) ceteth-20 (and) steareth-20; Methocel E3 the initial crystallization of the mixed phase co-crystal 35 refers to hydoxypropyl methylcellulose; and Suppircire material, mixing was continued for an additional 2 hours at 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.) (mcg/mL) (% w/w)

Control (Intact API) Hydrocortisone (HC) 240-242 3O2 100 DG-SB 20% Stearic Acid 80-188 3.18 87 DG-27 20% Cetostearyl Alcohol 85-195 319 8O DG-45A 10% Sorbitan Monopalmitate 86-191 376 87 DG-45C 30% Sorbitan Monopalmitate 79-187 375 77 DG-6Oa. 25% Sorbitan Monopalmitate 74-182 530 81 dg-60b 21% Sorbitan Monopalmitate, 4% Methocel E4M 70-18O 660 81 dg-60c 21% Sorbitan Monopalmitate, 4% Gelucire 44/14 68-182 530 82 dg-60d 21% Sorbitan Monopalmitate, 4% Ethocel 68-18O 440 76 dg-60e 25% Cetostearyl Alcohol 83-190 390 79 dg-60f 21% Cetostearyl Alcohol, 4% Methocel E4M 80-188 590 76 dg-60g 21% Cetostearyl Alcohol, 4% Gelucire 44/14 75-185 490 76 dg-60h 21% Cetostearyl Alcohol, 4% Ethocel 78-190 430 77 dg-61f 21% Cetostearyl Alcohol, 4% Methocel E4M 71-18O 481 8O

For each mixed phase co-crystal, only the highest melting point is specified US 9,682,043 B2 39 40 TABLE 2 Physical Properties of Hydrocortisone Acetate Mixed Phase Co-Crystals Assay Solubility Peak Mp Enthalpy Lot No. (% ww). (mcg/mL) (° C.) ((-) J/g) Ingredients Control NA 4.5 219.92 119. OS Hydrocortisone Acetate (Intact API) 47A NA 7.0 215.84 80.51 Cetostearyl Alcohol, NF 47D NA 6.9 212.14 72.59 Stearic Acid 57A NA S.1 222.17 90.81 Compritol 888 ATO 57B NA 2.6 NA NA Cetostearyl Alcohol, NF Emulcire 57C NA 6.1 217.31 84.84 Cetostearyl Alcohol, NF Gelucire 44/14 57D NA 6.7 216.09 88.70 Cetostearyl Alcohol, NF Povidone 57E NA 6.9 NA NA Cetostearyl Alcohol, NF PVA 57F NA 15.4 217.26 92.77 Cetostearyl Alcohol, NF Methocel E4M 61A 78.5 6.5 NA NA Cetostearyl Alcohol, NF Ethocel 61C 78.5 6.O NA NA 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 Ester 63C 82.1 7.4 218.02 82.10 Monosterol 63H 91.5 6.9 NA NA 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 69H 91.7 11.2 222.39 92.77 Suppercire Methocel E3

Tables 3 and 4 demonstrate the physical properties of TABLE 3-continued mixed phase co-crystals of cyclosporin. The materials were prepared by the method described in Example 4. Phospho- The Relative Water solubility of a series of lipon refers to a refined soy derived lecithin. - Cyclosporn Mixed phase CoCrystal Powers TABLE 3 Sample Code No. Solubility Factor 93. 15 The Relative Water Solubility of a Series of 94c. 12 CycloSporin Mixed phase Co-Crystal Powders 35 76a 8 94e 5 Sample Code No. Solubility Factor* 93f 4

93e93c. 2366 StySolubility ratioratio inin water at room temperatutemperature compared toO the amorphoush powderd

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 66 50% Ethocel 100–110, 89-104 4.0 61 66e 25% Compritol 888 ATO 80-86 4.5 69 66 25%. Sucrose Ester 1670 92-102 4.1 101 66g 25% Stearic Acid 58-65, 51–61f 3.6 85.7 7Ob 25% Sucrose Ester 1670, 25% Methocel E4M 85-123 3.9 93.8 70 50% Stearic Acid 57 59 3.2 59.5 70e 25% Stearic Acid, 25% Ethocel 55. 73 3.4 57.3 70 25% Cetosterol Alcohol 46-71 3.5 813 70g 25% Phospholipon 118-139 3.7 95.4 7Ol 25% Emulcire 42-8O 3.5 87.3 71 c. 50% Phospholipon 120-16S 2.7 43.2 71 66%. Sucrose Ester 1670 90-110 3.5 36.8 71e 25% Phospholipon, 25% Methocel E4M 104-130 3.2 54.5 71 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 US 9,682,043 B2 41 42 Tables 5 and 6 demonstrate the physical properties of Volpo S-10 refers to steareth-10; and Crodesta F110 refers to mixed phase co-crystals of itraconazole (see also FIG. 5). To Sucrose Stearate (and) Sucrose distearate. prepare the mixed co-crystals, itraconazole and crystal lat tice modifiers were dissolved in DMSO or n-methyl-pyr TABLE 5 5 rolidone or a blend of the two with gentle heating (60° C.) Intrinsic Dissolution of Itraconazole in 3% Sodium and Vortex mixing. The resulting solution was combined Lauryl Sulfate 20%. Isopropanol:0.1 NHCl (1:1 with water to intiate the crystallization of the mixed phase co-crystals and vortexed for 18 to 48 hours at room tem Sample Intrinsic Dissolution Rate perature. The mixed phase co-crystals were isolated by Code (mcg min/cm) filtration, washed with water, and dried. 10 745-4-8 6.4 745-7-8 7.45 In the case of 833-2A, -2B, -2C, and -2D, a solution of 745-48g 9.15 urea in water (50%) was combined with the solvent phase to Control 11.1 initiate crystallization. The resulting Suspensions were 745-71C 11.4 allowed to mix for 18 to 48 hours at room temperature, 745-71A 12.4 15 745-7-6 12.2 collected by filtration, washed with water, and dried. 745-71H 14.4 Capmul MCMC10 refrs to glyceryl monocaprate: SPAN 833-2A 55.3 40 refers to sorbitan palmitate; Pharmalan USP refers to 833-2B 17.7 lanolin; Crodesta F10 refers to sucrose distearate; Crodacol 833-2C 19.3 C-95 refers to cetyl alcohol; Acylan refrs to Acetylated 833-1A 19.9 2O 833-1B 18.5 Lanolin Protalan MOD; SPAN 60 refers to sorbitan monos 833-1C 15.4 tearate; Crodafos CES refers to dicetyl phosphate, cetearyl 833-1D 8.5 alcohol, ceteth-10 phosphate: Polychol 5 refers to laneth-5; Methocel K4M refers to hydoxypropyl methylcellulose; TABLE 6 Physical Properties of Itraconazole Mixed Phase Co-Crystals Assay Peak Yield (% Solubility Mp Enthalpy Lot No. (%) ww). (mcg/mL) (C.) ((-) J/g) Ingredients Control NAA NAA <.O1 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 Aci USP 745-4-2 7 O.S 69.8 O.O2 58.21 57.87 Stearic Acid CrOdesta F10 Pluronic Crodacol C-95, F68 NF 745-4-3 83.0 NFA O.OO 56.88 S2.31 Crodacol C SPAN 40 Crodacid B Capmul GMS 95, NF 745-4-4 85.O. NAA O.OO 56.90 56.28 Acylan Crodacol C-95, SPAN 60 Crodacid B NF 745-4-5 78.8 NA O.O2 56.82 52.10 Crodafos SPAN 60 Crodacid B Stearic Acid CES 745-4-6 77.0 74.9 O.47 61.82 65.32 Crodacid B Capmul GMS Cro afos 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 84S 70.7 O43 61.16 62.00 Capmul SPAN 60 Crodacid B Gelucire 44f14 MCM C10 745-7-1 103.0 NFA O.04 55.71 48.97 Campul SPAN 40 Stearic Pharmalan, Methoce MCM C10 Aci USP K4M 745-7-2 112.0 S9.3 O.78 53.56 45.62 Stearic Acid CrOdesta F10 Pluronic Crodacol C-95, Methoce F68 NF K4M 745-7-3 NAA NAA O.O3 52.76 46.14 Crodacol C SPAN 40 Crodacid B Capmul GMS Methoce 95, NF K4M 745-7-4 NAA NAA 0.27 55.67 48.28 Acylan Crodacol C-95, SPAN 60 Crodacid B Methoce NF K4M 745-7-5 NA 53.7 1.OO 49.88 41.93 Crodafos SPAN 60 Crodacid B Stearic Acid Methoce CES K4M 745-7-6 NiA 49.6 O.94 53.37 43.65 Crodacid B Capmul GMS Cradafos polychol 5 Methoce CES K4M 745-7-7 NA 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.O 73.0 O.31 61.12 S8.00 Capmul SPAN 60 Crodacid B Gelucire 44f14 Methoce MCM C10 K4M 745-11-1 81.3 NFA O.OO 52.88 54.60 Cholesterol, Dehydrocholic Crodacid B SPAN 60 NF Acid 745-11-2 87.8 NAA O.32 58.54 57.56 Choles-terol, Capmul MCM Gelucire Stearic Acid NF C10 44f14 745-11-3 94.3 NFA O.OO 55.77 28.69 Choles-terol, Dehydrocholic Compritol Solutol HS 15 NF Acid 888 ATO 745-11-4 72.0 713 O.93 60.06 61.21 Monosteol Crodacid B Solutol HS Capmul MCM 15 C10 US 9,682,043 B2 43 44 TABLE 6-continued Physical Properties of Itraconazole Mixed Phase Co-Crystals Assay Peak Yield (% Solubility Mp Enthalpy Lot No. (%) wiw). (mcg/mL) (C.) ((-) J/g) Ingredients 745-11-5 91.3 55.7 3.94 57.60 55.19 Ceto-steary Cholesterol, Monosteol Solutol HS 15 Alcohol, NF NF 745-11-6 87.O 65.4 O.S8 59.42 56.36 Camul GMS Solutol HS 15 Crodacid B Monosteol 745-11-7 93.3 NA O.OS 57.30 56.36 Crodesta F10 Stearic Acid Crodacol Capmul MCM C-95, NF C10 745-11-8 8O.S NA 1.28 54.66 NAA Solutol HS Stearic Acid Crodacol Dehydrocholic 15 C-95, NF Acid 745-14-1 78.1 NA 2.22 58.64 59.88 Cetostearyl Cholesterol, Monosteo Solutol HS 15 Alcohol, NF NF 745-14-2 87.1 NA O.OO 55.06 63.46 Cetostearyl Cholesterol, Monosteo Dehydrocholic Alcohol, NF NF Acid 745-14-3 84.2 NA O.O2 58.52 60.15 Cetostearyl Cholesterol, Monosteo Gelucire 44f14 Alcohol, NF NF 745-14-4 85.3 NA O.OO 58.13 64.86 Cetostearyl Cholesterol, Monosteo Pluronic F68 Alcohol, NF NF 745-14-5 82.9 NA O.OO 60.02 64.20 Cetostearyl Cholesterol, Monosteo CrOdesta F10 Alcohol, NF NF 745-14-6 79.3 NA O.78 58.87 62.33 Cetostearyl Cholesterol, Monosteo Volpo S-10 Alcohol, NF NF 745-14-7 69.8 NA O16 58.64 58.10 Cetostearyl Cholesterol, Monosteo CrOdesta F10 Alcohol, NF NF 745-14-8 77.5 NA O.OO 59.67 69.06 Cetostearyl Cholesterol, Monosteo Capmul MCM Alcohol, NF NF C10 745-40-A 60.8 NA 2.22 NA NAA Solutol HS Stearic Acid Crodacol Capmul MCM 15 C-95, NF C10 745-40-B 86.5 NA O.OO NA N/A Cetostearyl Cholesterol, Monosteo Solutol HS 15 Alcohol, NF NF

Table 7 demonstrates the physical properties of mixed phase co-crystals were isolated by filtration, washed with phase co-crystals of intraconazole. To prepare the mixed water, and dried. phase co-crystals, itraconazole and crystal lattice modifiers Volpo S-2 refers to steareth-2; Syncrowax AW1-C refers to a hard acid wax: Prolipid 141 refers to a composition of were dissolved in DMSO or n-methyl-pyrrolidone or a blend 35 glyceryl Stearate, behenyl alcohol, palmitic acid, Stearic of the two with gentle heating (60° C.) and vortex mixing. acid, lecithin, lauryl alcohol, myristyl alcohol, and cetyl The resulting solution was combined with water to intiate alcohol; Liposorb S-4 refers to polysorbate 61; Ganex the crystallization of the mixed phase co-crystals and Vor WP-660 and Ganex V-220 refer to PVP/eicosene copoly texed for 18 to 48 hours at room temperature. The mixed 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. (%) wiw). (mcg/mL) (C.) ((-) J/g) Ingredients

Control NAA NAA <.O1 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 NFA 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 20.92 75.28 Cholesterol, Compritol 888 Dehydrocholic Volpo S-10 NF ATO Acid 745-16-4 92.1 NFA 0.72 10.21 83.49 Cholesterol, Dehydrocholic Monosteol Volpo S-2 NF Acid 745-16-5 NAA NAA O43 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 15 745-1 6-7 99.1 88.0 1.56 12.17 91.12 Cholesterol, Capmul GMS Cetostearyl Solutol HS 15 NF Alcohol, NF 745-16-8 94.8 NFA O.78 12.49 95.38 Syncrowax Stearic Acid SPAN 60 Solutol HS 15 AW1-C 745-44-A 583 1.74 12.95 86.48 Crodacid B Compritol 888 Solutol HS 15 Volpo S-2 ATO US 9,682,043 B2 45 46 TABLE 7-continued Physical Properties of Itraconazole Mixed Phase Co-Crystals Assay Peak Yield (% Solubility Mp Enthalpy Lot No. (%) wiw). (mcg/mL) (C.) ((-) J/g) Ingredients 745-44-B 67.7 1.82 121.21 76.10 Cholesterol, Compritol 888 Solutol HS 15 Dehydrocholic NF ATO Acid 745-44-C 62.7 2.54 121.52 77.63 CrOdesta Volpo S-2 Solutol HS 15 Prolipid 141 F160 745-44-D 68.0 1.74 122.89 78.31 Capmul Compritol 888 Crodacid B Liposorb S-4 GMS ATO 745-44-E 53.5 2.33 123.66 82.42 Capmul Compritol 888 Crodacid B Solutol HS 15 Methocel GMS ATO E4M 745-44-F 72.6 1.15 11427 96.29 Capmul Compritol 888 Crodacid B Solutol HS 15 Ganex GMS ATO WP-660 745-44-G 72.3 1.84 123.37 81.92 Capmul Compritol 888 Crodacid B Solutol HS 15 Methocel GMS ATO A4K 745-44-H 69.6 1.19 114.15 87.68 Capmul Compritol 888 Crodacid B Solutol HS 15 Ganex GMS ATO V-22OF

All references, including publications, patent applica Accordingly, this invention includes all modifications and tions, and patents, cited herein are hereby incorporated by equivalents of the Subject matter recited in the claims reference to the same extent as if each reference were appended hereto as permitted by applicable law. Moreover, individually and specifically indicated to be incorporated by any combination of the above-described elements in all reference and were set forth in its entirety herein. 25 possible variations thereof is encompassed by the invention The use of the terms “a” and “an and “the' and similar unless otherwise indicated herein or otherwise clearly con referents in the context of describing the invention (espe tradicted by context. cially in the context of the following claims) are to be construed to cover both the singular and the plural, unless What is claimed is: otherwise indicated herein or clearly contradicted by con- 30 1. A method of preparing mixed phase co-crystal compo text. The terms “comprising,” “having,” “including,” and sition consisting of the steps of: “containing” are to be construed as open-ended terms (i.e., (a) forming a first solution of progesterone, hydroxypro meaning “including, but not limited to.”) unless otherwise pyl methylcellulose, and polyoxamer 188 dissolved in noted. Recitation of ranges of values herein are merely ethanol: intended to serve as a shorthand method of referring indi- 35 (b) mixing water with the first solution to form a second vidually to each separate value falling within the range, Solution; unless otherwise indicated herein, and each separate value is (c) mixing or allowing the second solution to stand for a incorporated into the specification as if it were individually sufficient period of time to form an initial kinetically recited herein. All methods described herein can be per favored meta-stable crystalline phase in the second formed in any suitable order unless otherwise indicated 40 Solution, herein or otherwise clearly contradicted by context. The use (d) forming the thermodynamically favored mixed phase of any and all examples, or exemplary language (e.g., “Such co-crystal composition from the meta-stable crystalline as') provided herein, is intended merely to better illuminate phase by allowing the initial meta-stable crystalline the invention and does not pose a limitation on the scope of phase to stand or by mixing of the initial meta-stable the invention unless otherwise claimed. No language in the 45 crystalline phase, specification should be construed as indicating any non (e) optionally, isolating the mixed phase co-crystal com claimed element as essential to the practice of the invention. position, Preferred embodiments of this invention are described (f) optionally, washing the mixed phase co-crystal com herein, including the best mode known to the inventors for position, and carrying out the invention. Variations of those preferred 50 (g) optionally, drying the mixed phase co-crystal compo embodiments may become apparent to those of ordinary sition, skill in the art upon reading the foregoing description. The wherein the progesterone, hydroxypropyl methylcellu inventors expect skilled artisans to employ such variations lose, and polyoxamer 188 are contained within the as appropriate, and the inventors intend for the invention to mixed phase co-crystal composition. be practiced otherwise than as specifically described herein. k k k k k