US 20050203115A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0203115 A1 Sancilio et al. (43) Pub. Date: Sep. 15, 2005

(54) NARCOTIC-NSAID ION PAIRS (52) U.S. Cl...... 514/282; 546/44; 546/232; 514/554; 514/317 (76) Inventors: Frederick D. Sancilio, Jupiter, FL (US); Grayson W. Stowell, Wilmington, NC (US); Linda B. (57) ABSTRACT Whittall, Wilmington, NC (US); David White, Wilmington, NC (US); Robert R. Whittle, Wilmington, NC (US) The present invention provides an ion pair compound of the formula narcotic A, wherein narcotic represents at Correspondence Address: least one cation of at least one narcotic agent or one or more FOLEY AND LARDNER Stereochemical isomers thereof and A represents at least SUTE 500 one anion of at least one NSAID or one or more stere 3000 KSTREET NW ochemical isomers thereof. An example of the ion pair WASHINGTON, DC 20007 (US) compound is propoxyphene diclofenate. The ion pair com (21) Appl. No.: 10/796,308 pounds, or their pharmaceutical compositions, are useful in methods of treating a wide variety of conditions that indicate (22) Filed: Mar. 10, 2004 analgesics, anti-inflammatory agents, or both. Under the conditions prescribed for their use, the ion pair compounds Publication Classification exhibit poor or complete insolubility but excellent chemical stability in low pH environments, such as those found in the (51) Int. Cl." ...... C07D 489/02; A61K 31/485; Stomach. The ion pair compounds readily dissolve and A61K 31/192; A61K 31/445; dissociate in higher pH environments Such as the Small A61K 31/205 intestine to release the constituent narcotic and NSAID.

Patent Application Publication Sep. 15, 2005 US 2005/0203115 A1

US 2005/0203115 A1 Sep. 15, 2005

NARCOTIC-NSAID ON PARS A. Andeev, Absorption and Drug Development. Solubility, Permeability, and Charge State, Wiley, New York (2003). In BACKGROUND OF THE INVENTION this regard, the absence of drug degradation products typi cally is associated with drugs that are Safer for patients. 0001. The present invention relates generally to the field Thus, it is vitally important to ensure the Safe passage of of new drug therapies that encompass at least one narcotic drugs through the Stomach. Consequently, it is Sometimes and at least one NSAID chemically united as an ion pair. necessary to increase the dosage of a drug to compensate for 0002 Many conventional therapeutic regimens rely upon the drug's decomposition in the Stomach, thus ensuring that combination therapies, that is, the co-administration of two a patient receives the therapeutically effective dose of the or more drugs, that often result in certain enhanced thera drug. However, administering greater doses of a drug can peutic effects that could not be achieved with a Single drug. present a number of undesirable Side effects, Such as, for Positive pharmacodynamic interactions between the drugs example, irritation or damaging of the Stomach lining. This in this regard thus fall generally into two broad categories. damage of the gastric mucosa may be especially pronounced Two co-administered drugs with Similar actions may simply with the use of non-Steroidal anti-inflammatory drugs yield an additive effect, essentially evaluated as the Sum of (NSAIDs). Additionally, many dosage forms incorporate the therapeutic effects of the individual drugs. For example, protective coatings and fillers to protect drugs from Stomach aspirin and codeine are often given together to enhance pain acid. The resultant increased bulk of the dosage forms is yet relief. another undesirable effect for the reasons mentioned above. 0003) Second, when two or more drugs are co-adminis 0007 One highly useful Subset of drug combinations is tered, one drug may exhibit a Synergistic effect on the other NSAIDs and narcotic analgesics (typically opioids). drug. That is to say, the combined therapeutic effect of both NSAIDs are typically thought to have a mode of action drugs is greater than the Sum of the therapeutic effects through the arachidonic acid cascade and primarily work at ascribed to the individual drugs. A significant advantage in the compartment of injury, resulting in a decrease in the this regard is that lower dosages of one or more of the drugs amount of proinflammatory prostaglandins that are pro may result. To illustrate, in a meperidine (a narcotic anal duced by cyclooxygenase and lipoxygenase enzymes. On gesic) and promethazine (an antihistamine) combination, the other hand, analgesics are thought to bind to various promethazine enhances the effect of meperidine, thereby types of opioid receptors preventing painful Stimuli from reaching the thalamus. It is possible that NSAIDs bind to allowing the practitioner to administer lower doses of the opioid receptors and that opioid analgesics bind to cyclooxy narcotic. genases and lipoxygenases, albeit weakly. Together, co 0004 Combination therapies, as outlined above, present administration of NSAIDs and opioid analgesics have the a number of disadvantages. First, as the description implies, potential of acting via Several mechanisms to ensure the combination therapy implicates the administration of at least reduction of pain Sensation. Additionally, the pairing of an two drugs, thereby requiring a patient to accept multiple NSAID with a narcotic can result in additive and possibly and/or larger dosage forms of the drugs. Such therapies Synergistic analgesic effects and thus minimize the dose of require careful mixing of the drugs to ensure accurate doses the narcotic and NSAID and their respective side effects. For of each drug. Scenarios in which the drugs may exhibit other reasons as outlined above, however, it may not be negative additive or Synergistic effects prescribe additional necessary or desirable to administer a narcotic and NSAID care to achieve the correct relative dosages and thereby at full doses to achieve the intended therapeutic effect. avoid potential adverse effects. Additionally, multiple doses Employing lowered narcotic and/or NSAID doses but tend to Strain patient compliance, particularly among the obtaining the full therapeutic advantages of the narcotic and pediatric and geriatric populations. Thus it would be desir NSAID would thus present a significant advance over con able to co-administer two or more drugs in a single dose in ventional therapies. controlled, if not rigorously fixed, proportions. 0008 Although the mechanism by which NSAIDs cause 0005 Second, a substantial Subset of drugs is salts or salt gastric mucosal damage is not known with certainty, two prodrugs that, as a consequence of their ionic nature, greatly theories are postulated in the Scientific and medical litera facilitate their water solubility and resultant bioavailability. ture. The first model assumes that the protonated acidic The Salts necessarily introduce counterions, which although NSAID is sufficiently lipophilic to penetrate the cell wall. At physiologically tolerable, nonetheless represent needleSS the pH interior to the cell, the acidic NSAID loses its proton masses of therapeutically irrelevant material that are admin and becomes trapped in the gastric mucosal cell, causing istered to a patient. damage. The Second model postulates that a non-Selective NSAID binds both isoforms of cyclooxygenase, COX-1 and 0006 When administered to humans, many drugs do not COX-2. The binding to COX-1 prevents the production of tolerate the harsh conditions of the stomach, where the lower pH values in the range from about 5.0 (fed) to about 1.7 prostaglandins that are thought to repair gastric mucosal (fasted) are more than adequate to induce serious chemical damage. Therefore, to prevent gastric mucosal damage, it is degradation of the drugs. Moreover, drugs generally are not desirable to modify the chemical form of the NSAID so that absorbed in the stomach but rather in the duodenum (pH = it is not possible for the proton transfer reaction to occur in ~4.6, fasted), jejunum (pH =~4.5-5.5, fed; -6.1-6.5, fasted), the Stomach. An advantageous result of Such modification ileum (pH=-6.5), and colon (pH=-8.0) where the pH ranges would result in an NSAID that is insoluble in the acidic pH typically do not facilitate decomposition of the drugs that are range of the Stomach, but Soluble in the neutral to basic pH acid labile. The foregoing pH ranges may vary from perSon range of the remainder of the alimentary canal. to perSon, while other ranges may pertain to other species. 0009. In light of the foregoing shortcomings of conven A more complete discussion of these pH ranges is given by tional combination therapies, there exist the needs to co US 2005/0203115 A1 Sep. 15, 2005

administer a narcotic and NSAID as a single chemical entity, to conditions under which the individual free narcotics free of unnecessary counterions, that could achieve the full and/or NSAIDS may decompose or potentially cause gastric therapeutic effects of the narcotic and NSAID but avoid the mucosal damage. full narcotic dosage of conventional narcotic therapies. Accordingly, the present invention Satisfies all of these needs 0017) Ion Pair Compounds and more by providing an NSAID and narcotic ion pair. 0018. The narcotics that are suitable in the context of this invention are not limited in any particular manner. Accord SUMMARY OF THE INVENTION ing to general formula (I), the narcotic should be available in a form that is amenable to the formation of a cation. Most 0.010 The present invention thus provides as one object narcotic agents meet this requirement by virtue of their an ion pair compound according to general formula I: bearing Brönsted acidic moieties, Such as amine or amino groups, that can be ionized according to the process of this narcotic"A (I) invention as described more fully below. Additionally, the 0.011 The moiety denoted “narcotic” represents at invention contemplates all Stereochemical isomers, where least one cation of at least one narcotic agent or one or more applicable, of the narcotic. Stereochemical isomers thereof, while A represents at 0019 Preferred narcotics in this regard include but are least one anion of at least one NSAID or one or more not limited to ketamine, Oxycodone, propoxyphene, metha Stereochemical isomers thereof. The ion pair compound may done, hydrocodone, morphine, codeine, fentanyl, meperi also exist as a pharmaceutically acceptable Solvate, hydrate, dine, hydromorphone, oxymorphone, dihydrocodeine, nal one or more polymorphs, or isotopically labeled version buphine, and buprenorphine. More preferred are meperidine, thereof. ketamine, Oxycodone, propoxyphene, methadone, hydroc 0012. The invention provides as another object a phar odone, morphine, and codeine. Even more preferred are maceutical composition comprising a therapeutically effec meperidine, morphine, codeine, methadone, oxycodone, and tive amount of the inventive ion pair compound and a propoxyphene. The most preferred narcotic is pro pharmaceutically acceptable carrier, diluent, excipient, poxyphene. Stimulant, or combination thereof. In one embodiment, the 0020. In principle, any NSAID is appropriate for use in pharmaceutical composition comprises an additional this invention. According to general formula (I), the NSAID NSAID, which can be the same or different as the NSAID is capable of forming an anion So as to provide charge represented by A in general formula (I). neutrality for the positively charged narcotic ion. Preferred 0013 Another object of the invention provides a method classes of NSAIDs include but are not limited to non of treating a condition for which an analgesic is indicated in Selective COX inhibitors, selective COX-2 inhibitors, selec animals comprising administering to an animal in need of tive COX-1 inhibitors, COX-LOX inhibitors, and PLA treatment a therapeutically effective amount of the instant inhibitors. The NSAID may be present as one or more ion pair compound. In one alternative, the condition may Stereochemical isomers, where applicable. Exemplary indicate an anti-inflammatory agent. In another alternative, NSAIDS include diclofenac, etodolac, Sulindac, alclofenac, the condition may indicate both an analgesic and an anti fenclofenac, diflunisal, benorylate, foSfosal, Salicylic acid, inflammatory agent. In the foregoing methods, it is possible acetylsalicylic acid, ibuprofen, ketoprofen, naproxen, car to employ either the presention pair compound itself or the profen, fenbufen, flurbiprofen, Oxaprozin, Suprofen, triapro present pharmaceutical compositions. All of these combina fenic acid, fenoprofen, indoprofen, piroprofen, flufenamic, tions are contemplated. mefenamic, meclofenamic, niflumic, Salsalate, rolmerin, fentiazac, tilomisole, OxyphenbutaZone, phenylbutaZone, 0.014. It is yet another object of this invention to provide apaZone, feprazone, Sudoxicam, iSoxicam, tenoxicam, for a process of preparing the ion pair compound of general piroXicam, indomethacin, meloxicam, nabumetone, tol formula (I). The process comprises contacting a salt of the metin, lumiracoxib, and parecoxib. Preferably, the NSAID is formula narcotic'}X* with a salt of the formula AB", diclofenac. In the context of this invention, NSAID is wherein X is 1, 2, or 3. X is an anion with a charge of -X and understood to exclude acetaminophen. B" is a cation. 0021. The invention thus contemplates all possible com binations of narcotics and NSAIDS according to general BRIEF DESCRIPTION OF THE DRAWINGS formula (I). Exemplary ion pair compounds in this regard 0015 FIG. 1 is an ORTEP of codeine diclofenate mono include but are not limited to: propoxyphene naproxenate, hydrate showing Selected atom labels (hydrogen atoms not propoxyphene etodolate, propoxyphene ketoprofenate, pro shown for clarity; 40% thermal ellipsoids). poxyphene Sulindate, propoxyphene Suprofenate, pro poxyphene flurbiprofenate, propoxyphene tolmetinate, pro DETAILED DESCRIPTION OF THE poxyphene fenoprofenate, propoxyphene oxaprozinate, PREFERRED EMBODIMENTS propoxyphene difunisalate, propoxyphene loxoprofenate, ketamine ibuprofenate, ketamine acetylsalicylate, ketamine 0016. The inventors surprisingly discovered that a wide indomethacinate, ketamine naproxenate, ketamine etod range of narcotic agents, available in their cationic forms, olate, ketamine Sulindate, ketamine ketoprofenate, ketamine combine readily with NSAIDs in their anionic forms, to Suprofenate, ketamine flurbiprofenate, ketamine tolmetinate, yield acid insoluble or acid poorly Soluble ion pair com ketamine fenoprofenate, ketamine Oxaprozinate, ketamine pounds of general formula (I) as Summarized above. The difunisalate, ketamine loxoprofenate, ketamine Salicylate, inventive compounds thus provide a convenient Source of ketamine diclofenate, methadone ibuprofenate, methadone two active agents that exhibit remarkable chemical Stability acetylsalicylate, methadone Salicylate, methadone US 2005/0203115 A1 Sep. 15, 2005

indomethacinate, methadone naproxenate, methadone etod dihydrocodeine fenoprofenate, dihydrocodeine olate, methadone Sulinate, methadone ketoprofenate, metha Oxaprozinate, dihydrocodeine difunisalate, and dihydroco done Suprofenate, methadone flurbiprofenate, methadone deine loxoprofenate. tolimetinate, methadone fenoprofenate, methadone 0022 Preferred embodiments of the ion pair compound Oxaprozinate, methadone difunisalate, methadone loxopro include propoxyphene diclofenate, ketamine diclofenate, fenate, hydrocodone ibuprofenate, hydrocodone acetylsali methadone diclofenate, hydrocodone diclofenate, codeine cylate, hydrocodone Salicylate, hydrocodone indomethaci diclofenate, propoxyphene Salicylate, propoxyphene acetyl nate, hydrocodone naproxenate, hydrocodone etodolate, Salicylate, propoxyphene ibuprofenate, morphine hydrocodone Sulindate, hydrocodone ketoprofenate, hydro diclofenate, and oxycodone diclofenate. More preferably, codone Suprofenate, hydrocodone flurbiprofenate, hydroc the ion pair compound is Selected from propoxyphene odone tolmetinate, hydrocodone fenoprofenate, hydroc diclofenate, ketamine diclofenate, methadone diclofenate, odone Oxaprozinate, hydrocodone difunisalate, hydrocodone diclofenate, codeine diclofenate, morphine hydrocodone loxoprofenate, codeine ibuprofenate, codeine diclofenate, and oxycodone diclofenate. The most preferred acetylsalicylate, codeine Salicylate, codeine indomethaci ion pair compound is propoxyphene diclofenate. In other nate, codeine naproxenate, codeine etodolate, codeine Sulin embodiments, the ion pair compound is propoxyphene Sali date, codeine ketoprofenate, codeine Suprofenate, codeine cylate, propoxyphene acetylsalicylate, and propoxyphene flurbiprofenate, codeine tolmetinate, codeine fenoprofenate, ibuprofenate. codeine oxaprozinate, codeine difunisalate, codeine loXo 0023. In other embodiments, the ion pair compound profenate, morphine ibuprofenate, morphine acetylsalicy preferably is propoxyphene lumiracoxibate, ketamine late, morphine Salicylate, morphine indomethacinate, mor lumiracoxibate, methadone lumiracoxibate, hydrocodone phine naproxenate, morphine etodolate, morphine Sulindate, lumiracoxibate, codeine lumiracoxibate, morphine lumira morphine ketoprofenate, morphine Suprofenate, morphine coXibate, or oxycodone lumiracoxibate. Alternatively, the flurbiprofenate, morphine tolmetinate, morphine fenopro ion pair compound is Selected from the group consisting of fenate, morphine oxaprozinate, morphine difunisalate, mor propoxyphene parecoxibate, ketamine parecoxibate, metha phine loxoprofenate, levorphanol ibuprofenate, levorphanol done parecoxibate, hydrocodone parecoxibate, codeine acetylsalicylate, levorphanol Salicylate, levorphanol parecoxibate, morphine parecoxibate, and oxycodone pare indomethacinate, levorphanol naproxenate, levorphanol coXibate. etodolate, levorphanol Sulindate, levorphanol ketoprofenate, 0024. The ion pair compound may exist as a pharmaceu levorphanol Suprofenate, levorphanol flurbiprofenate, levor tically acceptable Solvate, hydrate, polymorph, or isotopi phanol tolmetinate, levorphanol fenoprofenate, levorphanol cally labeled version. Pharmaceutically acceptable Solvates Oxaprozinate, levorphanol difunisalate, levorphanol loXo are those that include, for example, N,N-dimethylformamide profenate, oxycodone ibuprofenate, Oxycodone acetylsali (DMF), dimethylsulfoxide (DMSO), acetone, ethers such as cylate, Oxycodone Salicylate, Oxycodone indomethacinate, diethylether, and alcohols Such as methanol and ethanol. Oxycodone naproxenate, oxycodone etodolate, oxycodone 0025 The ion pair compound, when crystalline or micro Sulindate, oxycodone ketoprofenate, oxycodone Supro crystalline, may exhibit or display a preferred morphology. fenate, Oxycodone flurbiprofenate, oxycodone tolmetinate, However, the ion pair compound may exist in one or more Oxycodone fenoprofenate, oxycodone oxaprozinate, oxyc other crystal morphologies. Thus, a bulk sample of the odone difunisalate, oxycodone loxoprofenate; fentanyl compound can include one or more crystal morphologies. naproxenate, fentanyl etodolate, fentanylketoprofenate, fen tanyl Sulindate, fentanyl Suprofenate, fentanyl flurbipro 0026. The invention also contemplates isotopically fenate, fentanyl tolmetinate, fentanyl fenoprofenate, fenta labeled ion pair compounds at one or more atoms. Useful nyl oxaprozinate, fentanyl difunisalate, fentanyl labels in this regard include but are not limited to deuterium, loxoprofenate, meperidine naproxenate, meperidine etod tritium, “C, C, pure C, C, 7O, “N, N, C1, and olate, meperidine ketoprofenate, meperidine Sulindate, mep 37C1. eridine Suprofenate, meperidine flurbiprofenate, meperidine 0027. The bulk ion pair compound thus may comprise tolimetinate, meperidine fenoprofenate, meperidine any and all combinations of Solvates, hydrates, polymorphs, Oxaprozinate, meperidine difunisalate, meperidine loxopro and isotopically labeled versions. fenate, hydromorphone naproxenate, hydromorphone etod olate, hydromorphone ketoprofenate, hydromorphone Sulin 0028. The inventors were surprised to discover that, date, hydromorphone Suprofenate, hydromorphone relative to an individual narcotic or NSAID, the inventive flurbiprofenate, hydromorphone tolmetinate, hydromor ion pair compound is decreasingly Soluble at lower than phone fenoprofenate, hydromorphone oxaprozinate, hydro neutral pH values, typically becoming completely or at least morphone difinisalate, hydromorphone loxoprofenate, Oxy virtually insoluble at low pH values (e.g., about pH 3 and morphone naproXenate, Oxymorphone etodolate, lower). By contrast, the ion pair compound typically exhibits Oxymorphone ketoprofenate, oxymorphone Sulindate, Oxy maximum solubility at pH values of about 7 and higher. morphone Suprofenate, oxymorphone flurbiprofenate, Oxy 0029 While not wishing to be bound by any particular morphone tolmetinate, oxymorphone fenoprofenate, Oxy theory, the inventors believe that the foregoing solubility morphone oxaprozinate, oxymorphone difunisalate, properties advantageously permit the ion pair compound to Oxymorphone loxoprofenate, dihydrocodeine naproxenate, exist generally undeterred in the acidic gastric juice of a dihydrocodeine etodolate, dihydrocodeine ketoprofenate, patient. Under these conditions, the ion pair compound does dihydrocodeine Sulindate, dihydrocodeine Suprofenate, not Solubilize, and thus essentially protects a patient against dihydrocodeine flurbiprofenate, dihydrocodeine tolmetinate, the risk of the narcotic and/or NSAID decomposing in the US 2005/0203115 A1 Sep. 15, 2005

Stomach, and thereby frequently allows lower dosing. Addi desired, the Solid pharmaceutical compositions may include tionally, the insolubility at low pH avoids, or in the least, other components Such as bulking agents and/or granulating minimizes, the potential for gastrointestinal toxicity, Such as agents, and the like. The compositions of the invention can that of the NSAID irritating or inflaming the stomach lining be formulated So as to provide normal, Sustained, or delayed that is typically observed with NSAIDs generally exhibiting release of the ion pair compound after administration to the Solubility in the acidic Stomach environment. Once the ion patient by employing procedures well known in the art. pair compound passes into the Small intestine, where the pH is greater (i.e., about 7), the ion pair compound Solubilizes 0034. The pharmaceutical composition also may include to render the narcotic and NSAID agents as bioavailable one or more Stimulants, Suitable Stimulants in this regard therapeutic agents. Thus, the ion pair compound conve include but are not limited to an effective amount of an niently affords the narcotic and NSAID in one chemical amphetamine, Such as amphetamine Sulfate, dextroamphet entity that withstands the harsh conditions of the Stomach, amine Sulfate, methamphetamine hydrochloride, combina but readily evolves the drugs in the anatomy where they can tions of amphetamines, derivatives and pharmaceutically be absorbed. Salts thereof; pemoline, derivatives and pharmaceutically acceptable Salts thereof, methylphenidate, derivatives and 0030 The invention also contemplates a composition pharmaceutically acceptable Salts thereof; caffeine, deriva comprising a plurality of ion pair compounds, their phar tives and pharmaceutically acceptable Salts thereof, and maceutically acceptable Solvates, hydrates, polymorphs, centrally acting alpha-1 agonists Such as modafinil, epineph and/or isotopically labeled versions thereof. The composi rine, norepinephrine, phenylephrine, derivatives thereof and tion thus represents the bulk Solid that conforms to general pharmaceutically acceptable Salts thereof. The Stimulant is formula (I). Any of the foregoing combinations are included intended to reduce or prevent possible dizziness, depression, in the invention. For example, the composition provides for difficulty in being mobile, drowsiness, lethargy, weakness in ion pair compounds that have different narcotic agents the extremities, and orthoStatic hypotension associated with and/or NSAIDs. Preferably, however, the composition is administering the ion pair compound of this invention. The homogeneous with respect to the narcotic agent and NSAID. preferred stimulant for the treatment of the side effects In other embodiments, for example, the composition encom mentioned above is caffeine. passes one or more polymorphs of the ion pair compound. 0035) Some individuals may require a non-amphetamine 0.031) Pharmaceutical Composition based Stimulant or cannot otherwise receive additional or increased amphetamine doses due to cardiovascular risk 0.032 The invention also contemplates pharmaceutical concerns. In an alternative embodiment, therefore, a cen compositions that comprise a therapeutically effective trally acting alpha-1 agonist, Such as modafinil, can be used amount of at least one ion pair compound according to this as a Substitute or adjunct for an amphetamine(s), as the invention and a pharmaceutically acceptable carrier, diluent, Stimulant. excipient, Stimulant, or combination thereof, the Selection of which is known to the skilled artisan. In one embodiment, a 0036) A preferred pharmaceutical composition comprises Solid pharmaceutical composition of the present invention is at least one dispersing agent Selected from the group con blended with at least one pharmaceutically acceptable Sisting of polymer-based dispersing agents and carbohy excipient, diluted by an excipient or enclosed within Such a drate-based dispersing agents and at least one Solubilizing carrier that can be in the form of a capsule, Sachet, tablet, agent. The ratio of the ion pair compound to the polymer buccal, lozenge, paper, or other container. When the excipi based dispersing agent falls in the range from about 3:1 ent Serves as a diluent, it may be a Solid, Semi-Solid, or liquid (w/w) to about 1:50 (w/w), while the ratio of the ion pair material which acts as a vehicle, carrier, or medium for the compound to the carbohydrate-based dispersing agent is ion pair compound. Thus, the formulations can be in the from about 3:1 (w/w) to about 1:20 (w/w). Exemplary form of tablets, pills, powders, elixirs, Suspensions, emul compositions of this type are described, for example, in U.S. Sions, Solutions, Syrups, capsules (such as, for example, Soft Pat. No. 6,365,180 to Meyer et al. and U.S. Pat. No. and hard gelatin capsules), Suppositories, lozenges, buccal 6,287,594 to Wilson et al. Such dispersing agents are well dosage forms, Sterile injectable Solutions, and Sterile pack known in the art and include, for example, the polymer aged powders. based dispersing agents which include, for example, poly vinylpyrrolidone (PVP; commercially known as Plasdon 0.033 Examples of suitable excipients include, but are not e.RTM.), and the carbohydrate-based dispersing agents Such limited to, Starches, gum arabic, calcium Silicate, microc as, for example, hydroxypropylmethylcellulose (HPMC), rystalline cellulose, polyvinylpyrrollidone, cellulose, water, hydroxypropylcellulose (HPC), and the cyclodextrins. Pre Syrup, and methyl cellulose. The compositions can addition ferred dispersing agents include PVP K29-32, dextrins, ally include lubricating agents Such as, for example, talc, Starch, derivatized Starch and dextrans, while of the dextrins, magnesium Stearate and mineral oil, wetting agents, emul derivatized cyclodextrins are especially preferred. Of Such Sifying and Suspending agents, preserving agents. Such as cyclodextrins, hydroxypropyl beta.-cyclodextrin and methyl- and propyl hydroxybenzoates, Sweetening agents, gamma.-cyclodeXrin are especially preferred. The numbers or flavoring agents. Polyols, buffers, and inert fillerS may the polymer names refer to the molecular weight of the also be used. Examples of polyols include, but are not polymer wherein, for example, PVP K-30 has an average limited to: mannitol, Sorbitol, Xylitol, Sucrose, maltose, molecular weight of about 30,000, with attendant viscosity glucose, lactose, dextrose, and the like. Suitable buffers characteristics. One or more dispersing agents can be used. encompass, but are not limited to, phosphate, citrate, tar trate, Succinate, and the like. Other inert fillers which may be 0037 Solubilizing agents suitable for use in the present used encompass those which are known in the art and are context are well known in the art and are typically repre useful in the manufacture of various dosage forms. If Sented by the family of compounds known as polyethylene US 2005/0203115 A1 Sep. 15, 2005 glycols (PEG) having molecular weights from about 200 to in the pharmaceutical formulation art and include readily about 8,000. For compositions of the present invention when available Surfactants having a concentration from about Zero a liquid is desired for the final formulation or a liquid is to percent to about 90 percent Such as, for example, macro gel be used to fill Soft capsules, preferably Soft gelatin capsules, esters (Labrafils), Tandem 522. RTM., Span 80.RTM., Gelu preferred molecular weights range from about 200 to about cieres. RTM. Such as, for example, tocopherol polyethylene 600 with PEG 400 being especially preferred. For compo glycol 1000 succinate, polysorbate 20, and polysorbate 80. Sition of the present invention when a Semi-Solid is pre Of these, polysorbate 20 and polysorbate 80 are preferred. ferred, especially for filling a hard capsule, preferably a hard 0043. As used in the present invention, the concentration gelatin capsule, preferred molecular weight is about 3350 of the Sum of non-ionic Surfactant utilized, wherein more while an especially preferred molecular weight is 3350 plus than one Such Surfactant can be utilized, is from about Zero sufficient 400 molecular weight PEG to improve capsule percent to about 10 percent (w/w), with a range from about filling characteristics. 1 percent to about 5 percent (w/w) being preferred. An 0.038 Another solubilizing agent which may be utilized especially preferred concentration is about 3 percent (w/w). in compositions of the present invention is water, especially 0044) In the event that the foregoing compositions are to purified, and most preferably, deionized. For Such compo be used for parenteral administration, Such a formulation Sitions, the concentration of water is from about Zero percent typically comprises Sterile aqueous and non-aqueous injec to about ninety-nine percent (w/w). More particularly for tion Solutions comprising the ion pair compound, for which compositions of the present invention to be filled into soft preparations are preferably isotonic with the blood of the capsules, a maximum water concentration from about 0% to intended recipient. These preparations may contain anti about 5% is preferred, although the concentration of total oxidants, buffers, bacterioStats, and Solutes which render the Solubilizing agent may be the full concentration range taught formulation isotonic with the blood of the intended recipi herein. ent. Aqueous and non-aqueous Sterile Suspensions may 0039. As used in the present compositions, the concen include Suspending agents and thickening agents. tration of the Sum of Solubilizing agent utilized, wherein more than one plasticizing agent can be utilized, is from 004.5 The compositions may be presented in unit-dose or about 0 percent (just greater than Zero) to about 99 percent multi-dose containers, for example Sealed ampules and Vials. (w/w). The preferred concentration of Solubilizing agent in Extemporaneous injection Solutions and Suspensions may be the present compositions is from about 60 percent to about prepared from Sterile powders, granules and tablets of the 90 percent (w/w). kind previously described. 0046. In preferred embodiments of the invention, the 0040. One optional component of compositions of the composition may be made into the form of dosage units for present invention, but which should be used when such oral administration. The ion pair compound may be mixed compositions are to be filled in Soft capsules, is at least one with a Solid, pulverant carrier Such as, for example, lactose, pharmaceutically acceptable and non-toxic plasticizing Saccharose, Sorbitol, mannitol, Starch, amylopectin, cellu agent. Such plasticizing agents, which are well known in the lose derivatives or gelatin, as well as with an antifriction pharmaceutical formulation art, include, for example, glyc agent Such as, for example, magnesium Stearate, calcium erin, propylene glycol, and Sorbitol. Such commercially Stearate, and polyethylene glycol waxes. The mixture is then available plasticizers can be prepared to include more than pressed into tablets. If coated tablets are desired, the above one plasticizing agent component, but the preferred plasti prepared core may be coated with a concentrated Solution of cizing agent for the present compositions is glycerin. In Sugar, which may contain gum arabic, gelatin, talc, titanium addition to its use as a plasticizing agent, propylene glycol dioxide, or with a lacquer dissolved in Volatile organic can be used as a Solubilizing agent when used alone or in Solvent or mixture of Solvents. To this coating, various dyes combination with another Solubilizing agent as taught may be added in order to distinguish among tablets with herein. different active compounds or with different amounts of the 0041 AS used in the present invention, the concentration active compound present. of the Sum of plasticizing agent utilized, wherein more than 0047 Soft capsules also may be prepared in which cap one plasticizing agent can be utilized, is from about Zero Sules contain a mixture of the ion pair compound and percent (just greater than Zero) to about 75 percent (w/w). vegetable oil or non-aqueous, water miscible materials. Such The preferred concentration of plasticizing agent is from as, for example, polyethylene glycol and the like. Hard about Zero percent (0%) to about fifty percent (50%), and an capsules may contain granules of the ion pair compound in especially preferred concentration in a range from about one combination with a Solid, pulverulent carrier, Such as, for percent (1%) to about thirty percent (30%). When the example, lactose, Saccharose, Sorbitol, mannitol, potato compositions of the present invention are used to fill Soft Starch, corn Starch, amylopectin, cellulose derivatives, or capsules, the preferred concentration of Such plasticizing gelatin. agent is from about 5 percent to about 10 percent (w/w). Such plasticizers are especially useful with Soft capsule 0048 Dosage units for rectal administration may be preparations because, without which, Such capsules tend to prepared in the form of Suppositories which may contain the harden and lose their beneficial properties by potentially ion pair compound in a mixture with a neutral fat base, or cracking or becoming brittle. they may be prepared in the form of gelatin-rectal capsules 0.042 Another optional component of the present com which contain the active Substance in a mixture with a positions, which is a preferred component, is at least one vegetable oil or paraffin oil. pharmaceutically acceptable, non-toxic, Surfactant, prefer 0049 Liquid preparations for oral administration may be ably a non-ionic Surfactant. Such Surfactants are well known prepared in the form of Syrups or Suspensions, e.g., Solutions US 2005/0203115 A1 Sep. 15, 2005 containing an ion pair compound, Sugar, and a mixture of 0055 Additional NSAID or Narcotic ethanol, water, glycerol, and propylene glycol. If desired, 0056. As mentioned above, an advantage of the inventive Such liquid preparations may contain coloring agents, fla ion pair compound is the ability to dose a narcotic and Voring agents, and Saccharin. Thickening agents Such as NSAID in one chemical entity to a patient. However, in carboxymethylcellulose may also be used. Some circumstances, the Stoichiometry between the narcotic 0050 Tablets for oral use are typically prepared in the and NSAID (e.g., 1:1) may not accommodate the prescribed following manner, although other techniques may be overall dosage of the NSAID. Therefore, certain embodi employed. The Solid Substances are gently ground or Sieved ments of the pharmaceutical composition comprise a thera to a desired particle size, and the binding agent is homog petucially effective amount of an additional NSAID, or a enized and Suspended in a Suitable Solvent. The ion pair pharmaceutically acceptable Salt, Solvate, hydrate, poly compound and auxiliary agents are mixed with the binding morph, or isotopically labeled version thereof. In these agent Solution. The resulting mixture is moistened to form a embodiments, the additional NSAID may be the same or uniform Suspension. The moistening typically causes the different from the NSAID represented by “A” in general particles to aggregate slightly, and the resulting mass is formula (I). gently pressed through a stainless Steel Sieve having a 0057 Alternatively, some relative dosage requirements desired size. The layers of the mixture are then dried in for a given NSAID and narcotic warrant adding to the controlled drying units for determined length of time to pharmaceutical composition an additional and therapeuti achieve a desired particle Size and consistency. The granules cally effective amount of a narcotic or a pharmaceutically of the dried mixture are gently Sieved to remove any powder. acceptable Salt, Solvate, hydrate, polymorph, or isotopically To this mixture, disintegrating, anti-friction, and anti-adhe labeled version thereof. In this regard, the narcotic need not Sive agents are added. Finally, the mixture is pressed into be the same as the narcotic represented by general formula tablets using a machine with the appropriate punches and (I). Preferably, however, the additional narcotic is the same dies to obtain the desired tablet size. The operating param as the narcotic in general formula (I). eters of the machine may be Selected by the skilled artisan. 0058. A preferred composition in this context comprises 0051 Typically, preparation of lozenge and buccal dos propoxyphene diclofenate. In this embodiment, the addi age forms are prepared by methods known to one of ordinary tional NSAID may be present as diclofenac free acid or a skill in the art. pharmaceutically acceptable Salt thereof. Exemplary Salts in this regard include the Sodium and potassium salts of 0.052 In other embodiments, the ion pair compound may diclofenac. be present in a core Surrounded by one or more layers including, for example, an enteric coating layer with or 0059. In preferred embodiments, the additional NSAID without a protective Sub-coating as known to the ordinarily or narcotic may be contained in an external or enteric skilled artisan relative to pharmaceutical formulations. coating as described above. The additional NSAID or nar cotic thus is available for immediate, Slow, delayed, Sus 0053. The final dosage form encompassing the above tained, pseudo-first order, pseudo-Zero order, timed, con embodiments may be either an enteric coated tablet or trolled release, or combinations thereof. The additional capsule or in the case of enteric coated pellets, pellets NSAID or narcotic agent can be applied to the Surface of a dispensed in hard capsules or Sachets or pellets formulated dosage form according to common methods that are known into tablets. It is desirable for long term stability during to those of ordinary skill Such as applying to its Surface Storage that the water content of the final dosage form Solids in Solution or Suspension through the use of a sprayer containing the ion pair compound (enteric coated tablets, that spreads them uniformly over the core or by employing capsules or pellets) be kept low. As a consequence, the final nucleated compression or other Suitable methods known to package containing hard capsules filled with enteric coated those of ordinary skill in the art. The external coat can pellets preferably also contain a desiccant, which reduces the comprise poly(vinyl pyrrolidone) (PVP) and poly(ethylene water content of the capsule shell to a level where the water glycol) (PEG) and can further comprise materials Such as, by content of the enteric coated pellets filled in the capsules way of example and without limitation, hydroxypropyl does not exceed a certain level. methylcellulose (HPMC), ethylcellulose (EC), hydroxyeth ylcellulose (HEC), sodium carboxymethyl-cellulose 0.054 Accordingly, the ion pair compounds and compo (CMC), dimethylaminoethyl methacrylate-methacrylic acid Sitions of the present invention are preferably formulated in ester copolymer, ethylacrylate-methylmethacrylate copoly a unit dosage form, each dosage containing from about 5 mg mer (GA-MMA), C-5 or 60 SH-50 (Shin-Etsu Chemical to about 200 mg, and more preferably the amount set forth Corp.) and combinations thereof. The external coat can also herein. The term “unit dosage form” refers to physically comprise dissolution aids, Stability modifiers, and bioab discrete units, Such as capsules or tablets Suitable as unitary Sorption enhancers. dosages for human patients and other mammals, each unit containing a predetermined quantity of one or more ion pair 0060. The amount of the additional NSAID or narcotic compound(s) calculated to produce the desired therapeutic depends upon the individual NSAID or narcotic and its effect, in association with at least one pharmaceutically dosage requirements that are known to the perSon of skill in acceptable carrier, diluent, excipient, or combination the art. thereof. Generally, preferred dosages of the ion pair com pounds in Such unit dosage forms are from about 5 mg to 0061 Methods of Treatment about 15 mg, about 20 mg to about 30 mg, about 40 mg to 0062) The invention also provides methods of treating a about 60 mg, and about 65 mg to about 120 mg, especially condition in an animal in need of treatment comprising 12 mg, 25 mg, and 48 mg, and 95 mg per dosage unit. administering to the animal a therapeutically effective US 2005/0203115 A1 Sep. 15, 2005 amount of the ion pair compound or a pharmaceutical individual requirement of each patient, the route of admin composition as described above. In Some embodiments, the istration, and the disease. One advantage of the ion pair condition is one for which is indicated an analgesic. In other compound in this regard is that the dosage Strength of the embodiments, an anti-inflammatory agent is indicated. In compound may closely match the dosages of the individual still other embodiments, the condition indicates both an narcotic and NSAID, which are well-known to the person of analgesic and anti-inflammatory agent. skill in the art. An attending physician may adjust the dosage 0.063 Preferably, the animal suffering from the condition rate based on these and other criteria if he or She So desires. is a mammal. More preferably, the mammal is a human AS an example, a Suitable oral dosage form may encompass being. from about 5 to about 1000 mg total daily dose, typically administered in one Single dose or equally divided doses. A 0064. As used herein, the term “treatment” or “treating” more preferred range is from about 15 mg to about 600 mg contemplates partial or complete inhibition of the Stated total daily dose, and a most preferred range is from about 30 condition or disease State when an ion pair compound or its mg to about 300 mg total daily dose. Additionally, the ion pharmaceutical composition is administered prophylacti pair compound(s) may be administered as a Suspension, and, cally or following the onset of the condition for which the as an example, the daily doses Set forth above may be compound or composition is administered. For the purposes employed. In one embodiment, the ion pair compound(s) of this invention, the term “prophylaxis” refers to the may be added in appropriate amounts to a liquid Such that administration of the ion pair compound to an animal to the resultant Suspension comprises, for example, from about protect the animal from any of the conditions Set forth 0.1 mg/mL to about 10 mg/mL of the ion pair compound(s). herein. It should be noted that daily doses other than those described above may be administered to a Subject, as appreciated by an 0065. The inventive ion pair compound may treat a attending physician. number of conditions including arthritic disorders, gas trointestinal conditions, inflammatory conditions, pulmo 0070 Process for Preparing nary inflammation, opthalmic diseases, central nervous SyS tems disorders, pain, fever, inflammation-related 0071. The invention also provides a process for preparing cardiovascular disorders, angiogenesis-related disorders, the ion pair compound represented by general formula (I). In benign and malignant tumors, adenomatous polyps, fibrosis general, as described Summarily above, the narcotic is which occurs with radiation treatment, endometriosis, introduced as a cation according to the formula narcotic Osteoporosis, dySmenorrhea, premature labor, asthma, eosi }X. In this regard, X is 1, 2, or 3, while X is a charge nophil-related disorders, pyrexia, bone resorption, nephro balancing anion with an overall charge of -X. Anions toxicity, hypotension, arthrosis, joint Stiffness, kidney dis represented by X include but are not limited to halides, such ease, liver disease, acute mastitis, diarrhea, colonic as chloride, bromide, and iodide, Sulfate, nitrate; and phos adenomas, bronchitis, allergic neuritis, cytomegalovirus phate. X may also represent one of many organic anions, infectivity, apoptosis, HIV-induced apoptosis, lumbago, pSo Such as carboxylates and organic Sulfates or Sulfonates. riasis, eczema, acne, burns, dermatitis, ultraViolet radiation Exemplary anions in this regard include napSylate, tereph damage, allergic rhinitis, respiratory distreSS Syndrome, and thalate, citrate, bitartrate, and tartrate. Additional anions endotoxin shock Syndrome. include the conjugate bases of the acids that are described below. It is thus possible to employ narcotic Starting mate 0.066 The invention is particularly effective in the treat rials that incorporate multiple narcotic cations. Many nar ment of arthritic disorders. These include but are not limited cotics are available commercially as Salts represented by to rheumatoid arthritis, Osteoarthritis, and acute gouty arthri {narcotic X. Typically, X is 1. Examples in this regard tis. include hydrohalogen acid Salts, Such as hydrochloride Salts. 0067. Other conditions against which the invention is 0072. Where the narcotic is not available as a salt, acid effective include primary dySmenorrhea, anklosing addition Salts of the narcotic may be prepared Straightfor spondylitis, and inflammatory disorders. Exemplary inflam Wardly. Acids Suitable for making Such Salts include but are matory disorders in this context include tendonitis and not limited to hydrohalogen acids, Sulfuric, phosphoric, bursitis. nitric, and perchloric acids, aliphatic, alicyclic, aromatic, 0068. By virtue of incorporating a narcotic and NSAID, heterocyclic carboxy or Sulfonic acids, Such as formic, the ion pair compound is also highly effective in the treat acetic, propionic, Succinic, glycolic, lactic, malic, tartaric, ment of many types of pain. Certain types of pain contem citric, ascorbic, maleic, hydroxymaleic, pyruvic, phenylace plated by this invention arise from pre-operative, post tic, benzoic, p-aminobenzoic, antranilic, p-hydroxybenzoic, operative, and both pre- and post-operative procedures. Salicylic or p-aminosalicylic acid, embonic, methane Examples of pain that are treated by this invention thus Sulfonic, ethaneSulfonic, hydroxyethaneSulfonic, ethylene include anogenital, minor arthritic, dental, topical, asSoci Sulfonic, halogenbenzeneSulfonic, toluenesulfonic, naphtyl ated with an upper respiratory infection, general, joint, Sulfonic or Sulfanilic acids, methionine, tryptophane, lysine menstrual, mild, mild to moderate, acute musculo-skeletal, or arginine. moderate to moderately Severe, moderate to Severe, muscu lar, neurogenic, obstetrical, ocular, oral mucosal and gingi 0073. The narcotic salt of the formula narcotic X* val, post operative, pre-operative, pre- and post-operative, is contacted with an NSAID salt of the formula AB", Severe, short term, urinary tract, and pain associated with where B represents the charge balancing cation for the gastric hyperacidity. negatively charged NSAID. Many NSAIDs already are available commercially as salts of this formula. For 0069. Typical doses of the ion pair compound will example, a preferred Salt in this regard is Sodium diclofenac. depend upon various factorS Such as, for example, the Salts of the formula AB" can be prepared where an US 2005/0203115 A1 Sep. 15, 2005

NSAID is not readily available as a salt. Such salts typically tant was decanted and the residual oily material dried under are prepared from an NSAID that bears at least one “acidic' reduced pressure. Methanol (25 mL) was added to dissolve proton. The proton may be removed, for example, by a type the oily material, and any Solid material removed by filtra of base that allows for the formation of an anionic Species of tion through 0.45-lum polytetrafluoroethylene (PTFE). Sol the NSAID countered by the cation. Some embodiments vent was removed by evaporation under a stream of nitro encompass polar, protic environments, in which alkali or gen, which resulted in the formation of an oily material. This alkaline metal hydroxide or alkaline metal alkoxides present oily material was dissolved in dichloromethane (30 mL), are effective in an alcohol or in mixed organic Solvent Such which resulted in the formation of a precipitate, which was as a 2-butanone-toluene mixture. removed by filtration through 0.45-lim PTFE. The dichlo 0.074 The narcotic and NSAID salts, as set forth above, romethane was removed by evaporation under nitrogen to may be combined in a variety of ways to yield the present produce the desired product as an oil or glass. The product ion pair compound. In one embodiment, the compounds of was characterized by means of Fourier Transform Infra-Red formulae narcotic'}X* and AB" thus are dissolved Spectroscopy (FTIR). Representative bands are listed in the in Separate Volumes of the same Solvent or in different Table 1. solvents. When combined, the resultant solution thus yields the ion pair compound of general formula (I) and the TABLE 1. Stoichiometric amounts of the undesired counterions X Observed bands for FTIR spectrum from Example 1. and B". The Solvent or solvent mixture can be selected Such that the ion pair compound precipitates when the Separate Band (cm) Intensity volumes of narcotic'}X and AIB" are combined, 3243 weak, broad thereby allowing the easy isolation of the ion pair com 3061 Weak pound. Alternatively, the ion pair compound is Soluble in the 3O32 Weak combined volumes of Solvent or different Solvents. In this 2977 moderate 2.942 moderate Scenario, the Solvent(s) may be removed to yield the ion pair 2819 Weak compound, which can then be purified according to Standard 2764 Weak purification techniques known to those who are skilled in the 2819 Weak art. 2764 Weak 1733 strong 0075. In another embodiment, the compounds according 1603 moderate 1577 strong to formulae narcotic'}X and AIB" are contacted 156 moderate effectively with each other on a cation eXchange medium, 1498 strong Such as on a cation exchange chromatography column. In 1453 very strong 135 moderate this embodiment, the narcotic" is retained on the cation 128O moderate exchange column when {narcotic X is introduced. 1178 strong When AB" is passed through the cation exchange 108 moderate column, the B is retained and the desired narcotic"A 1O2O moderate ion pair compound is recovered and Subsequently isolated 773 moderate 745 moderate according to conventional techniques in the art. 704 strong 0.076 The following examples are intended to further describe the invention by way of illustration, and thus should not be construed as limiting the Scope of the invention in any EXAMPLE 2 way. 0.077 All publicly available documents cited in this Preparation of d-Propoxyphene Diclofenate from description are incorporated by reference as if fully Set forth Sodium Diclofenac and d-Propoxyphene Napsylate herein. Hydrate by Ion Exchange Chromatography

EXAMPLE 1. 0079 d-Propoxyphene napsylate hydrate (1.8228 g, 3.222 mmol) in methanol (60 mL) was placed on a Varian Preparation of d-Propoxyphene Diclofenate from MegaBond Elut strong cation exchange column (SCX), Sodium Diclofenac and d-Propoxyphene Napsylate which was pre-treated with methanol. A Solution of Sodium Hydrate diclofenac (1.0283 g, 3.232 mmol) in methanol (3 mL) was added to the column and the product eluted with exceSS 0078 Sodium 2-(2,6-dichlorophenyl)amino)pheny methanol. The methanol Solution was concentrated by rotary lacetate (referred to herein as sodium diclofenac) (0.3283 g, evaporation, reconstituted in dichloromethane (30 mL) with 1.032 mmol) was dissolved in methanol (25 mL) to which Sufficient methanol to dissolve the material The Solution was was added a methanol solution (25 mL) of (2S,3R)-(+)-4- placed in a nitrogen cabinet for approximately 12 hours. The (dimethylamino)-3-methyl-1,2-diphenyl-2-butanol propi Sample was removed from the nitrogen cabinet and the onate (referred to herein as d-propoxyphene) napsylate remaining Solvent removed by rotary evaporation, which hydrate (0.5633 g, 0.996 mmol). The two solutions were resulted in the formation of a white Solid. The Solid was mixed well and the methanol removed over several hours by dissolved in methanol and placed in the nitrogen cabinet for evaporation under an air purge. An oily material, which approximately 48 hours to remove the Solvent by evapora contained a white residue, was formed. Water (100 mL) was tion. The resulting Viscous oil containing crystalline plates added to the oily material and Solution formation enhanced was washed with acetone to dissolve the oil. The acetone by means of Sonication (5 minutes). The aqueous Superna Solution was decanted from the insoluble crystalline plates US 2005/0203115 A1 Sep. 15, 2005

into a Small beaker. A Small amount of diethyl ether was bottom flask. An acqueous Solution of d-propoxyphene added to the acetone Solution to induce recrystallization and hydrochloride (0.4384 g, 1.166 mmol in 50 mL of water) the Solution placed in a nitrogen cabinet to remove the was added to the round bottom flask with stirring, which Solvent by evaporation, which resulted in the formation of an resulted in the formation of a white precipitate. The water oily material. Multiple attempts at recrystallization of the was decanted a Small portion of the Solid was analyzed by oily material using different Solvents and conditions did not means of FTIR. Representative bands are listed in Table 3. yield a crystalline product. A Small portion of the oily The residual solid was dissolved in toluene (80 mL) and material from this Series of attempts was dissolved in a transferred to a separatory funnel. The organic layer was Solution of methanol and water (5:1) resulting in the forma washed with water (3x40 mL), dried (MgSO), and the tion of a white precipitate. The precipitate was Separated by resulting Solid Separated by filtration through a 0.45-lim filtration through Whatman #4 filter paper and dried under polyvinylidene fluoride (PVDF) filter. The solvent was nitrogen. The product was characterized by FTIR spectros removed by rotary evaporation, which resulted in an oily copy. Representative bands are listed in the Table 2. material. The product was assayed by Supercritical fluid chromatography (SFC; 101.10% propoxyphene; 99.6% TABLE 2 diclofenate). Observed bands for FTIR spectrum from Example 2. TABLE 3 Band (cm) Intensity Observed bands for FTIR spectrum from Example 4. 3378 weak, broad 3059 weak Band (cm) Intensity 3O31 weak 2976 weak 3243 weak, broad 2923 weak 3061 Weak 2852 weak 3O31 Weak 1734 strong 2976 OCleate 1603 moderate 2940 OCleate 1577 strong 281.8 Weak 1560 moderate 2763 Weak 1733 strong 1497 strong 1577 OCleate 1454 very strong 1506 strong 1384 weak 1497 strong 11.89 strong 1452 very strong 1091 moderate 1350 OCleate 1031 moderate 1281 OCleate 972 weak 1177 strong 867 weak 828 weak 108O OCleate 774 moderate 1019 OCleate 748 moderate 865 Weak 705 moderate 773 OCleate 676 moderate 746 OCleate 648 weak 704 strong 624 weak 646 Weak 569 weak 579 Weak 531 Weak

EXAMPLE 3 EXAMPLE 5 Preparation of d-Propoxyphene Diclofenate from Sodium Diclofenac and d-Propoxyphene Preparation of d-Propoxyphene Diclofenate from Hydrochloride Potassium Diclofenate and d-Propoxyphene 0080 Sodium diclofenac (0.9543 g, 3.000 mmol) in Hydrochloride water (200 mL) was placed in a 500 mL Erlenmeyer flask. 0082 Potassium diclofenate (3.3761 g, 10.101 mmol) in d-Propoxyphene hydrochloride (1.1219 g, 2.984 mmol) in water (600 mL) was placed in a 1 L Erlenmeyer flask. water (200 mL) was added to the diclofenate solution d-Propoxyphene hydrochloride (3.7884g, 10.077 mmol) in resulting in the formation of a white precipitate. After water (100 mL) was added to the diclofenate solution mixing, the water was removed by decantation and the forming a white precipitate. After mixing for 15 minutes, the residual Solid dissolved in an appropriate amount of diethyl contents of the 1 L Erlenmeyer flask were transferred to a ether and transferred to a 200 mL round bottom flask. The separatory funnel with the aid of a small portion of diethyl Solvent was removed by rotary evaporation and the product ether. Diethyl ether (250 mL) was added to the separatory dried under vacuum. The resulting product was a white funnel and any remaining precipitate was dissolved with Solid. Shaking. The organic and aqueous layers were separated and EXAMPLE 4 the aqueous layer washed with additional diethyl ether (2x250 mL) to extract any remaining product. The organic Preparation of d-Propoxyphene Diclofenate from layers were combined and the solvent removed by rotary Potassium Diclofenac and d-Propoxyphene evaporation. The resulting oily material was placed under Hydrochloride reduced pressure to form a white Solid. After trying to 0081 Potassium diclofenac (0.3828 g, 1.145 mmol) was constant weight, the white Solid was characterized by Super dissolved in water (100 mL) and placed in a 250 mL round critical fluid chromatography (SFC): 100.7% propoxyphene; US 2005/0203115 A1 Sep. 15, 2005

98.7% diclofenate; elemental analysis (CHN): Expected: 68.03% C, 6.34% H, 4.41% N, Obtained; 67.90% C, 6.22% TABLE 4a-continued H, 42% N; and differential scanning calorimetry (DSC): Observed resonances for the "H NMR spectrum from Example 7 obtained Glass transition (T,): 30.1° C.; degradation 189° C). in d-DMSO solution. EXAMPLE 6 Resonance (ppm) Multiplicity* Number of Protons Preparation of d-Propoxyphene Diclofenate from 699-7.01 Potassium Diclofenate and d-Propoxyphene 6.84 Hydrochloride 6.29 3.8O 0.083 Aqueous solutions of potassium diclofenac (5.0227 3.67 2.63 g, 15.027 mmol in 1 L of water) and d-propoxyphene 240 hydrochloride (5.6627g, 15.063 mmol in 300 mL of water) 2.27 ddd were combined into a 2 L round bottom flask. A white 2.06 precipitate formed and the solution was stirred for 30 1.60 minutes. An appropriate amount of diethyl ether was added O.94-109 d to the 2 L round bottom flask containing the aqueous *s - singlet, d - doublet, dd - doublet of doublets, m - multiplet, b - broad, Solution and precipitate. Upon addition of the diethyl ether, t - triplet, q – quartet. the precipitate dissolved with Stirring. The resulting aque ous/organic Solution was transferred to a separatory funnel in Several portions and the organic and aqueous layers 0085 Separated. The organic layers were combined, the diethyl ether removed by rotary evaporation and the product placed TABLE 4b under vacuum. The resulting white Solid was assayed by Observed resonances for the "C NMR spectrum from Example 7 obtained SFC: propoxyphene 100.2%; diclofenac 99.6%. from de-DMSO solution

EXAMPLE 7 Resonance (ppm) 173.67 Preparation of d-Propoxyphene Diclofenate from 72.57 Potassium Diclofenac and d-Propoxyphene 42.68 Hydrochloride 39.35 37.22 0084 Potassium diclofenac (8.3559 g, 25.000 mmol) was 36.54 dissolved in water (800 mL). An aqueous solution of pro 30.75 29.96 poxyphene hydrochloride (9.3889 g, 24.974 mmol in 500 29.8O mL of water) was added to the diclofenac solution in a 4L 29.13 Erlenmeyer flask. A white precipitate formed and the Solu 27.81 tion was Stirred for 30 minutes. An appropriate amount of 27.47 27.21 diethyl ether was added to the 4 L Erlenmeyer flask con 26.82 taining the aqueous Solution and precipitate. Upon addition 26.38 of the diethyl ether, the precipitate dissolved with Stirring. 24.55 The resulting aqueous/organic Solution was transferred to a 20.64 15.89 Separatory funnel in Several portions and the organic and 87.62 aqueous layerS Separated. The organic layers were com 60.75 bined, the diethyl ether removed by rotary evaporation and 45.31 the product placed under Vacuum. The resulting white Solid 38.59 36.43 was characterized by SFC: 98.9% propoxyphene; 99.6% 28.32 diclofenac; and Nuclear Magnetic Resonance (NMR) Spec 1431 troscopy. Resonances for the H and 'C NMR spectra 8.99 obtained in d-dimethylsulfoxide (DMSO) solution are listed in Tables 4a and 4b, respectively. EXAMPLE 8 TABLE 4a Observed resonances for the "H NMR spectrum from Example 7 obtained Preparation of rac-Ketamine Diclofenate from in d-DMSO solution. Sodium Diclofenac and rac-Ketamine Hydrochloride Resonance (ppm) Multiplicity* Number of Protons 0.086 Aqueous solutions of sodium diclofenac (0.6378 g, 7.62 S 2.005 mmol in 150 mL of water) and (+)-2-(2-chlorophe 7.36-7.50 nyl)-2-(methylamino)cyclohexanone (referred to herein as 7.38 d 7.27-7.34 rac-ketamine) hydrochloride (0.5427 g, 1.979 mmol in 50 7.15-7.23 mL of water) were combined into a 250 mL Erlenmeyer 7.04 . flask. A white precipitate formed and the Solution was Stirred for 15 minutes. The Solid material was separated by filtration US 2005/0203115 A1 Sep. 15, 2005 11 through a 0.45-lum polyvinylidene fluoride (PVDF) filter and the filter cake dissolved in methanol (25 mL). The methanol TABLE 5b-continued Solution was removed by evaporation under nitrogen and the resulting oily material transferred to a round bottom flask Observed bands for FT-Raman spectrum from Example 8. using a small amount of diethyl ether. The diethyl ether was removed by rotary evaporation forming a white Solid. The Band (cm) Intensity flask placed under Vacuum to obtain a white Solid product. The product was characterized by elemental analysis: 404 weak Expected: 60.74% C, 5.10% H, 5.25% N, Obtained: 59.88% wn C, 4.87% H, 5.14% N; DSC: T.: 40.3°C.; H and 'C NMR, 216 W. FTIR, and FT-Raman Spectroscopy (FT-Raman). Represen- 177 W. tative bands observed in the FTIR and FT-Raman spectra are Wea listed in the Tables 5a and 5b, respectively. Resonances for the H and 'C NMR spectra are listed in Tables 6a and 6b, respectively. 0088)

TABLE 5a TABLE 6a Observed bands for FTIR spectrum from Example 8. Observed resonances for the "H NMR spectrum from Example 8 obtained from d-DMSO solution. Band (cm) Intensity 2.942 Weak Resonance (ppm) Multiplicity* Number of Protons 724 moderate 578 moderate 7.6O did 1. 505 strong 7.52 d 2 452 very strong 7.26-7.39 3 375 Weak 717-7.22 d, t 2 304 moderate 7.06 t 1. 229 Weak 6.86 t 1. 196 Weak 6.29 did 1. 149 Weak 3.7O S 2 113 Weak 2.28-2.53 3 O88 Weak 1.96 S 3 O49 Weak 1.61-1.94 3 947 Weak 892 Weak *s - singlet, d - doublet, dd - doublet of doublets, m - multiplet, b - broad, 867 Weak t - triplet, q – quartet. 747 strong 715 moderate 0089) 0087 TABLE 6b Observed resonances for the 'C NMR spectrum from Example 8 obtained TABLE 5b from d-DMSO solution. Observed bands for FT-Raman spectrum from Example 8. Resonance (ppm) Band (cm) Intensity 2O4.55 3070 very strong 73.34 2987 moderate 42.65 2969 moderate 39.72 2869 Weak 37.12 1725 Weak 32.44 1603 strong 30.85 1587 strong 30.55 1577 very strong 29.99 1448 Weak 29.15 1277 Weak 28.43 1250 Weak 27.46 1234 moderate 26.76 1194 Weak 25.51 1159 Weak 23.98 1093 Weak 20.73 1070 moderate 15.94 1047 strong 68.63 891 Weak 38.29 837 Weak 37.94 717 Weak 37.85 653 Weak 29.33 605 Weak 25.01 517 Weak 20.43 443 moderate US 2005/0203115 A1 Sep. 15, 2005 12

EXAMPLE 9 TABLE 7b-continued Preparation of rac-Methadone Diclofenate from Sodium Diclofenac and rac-Methadone Observed bands for FT-Raman spectrum from Example 9. Hydrochloride 0090 Sodium diclofenac (0.6400 g, 2.012 mmol) was Band (cm) Intensity dissolved in water (150 mL) and placed in a 250 mL Erlenmeyer flask. A Solution of (+)-6-dimethylamino-4,4- 705 Weak diphenyl-3-heptanone (herein referred to as rac-methadone) 6O1 strong hydrochloride (0.6907g, 1.997 mmol) in water (50 mL) was 57.7 strong added to the diclofenate Solution. A white precipitate formed 451 Weak and the Solution was stirred for 15 minutes. After an attempt 274 Weak to remove the precipitate by filtration was unsuccessful, the aqueous Solution and precipitate were transferred to a sepa 248 Weak ratory funnel using a Small portion of diethyl ether to aid in 236 moderate the transfer. Additional diethyl ether was added to the 191 moderate Separatory funnel (250 mL) and any remaining precipitate 159 moderate was dissolved with Shaking. After Separation of the organic O93 Weak and aqueous layers, the aqueous Solution was washed with O71 Weak additional diethyl ether (2x250 mL) to extract any remaining O45 moderate product. The organic layers were combined and the Solvent removed by rotary evaporation and the product placed under O35 moderate reduced pressure overnight. The resulting white Solid was OO2 strong characterized by elemental analysis: Expected: 69.42% C, 838 Weak 6.33% H, 4.63% N; Obtained: 68.78% C, 6.36% H, 4.55% 766 Weak N; DSC: T: 31.4° C.; NMR, FTIR, and FT-Raman. Rep 718 Weak resentative bands observed in the FTIR and FT-Raman 619 Weak spectra are listed in the Tables 7a and 7b, respectively. Resonances for the and 'C NMR spectra are listed in 605 Weak Tables 8a and 8b, respectively. 547 Weak 532 Weak TABLE 7a 517 Weak 444 Weak Observed bands for FTIR spectrum from Example 9. 404 Weak Band (cm) Intensity 366 Weak 317 Weak 3061 Weak 3028 Weak 289 Weak 2969 Weak 238 Weak 2936 Weak 215 Weak 17O6 moderate 1587 moderate 1577 moderate 1560 Weak 1497 moderate 0092) 1451 very strong 1374 Weak TABLE 8a. 1305 Weak 1195 Weak 1150 Weak Observed resonances for the "H NMR spectrum from Example 9 obtained 1095 Weak from di-DMSO solution. 1046 Weak Resonance (ppm) Multiplicity* Number of Protons 934 Weak 867 Weak 7.88 bs 765 strong 7.5 d 2 747 strong 7.24-7.36 1O 703 very strong 7.14-7.18 d, t 2 7.03 t 6.83 t 6.28 did 0091) 3.64 S 2 2.9 did TABLE 7b 2.4 C 2.30 2 Observed bands for FT-Raman Spectrum from Example 9. 2.18 S 6 2O3 did Band (cm) Intensity O.73 t 3 O46 d 3 3.064 very strong 2969 moderate *s-singlet, d-doublet, dd-doublet of doublets, m-multiplet, b-broad, 2936 moderate t-triplet, q-quartet. US 2005/0203115 A1 Sep. 15, 2005 13

0093) (herein referred to as codeine) sulfate (1.4077g, 2.020 mmol in 60 mL of water) were combined into a 250 mL round TABLE 8b bottom flask. A white precipitate formed and the solution was stirred for 30 minutes. The contents of the 250 mL round Observed resonances for the 'C NMR spectrum from Example 9 obtained bottom flask were transferred to a separatory funnel using a from d-DMSO solution. small portion of diethyl ether to aid in the transfer. Diethyl Resonance (ppm) ether (90 mL) and chloroform (90 mL) were added to the Separatory funnel and any remaining precipitate was dis 209.34 73.93 Solved with Shaking. The organic layer was separated and 42.75 the Solvent removed by rotary evaporation. The resulting 42.52 white solid was dissolved in diethyl ether (100 mL) and the 41.98 Solvent again removed by rotary evaporation. The resulting 37.32 30.68 white solid was dried under reduced pressure overnight (30° 29.66 C.). The product was characterized by means of DSC: T at 29.60 43.2 C. degradation at 182 C.; and spectroscopically by 29.12 28.84 NMR, FTIR, and FT-Raman. Representative bands observed 28.2O in the FTIR and FT-Raman spectra are listed in Tables 9a 27.89 and 9b, respectively. Resonances for the H and 'C NMR 27.05 spectra are listed in Tables 10a and 10b, respectively. 26.91 26.58 25.10 TABLE 9a 25.02 20.57 Observed bands for FTIR Spectrum from Example 11. 15.89 64.32 Band (cm) Intensity 55.48 2936 Wea 41.42 31.53 2841 Wea 634 Wea 12.28 605 Wea 9.25 587 OC erate 57.7 OC erate 560 Wea 8 SO4 strong EXAMPLE 10 452 very strong 369 Wea 8 Purity Determination of Propoxyphene Diclofenate 303 Wea 8 by Supercritical Fluid Chromatography 285 OC erate 274 OC erate 0094. The purity of the propoxyphene diclofenate pre 192 Wea 18O Wea pared in the foregoing examples was determined by utilizing 159 Wea Supercritical fluid chromatography (“SFC) according to the 121 Wea following procedure. O90 Wea O71 Wea 0.095 SFC was performed with the Analytical SFC sys O50 Wea tem (Berger Instrumets, Newark, Del.), utilizing a 4.6x250 O24 Wea 973 Wea mm cyano column (Berger instruments) maintained at 40 942 Wea C. The mobile phase contained a 90:10 mixture of carbon 930 Wea dioxide: 2.5 mM ammonium acetate in methanol. The 919 Wea column outlet pressure was held at 120 bar at a flow rate of 872 Wea 836 Wea 3.0 mL/minute. Standards and Sample Solution were pre 749 very strong pared in methanol at about 0.5 mg/mL. Injection volume for 717 OC erate Sample and Standard preparations (USP diclofenac Sodium; 696 Wea 8 USP propoxyphene HCl) was 10 ul and run time was less 666 Wea 8 than 10 minutes. UV detection was performed at 208 nm. The chromatographic data peak areas were collected and analyzed using Millenium chromatography Software O097 (Waters Corporation, Milford, Mass.) to generate the 76 w/w assay values for the Samples. TABLE 9b

EXAMPLE 11 Observed bands for FT-Raman spectrum from Example 11. Band (cm) Intensity Preparation of 5R,6S,9R,13S,14R Codeine 3069 strong Diclofenate from Sodium Diclofenac and 2986 very strong 5R,6S,9R,13S,14R-Codeine Sulfate 2947 strong 2837 weak 0096 Aqueous solutions of sodium diclofenac (1.2729 g, 1635 weak 4.001 mmol in 100 mL of water) and 7,8-didehydro-4,5R 1603 strong epoxy-3-methoxy-9R,13S,14R,17-methylmorphinan-6S-ol US 2005/0203115 A1 Sep. 15, 2005 14

TABLE 9b-continued TABLE 10b-continued Observed bands for FT-Raman spectrum from Example 11. Observed resonances for the "C NMR spectrum from Example 11 obtained from di-DMSO solution. Band (cm) Intensity Resonance (ppm) 1578 strong 1451 Weak 130.76 128O Weak 129.79 1235 Weak 129.15 1195 Weak 127.78 1160 Weak 127.24 1092 Weak 126.73 1072 Weak 125.28 1046 moderate 124.59 837 Weak 120.67 715 Weak 118.47 667 Weak 115.92 628 Weak 113.37 532 Weak 91.77 443 Weak 79.16 366 Weak 66.35 312 Weak 58.04 263 Weak 56.O1 45.76 42.65 42.17 0098) 38.74 34.73 20.48 TABLE 10a Observed resonances for the "H NMR spectrum from Example 11 obtained from d-DMSO solution. 0100. An attempt to recrystallize the product was per formed. A portion of the Solid (9 mg) was dissolved in a test Resonance (ppm) Multiplicity* Number of Protons tube with several drops of acetone. Water was added until a 7.62 precipitate formed and the contents of the test tube trans 7.51 ferred to a separatory funnel containing diethyl ether (8 mL). 7.15-7.2O sS t : 7.05 The solid product was dissolved in the diethyl ether, and 6.85 then was extracted and the organic layer Separated and Set 6.63 aside to evaporate. Upon evaporation of the diethyl ether, the 4.48 6.28 resulting product was characterized by Single crystal X-ray 5.55 crystallography as codeine diclofenate monohydrate. An 5.25 ORTEP representation of the product is shown in FIG. 1. 4.69 d: Pertinent bond distances and angles corresponding to this 4.11 3.72 3 structure are listed below in Tables 11a and 11b, respec 3.67 tively. Representative bands observed in the FTIR spectrum 3.41 of the crystalline product are listed in Table 11c. 2.97 2.57-2.65 d d 2 240 3 TABLE 11a. 2.30-236 2O3 Selected Bond Distances from Example 11 crystalline product. 1.66 d d Bond Distance (A) *s-singlet, d-doublet, dd-doublet of doublets, m-multiplet, b-broad, Cl11-C11 .722(3) t-triplet, q-quartet. O1-C1 .243(3) N9-C10 .388(3) C1-C2 .538(3) 0099) C3-C4 .390(3) C4-C5 .394(5) TABLE 10b C6-C7 .374(4) C10-C15 .389(4) Observed resonances for the "C NMR spectrum from Example 11 C11-C12 .381 (4) obtained from da-DMSO solution. C13-C14 .384(4) O21-C21 .367(3) Resonance (ppm) O23-C22 .368(2) O25-C25 .416(3) 173.8O N32-C31 .490(3) 147.20 C21-C37 .385(3) 142.71 C22-C38 .371(3) 141.35 C24-C29 .542(3) 137.23 C26-C27 .323(3) 133.62 C28-C29 .539(2) US 2005/0203115 A1 Sep. 15, 2005 15

TABLE 11a-continued TABLE 11b-continued Selected Bond Distances from Example 11 crystalline product. Selected Bond Angles from Example 11 crystalline product. Bond Distance (A) Bond Angle Degree .509(2) O9.8(1) .512(3) 24.1(2) 511(3) 6.5(2) 398(3) 7.9(3) .746(2) 20.7(2) .260(3) 9.6(3) 408(3) 21.5(3) .509(4) 21.6(3) .403(4) 22.8(2) .372(6) 5.4(2) .393(4) 8.8(2) .411(3) 20.1(3) 375(5) 23.7(2) 376(4) 8.2(2) .414(3) 07.0(1) 471(2) 3.8(2) 486(3) 26.7(2) .513(2) 6.7(2) .393(2) 25.7(2) 531(3) 0.7(2) 501(3) 1.7(2) .513(3) 3.2(2) .543(3) 9.6(2) 536(2) O8.7(1) .543(3) 07.7(2) O5.4(1) .383(2) 00.5(1) .388(3) 6.1(2) 111.1(2) 2.4(2) 01.01 4.9(2) 8.5(2) 21.1(2) TABLE 11b 22.8(2) Selected Bond Angles from Example 11 crystalline product. 26.6(2) Bond Angle Degree 22.7(2) 0102) TABLE 11c Observed bands for FTIR spectrum from Example 11 crystalline product. Band (cm) Intensity 3282 OC Ca e, broad 3221 OC Ca e, broad 3072 OC Ca 3O38 OC Ca 3O13 OC Ca 2969 OC Ca 2945 OC Ca 2923 OC Ca 2834 Wea 8 2778 Wea 8 1631 OC Ca 16O2 OC Ca 1586 OC Ca 1575 OC Ca 1560 OC Ca 15O1 strong 1466 Ca 1448 strong 1369 Ca 1307 strong 1272 strong 1212 OC Ca 1190 OC Ca 1176 OC Ca US 2005/0203115 A1 Sep. 15, 2005 16

TABLE 11c-continued TABLE 12a-continued Observed bands for FTIR spectrum from Observed bands for FTIR spectrum from Example 12. Example 11 crystalline product. Band (cm) Intensity Band (cm) Intensity 1346 OCleate 1161. moderate 1323 OCleate 1151 moderate 1304 OCleate 1122 strong 1259 OCleate 1097 strong 1175 strong 1044 strong 1140 OCleate 1019 moderate 1081 OCleate 982 Weak 1027 OCleate 968 moderate 971 Weak 943 moderate 916 Weak 931 moderate 891 Weak 917 Weak 858 OCleate 883 Weak 807 OCleate 866 moderate 761 strong 840 moderate 726 OCleate 791 moderate 704 very strong 771 strong 666 OCleate 753 very strong 717 Weak 696 Weak 676 Weak 01.04] TABLE 12b EXAMPLE 12 Observed resonances for the "H NMR spectrum from Example 12 obtained from d-DMSO solution. Preparation of Propoxyphene Salicylate from Propoxyphene Hydrochloride and Sodium Salicylate Resonance (ppm) Multiplicity* Number of Protons 0103) d-Propoxyphene hydrochloride (1.5020 g, 4.00 7.70 mmol) in water (50 mL) was placed in a 250 mL breaker. 7.69-7.71 Sodium salicylate (0.6399 g, 4.00 mmol) in water (50 mL) 7.32-7.40 was added to the propoxyphene Solution forming a white 7.20-7.25 7.O2-7.04 Sd d precipitate. After mixing for 2 hours, the contents of the 6.66-6.72 beaker were transferred to a separatory funnel with the aid 3.82 of a small portion of diethyl ether. Additional diethyl ether 3.23 2.70 was added to the separatory funnel (100 mL) and any 2.57 remaining precipitate dissolved with Shaking. The aqueous 2.25-2.40 and organic layers were Separated and the aqueous layer was 1.05 washed with an additional portion of diethyl ether (100 mL) 0.97 to extract any remaining product. The organic and aqueous *s - singlet, d - doublet, dd - doublet of doublets, m - multiplet, b - broad, layers were separated again, the organic layers combined, t - triplet, q – quartet. washed with water (50 mL), and the solvent removed by rotary evaporation. The resulting oily material was placed under reduced preSSure to form a white Solid. After drying 01.05 to constant weight, the white Solid was characterized by elemental analysis: Expected: 72.93% C, 7.39% H, 2.98% TABLE 12c N; Obtained: 72.32% C, 7.38% H, 2.94% N; NMR, and Observed resonances for the ''C NMR spectrum from Example 12 FTIR. Representative bands are listed in Table 12a. Reso obtained from di-DMSO solution. nances for the H and 'C NMR are listed in Tables 12b and 12c, respectively. Resonance (ppm) 17269 TABLE 12a 172.16 162.17 Observed bands for FTIR Spectrum from Example 12. 138.91 136.O2 Band (cm) Intensity 132.28 130.02 2974 weak 128.OO 1736 moderate 127.77 1631 moderate 127.14 1594 moderate 126.61 1486 strong 126.2O 1456 strong 118.74 1380 strong 116.75 US 2005/0203115 A1 Sep. 15, 2005 17

TABLE 12c-continued TABLE 13a-continued Observed resonances for the "C NMR spectrum from Example 12 Observed bands for FTIR spectrum from Example 13. obtained from da-DMSO solution. Band (cm) Intensity Resonance (ppm) 964 moderate, broad 116.00 707 weak 86.64 59.36 43.36 38.05 01.07 35.42 28.05 TABLE 1.3b 1422 8.82 Observed resonances for the "H NMR spectrum from Example 13 obtained from d-DMSO solution.

EXAMPLE 13 Resonance (ppm) Multiplicity* Number of Protons 7.34-7.37 Preparation of d-Propoxyphene Ibuprofenate from 7.27-7.29 d-Propoxyphene Hydrochloride and rac-Ibuprofen 7.16-7.23 7.09 7.02 d 0106 A solution of (+)-2-(4-Isobutylphenyl)propionic 3.81 acid (herein referred to as rac-libuprofen) (0.3071 g, 1.49 3.62 mmol) in ethanol (20 mL) was placed in a 50 mL breaker. 2.63 2.41 Potassium hydroxide (0.083512 g, 1.49 mmol) in ethanol (5 223-2.28 mL) was added to the ibuprofen solution and stirred for 1 1.98 hour. The Solvent was removed by rotary evaporation and 18O 1.49 the product dissolved in water (100 mL). Propoxyphene 1.35 hydrochloride (0.5611 g, 1.49 mmol) in water (100 mL) was O.92-O.99 d placed in a 500 mL beaker. The aqueous ibuprofen Solution O.85 was added to the propoxyphene Solution forming a white precipitate. After mixing for 1.5 hours, the contents of the *s - singlet, d - doublet, dd - doublet of doublets, m - multiplet, b - broad, 500 mL beaker were transferred to a separatory funnel with t - triplet, q – quartet. the aid of a small portion of diethyl ether. Additional diethyl ether was added to the separatory funnel (125 mL) and any 0108) remaining precipitate was dissolved with Shaking. The aque ous and organic layers were separated and the aqueous layer TABLE 13c washed with additional portions of diethyl ether (2x125 mL) Observed resonances for the 'C NMR spectrum from Example 13 to extract any remaining product. The organic layers were obtained from d-DMSO solution. combined, washed with water (2x100 mL), and the solvent removed by rotary evaporation. The resulting oily material Resonance (ppm) was placed under reduced pressure. After drying to constant 175.48 weight, the oily material was characterized by elemental 172.57 139.47 analysis: Expected: 77.03% C, 8.68% H, 2.57 % N, 138.54 Obtained: 77.11% C, 8.63% H, 2.55% N; NMR, and FTIR. 136.65 Representative bands are listed in Table 13a. Resonances for 129.96 128.90 the H and 'C NMR spectra are listed in Tables 13b and 127.79 13c, respectively. 127.43 127.07 TABLE 1.3a 126.78 126.44 Observed bands for FTIR Spectrum from Example 13. 126.32 87.79 Band (cm) Intensity 61.04 45.72 2955 moderate, broad 44.33 2872 weak 44.21 1731 strong 38.7O 1601 weak 36.63 1499 weak 29.59 1459 moderate 28.37 1384 weak 22.16 1223 strong 18.53 1083 weak 14.35 1079 weak 9.04 1025 moderate US 2005/0203115 A1 Sep. 15, 2005

EXAMPLE 1.4 TABLE 14b-continued Preparation of 5R,6S,9R,13S,14R-Morphine Diclofenate from 5R,6S,9R,13S,14R-Morphine Observed resonances for the "H NMR spectrum from Example 14 obtained Sulfate Pentahydrate and Sodium Diclofenac from d-DMSO solution. 0109) An aqueous solution (20 mL) of 7,8-didehydro-4, 5R-epoxy-9R,13S, 14R,17-methylmorphinan-3,6S-diol Resonance (ppm) Multiplicity* Number of Protons (referred to herein as morphine) Sulfate pentahydrate 6.29 did 1. 5.55 d 1. (0.1508 g., 0.199 mmol) in water (20 mL) was placed in a 5.24 1. 100 mL round bottom flask. Sodium diclofenac (0.1227g, 4.67 did 1. 0.386 mmol) in water (20 mL) was added to the morphine 4.09 1. Solution forming a white precipitate. After mixing for 1 hour, 3.66 S 2 3.40 1. the precipitate was removed by filtration through a 0.45 um 2.93 d 1. polyvinylidene fluoride (PVDF) filter. The filtrate was trans 2.58-2.63 d, dd 2 ferred to a 50 mL round bottom flask with a small amount 240 S 3 of acetonitrile and the Solvent removed by rotary evapora 2.27-239 did, did 2 tion. The precipitate was dried under reduced pressure at 44 199-2O6 1. C. The white solid was characterized by FTIR with repre 1.65 did 1. sentative bands listed in Table 14a. Resonances for the "H *s - singlet, d - doublet, dd - doublet of doublets, m - multiplet, b - broad, and 'C NMR spectra are listed in Tables 14b and 14c, t - triplet, q – quartet. respectively 0111 TABLE 14a TABLE 1.4c Observed bands for FTIR Spectrum from Example 14. Observed resonances for the 'C NMR spectrum from Example 14 Band (cm) Intensity obtained from d-DMSO solution. 3O34 Weak Resonance (ppm) 2936 Weak 636 Weak 73.83 603 moderate 46.2O 577 moderate 42.7 557 moderate 38.56 503 strong 37.24 453 very strong 33.63 373 moderate 30.74 313 moderate 30.53 277 moderate 29.76 248 moderate 29.14 192 Weak 27.76 176 moderate 27.19 159 moderate 25.24 123 moderate 24.74 O70 Weak 24.68 O21 Weak 20.64 961 Weak 18.56 944 Weak 16.4 871 Weak 15.9 836 Weak 91.2 782 strong 66.23 747 strong 58.14 71.4 moderate 45.83 42.62 42.14 38.87 0110 34.69 20.45 TABLE 1.4b Observed resonances for the "H NMR spectrum from Example 14 obtained from d-DMSO solution. EXAMPLE 1.5 Preparation of 5R.9R,13R,14S-Oxycodone Resonance (ppm) Multiplicity* Number of Protons Diclofenate from 5R,9R,13R,14S-Oxycodone 7.68 S Hydrochloride and Sodium Diclofenac 7.51 7.15-7.2O t 0112 An aqueous solution (20 mL) of 4.5R-epoxy-14S 7.05 6.85 hydroxy-3-methoxy-9R,13R,17-methylmorphinan-6-one 6.46 (herein referred to as oxycodone) hydrochloride (0.3433 g, 6.36 0.976 mmol) in water (20 mL) was placed in a 100 mL round bottom flask. Sodium diclofenac (0.3125 g, 0.982 mmol) in US 2005/0203115 A1 Sep. 15, 2005 water (20 mL) was added to the oxycodone Solution forming a white precipitate. After mixing for 1 hour, the aqueous TABLE 1.5b-continued Solution and precipitate were transferred to a separatory funnel and diethyl ether was added (20 mL). Diethyl ether Observed resonances for the "H NMR spectrum from Example 15 obtained (20 mL) was also added to the 100 mL round bottom flask from d-DMSO solution. to dissolve any remaining precipitate. This Solution was added to the Separatory funnel, and any precipitate in the Resonance (ppm) Multiplicity* Number of Protons Separatory funnel was dissolved with Shaking. the organic 2.01-2.11 m, did 2 layer Separated and the Solvent removed by rotary evapora 1.75-18O 1. 1.45 1. tion. The resulting oily material was placed under reduced 1.31 did 1. pressure to form a white solid. The white solid was charac terized by elemental analysis: Expected: 62.85% C, 5.27% *s - singlet, d - doublet, dd - doublet of doublets, m - multiplet, b - broad, H, 4.58% N; Obtained: 62.44% C, 5.37% H, 4.41% N; t - triplet, q – quartet. NMR, and FTIR. The representative bands listed in Table 15a. Resonances for the H and 'C NMR spectra are listed 0114 in Tables 15b and 15c, respectively. TABLE 1.5c TABLE 1.5a Observed resonances for the ''C NMR spectrum from Example 15 Observed bands for FTIR Spectrum from Example 15. obtained from di-DMSO solution. Band (cm) Intensity Resonance (ppm) 208.35 2932 Weak 73.60 2836 Weak 44.41 1727 moderate 42.68 1605 Weak 42O3 1578 moderate 37.19 1505 strong 30.79 1451 very strong 29.86 1383 moderate 129.42 1279 strong 29.14 1231 Weak 27.28 1163 moderate 25.34 1148 moderate 25.30 1112 Weak 24.39 1071 Weak 20.66 1036 moderate 1933 986 Weak 15.90 944 moderate 14.79 906 Weak 89.71 881 Weak 69.82 848 Weak 63.8O 772 strong 56.32 746 strong 49.42 713 Weak 45.14 38.45 35.58 31.14 0113) 29.52 21.66 TABLE 1.5b. Observed resonances for the "H NMR spectrum from Example 15 obtained from d-DMSO solution. EXAMPLE 16

Resonance (ppm) Multiplicity* Number of Protons Preparation of d-Propoxyphene Acetylsalicylate 7.54 from d-Propoxyphene Hydrochloride and 7.51 Acetylsalicylic Acid 7.15-7.21 sS t 7.05 0115 Acetylsalicylic acid (0.5459 g, 3.03 mmol) in etha 6.85 nol (60 mL) was placed in a 100 mL beaker. Potassium 6.76 6.68 hydroxide (0.1694 g., 3.02 mmol) in ethanol (40 mL) was 6.29 d added to the acetylsalicylic acid Solution and Stirred for 1 4.84 hour. d-Propoxyphene hydrochloride (1.1278 g., 3.00 mmol) 3.79 in water (80 mL) was placed in a 250 mL beaker. The 3.68 ethanolic acetylsalicylate Solution was added to the pro 3.14 2.87-2.97 poxyphene solution. The solution was transferred to a 500 2.56 mL round bottom flask and the volume reduced to 60 mL by 2.37-2.45 S rotary evaporation. After reduction, a white precipitate was observed. The contents of the 500 mL round bottom flask US 2005/0203115 A1 Sep. 15, 2005 2O were transferred to a separatory funnel with the aid of a (0.05611 g, 1.00 mmol) dissolved in a minimal volume of Small amount of diethyl ether. Additional diethyl ether (90 ethanol (20 mL) and stirred for 1 hour. d-Propoxyphene mL) was added to the separatory funnel and any remaining hydrochloride (0.3759 g, 1.00 mmol) is dissolved in a precipitate was dissolved with Shaking. The aqueous and minimal volume of water and combined with the ethanolic organic layers were separated and the aqueous layer was etodolate Solution. The resulting Solution is stirred and the washed with additional diethyl ether (3x90 mL) to extract total Volume reduced to approximately 30 mL. The concen any remaining product. The organic layers were combined trated Solution is transferred to a separatory funnel and the and the Solvent removed by rotary evaporation forming a desired product extracted with diethyl ether (4x90 mL). The Viscous liquid. The Viscous liquid was characterized by organic layers are combined and the Solvent removed by elemental analysis: Expected: 70.94% C, 7.94% H, 2.51% rotary evaporation. The product is dried under Vacuum N: Obtained: 70.22% C, 7.16% H, 2.44% N (corrected for overnight. residual solvent content); TGA: 5.4% weight loss up to 160 C. and DSC: degradation >170° C. EXAMPLE 2.0 EXAMPLE 1.7 Preparation of d-Propoxyphene (S)-Ketoprofenate from d-Propoxyphene Hydrochloride and Preparation of d-Propoxyphene Indomethacinate (S)-Ketoprofen from d-Propoxyphene Hydrochloride and Indomethacin 0119) d-Propoxyphene (S)-ketoprofenate may be pre pared using the following Synthetic Scheme. A Solution of 0116 d-Propoxyphene Indomethacinate may be prepared (S)-2-(3-benzoylphenyl)propionic acid (herein referred to as using the following Synthetic Scheme. A Solution is prepared ketoprofen) (0.2543 g, 1.00 mmol) prepared in a minimal in a minimum volume of ethanol of 1-(4-chlorobenzoyl)-5- volume of ethanol is combined with potassium hydroxide methoxy-2-methyl-1H-indole-3-acetic acid (herein referred (0.05611 g, 1.00 mmol) dissolved in a minimal volume of to as indomethacin) (0.3578 g, 1.00 mmol) and combined ethanol and stirred for 1 hour. d-Propoxyphene hydrochlo with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved ride (0.3759 g, 1.00 mmol) is dissolved in a minimal volume in a minimal volume of ethanol and Stirred for one hour. of water and combined with the ethanolic etodolate Solution. d-Propoxyphene hydrochloride (0.3759 g, 1.00 mmol) is The resulting Solution is stirred and the total Volume reduced dissolved in a minimal volume of water and combined with to approximately 30 mL. The concentrated Solution is trans the ethanolic indomethacinate Solution. The resulting Solu ferred to a separatory funnel and the desired product tion is stirred and the total Volume reduced to approximately extracted with diethyl ether (4x90 mL). The organic layers 30 mL. The concentrated Solution is transferred to a sepa are combined and the Solvent removed by rotary evapora ratory funnel and the desired product extracted with diethyl tion. The product is dried under vacuum overnight. ether (4x90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried EXAMPLE 21 under Vacuum overnight. Preparation of d-Propoxyphene Sulindate from EXAMPLE 1.8 d-Propoxyphene Hydrochloride and Sulindac Preparation of d-Propoxyphene (S)-Naproxenate 0120 d-Propoxyphene Sulindate may be prepared using from d-Propoxyphene Hydrochloride and the following synthetic scheme. A solution of (Z)-5-Fluoro (S)-Naproxen Sodium 2-methyl-1-p-(methylsulfinyl)benzilidinelindenyl-3-acetic acid (herein referred to as Sulindac) (0.3564 g, 1.00 mmol) 0117 d-Propoxyphene naproxenate may be prepared is prepared in a minimal volume of ethanol and is combined using the following Synthetic Scheme. Aqueous Solutions of with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved (S)-6-methoxy-a-methyl-2-naphthaleneacetate (herein in a minimal volume of ethanol and stirred for 1 hour. referred to as naproxen) sodium (0.2522g, 1.00 mmol) and d-Propoxyphene hydrochloride (0.3759 g, 1.00 mmol) is d-propoxyphene hydrochloride (0.3759 g, 1.00 mmol) are dissolved in a minimal volume of water and combined with combined. The Solution is stirred for 60 minutes. The the ethanolic Sulindate Solution. The resulting Solution is resulting solution is extracted with diethyl ether (4x90 mL). stirred and the total volume reduced to approximately 30 The organic layers are combined and the Solvent removed by mL. The concentrated Solution is transferred to a separatory rotary evaporation. The product is dried under vacuum funnel and the desired product extracted with diethyl ether overnight. (4x90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under EXAMPLE 1.9 Vacuum overnight. Preparation of d-Propoxyphene Etodolate from EXAMPLE 22 d-Propoxyphene Hydrochloride and Etodolac Preparation of d-Propoxyphene Suprofenate from 0118 d-Propoxyphene etodolate may be prepared using d-Propoxyphene Hydrochloride and Suprofen the following synthetic scheme. A solution of 1,8-diethyl 1,3,4,9-tetrahydropyrano3,4-bindole-1-acetic acid (herein 0121 d-Propoxyphene Suprofenate may be prepared referred to as etodolac) (0.2874 g, 1.00 mmol) in a minimal using the following Synthetic Scheme. A Solution of (C)- volume of ethanol is combined with potassium hydroxide methyl-p-(2-thenoyl)phenylacetic acid (herein referred to as US 2005/0203115 A1 Sep. 15, 2005 suprofen) (0.2543 g, 1.00 mmol) is prepared in a minimal and the desired product extracted with diethyl ether (4x90 Volume of ethanol and is combined with potassium hydrox mL). The organic layers are combined and the Solvent ide (0.05611 g, 1.00 mmol) dissolved in a minimal volume removed by rotary evaporation. The product is dried under of ethanol and stirred for 1 hour. d-Propoxyphene hydro Vacuum overnight. chloride (0.3759 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic Supro EXAMPLE 26 fenate Solution. The resulting Solution is stirred and the total volume reduced to approximately 30 mL. The solution is Preparation of d-Propoxyphene Oxaprozinate from transferred to a separatory funnel and the desired product d-Propoxyphene Hydrochloride and Oxaprozin extracted with diethyl ether (4x90 mL). The organic layers 0.125 d-Propoxyphene oxaprozinate may be prepared are combined and the Solvent removed by rotary evapora using the following Synthetic Scheme. A Solution of 4,5- tion. The product is dried under vacuum overnight. diphenyl-2-oxazolepropionic acid (herein referred to as oxaprozin) (0.2933 g, 1.00 mmol) is prepared in a minimal EXAMPLE 23 Volume of ethanol and is combined with potassium hydrox Preparation of d-Propoxyphene (S)-Flurbiprofenate ide (0.05611 g, 1.00 mmol) dissolved in a minimal volume from d-Propoxyphene Hydrochloride and of ethanol and stirred for 1 hour. d-Propoxyphene hydro chloride (0.3759 g, 1.00 mmol) is dissolved in a minimal (S)-Flurbiprofen volume of water and combined with the ethanolic 0122 d-Propoxyphene (S)-flurbiprofenate may be pre Oxaprozinate Solution. The resulting Solution is Stirred and pared using the following Synthetic Scheme. A Solution of the total volume reduced to approximately 30 mL. The (S)-2-Fluoro-O-methyl-4-biphenylacetic acid (herein concentrated Solution is transferred to a separatory funnel referred to as flurbiprofen) (0.2443 g, 1.00 mmol) is pre and the desired product extracted with diethyl ether (4x90 pared in a minimal volume of ethanol and is combined with mL). The organic layers are combined and the Solvent potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a removed by rotary evaporation. The product is dried under minimal volume of ethanol and stirred for 1 hour. d-Pro Vacuum overnight. poxyphene hydrochloride (0.3759 g, 1.00 mmol) is dis Solved in a minimal volume of water and combined with the EXAMPLE 27 ethanolic flurbiprofenate solution. The solution is stirred and the total volume reduced to approximately 30 mL. The Preparation of d-Propoxyphene Difunisalate from Solution is transferred to a separatory funnel and the desired d-Propoxyphene Hydrochloride and Difusinal product extracted with diethyl ether (4x90 mL). The organic 0.126 d-Propoxyphene difunisalate may be prepared layers are combined and the Solvent removed by rotary using the following Synthetic Scheme. A Solution of 5-(2,4- evaporation. The product is dried under vacuum overnight. difluorophenyl)salicylic acid (herein referred to as difunisal) (0.2502 g, 1.00 mmol) is prepared in a minimal volume of EXAMPLE 24 ethanol and is combined with potassium hydroxide (0.05611 Preparation of d-Propoxyphene Tolimetinate from g, 1.00 mmol) dissolved in a minimal volume of ethanol and d-Propoxyphene Hydrochloride and Tolimetin stirred for 1 hour. d-Propoxyphene hydrochloride (0.3759 g, 1.00 mmol) is dissolved in a minimal volume of water and Sodium Dihydrate combined with the ethanolic difunisalate Solution. The 0123 d-Propoxyphene tolmetinate may be prepared resulting Solution is stirred and the total volume reduced to using the following Synthetic Scheme. Aqueous Solutions of approximately 30 mL. The concentrated Solution is trans 1-methyl-5-(p-toluoyl)pyrrole-2-acetic acid (herein referred ferred to a separatory funnel and the desired product to as tolmetin) sodium dihydrate (0.3153 g, 1.00 mmol) and extracted with diethyl ether (4x90 mL). The organic layers d-Propoxyphene hydrochloride (0.3759 g, 1.00 mmol) are are combined and the Solvent removed by rotary evapora combined into an Suitable flask and stirred for 60 minutes. tion. The product is dried under vacuum overnight. The resulting Solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4x90 EXAMPLE 28 mL). The organic layers are combined and the Solvent removed by rotary evaporation. The product is dried under Preparation of d-Propoxyphene Loxoprofenate from Vacuum overnight. d-Propoxyphene Hydrochloride and Loxoprofen 0127 d-Propoxyphene loxoprofenate may be prepared EXAMPLE 25 using the following Synthetic Scheme. A Solution of C-me Preparation of d-Propoxyphene Fenoprofenate from thyl-4-(2-oxocyclopentyl)methyl)phenylacetic acid d-Propoxyphene Hydrochloride and Fenoprofen (herein referred to as loxoprofen) (0.2463 g, 1.00 mmol) is prepared in a minimal volume of ethanol and is combined Calcium Trihydrate with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved 0.124 d-Propoxyphene fenoprofenate may be prepared in a minimal volume of ethanol and stirred for 1 hour. using the following Synthetic Scheme. Aqueous Solutions of d-Propoxyphene hydrochloride (0.3759 g, 1.00 mmol) is (E)-2-(3-phenoxyphenyl)propionic acid (herein referred to dissolved in a minimal volume of water and combined with as fenoprofen) calcium trihydrate (0.2884g, 0.50 mmol) and the ethanolic loxoprofenate Solution. The resulting Solution d-propoxyphene hydrochloride (0.3759 g, 1.00 mmol) are is stirred and the total volume reduced to approximately 30 combined into an Suitable flask and stirred for 60 minutes. mL. The concentrated Solution is transferred to a separatory The resulting Solution is transferred to a separatory funnel funnel and the desired product extracted with diethyl ether US 2005/0203115 A1 Sep. 15, 2005 22

(4x90 mL). The organic layers are combined and the solvent g, 1.00 mmol) dissolved in a minimal volume of ethanol is removed by rotary evaporation. The product is dried under combined with potassium hydroxide (0.05611 g, 1.00 mmol) Vacuum overnight. dissolved in a minimal volume of ethanol and stirred for 1 hour. rac-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is EXAMPLE 29 dissolved in a minimal volume of water and combined with the ethanolic indomethacinate Solution. The resulting Solu Preparation of rac-Ketamine Ibuprofenate from tion is stirred and the total Volume reduced to approximately rac-Ketamine Hydrochloride and Ibuprofen 30 mL. The concentrated Solution is transferred to a sepa 0128 rac-Ketamine ibuprofenate may be prepared using ratory funnel and the desired product extracted with diethyl the following synthetic scheme. Ibuprofen (0.2063 g, 1.00 ether (4x90 mL). The organic layers are combined and the mmol) dissolved in a minimal volume of ethanol is com solvent removed by rotary evaporation. The product is dried bined with potassium hydroxide (0.05611 g, 1.00 mmol) under Vacuum overnight. dissolved in a minimal volume of ethanol and stirred for 1 hour. rac-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is EXAMPLE 33 dissolved in a minimal volume of water and combined with the ethanolic ibuprofenate Solution. The resulting Solution is Preparation of rac-Ketamine NaproXenate from stirred and the total volume reduced to approximately 30 rac-Ketamine Hydrochloride and Naproxen Sodium mL. The concentrated Solution is transferred to a separatory 0132 rac-Ketamine naproxenate may be prepared using funnel and the desired product extracted with diethyl ether the following Synthetic Scheme. Aqueous Solutions of (4x90 mL). The organic layers are combined and the solvent naproxen sodium (0.2522 g, 1.00 mmol) and of rac-ket removed by rotary evaporation. The product is dried under amine hydrochloride (0.2742 g, 1.00 mmol) are combined Vacuum overnight. into a Suitable flask and Stirred for approximately 60 min EXAMPLE 30 utes. The resulting Solution is transferred to a separatory funnel and the desired product extracted with diethyl ether Preparation of rac-Ketamine Acetylsalicylate from (4x90 mL). The organic layers are combined and the solvent rac-Ketamine Hydrochloride and Acetylsalicylic removed by rotary evaporation. The product is dried under Acid Vacuum overnight. 0129 rac-Ketamine acetylsalicylate may be prepared EXAMPLE 34 using the following Synthetic Scheme. Acetylsalicylic acid (0.3003 g, 1.00 mmol) dissolved in a minimal volume of Preparation of rac-Ketamine Etodolate from ethanol is combined with potassium hydroxide (0.05611 g, rac-Ketamine Hydrochloride and Etodolac 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. rac-Ketamine hydrochloride (0.2742 g, 0.133 rac-Ketamine etodolate may be prepared using the 1.00 mmol) is dissolved in a minimal volume of water and following synthetic scheme. Etodolac (0.2874g, 1.00 mmol) combined with the ethanolic acetylsalicylate solution. The dissolved in a minimal volume of ethanol is combined with resulting Solution is stirred and the total volume reduced to potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a approximately 30 mL. The solution is transferred to a minimal volume of ethanol and stirred for 1 hour. rac Separatory funnel and the desired product extracted with Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved diethyl ether (4x90 mL). The organic layers are combined in a minimal volume of water and combined with the and the Solvent removed by rotary evaporation. The product ethanolic etodolate Solution. The resulting Solution is stirred is dried under vacuum overnight. and the total volume reduced to approximately 30 mL. The concentrated Solution is transferred to a separatory funnel EXAMPLE 31 and the desired product extracted with diethyl ether (4x90 mL). The organic layers are combined and the Solvent Preparation of rac-Ketamine Salicylate from removed by rotary evaporation. The product is dried under rac-Ketamine Hydrochloride and Sodium Salicylate Vacuum overnight. 0130 rac-Ketamine Salicylate may be prepared using the following Synthetic Scheme. Aqueous Solutions of Sodium EXAMPLE 35 salicylate (0.1601 g, 1.00 mmol) and of rac-ketamine hydro chloride (0.2742g, 1.00 mmol) are combined into a suitable Preparation of rac-Ketamine Sulindate from flask and stirred for 60 minutes. The resulting solution is rac-Ketamine Hydrochloride and Sulindac transferred to a separatory funnel and the desired product 0.134 rac-Ketamine Sulindate may be prepared using the extracted with diethyl ether (4x90 mL). The organic layers following synthetic scheme. Sulindac (0.3564g, 1.00 mmol) are combined and the Solvent removed by rotary evapora dissolved in a minimal volume of ethanol is combined with tion. The product is dried under vacuum overnight. potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. rac EXAMPLE 32 Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the Preparation of rac-Ketamine Indomethacinate from ethanolic Sulindate Solution. The resulting Solution is stirred rac-Ketamine Hydrochloride and Indomethacin and the total volume reduced to approximately 30 mL. The 0131 rac-Ketamine indomethacinate may be prepared concentrated Solution is transferred to a separatory funnel using the following synthetic scheme. Indomethacin (0.3578 and the desired product extracted with diethyl ether (4x90 US 2005/0203115 A1 Sep. 15, 2005 23 mL). The organic layers are combined and the Solvent EXAMPLE 39 removed by rotary evaporation. The product is dried under Vacuum overnight. Preparation of rac-Ketamine Tolimetinate from rac-Ketamine Hydrochloride and Tolimetin Sodium EXAMPLE 36 Dihydrate 0.138 rac-Ketamine tolmetinate may be prepared using Preparation of rac-Ketamine (S)-Ketoprofenate the following Synthetic Scheme. Aqueous Solutions of tol from rac-Ketamine Hydrochloride and metin sodium dihydrate (0.3153 g, 1.00 mmol) and of (S)-Ketoprofen rac-ketamine hydrochloride (0.2742 g, 1.00 mmol) are com 0135 rac-Ketamine (S)-ketoprofenate may be prepared bined into a Suitable flask and stirred for 60 minutes. The using the following Synthetic Scheme. (S)-Ketoprofen resulting Solution is transferred to a separatory funnel and (0.2543 g, 1.00 mmol) dissolved in a minimal volume of the desired product extracted with diethyl ether (4x90 mL). ethanol is combined with potassium hydroxide (0.05611 g, The organic layers are combined and the Solvent removed by 1.00 mmol) dissolved in a minimal volume of ethanol and rotary evaporation. The product is dried under Vacuum stirred for 1 hour. rac-Ketamine hydrochloride (0.2742 g, overnight. 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic ketoprofenate solution. The EXAMPLE 40 resulting Solution is stirred and the total volume reduced to Preparation of rac-Ketamine Fenoprofenate from approximately 30 mL. The concentrated Solution is trans rac-Ketamine Hydrochloride and Fenoprofen ferred to a separatory funnel and the desired product extracted with diethyl ether (4x90 mL). The organic layers Calcium Trihydrate are combined and the Solvent removed by rotary evapora 0.139 rac-Ketamine fenoprofenate may be prepared using tion. The product is dried under vacuum overnight. the following Synthetic Scheme. Aqueous Solutions of feno profen calcium trihydrate (0.2884 g., 0.50 mmol) and of EXAMPLE 37 rac-ketamine hydrochloride (0.2742 g, 1.00 mmol) are com bined into a Suitable flask and stirred for 60 minutes. The Preparation of rac-Ketamine Suprofenate from resulting Solution is transferred to a separatory funnel and rac-Ketamine Hydrochloride and Suprofen the desired product extracted with diethyl ether (4x90 mL). The organic layers are combined and the Solvent removed by 0.136 rac-Ketamine Suprofenate may be prepared using rotary evaporation. The product is dried under Vacuum the following synthetic scheme. Suprofen (0.2603 g, 1.00 overnight. mmol) dissolved in a minimal volume of ethanol is com bined with potassium hydroxide (0.05611 g, 1.00 mmol) EXAMPLE 41 dissolved in a minimal volume of ethanol and stirred for 1 hour. rac-Ketamine hydrochloride (0.2742 g, 1.00 mmol) Preparation of rac-Ketamine Oxaprozinate from dissolved in a minimal volume of water is combined with the rac-Ketamine Hydrochloride and Oxaprozin ethanolic Suprofenate Solution. The resulting Solution is 0140 rac-Ketamine oxaprozinate may be prepared using stirred and the total volume reduced to approximately 30 the following synthetic scheme. Oxaprozin (0.2933 g, 1.00 mL. The concentrated Solution is transferred to a separatory mmol) dissolved in a minimal volume of ethanol is com funnel and the desired product extracted with diethyl ether bined with potassium hydroxide (0.05611 g, 1.00 mmol) (4x90 mL). The organic layers are combined and the solvent dissolved in a minimal volume of ethanol and stirred for 1 removed by rotary evaporation. The product is dried under hour. rac-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is Vacuum overnight. dissolved in a minimal volume of water and combined with the ethanolic oxaprozinate Solution. The resulting Solution is EXAMPLE 38 stirred and the total volume reduced to approximately 30 mL. The concentrated Solution is transferred to a separatory Preparation of rac-Ketamine (S)-Flurbiprofenate funnel and the desired product extracted with diethyl ether from rac-Ketamine Hydrochloride and (4x90 mL). The organic layers are combined and the solvent (S)-Flurbiprofen removed by rotary evaporation. The product is dried under 0137 rac-Ketamine (S)-Flurbiprofenate may be prepared Vacuum overnight. using the following synthetic scheme. (S)-Flurbiprofen (0.2443 g, 1.00 mmol) dissolved in a minimal volume of EXAMPLE 42 ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and Preparation of rac-Ketamine Difunisalate from stirred for 1 hour. rac-Ketamine hydrochloride (0.2742 g, rac-Ketamine Hydrochloride and Difunisal 1.00 mmol) is dissolved in a minimal volume of water and 0141 rac-Ketamine difunisalate may be prepared using combined with the ethanolic flurbiprofenate solution. The the following synthetic scheme. Difunisal (0.2502 g, 1.00 resulting Solution is stirred and the total volume reduced to mmol) dissolved in a minimal volume of ethanol is com approximately 30 mL. The solution is transferred to a bined with potassium hydroxide (0.05611 g, 1.00 mmol) Separatory funnel and the desired product extracted with dissolved in a minimal volume of ethanol and stirred for 1 diethyl ether (4x90 mL). The organic layers are combined hour. rac-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is and the Solvent removed by rotary evaporation. The product dissolved in a minimal volume of water and combined with is dried under vacuum overnight. the ethanolic difunisalate Solution. The resulting Solution is US 2005/0203115 A1 Sep. 15, 2005 24 stirred and the total volume reduced to approximately 30 are combined and the Solvent removed by rotary evapora mL. The concentrated Solution is transferred to a separatory tion. The product is dried under vacuum overnight. funnel and the desired product extracted with diethyl ether (4x90 mL). The organic layers are combined and the solvent EXAMPLE 45 removed by rotary evaporation. The product is dried under Vacuum overnight. Preparation of (S)-Ketamine Salicylate from (S)-Ketamine Hydrochloride and Sodium Salicylate EXAMPLE 42 0145 (S)-Ketamine Salicylate may be prepared using the following Synthetic Scheme. Aqueous Solutions of Sodium Preparation of rac-Ketamine LOXOprofenate from salicylate (0.1601 g, 1.00 mmol) and of (S)-ketamine hydro rac-Ketamine Hydrochloride and Loxoprofen chloride (0.2742 g, 1.00 mmol) are combined into a suitable 0.142 rac-Ketamine loxoprofenate may be prepared using flask and stirred for 60 minutes. The resulting solution is the following synthetic scheme. Loxoprofen (0.2463 g, 1.00 transferred to a separatory funnel and the desired product mmol) dissolved in a minimal volume of ethanol is com extracted with diethyl ether (4x90 mL). The organic layers bined with potassium hydroxide (0.05611 g, 1.00 mmol) are combined and the Solvent removed by rotary evapora dissolved in a minimal volume of ethanol and stirred for 1 tion. The product is dried under vacuum overnight. hour. rac-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is EXAMPLE 46 dissolved in a minimal volume of water and combined with the ethanolic loxoprofenate Solution. The resulting Solution Preparation of (S)-Ketamine Indomethacinate from is stirred and the total volume reduced to approximately 30 (S)-Ketamine Hydrochloride and Indomethacin mL. The concentrated Solution is transferred to a separatory funnel and the desired product extracted with diethyl ether 0146 (S)-Ketamine indomethacinate may be prepared (4x90 mL). The organic layers are combined and the solvent using the following synthetic scheme. Indomethacin (0.3578 removed by rotary evaporation. The product is dried under g, 1.00 mmol) dissolved in a minimal volume of ethanol is Vacuum overnight. combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 EXAMPLE 43 hour. (S)-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with Preparation of (S)-Ketamine Ibuprofenate from the ethanolic indomethacinate Solution. The resulting Solu (S)-Ketamine Hydrochloride and Ibuprofen tion is stirred and the total Volume reduced to approximately 30 mL. The concentrated Solution is transferred to a sepa 0143 (S)-Ketamine ibuprofenate may be prepared using ratory funnel and the desired product extracted with diethyl the following synthetic scheme. Ibuprofen (0.2063 g, 1.00 ether (4x90 mL). The organic layers are combined and the mmol) dissolved in minimal volume of ethanol is combined solvent removed by rotary evaporation. The product is dried with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved under Vacuum overnight. in a minimal volume of ethanol and stirred for 1 hour. (S)-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dis EXAMPLE 47 Solved in a minimal volume of water and combined with the ethanolic ibuprofenate Solution. The resulting Solution is Preparation of (S)-Ketamine Naproxenate from stirred and the total volume reduced to approximately 30 (S)-Ketamine Hydrochloride and Naproxen Sodium mL. The concentrated Solution is transferred to a separatory 0147 (S)-Ketamine Naproxenate may be prepared using funnel and the desired product extracted with diethyl ether the following Synthetic Scheme. Aqueous Solutions of (4x90 mL). The organic layers are combined and the solvent naproxen sodium (0.2522 g, 1.00 mmol) and of (S)-ket removed by rotary evaporation. The product is dried under amine hydrochloride (0.2742 g, 1.00 mmol) are combined Vacuum overnight. into a suitable flask and stirred for 60 minutes. The resulting Solution is transferred to a separatory funnel and the desired EXAMPLE 44 product extracted with diethyl ether (4x90 mL). The organic layers are combined and the Solvent removed by rotary Preparation of (S)-Ketamine Acetylsalicylate from evaporation. The product is dried under vacuum overnight. (S)-Ketamine Hydrochloride and Acetylsalicylic Acid EXAMPLE 48 0144) (S)-Ketamine acetylsalicylate may be prepared using the following Synthetic Scheme. Acetylsalicylic acid Preparation of (S)-Ketamine Etodolate from (0.3003 g, 1.00 mmol) dissolved in a minimal volume of (S)-Ketamine Hydrochloride and Etodolac ethanol is combined with potassium hydroxide (0.05611 g, 0148 (S)-Ketamine etodolate may be prepared using the 1.00 mmol) dissolved in a minimal volume of ethanol and following synthetic scheme. Etodolac (0.2874g, 1.00 mmol) stirred for 1 hour. (S)-Ketamine hydrochloride (0.2742 g, dissolved in a minimal volume of ethanol is combined with 1.00 mmol) is dissolved in a minimal amount of water and potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a combined with the ethanolic acetylsalicylate solution. The minimal volume of ethanol and stirred for 1 hour. (S)- resulting Solution is stirred and the total volume reduced to Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved approximately 30 mL. The concentrated Solution is trans in a minimal volume of water and combined with the ferred to a separatory funnel and the desired product ethanolic etodolate Solution. The resulting Solution is stirred extracted with diethyl ether (4x90 mL). The organic layers and the total volume reduced to approximately 30 mL. The US 2005/0203115 A1 Sep. 15, 2005 25 concentrated Solution is transferred to a separatory funnel EXAMPLE 52 and the desired product extracted with diethyl ether (4x90 mL). The organic layers are combined and the Solvent Preparation of (S)-Ketamine (S)-Flurbiprofenate removed by rotary evaporation. The product is dried under from (S)-Ketamine Hydrochloride and (S)-Flurbi Vacuum overnight. profen 0152 (S)-Ketamine (S)-flurbiprofenate may be prepared EXAMPLE 49 using the following synthetic scheme. (S)-Flurbiprofen (0.2443 g, 1.00 mmol) dissolved in a minimal volume of Preparation of (S)-Ketamine Sulindate from ethanol is combined with potassium hydroxide (0.05611 g, (S)-Ketamine Hydrochloride and Sulindac 1.00 mmol) dissolved in a minimal volume of ethanol and 0149 (S)-Ketamine Sulindate may be prepared using the stirred for 1 hour. (S)-Ketamine hydrochloride (0.2742 g, following synthetic scheme. Sulindac (0.3564g, 1.00 mmol) 1.00 mmol) is dissolved in a minimal volume of water and dissolved in a minimal volume of ethanol is combined with combined with the ethanolic flurbiprofenate solution. The potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a resulting Solution is stirred and the total volume reduced to minimal volume of ethanol and stirred for 1 hour. (S)- approximately 30 mL. The concentrated Solution is trans Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved ferred to a separatory funnel and the desired product in a minimal volume of water and combined with the extracted with diethyl ether (4x90 mL). The organic layers ethanolic Sulindate Solution. The resulting Solution is stirred are combined and the Solvent removed by rotary evapora and the total volume reduced to approximately 30 mL. The tion. The product is dried under vacuum overnight. concentrated Solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4x90 EXAMPLE 53 mL). The organic layers are combined and the Solvent removed by rotary evaporation. The product is dried under Preparation of (S)-Ketamine Tolmetinate from Vacuum overnight. (S)-Ketamine Hydrochloride and Tolmetin Sodium Dihydrate EXAMPLE 50 0153 (S)-Ketamine tolmetinate may be prepared using the following Synthetic Scheme. Aqueous Solutions of tol Preparation of (S)-Ketamine (S)-Ketoprofenate metin sodium dihydrate (0.3153 g, 1.00 mmol) and of from (S)-Ketamine Hydrochloride and (S)-Ketopro (S)-ketamine hydrochloride (0.2742g, 1.00 mmol) are com fen bined into a Suitable flask and stirred for 60 minutes. The 0150 (S)-Ketamine (S)-ketoprofenate may be prepared resulting Solution is transferred to a separatory funnel and using the following Synthetic Scheme. (S)-Ketoprofen the desired product extracted with diethyl ether (4x90 mL). (0.2543 g, 1.00 mmol) dissolved in a minimal volume of The organic layers are combined and the Solvent removed by ethanol is combined with potassium hydroxide (0.05611 g, rotary evaporation. The product is dried under Vacuum 1.00 mmol) dissolved in a minimal volume of ethanol and overnight. stirred for 1 hour. (S)-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and EXAMPLE 54 combined with the ethanolic ketoprofenate solution. The resulting Solution is stirred and the total volume reduced to Preparation of (S)-Ketamine Fenoprofenate from approximately 30 mL. The concentrated Solution is trans (S)-Ketamine Hydrochloride and Fenoprofen ferred to a separatory funnel and the desired product Calcium Trihydrate extracted with diethyl ether (4x90 mL). The organic layers 0154 (S)-Ketamine Fenoprofenate may be prepared are combined and the Solvent removed by rotary evapora using the following Synthetic Scheme. Aqueous Solutions of tion. The product is dried under vacuum overnight. fenoprofen calcium trihydrate (0.2884g, 0.50 mmol) and of (S)-ketamine hydrochloride (0.2742 g, 1.00 mmol) are com EXAMPLE 51 bined into a Suitable flask and stirred for 60 minutes. The resulting Solution is transferred to a separatory funnel and Preparation of (S)-Ketamine Suprofenate from the desired product extracted with diethyl ether (4x90 mL). (S)-Ketamine Hydrochloride and Suprofen The organic layers are combined and the Solvent removed by 0151 (S)-Ketamine suprofenate may be prepared using rotary evaporation. The product is dried under Vacuum the following synthetic scheme. Suprofen (0.2603 g, 1.00 overnight. mmol) dissolved in a minimal volume of ethanol is com bined with potassium hydroxide (0.05611 g, 1.00 mmol) EXAMPLE 55 dissolved in a minimal volume of ethanol and stirred for 1 hour. (S)-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is Preparation of (S)-Ketamine Oxaprozinate from dissolved in a minimal volume of water and combined with (S)-Ketamine Hydrochloride and Oxaprozin the ethanolic Suprofenate Solution. The resulting Solution is 0155 (S)-Ketamine oxaprozinate may be prepared using Stirred and total Volume reduced to approximately 30 mL. the following synthetic scheme. Oxaprozin (0.2933 g, 1.00 The concentrated Solution is transferred to a separatory mmol) dissolved in a minimal volume of ethanol is com funnel and the desired product extracted with diethyl ether bined with potassium hydroxide (0.05611 g, 1.00 mmol) (4x90 mL). The organic layers are combined and the solvent dissolved in a minimal volume of ethanol and stirred for 1 removed by rotary evaporation. The product is dried under hour. (S)-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is Vacuum overnight. dissolved in a minimal volume of water and combined with US 2005/0203115 A1 Sep. 15, 2005 26 the ethanolic oxaprozinate Solution. The resulting Solution is 1.00 mmol) dissolved in a minimal volume of ethanol is stirred and the total volume reduced to approximately 30 combined with potassium hydroxide (0.05611 g, 1.00 mmol) mL. The concentrated Solution is transferred to a separatory dissolved in a minimal volume of ethanol and stirred for 1 funnel and the desired product extracted with diethyl ether hour. rac-Methadone hydrochloride (0.3459 g, 1.00 mmol) is (4x90 mL). The organic layers are combined and the solvent dissolved in a minimal volume of water and combined with removed by rotary evaporation. The product is dried under the ethanolic ibuprofenate Solution. The resulting Solution is Vacuum overnight. stirred and the total volume is reduced to approximately 30 mL. The concentrated Solution is transferred to a separatory EXAMPLE 56 funnel and the desired product extracted with diethyl ether Preparation of (S)-Ketamine Difunisalate from (4x90 mL). The organic layers are combined and the solvent (S)-Ketamine Hydrochloride and Difunisal removed by rotary evaporation. The product is dried under Vacuum overnight. 0156 (S)-Ketamine difunisalate may be prepared using the following synthetic scheme. Difunisal (0.2502 g, 1.00 EXAMPLE 58 mmol) dissolved in a minimal volume of ethanol is com bined with potassium hydroxide (0.05611 g, 1.00 mmol) Preparation of rac-Methadone Acetylsalicylate from dissolved in a minimal volume of ethanol and stirred for 1 rac-Methadone Hydrochloride and Acetylsalicylic hour. (S)-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is Acid dissolved in a minimal volume of water and combined with the ethanolic difunisalate Solution. The resulting Solution is 0160 rac-Methadone acetylsalicylate may be prepared stirred and the total volume reduced to approximately 30 using the following Synthetic Scheme. Acetylsalicylic acid mL. The concentrated Solution is transferred to a separatory (0.3003 g, 1.00 mmol) dissolved in a minimal volume of funnel and the desired product extracted with diethyl ether ethanol is combined with potassium hydroxide (0.05611 g, (4x90 mL). The organic layers are combined and the solvent 1.00 mmol) dissolved in a minimal volume of ethanol and removed by rotary evaporation. stirred for 1 hour. rac-Methadone hydrochloride (0.3459 g, 1.00 mmol) is dissolved in a minimal volume of water and EXAMPLE 55 combined with the ethanolic acetylsalicylate solution. The resulting Solution is stirred and the total volume reduced to Preparation of (S)-Ketamine Loxoprofenate from approximately 30 mL. The solution is transferred to a (S)-Ketamine Hydrochloride and Loxoprofen separatory funnel and the desired product extracted with 0157 (S)-Ketamine loxoprofenate may be prepared using diethyl ether (4x90 mL). The organic layers are combined the following synthetic scheme. Loxoprofen (0.2463 g, 1.00 and the Solvent removed by rotary evaporation. The product mmol) dissolved in a minimal volume of ethanol is com is dried under vacuum overnight. bined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 EXAMPLE 59 hour. (S)-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with Preparation of rac-Methadone Salicylate from the ethanolic loxoprofenate Solution. The resulting Solution rac-Methadone Hydrochloride and Sodium is stirred and the total volume reduced to approximately 30 Salicylate mL. The concentrated Solution is transferred to a separatory funnel and the desired product extracted with diethyl ether 0.161 rac-Methadone salicylate may be prepared using (4x90 mL). The organic layers are combined and the solvent the following Synthetic Scheme. Aqueous Solutions of removed by rotary evaporation. The product is dried under sodium salicylate (0.1601 g, 1.00 mmol) and of rac-metha Vacuum overnight. done hydrochloride (0.3459 g, 1.00 mmol) are combined into a suitable flask and stirred for 60 minutes. The resulting EXAMPLE 56 Solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4x90 mL). The organic Preparation of (S)-Ketamine Diclofenate from of layers are combined and the Solvent removed by rotary (S)-Ketamine Hydrochloride and Sodium evaporation. The product is dried under vacuum overnight. Diclofenac 0158 (S)-Ketamine diclofenate may be prepared using EXAMPLE 60 the following Synthetic Scheme. Aqueous Solutions of sodium diclofenac (0.3181 g, 1.00 mmol) and of (S)-ket Preparation of rac-Methadone Indomethacinate amine hydrochloride (0.2742 g, 1.00 mmol) are combined from rac-Methadone Hydrochloride and into a suitable flask and stirred for 60 minutes. The resulting Indomethacin Solution is transferred to a separatory funnel and the desired 0162 rac-Methadone indomethacinate may be prepared product extracted with diethyl ether (4x90 mL). The organic using the following synthetic scheme. Indomethacin (0.3578 layers are combined and the Solvent removed by rotary g, 1.00 mmol) dissolved in a minimal volume of ethanol is evaporation. The product is dried under vacuum overnight. combined with potassium hydroxide (0.05611 g, 1.00 mmol) EXAMPLE 57 dissolved in a minimal volume of ethanol and stirred for 1 hour. rac-Methadone hydrochloride (0.3459 g, 1.00 mmol) is Preparation of rac-Methadone Ibuprofenate from dissolved in a minimal volume of water and combined with rac-Methadone Hydrochloride and Ibuprofen the ethanolic indomethacinate Solution. The resulting Solu 0159 rac-Methadone ibuprofenate may be prepared tion is stirred and the total Volume reduced to approximately using the following synthetic scheme. Ibuprofen (0.2063 g, 30 mL. The concentrated Solution is transferred to a sepa US 2005/0203115 A1 Sep. 15, 2005 27 ratory funnel and the desired product extracted with diethyl (0.2543 g, 1.00 mmol) dissolved in a minimal volume of ether (4x90 mL). The organic layers are combined and the ethanol is combined with potassium hydroxide (0.05611 g, solvent removed by rotary evaporation. The product is dried 1.00 mmol) dissolved in a minimal volume of ethanol and under Vacuum overnight. stirred for 1 hour. rac-Methadone hydrochloride (0.3459 g, 1.00 mmol) is dissolved in a minimal volume of water and EXAMPLE 61 combined with the ethanolic ketoprofenate solution. The resulting Solution is stirred and the total volume reduced to Preparation of rac-Methadone Naproxenate from approximately 30 mL. The concentrated Solution is trans rac-Methadone Hydrochloride and Naproxen ferred to a separatory funnel and the desired product Sodium extracted with diethyl ether (4x90 mL). The organic layers 0163 rac-Methadone naproxenate may be prepared using are combined and the Solvent removed by rotary evapora the following Synthetic Scheme. Aqueous Solutions of tion. The product is dried under vacuum overnight. naproxen sodium (0.2522 g, 1.00 mmol) and of rac-metha done hydrochloride (0.3459 g, 1.00 mmol) are combined EXAMPLE 65 into a suitable flask and stirred for 60 minutes. The resulting Solution is transferred to a separatory funnel and the desired Preparation of rac-Methadone Suprofenate from product extracted with diethyl ether (4x90 mL). The organic rac-Methadone Hydrochloride and Suprofen layers are combined and the Solvent removed by rotary 0.167 rac-Methadone suprofenate may be prepared using evaporation. The product is dried under vacuum overnight. the following synthetic scheme. Suprofen (0.2603 g, 1.00 EXAMPLE 62 mmol) dissolved in a minimal volume of ethanol is com bined with potassium hydroxide (0.05611 g, 1.00 mmol) Preparation of rac-Methadone Etodolate from dissolved in a minimal volume of ethanol and stirred for 1 rac-Methadone Hydrochloride and Etodolac hour. rac-Methadone hydrochloride (0.3459 g, 1.00 mmol) is 0164 rac-Methadone etodolate may be prepared using dissolved in a minimal volume of water and combined with the following synthetic scheme. Etodolac (0.2874 g, 1.00 the ethanolic Suprofenate Solution. The resulting Solution is mmol) dissolved in a minimal volume of ethanol is com stirred and the total volume reduced to approximately 30 bined with potassium hydroxide (0.05611 g, 1.00 mmol) mL. The concentrated Solution is transferred to a separatory dissolved in a minimal volume of ethanol and stirred for 1 funnel and the desired product extracted with diethyl ether hour. rac-Methadone hydrochloride (0.3459 g, 1.00 mmol) is (4x90 mL). The organic layers are combined and the solvent dissolved in a minimal volume of water and combined with removed by rotary evaporation. The product is dried under the ethanolic etodolate Solution. The resulting Solution is Vacuum overnight. stirred and the total volume reduced to approximately 30 mL. The concentrated Solution is transferred to a separatory EXAMPLE 66 funnel and the desired product extracted with diethyl ether (4x90 mL). The organic layers are combined and the solvent Preparation of rac-Methadone (S)-Flurbiprofenate removed by rotary evaporation. The product is dried under from rac-Methadone Hydrochloride and Vacuum overnight. (S)-Flurbiprofen 0168 rac-Methadone (S)-flurbiprofen may be prepared EXAMPLE 63 using the following synthetic scheme. (S)-Flurbiprofen Preparation of rac-Methadone Sulindate from (0.2443 g, 1.00 mmol) dissolved in a minimal volume of rac-Methadone Hydrochloride and Sulindac ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and 0.165 rac-Methadone Sulindate may be prepared using stirred for 1 hour. rac-Methadone hydrochloride (0.3459 g, the following synthetic scheme. Sulindac (0.3564 g, 1.00 1.00 mmol) is dissolved in a minimal volume of water and mmol) dissolved in a minimal volume of ethanol is com combined with the ethanolic flurbiprofenate solution. The bined with potassium hydroxide (0.05611 g, 1.00 mmol) resulting Solution is stirred and the total volume reduced to dissolved in a minimal volume of ethanol and stirred for 1 approximately 30 mL. The concentrated Solution is trans hour. rac-Methadone hydrochloride (0.3459 g, 1.00 mmol) is ferred to a separatory funnel and the desired product dissolved in a minimal volume of water and combined with extracted with diethyl ether (4x90 mL). The organic layers the ethanolic Sulindate Solution. The resulting Solution is are combined and the Solvent removed by rotary evapora stirred and the total volume reduced to approximately 30 tion. The product is dried under vacuum overnight. mL. The concentrated Solution is transferred to a separatory funnel and the desired product extracted with diethyl ether EXAMPLE 67 (4x90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under Preparation of rac-Methadone Tolmetinate from Vacuum overnight. rac-Methadone Hydrochloride and Tolimetin EXAMPLE 64 Sodium Dihydrate 0169 rac-Methadone tolmetinate may be prepared using Preparation of rac-Methadone (S)-Ketoprofenate the following Synthetic Scheme. Aqueous Solutions of tol from rac-Methadone Hydrochloride and metin sodium dihydrate (0.3153 g, 1.00 mmol) and of (S)-Ketoprofen rac-Methadone hydrochloride (0.3459 g, 1.00 mmol) are 0166 rac-Methadone (S)-ketoprofen may be prepared combined into a Suitable flask and stirred for 60 minutes. using the following Synthetic Scheme. (S)-Ketoprofen The resulting Solution is transferred to a separatory funnel US 2005/0203115 A1 Sep. 15, 2005 28 and the desired product extracted with diethyl ether (4x90 g, 1.00 mmol) is dissolved in a minimal volume of ethanol mL). The organic layers are combined and the Solvent and combined with potassium hydroxide (0.05611 g, 1.00 removed by rotary evaporation. The product is dried under mmol) dissolved in a minimal volume of ethanol and stirred Vacuum overnight. for 1 hour. rac-Methadone hydrochloride (0.3459 g, 1.00 mmol) is dissolved in a minimal volume of water and EXAMPLE 68 combined with the ethanolic loxoprofenate solution. The resulting Solution is stirred and the total volume reduced to Preparation of rac-Methadone Fenoprofenate from approximately 30 mL. The concentrated Solution is trans rac-Methadone Hydrochloride and Fenoprofen ferred to a separatory funnel and the desired product Calcium Trihydrate extracted with diethyl ether (4x90 mL). The organic layers 0170 rac-Methadone fenoprofenate may be prepared are combined and the Solvent removed by rotary evapora using the following Synthetic Scheme. Aqueous Solutions of tion. The product is dried under vacuum overnight. fenoprofen calcium trihydrate (0.2884g, 0.50 mmol) and of rac-methadone hydrochloride (0.3459 g, 1.00 mmol) are EXAMPLE 72 combined into a Suitable flask and stirred for 60 minutes. The resulting Solution is transferred to a separatory funnel Preparation of 5R.9R,13S,14R-Hydrocodone and the desired product extracted with diethyl ether (4x90 Ibuprofenate from 5R,9R,13S,14R-Hydrocodone mL). The organic layers are combined and the Solvent Bitartrate Hemipentahydrate and Ibuprofen removed by rotary evaporation. The product is dried under 0174 5R.9R,13S,14R-Hydrocodone ibuprofenate may Vacuum overnight. be prepared using the following Synthetic Scheme. Ibuprofen EXAMPLE 69 (0.2063 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, Preparation of rac-Methadone Oxaprozinate from 1.00 mmol) dissolved in a minimal volume of ethanol and rac-Methadone Hydrochloride and Oxaprozin stirred for 1 hour. 5R,9R,13S, 14R-hydrocodone bitaritrate 0171 rac-Methadone oxaprozinate may be prepared hemipentahydrate (0.4549 g, 1.00 mmol) is dissolved in a using the following Synthetic Scheme. Oxaprozin (0.2933 g, minimal volume of water and combined with the ethanolic 1.00 mmol) dissolved in a minimal volume of ethanol is ibuprofenate Solution. The resulting Solution is stirred and combined with potassium hydroxide (0.05611 g, 1.00 mmol) the total volume reduced to approximately 30 mL. The dissolved in a minimal volume of ethanol and stirred for 1 concentrated Solution is transferred to a separatory funnel hour. rac-Methadone hydrochloride (0.3459 g, 1.00 mmol) is and the desired product extracted with diethyl ether (4x90 dissolved in a minimal volume of water and combined with mL). The organic layers are combined and the Solvent the ethanolic oxaprozinate Solution. The resulting Solution is removed by rotary evaporation. The product is dried under stirred and the total volume reduced to approximately 30 Vacuum overnight. mL. The concentrated Solution is transferred to a separatory funnel and the desired product extracted with diethyl ether EXAMPLE 73 (4x90 mL). The organic layers are combined and the solvent Preparation of 5R.9R,13S,14R-Hydrocodone removed by rotary evaporation. The product is dried under Acetylsalicylate from 5R,9R,13S,14R-Hydrocodone Vacuum overnight. Bitartrate Hemipentahydrate and Acetylsalicylic EXAMPLE 70 Acid 0175 5R,9R,13S, 14R-Hydrocodone acetylsalicylate Preparation of rac-Methadone Difunisalate from may be prepared using the following Synthetic Scheme. rac-Methadone Hydrochloride and Difunisal Acetylsalicylic acid (0.3003 g, 1.00 mmol) dissolved in a 0172 rac-Methadone difunisalate may be prepared using minimal volume of ethanol is combined with potassium the following synthetic scheme. Difunisal (0.2502 g, 1.00 hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal mmol) dissolved in a minimal volume of ethanol is com volume of ethanol and stirred for 1 hour. 5R,9R,13S,14R bined with potassium hydroxide (0.05611 g, 1.00 mmol) hydrocodone bitartrate hemipentahydrate (0.4945 g, 1.00 dissolved in a minimal volume of ethanol and stirred for 1 mmol) is dissolved in a minimal volume of water and hour. rac-Methadone hydrochloride (0.3459 g, 1.00 mmol) is combined with the ethanolic acetylsalicylate solution. The dissolved in a minimal volume of water and combined with resulting Solution is stirred and the total volume reduced to the ethanolic difunisalate Solution. The resulting Solution is approximately 30 mL. The solution is transferred to a stirred and the total volume reduced to approximately 30 Separatory funnel and the desired product extracted with mL. The concentrated Solution is transferred to a separatory diethyl ether (4x90 mL). The organic layers are combined funnel and the desired product extracted with diethyl ether and the Solvent removed by rotary evaporation. The product (4x90 mL). The organic layers are combined and the solvent is dried under vacuum overnight. removed by rotary evaporation. The product is dried under Vacuum overnight. EXAMPLE 74 EXAMPLE 71 Preparation of 5R.9R,13S,14R-Hydrocodone Preparation of rac-Methadone Loxoprofenate from Salicylate from 5R,9R,13S,14R-Hydrocodone rac-Methadone Hydrochloride and Loxoprofen Bitartrate Hemipentahydrate and Sodium Salicylate 0173 rac-Methadone loxoprofenate may be prepared 0176) 5R.9R,13S,14R-Hydrocodone salicylate may be using the following Synthetic Scheme. Loxoprofen (0.2463 prepared using the following Synthetic Scheme. Aqueous US 2005/0203115 A1 Sep. 15, 2005 29 solutions of sodium salicylate (0.1601 g, 1.00 mmol) and of desired product extracted with diethyl ether (4x90 mL). The 5R,9R,13S, 14R-hydrocodone bitaritrate hemipentahydrate organic layers are combined and the Solvent removed by (0.4945 g, 1.00 mmol) are combined into a suitable flaskand rotary evaporation. The product is dried under Vacuum stirred for 60 minutes. The resulting solution is transferred overnight. to a separatory funnel and the desired product extracted with diethyl ether (4x90 mL). The organic layers are combined EXAMPLE 78 and the Solvent removed by rotary evaporation. The product is dried under vacuum overnight. Preparation of 5R.9R,13S,14R-Hydrocodone Sulindate from 5R.9R,13S,14R-Hydrocodone EXAMPLE 75 Bitartrate Hemipentahydrate and Sulindac Preparation of 5R.9R,13S,14R-Hydrocodone 0180 R,9R,13S,14R-Hydrocodone sulindate may be pre pared using the following Synthetic Scheme. Sulindac Indomethacinate from (0.3564 g, 1.00 mmol) dissolved in a minimal volume of 5R,9R,13S,14R-Hydrocodone Bitartrate ethanol is combined with potassium hydroxide (0.05611 g, Hemipentahydrate and Indomethacin 1.00 mmol) dissolved in a minimal amount of ethanol and 0177 5R.9R,13S,14R-Hydrocodone indomethacinate stirred for 1 hour. 5R,9R,13S,14R-Hydrocodone bitaritrate may be prepared using the following Synthetic Scheme. hemipentahydrate (0.4945 g, 1.00 mmol) is dissolved in a Indomethacin (0.3578 g, 1.00 mmol) dissolved in a minimal minimal volume of water and combined with the ethanolic volume of ethanol is combined with potassium hydroxide Sulindate Solution. The resulting Solution is stirred and the (0.05611 g, 1.00 mmol) dissolved in a minimal volume of total Volume reduced to approximately 30 mL. The concen ethanol and stirred for 1 hour. 5R,9R,13S, 14R-Hydrocodone trated Solution is transferred to a separatory funnel and the bitaritrate hemipentahydrate (0.4945 g, 1.00 mmol) is dis desired product extracted with diethyl ether (4x90 mL). The Solved in a minimal volume of water and combined with the organic layers are combined and the Solvent removed by ethanolic indomethacinate Solution. The resulting Solution is rotary evaporation. The product is dried under Vacuum stirred and the total volume reduced to approximately 30 overnight. mL. The Solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4x90 mL). The EXAMPLE 79 organic layers are combined and the Solvent removed by rotary evaporation. The product is dried under vacuum Preparation of 5R.9R,13S, 14R-Hydrocodone overnight. (S)-Ketoprofenate from 5R,9R,13S,14R-Hydrocodone Bitartrate EXAMPLE 76 Hemipentahydrate and (S)-Ketoprofen Preparation of 5R.9R,13S,14R-Hydrocodone 0181 5R.9R,13S,14R-Hydrocodone (S)-ketoprofenate Naproxenate from 5R,9R,13S,14R-Hydrocodone may be prepared using the following Synthetic Scheme. Bitartrate Hemipentahydrate and Naproxen Sodium (S)-Ketoprofen (0.2543 g, 1.00 mmol) dissolved in a mini mal volume of ethanol is combined with potassium hydrox 0178) 5R.9R,13S,14R-Hydrocodone naproxenate may be ide (0.05611 g, 1.00 mmol) dissolved in a minimal volume prepared using the following Synthetic Scheme. Aqueous of ethanol and stirred for 1 hour. 5R,9R,13S, 14R-Hydroc solutions of naproxen sodium (0.2522g, 1.00 mmol) and of odone bit artrate hemipentahydrate (0.4945 g, 1.00 mmol) is 5R,9R,13S, 14R-hydrocodone bitaritrate hemipentahydrate dissolved in a minimal volume of water and combined with (0.4945 g, 1.00 mmol) are combined into a suitable flaskand the ethanolic ketoprofenate Solution. The resulting Solution stirred for 60 minutes. The resulting solution is transferred is stirred and the total volume reduced to approximately 30 to a separatory funnel and the desired product extracted with mL. The Solution is transferred to a separatory funnel and the diethyl ether (4x90 mL). The organic layers are combined desired product extracted with diethyl ether (4x90 mL). The and the Solvent removed by rotary evaporation. The product organic layers are combined and the Solvent removed by is dried under vacuum overnight. rotary evaporation. The product is dried under Vacuum overnight. EXAMPLE 77 EXAMPLE 8O Preparation of 5R.9R,13S,14R-Hydrocodone Etodolate from 5R,9R,13S,14R-Hydrocodone Preparation of 5R.9R,13S,14R-Hydrocodone Bitartrate Hemipentahydrate and Etodolac Suprofenate from 5R,9R,13S, 14R-Hydrocodone 0179 5R.9R,13S,14R-Hydrocodone etodolate may be Bitartrate Hemipentahydrate and Suprofen prepared using the following Synthetic Scheme. Etodolac 0182 5R.9R,13S,14R-Hydrocodone suprofenate may be (0.2874 g, 1.00 mmol) dissolved in a minimal volume of prepared using the following Synthetic Scheme. Suprofen ethanol is combined with potassium hydroxide (0.05611 g, (0.2603 g, 1.00 mmol) is dissolved in a minimal volume of 1.00 mmol) dissolved in a minimal volume of ethanol and ethanol and combined with potassium hydroxide (0.05611 g, stirred for 1 hour. 5R,9R,13S,14R-Hydrocodone bitaritrate 1.00 mmol) dissolved in a minimal volume of ethanol and hemipentahydrate (0.4945 g, 1.00 mmol) is dissolved in a stirred for 1 hour. 5R,9R,13S,14R-Hydrocodone bitaritrate minimal volume of water and combined with the ethanolic hemipentahydrate (0.4945 g, 1.00 mmol) is dissolved in a etodolate Solution. The resulting Solution is stirred and the minimal volume of water and combined with the ethanolic total Volume reduced to approximately 30 mL. The concen Suprofenate Solution. The resulting Solution is stirred and the trated Solution is transferred to a separatory funnel and the total Volume reduced to approximately 30 mL. The concen US 2005/0203115 A1 Sep. 15, 2005 30 trated Solution is transferred to a separatory funnel and the EXAMPLE 84 desired product extracted with diethyl ether (4x90 mL). The organic layers are combined and the Solvent removed by Preparation of 5R.9R,13S,14R-Hydrocodone rotary evaporation. The product is dried under vacuum Oxaprozinate from 5R,9R,13S,14R-Hydrocodone overnight. Bitartrate Hemipentahydrate and Oxaprozin 0186 5R,9R,13S, 14R-Hydrocodone oxaprozinate may EXAMPLE 81 be prepared using the following Synthetic Scheme. Oxaprozin (0.2933 g, 1.00 mmol) dissolved in a minimal Preparation of 5R.9R,13S,14R-Hydrocodone volume of ethanol is combined with potassium hydroxide (S)-Flurbiprofenate from (0.05611 g, 1.00 mmol) dissolved in a minimal volume of 5R,9R,13S,14R-Hydrocodone Bitartrate ethanol and stirred for 1 hour. 5R, 9R, 13S, 14R-Hydroc Hemipentahydrate and (S)-Flurbiprofen odone bit artrate hemipentahydrate (0.4945 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with 0183) 5R.9R,13S,14R-Hydrocodone (S)-flurbiprofenate the ethanolic oxaprozinate Solution. The resulting Solution is may be prepared using the following Synthetic Scheme. stirred and the total volume reduced to approximately 30 (S)-Flurbiprofen (0.2443 g, 1.00 mmol) dissolved in a mL. The concentrated Solution is transferred to a separatory minimal volume of ethanol is combined with potassium funnel and the desired product extracted with diethyl ether hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal (4x90 mL). The organic layers are combined and the solvent volume of ethanol and stirred for 1 hour. 5R,9R,13S,14R removed by rotary evaporation. The product is dried under Hydrocodone bit artrate hemipentahydrate (0.4945 g, 1.00 Vacuum overnight. mmol) is dissolved in a minimal volume of water and combined with the ethanolic flurbiprofenate solution. The EXAMPLE 85 resulting Solution is stirred and the total volume reduced to approximately 30 mL. The concentrated Solution is trans Preparation of 5R.9R,13S,14R-Hydrocodone ferred to a separatory funnel and the desired product Difunisalate from 5R,9R,13S, 14R-Hydrocodone extracted with diethyl ether (4x90 mL). The organic layers Bitartrate Hemipentahydrate and Difunisal are combined and the Solvent removed by rotary evapora tion. The product is dried under vacuum overnight. 0187 5R.9R,13S,14R-Hydrocodone difunisalate may be prepared using the following Synthetic Scheme. Difunisal EXAMPLE 82 (0.2502 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, Preparation of 5R.9R,13S,14R-Hydrocodone 1.00 mmol) dissolved in a minimal volume of ethanol and Tolmetinate from 5R.9R,13S,14R-Hydrocodone stirred for 1 hour. 5R,9R,13S,14R-Hydrocodone bitaritrate Bitartrate Hemipentahydrate and Tolmetin Sodium hemipentahydrate (0.4945 g, 1.00 mmol) is dissolved in a Dihydrate minimal volume of water and combined with the ethanolic difunisalate Solution. The resulting Solution is stirred and the 018.4 5R.9R,13S,14R-Hydrocodone tolmetinate may be total Volume reduced to approximately 30 mL. The concen prepared using the following Synthetic Scheme. Aqueous trated Solution is transferred to a separatory funnel and the solutions of tolmetin sodium dihydrate (0.3153 g, 1.00 desired product extracted with diethyl ether (4x90 mL). The mmol) and of 5R.9R,13S,14R-Hydrocodone bitartrate hemi organic layers are combined and the Solvent removed by pentahydrate (0.4945 g, 1.00 mmol) are combined into a rotary evaporation. The product is dried under Vacuum suitable flask and stirred for 60 minutes The resulting overnight. Solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4x90 mL). The organic EXAMPLE 86 layers are combined and the Solvent removed by rotary evaporation. The product is dried under vacuum overnight. Preparation of 5R.9R,13S,14R-Hydrocodone Loxoprofenate from 5R,9R,13S, 14R-Hydrocodone EXAMPLE 83 Bitartrate Hemipentahydrate and Loxoprofen Preparation of 5R.9R,13S,14R-Hydrocodone 0188 5R.9R,13S,14R-Hydrocodone loxoprofenate may Fenoprofenate from 5R,9R,13S, 14R-Hydrocodone be prepared using the following Synthetic Scheme. LOXO Bitartrate Hemipentahydrate and Fenoprofen profen (0.2463 g, 1.00 mmol) dissolved in a minimal volume Calcium Trihydrate of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and 0185 5R.9R,13S,14R-Hydrocodone fenoprofenate may stirred for 1 hour. 5R,9R,13S,14R-Hydrocodone bitaritrate be prepared using the following Synthetic Scheme. Aqueous hemipentahydrate (0.4945 g, 1.00 mmol) is dissolved in a solutions of fenoprofen calcium trihydrate (0.2884 g., 0.50 minimal volume of water and combined with the ethanolic mmol) and of 5R.9R,13S,14R-hydrocodone bitartrate hemi loxoprofenate Solution. The resulting Solution is Stirred and pentahydrate (0.4945 g, 1.00 mmol) are combined into a the total volume reduced to approximately 30 mL. The suitable flask and stirred for 60 minutes. The resulting concentrated Solution is transferred to a separatory funnel Solution is transferred to a separatory funnel and the desired and the desired product extracted with diethyl ether (4x90 product extracted with diethyl ether (4x90 mL). The organic mL). The organic layers are combined and the Solvent layers are combined and the Solvent removed by rotary removed by rotary evaporation. The product is dried under evaporation. The product is dried under vacuum overnight. Vacuum overnight. US 2005/0203115 A1 Sep. 15, 2005 31

EXAMPLE 87 minimal volume of ethanol and combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal Preparation of 5R,6S,9R,13S,14R-Codeine volume of ethanol and stirred for 1 hour. Codeine Sulfate Ibuprofenate from 5R,6S,9R,13S,14R-Codeine (0.3484g, 0.50 mmol) is dissolved in a minimal volume of Sulfate and Ibuprofen water and combined with the ethanolic indomethacinate 0189 5R,6S,9R,13S,14R-Codeine ibuprofenate may be Solution. The resulting Solution is stirred and the total prepared using the following Synthetic Scheme. Ibuprofen Volume reduced to approximately 30 mL. The concentrated (0.2063 g, 1.00 mmol) dissolved in a minimal volume of Solution is transferred to a separatory funnel and the desired ethanol and combined with potassium hydroxide (0.05611 g, product extracted with diethyl ether (4x90 mL). The organic 1.00 mmol) dissolved in a minimal volume of ethanol and layers are combined and the Solvent removed by rotary stirred for 1 hour. Codeine sulfate (0.3484g, 0.50 mmol) is evaporation. The product is dried under vacuum overnight. dissolved in a minimal volume of water and combined with the ethanolic ibuprofenate Solution. The resulting Solution is EXAMPLE 91 stirred and the total volume reduced to approximately 30 mL. The concentrated Solution is transferred to a separatory Preparation of 5R,6S,9R,13S,14R-Codeine funnel and the desired product extracted with diethyl ether Naproxenate from 5R,6S,9R,13S,14R-Codeine (4x90 mL). The organic layers are combined and the solvent Sulfate and Naproxen Sodium removed by rotary evaporation. The product is dried under 0193 5R,6S,9R,13S,14R-Codeine naproxenate may be Vacuum overnight. prepared using the following Synthetic Scheme. Aqueous solutions of naproxen sodium (0.2522g, 1.00 mmol) and of EXAMPLE 88 codeine sulfate (0.3484 g., 0.50 mmol) are combined into a suitable flask and stirred for 60 minutes. The resulting Preparation of 5R,6S,9R,13S,14R-Codeine Solution is transferred to a separatory funnel and the desired Acetylsalicylate from 5R,6S,9R,13S,14R-Codeine product extracted with diethyl ether (4x90 mL). The organic Sulfate and Acetylsalicylic Acid layers are combined and the Solvent removed by rotary 0190 5R,6S,9R,13S,14R-Codeine acetylsalicylate may evaporation. The product is dried under vacuum overnight. be prepared using the following Synthetic Scheme. Acetyl salicylic acid (0.3003 g, 1.00 mmol) is dissolved in a EXAMPLE 92 minimal volume of ethanol and combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal Preparation of 5R,6S,9R,13S,14R-Codeine volume of ethanol and stirred for 1 hour. Codeine Sulfate Etodolate from 5R,6S,9R,13S, 14R-Codeine Sulfate (0.3484g, 0.50 mmol) is dissolved in a minimal volume of and Etodolac water and combined with the ethanolic acetylsalicylate 0194 5R,6S,9R,13S,14R-Codeine etodolate may be pre Solution. The resulting Solution is stirred and the total pared using the following Synthetic Scheme. Etodolac Volume reduced to approximately 30 mL. The concentrated (0.2874 g, 1.00 mmol) dissolved in a minimal volume of Solution is transferred to a separatory funnel and the desired ethanol is combined with potassium hydroxide (0.05611 g, product extracted with diethyl ether (4x90 mL). The organic 1.00 mmol) dissolved in a minimal volume of ethanol and layers are combined and the Solvent removed by rotary stirred for 1 hour. Codeine sulfate (0.3484g, 0.50 mmol) is evaporation. The product is dried under vacuum overnight. dissolved in a minimal volume of water and combined with the ethanolic etodolate Solution. The resulting Solution is EXAMPLE 89 stirred and the total volume reduced to approximately 30 mL. The concentrated Solution is transferred to a separatory Preparation of 5R,6S,9R,13S,14R-Codeine funnel and the desired product extracted with diethyl ether Salicylate from 5R,6S,9R,13S,14R-Codeine Sulfate (4x90 mL). The organic layers are combined and the solvent and Sodium Salicylate removed by rotary evaporation. The product is dried under 0191 5R,6S,9R,13S,14R-Codeine salicylate may be pre Vacuum overnight. pared using the following Synthetic Scheme. Aqueous Solu tions of sodium salicylate (0.1601 g, 1.00 mmol) and of EXAMPLE 93 codeine sulfate (0.3484 g., 0.50 mmol) are combined into a suitable flask and stirred for 60 minutes. The resulting Preparation of 5R,6S,9R,13S,14R-Codeine Solution is transferred to a separatory funnel and the desired Sulindate from 5R,6S,9R,13S, 14R-Codeine Sulfate product extracted with diethyl ether (4x90 mL). The organic and Sulindac layers are combined and the Solvent removed by rotary 0195 5R,6S,9R,13S,14R-Codeine sulindate may be pre evaporation. The product is dried under vacuum overnight. pared using the following Synthetic Scheme. Sulindac (0.3564 g, 1.00 mmol) dissolved in a minimal volume of EXAMPLE 90 ethanol is combined with potassium hydroxide (0.05611 g, Preparation of 5R,6S,9R,13S,14R-Codeine 1.00 mmol) dissolved in a minimal volume of ethanol and Indomethacinate from 5R,6S,9R,13S,14R-Codeine stirred for 1 hour. Codeine sulfate (0.3484g, 0.50 mmol) is Sulfate and Indomethacin dissolved in a minimal volume of water and combined with the ethanolic Sulindate Solution. The resulting Solution is 0192 5R,6S,9R,13S,14R-Codeine indomethacinate may stirred and the total volume reduced to approximately 30 be prepared using the following Synthetic Scheme. mL. The concentrated Solution is transferred to a separatory Indomethacin (0.3578 g, 1.00 mmol) is dissolved in a funnel and the desired product extracted with diethyl ether US 2005/0203115 A1 Sep. 15, 2005 32

(4x90 mL). The organic layers are combined and the solvent are combined and the Solvent removed by rotary evapora removed by rotary evaporation. The product is dried under tion. The product is dried under vacuum overnight. Vacuum overnight. EXAMPLE 97 EXAMPLE 94 Preparation of 5R,6S,9R,13S,14R-Codeine Preparation of 5R,6S,9R,13S,14R-Codeine Tolimetinate from 5R,6S,9R,13S, 14R-Codeine (S)-Ketoprofenate from 5R,6S,9R,13S, 14R-Codeine Sulfate and Tolimetin Sodium Dihydrate Sulfate and (S)-Ketoprofen 0199 5R,6S,9R,13S,14R-Codeine tolmetinate may be 0196) 5R,6S,9R,13S,14R-Codeine (S)-ketoprofenate prepared using the following Synthetic Scheme. Aqueous may be prepared using the following Synthetic Scheme. solutions of tolmetin sodium dihydrate (0.3153 g, 1.00 (S)-Ketoprofen (0.2543 g, 1.00 mmol) dissolved in a mini mmol) and of codeine sulfate (0.3484 g, 0.50 mmol) are mal volume of ethanol and combined with potassium combined into a Suitable flask and stirred for 60 minutes. hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal The resulting Solution is transferred to a separatory funnel volume of ethanol and stirred for 1 hour. Codeine Sulfate and the desired product extracted with diethyl ether (4x90 (0.3484g, 0.50 mmol) is dissolved in a minimal volume of mL). The organic layers are combined and the Solvent water and combined with the ethanolic ketoprofenate Solu removed by rotary evaporation. The product is dried under tion. The resulting Solution is stirred and the total volume Vacuum overnight. reduced to approximately 30 mL. The concentrated Solution EXAMPLE 98 is transferred to a separatory funnel and the desired product extracted with diethyl ether (4x90 mL). The organic layers Preparation of 5R,6S,9R,13S,14R-Codeine are combined and the Solvent removed by rotary evapora Fenoprofenate from 5R,6S,9R,13S,14R-Codeine tion. The product is dried under vacuum overnight. Sulfate and Fenoprofen Calcium Trihydrate EXAMPLE 95 0200 5R,6S,9R,13S,14R-Codeine fenoprofenate may be prepared using the following Synthetic Scheme. Aqueous Preparation of 5R,6S,9R,13S,14R-Codeine solutions of fenoprofen calcium trihydrate (0.2884 g., 0.50 Suprofenate from 5R,6S,9R,13S,14R-Codeine mmol) and of codeine sulfate (0.3484 g, 0.50 mmol) are Sulfate and Suprofen combined into a suitable flask and stirred for 60 minutes. The resulting Solution is transferred to a separatory funnel 0197) 5R,6S,9R,13S,14R-Codeine suprofenate may be and the desired product extracted with diethyl ether (4x90 prepared using the following Synthetic Scheme. Suprofen mL). The organic layers are combined and the Solvent (0.2603 g, 1.00 mmol) dissolved in a minimal volume of removed by rotary evaporation. The product is dried under ethanol is combined with potassium hydroxide (0.05611 g, Vacuum overnight. 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. Codeine sulfate (0.3484g, 0.50 mmol) is EXAMPLE 99 dissolved in a minimal volume of water and combined with the ethanolic Suprofenate Solution. The resulting Solution is Preparation of 5R,6S,9R,13S,14R-Codeine stirred and the total volume reduced to approximately 30 Oxaprozinate from 5R,6S,9R,13S,14R-Codeine mL. The condensed Solution is transferred to a separatory Sulfate and Oxaprozin funnel and the desired product extracted with diethyl ether 0201 5R,6S,9R,13S,14R-Codeine oxaprozinate may be (4x90 mL). The organic layers are combined and the solvent prepared using the following Synthetic Scheme. Oxaprozin removed by rotary evaporation. The product is dried under (0.2933 g, 1.00 mmol) dissolved in a minimal volume of Vacuum overnight. ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and EXAMPLE 96 stirred for 1 hour. Codeine sulfate (0.3484g, 0.50 mmol) is dissolved in a minimal volume of water and combined with Preparation of 5R,6S,9R,13S,14R-Codeine the ethanolic oxaprozinate Solution. The resulting Solution is (S)-Flurbiprofenate from stirred and the total volume reduced to approximately 30 5R,6S,9R,13S,14R-Codeine Sulfate and mL. The concentrated Solution is transferred to a separatory (S)-Flurbiprofen funnel and the desired product extracted with diethyl ether 0198 5R,6S,9R,13S,14R-Codeine (S)-flurbiprofenate (4x90 mL). The organic layers are combined and the solvent may be prepared using the following Synthetic Scheme. removed by rotary evaporation. The product is dried under (S)-Flurbiprofen (0.2443 g, 1.00 mmol) dissolved in a Vacuum overnight. minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal EXAMPLE 100 volume of ethanol and stirred for 1 hour. Codeine Sulfate Preparation of 5R,6S,9R,13S,14R-Codeine (0.3484g, 0.50 mmol) is dissolved in a minimal volume of Difunisalate from 5R,6S,9R,13S, 14R-Codeine water and combined with the ethanolic flurbiprofenate solu Sulfate and Difunisal tion. The resulting Solution is stirred and the total volume reduced to approximately 30 mL. The concentrated Solution 0202) 5R,6S,9R,13S,14R-Codeine difunisalate may be is transferred to a separatory funnel and the desired product prepared using the following Synthetic Scheme. Difunisal extracted with diethyl ether (4x90 mL). The organic layers (0.2502 g, 1.00 mmol) dissolved in a minimal volume of US 2005/0203115 A1 Sep. 15, 2005 33 ethanol is combined with potassium hydroxide (0.05611 g, drate (0.3794 g., 0.50 mmol) is dissolved in a minimal 1.00 mmol) dissolved in a minimal volume of ethanol and volume of water and combined with the ethanolic acetyl stirred for 1 hour. Codeine sulfate (0.3484g, 0.50 mmol) is Salicylate Solution. The resulting Solution is stirred and the dissolved in a minimal volume of water and combined with total Volume reduced to approximately 30 mL. The concen the ethanolic difunisalate Solution. The resulting Solution is trated Solution is transferred to a separatory funnel and the stirred and the total volume reduced to approximately 30 desired product extracted with diethyl ether (4x90 mL). The mL. The concentrated Solution is transferred to a separatory organic layers are combined and the Solvent removed by funnel and the desired product extracted with diethyl ether rotary evaporation. The product is dried under Vacuum (4x90 mL). The organic layers are combined and the solvent overnight. removed by rotary evaporation. The product is dried under Vacuum overnight. EXAMPLE 104 EXAMPLE 101 Preparation of 5R,6S,9R,13S,14R-Morphine Preparation of 5R,6S,9R,13S,14R-Codeine Salicylate from 5R,6S,9R,13S,14R-Morphine Loxoprofenate from 5R,6S,9R,13S, 14R-Codeine Sulfate Pentahydrate and Sodium Salicylate Sulfate and Loxoprofen 0206 5R,6S,9R,13S,14R-Morphine salicylate may be 0203 5R,6S,9R,13S,14R-Codeine loxoprofenate may be prepared using the following Synthetic Scheme. Aqueous prepared using the following Synthetic Scheme. LOXOprofen solutions of sodium salicylate (0.1601 g, 1.00 mmol) and of (0.2463 g, 1.00 mmol) dissolved in a minimal volume of morphine sulfate pentahydrate (0.3794 g., 0.50 mmol) are ethanol is combined with potassium hydroxide (0.05611 g, combined into a Suitable flask and stirred for 60 minutes. 1.00 mmol) dissolved in a minimal volume of ethanol and The resulting Solution is transferred to a separatory funnel stirred for 1 hour. Codeine sulfate (0.3484g, 0.50 mmol) is and the desired product extracted with diethyl ether (4x90 dissolved in a minimal volume of water and combined with mL). The organic layers are combined and the Solvent the ethanolic loxoprofenate Solution. The resulting Solution removed by rotary evaporation. The product is dried under is stirred and the total volume reduced to approximately 30 Vacuum overnight. mL. The concentrated Solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4x90 mL). The organic layers are combined and the solvent EXAMPLE 105 removed by rotary evaporation. The product is dried under Preparation of 5R,6S,9R,13S,14R-Morphine Vacuum overnight. Indomethacinate from 5R,6S,9R,13S, 14R-Morphine EXAMPLE 102 Sulfate Pentahydrate and Indomethacin 0207 5R,6S,9R,13S,14R-Morphine indomethacinate Preparation of 5R,6S,9R,13S,14R-Morphine may be prepared using the following Synthetic Scheme. Ibuprofenate from 5R,6S,9R,13S,14R-Morphine Indomethacin (0.3578 g, 1.00 mmol) dissolved in a minimal Sulfate Pentahydrate and Ibuprofen volume of ethanol is combined with potassium hydroxide 0204 5R,6S,9R,13S,14R-Morphine ibuprofenate may be (0.05611 g, 1.00 mmol) dissolved in a minimal volume of prepared using the following Synthetic Scheme. Ibuprofen ethanol and stirred for 1 hour. Morphine sulfate pentahy (0.2063 g, 1.00 mmol) dissolved in a minimal volume of drate (0.3794 g., 0.50 mmol) is dissolved in a minimal ethanol is combined with potassium hydroxide (0.05611 g, volume of water and combined with the ethanolic 1.00 mmol) dissolved in a minimal volume of ethanol and indomethacinate Solution. The resulting Solution is stirred stirred for 1 hour. Morphine sulfate pentahydrate (0.3794g, and the total volume reduced to approximately 30 mL. The 0.50 mmol) is dissolved in a minimal volume of water and Solution is transferred to a separatory funnel and the desired combined with the ethanolic ibuprofenate solution. The product extracted with diethyl ether (4x90 mL). The organic resulting Solution is stirred and the total volume reduced to layers are combined and the Solvent removed by rotary approximately 30 mL. The solution is transferred to a evaporation. The product is dried under vacuum overnight. Separatory funnel and the desired product extracted with diethyl ether (4x90 mL). The organic layers are combined EXAMPLE 106 and the Solvent removed by rotary evaporation. The product is dried under vacuum overnight. Preparation of 5R,6S,9R,13S,14R-Morphine Naproxenate from 5R,6S,9R,13S,14R-Morphine EXAMPLE 103 Sulfate Pentahydrate and Naproxen Sodium Preparation of 5R,6S,9R,13S,14R-Morphine 0208 5R,6S,9R,13S,14R-Morphine naproxenate may be prepared using the following Synthetic Scheme. Aqueous Acetylsalicylate from 5R,6S,9R,13S, 14R-Morphine solutions of naproxen sodium (0.2522g, 1.00 mmol) and of Sulfate Pentahydrate and Acetylsalicylic Acid morphine sulfate pentahydrate (0.3794 g., 0.50 mmol) are 0205 5R,6S,9R,13S,14R-Morphine acetylsalicylate may combined into a Suitable flask and stirred for 60 minutes. be prepared using the following Synthetic Scheme. Acetyl The resulting Solution is transferred to a separatory funnel salicylic acid (0.3003 g, 1.00 mmol) dissolved in a minimal and the desired product extracted with diethyl ether (4x90 volume of ethanol is combined with potassium hydroxide mL). The organic layers are combined and the Solvent (0.05611 g, 1.00 mmol) dissolved in a minimal volume of removed by rotary evaporation. The product is dried under ethanol and stirred for 1 hour. Morphine sulfate pentahy Vacuum overnight. US 2005/0203115 A1 Sep. 15, 2005 34

EXAMPLE 107 EXAMPLE 110 Preparation of 5R,6S,9R,13S,14R-Morphine Preparation of 5R,6S,9R,13S,14R-Morphine Suprofenate from 5R,6S,9R,13S,14R-Morphine Etodolate from 5R,6S,9R,13S,14R-Morphine Sulfate Pentahydrate and Suprofen Sulfate Pentahydrate and Etodolac 0212 5R,6S,9R,13S,14R-Morphine suprofenate may be 0209) 5R,6S,9R,13S,14R-Morphine etodolate may be prepared using the following Synthetic Scheme. Suprofen prepared using the following Synthetic Scheme. Etodolac (0.2603 g, 1.00 mmol) dissolved in a minimal volume of (0.2874 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and ethanol is combined with potassium hydroxide (0.05611 g, stirred for 1 hour. Morphine sulfate pentahydrate (0.3794g, 1.00 mmol) dissolved in a minimal volume of ethanol and 0.50 mmol) is dissolved in a minimal volume of water and stirred for 1 hour. Morphine sulfate pentahydrate (0.3794g, the ethanolic Suprofenate Solution. The resulting Solution is 0.50 mmol) is dissolved in a minimal volume of water and stirred and the total volume reduced to approximately 30 combined with the ethanolic etodolate Solution. The result mL. The concentrated Solution is transferred to a separatory ing Solution is stirred and the total Volume reduced to funnel and the desired product extracted with diethyl ether approximately 30 mL. The concentrated Solution is trans (4x90 mL). The organic layers are combined and the solvent ferred to a separatory funnel and the desired product removed by rotary evaporation. The product is dried under extracted with diethyl ether (4x90 mL). The organic layers Vacuum overnight. are combined and the Solvent removed by rotary evapora tion. EXAMPLE 111 Preparation of 5R,6S,9R,13S,14R-Morphine EXAMPLE 108 (S)-Flurbiprofenate from 5R,6S,9R,13S,14R-Morphine Sulfate Pentahydrate Preparation of 5R,6S,9R,13S,14R-Morphine and (S)-Flurbiprofen Sulindate from 5R,6S,9R,13S,14R-Morphine 0213 5R,6S,9R,13S,14R-Morphine (S)-flurbiprofenate Sulfate Pentahydrate and Sulindac may be prepared using the following Synthetic Scheme. (S)-Flurbiprofen (0.2443 g, 1.00 mmol) dissolved in a 0210 5R,6S,9R,13S,14R-Morphine sulindate may be minimal volume of ethanol is combined with potassium prepared using the following Synthetic Scheme. Sulindac hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal (0.3564 g, 1.00 mmol) dissolved in a minimal volume of volume of ethanol and stirred for 1 hour. Morphine sulfate ethanol is combined with potassium hydroxide (0.05611 g, pentahydrate (0.3794g, 0.50 mmol) is dissolved in a mini 1.00 mmol) dissolved in a minimal volume of ethanol and mal volume of water and combined with the ethanolic stirred for 1 hour. Morphine sulfate pentahydrate (0.3794g, flurbiprofenate Solution. The resulting Solution is stirred and 0.50 mmol) is dissolved in a minimal volume of water and the total volume reduced to approximately 30 mL. The combined with the ethanolic Sulindate Solution. The result concentrated Solution is transferred to a separatory funnel ing Solution is stirred and the total Volume is reduced to and the desired product extracted with diethyl ether (4x90 approximately 30 mL. The concentrated Solution is trans mL). The organic layers are combined and the Solvent ferred to a separatory funnel and the desired product removed by rotary evaporation. The product is dried under extracted with diethyl ether (4x90 mL). The organic layers Vacuum overnight. are combined and the Solvent removed by rotary evapora tion. The product is dried under vacuum overnight. EXAMPLE 112 Preparation of 5R,6S,9R,13S,14R-Morphine EXAMPLE 109 Tolmetinate from 5R,6S,9R,13S,14R-Morphine Sulfate Pentahydrate and Tolimetin Sodium Preparation of 5R,6S,9R,13S,14R-Morphine Dihydrate (S)-Ketoprofenate from 0214) 5R,6S,9R,13S,14R-Morphine tolmetinate may be 5R,6S,9R,13S,14R-Morphine Sulfate Pentahydrate prepared using the following Synthetic Scheme. Aqueous and (S)-Ketoprofen solutions of tolmetin sodium dihydrate (0.3153 g, 1.00 mol) 0211 5R,6S,9R,13S,14R-Morphine (S)-ketoprofenate and of Morphine sulfate pentahydrate (0.3794g, 0.50 mmol) may be prepared using the following Synthetic Scheme. are combined into a Suitable flask and stirred for 60 minutes. (S)-Ketoprofen (0.2543 g, 1.00 mmol) dissolved in a mini The resulting Solution is transferred to a separatory funnel mal volume of ethanol is combined with potassium hydrox and the desired product extracted with diethyl ether (4x90 ide (0.05611 g, 1.00 mmol) dissolved in a minimal volume mL). The organic layers are combined and the Solvent of ethanol and stirred for 1 hour. Morphine Sulfate pentahy removed by rotary evaporation. The product is dried under drate (0.3794 g., 0.50 mmol) is dissolved in a minimal Vacuum overnight. volume of water and combined with the ethanolic ketopro EXAMPLE 113 fenate Solution. The resulting Solution is stirred and the total Volume is reduced to approximately 30 mL. The concen Preparation of 5R,6S,9R,13S,14R-Morphine trated Solution is transferred to a separatory funnel and the Fenoprofenate from 5R,6S,9R,13S,14R-Morphine desired product extracted with diethyl ether (4x90 mL). The Sulfate Pentahydrate and Fenoprofen Calcium organic layers are combined and the Solvent removed by Trihydrate rotary evaporation. The product is dried under vacuum 0215 5R,6S,9R,13S,14R-Morphine fenoprofenate may overnight. be prepared using the following Synthetic Scheme. Aqueous US 2005/0203115 A1 Sep. 15, 2005 35 solutions of fenoprofen calcium trihydrate (0.2884 g., 0.50 approximately 30 mL. The concentrated Solution is trans mmol) and of morphine sulfate pentahydrate (0.3794g, 0.50 ferred to a separatory funnel and the desired product mmol) are combined into a suitable flask and stirred for 60 extracted with diethyl ether (4x90 mL). The organic layers minutes. The resulting Solution is transferred to a separatory are combined and the Solvent removed by rotary evapora funnel and the desired product extracted with diethyl ether tion. The product is dried under vacuum overnight. (4x90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under EXAMPLE 117 Vacuum overnight. Preparation of Levorphanol Ibuprofenate from Levorphanol Tartrate Dihydrate and Ibuprofen EXAMPLE 114 0219 Levorphanol ibuprofenate may be prepared using Preparation of 5R,6S,9R,13S,14R-Morphine the following synthetic scheme. Ibuprofen (0.2063 g, 1.00 mmol) dissolved in a minimal volume of ethanol is com Oxaprozinate from 5R,6S,9R,13S, 14R-Morphine bined with potassium hydroxide (0.05611 g, 1.00 mmol) Sulfate Pentahydrate and Oxaprozin dissolved in a minimal volume of ethanol and stirred for 1 0216) 5R,6S,9R,13S,14R-Morphine oxaprozinate may be hour. A solution of (l)-3-hydroxy-N-methylmorphinan prepared using the following Synthetic Scheme. Oxaprozin (herein referred to as levorphanol) tartrate dihydrate (0.4435 (0.2933 g, 1.00 mmol) dissolved in a minimal volume of g, 1.00 mmol) is prepared in a minimal volume of water and ethanol is combined with potassium hydroxide (0.05611 g, combined with the ethanolic ibuprofenate solution. The 1.00 mmol) dissolved in a minimal volume of ethanol and resulting Solution is stirred and the total volume reduced to stirred for 1 hour. Morphine sulfate pentahydrate (0.3794g, approximately 30 mL. The concentrated Solution is trans 0.50 mmol) is dissolved in a minimal volume of water and ferred to a separatory funnel and the desired product combined with the ethanolic oxaprozinate Solution. The extracted with diethyl ether (4x90 mL). The organic layers resulting Solution is stirred and the total volume reduced to are combined and the Solvent removed by rotary evapora approximately 30 mL. The concentrated Solution is trans tion. The product is dried under vacuum overnight. ferred to a separatory funnel and the desired product extracted with diethyl ether (4x90 mL). The organic layers EXAMPLE 118 are combined and the Solvent removed by rotary evapora Preparation of Levorphanol Acetylsalicylate from tion. The product is dried under vacuum overnight. Levorphanol Tartrate Dihydrate and Acetylsalicylic Acid EXAMPLE 1.15 0220 Levorphanol acetylsalicylate may be prepared using the following Synthetic Scheme. Acetylsalicylic acid Preparation of 5R,6S,9R,13S,14R-Morphine (0.3003 g, 1.00 mmol) dissolved in a minimal volume of Difunisalate from 5R,6S,9R,13S,14R-Morphine ethanol is combined with potassium hydroxide (0.05611 g, Sulfate Pentahydrate and Difunisal 1.00 mmol) dissolved in a minimal volume of ethanol and 0217 5R,6S,9R,13S,14R-Morphine difunisalate may be stirred for 1 hour. Levorphanol tartrate dihydrate (0.4435 g, prepared using the following Synthetic Scheme. Difunisal 1.00 mmol) is dissolved in a minimal volume of water and (0.2502 g, 1.00 mmol) dissolved in a minimal volume of combined with the ethanolic acetylsalicylate solution. The ethanol is combined with potassium hydroxide (0.05611 g, resulting Solution is stirred and the total volume reduced to 1.00 mmol) dissolved in a minimal volume of ethanol and approximately 30 mL. The concentrated Solution is trans stirred for 1 hour. Morphine sulfate pentahydrate (0.3794g, ferred to a separatory funnel and the desired product 0.50 mmol) is dissolved in a minimal volume of water and extracted with diethyl ether (4x90 mL). The organic layers combined with the ethanolic difunisalate Solution. The are combined and the Solvent removed by rotary evapora resulting Solution is stirred and the total volume reduced to tion. The product is dried under vacuum overnight. approximately 30 mL. The concentrated Solution is trans ferred to a separatory funnel and the desired product EXAMPLE 119 extracted with diethyl ether (4x90 mL). The organic layers Preparation of Levorphanol Salicylate from are combined and the Solvent removed by rotary evapora Levorphanol Tartrate Dihydrate and Sodium tion. The product is dried under vacuum overnight. Salicylate 0221) Levorphanol Salicylate may be prepared using the EXAMPLE 116 following Synthetic Scheme. Aqueous Solutions of Sodium salicylate (0.1601 g, 1.00 mmol) and of levorphanol tartrate Preparation of 5R,6S,9R,13S,14R-Morphine dihydrate (0.4435 g, 1.00 mmol) are combined into a suit Loxoprofenate from 5R,6S,9R,13S,14R-Morphine able flask and stirred for 60 minutes. The resulting solution Sulfate Pentahydrate and Loxoprofen is transferred to a separatory funnel and the desired product 0218 5R,6S,9R,13S,14R-Morphine loxoprofenate may extracted with diethyl ether (4x90 mL). The organic layers be prepared using the following Synthetic Scheme. LOXO are combined and the Solvent removed by rotary evapora profen (0.2463 g, 1.00 mmol) dissolved in a minimal volume tion. The product is dried under vacuum overnight. of ethanol is combined with potassium hydroxide (0.05611 EXAMPLE 120 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. Morphine sulfate pentahydrate (0.3794g, Preparation of Levorphanol Indomethacinate from 0.50 mmol) is dissolved in a minimal volume of water and Levorphanol Tartrate Dihydrate and Indomethacin combined with the ethanolic loxoprofenate solution. The 0222 Levorphanol indomethacinate may be prepared resulting Solution is stirred and the total volume reduced to using the following synthetic scheme. Indomethacin (0.3578 US 2005/0203115 A1 Sep. 15, 2005 36 g, 1.00 mmol) dissolved in a minimal volume of ethanol is mL). The organic layers are combined and the Solvent combined with potassium hydroxide (0.05611 g, 1.00 mmol) removed by rotary evaporation. The product is dried under dissolved in a minimal volume of ethanol and stirred for 1 Vacuum overnight. hour. Levorphanol tartrate dihydrate (0.4435 g, 1.00 mmol) is dissolved in a minimal volume of water and combined EXAMPLE 124 with the ethanolic indomethacinate Solution. The resulting Solution is Stirred and the total Volume reduced to approxi Preparation of Levorphanol (S)-Ketoprofenate from mately 30 mL. The concentrated Solution is transferred to a Separatory funnel and the desired product extracted with Levorphanol Tartrate Dihydrate and (S)-Ketoprofen diethyl ether (4x90 mL). The organic layers are combined 0226 Levorphanol (S)-ketoprofenate may be prepared and the Solvent removed by rotary evaporation. The product using the following Synthetic Scheme. (S)-Ketoprofen is dried under vacuum overnight. (0.2543 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, EXAMPLE 121 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. Levorphanol tartrate dihydrate (0.4435 g, Preparation of Levorphanol Naproxenate from 1.00 mmol) is dissolved in a minimal volume of water and Levorphanol Tartrate Dihydrate and Naproxen combined with the ethanolic ketoprofenate solution. The Sodium resulting Solution is stirred and the total volume reduced to 0223 Levorphanol naproxenate may be prepared using approximately 30 mL. The concentrated Solution is trans the following Synthetic Scheme. Aqueous Solutions of ferred to a separatory funnel and the desired product naproxen sodium (0.2522 g, 1.00 mmol) and of levorphanol extracted with diethyl ether (4x90 mL). The organic layers tartrate dihydrate (0.4435 g, 1.00 mmol) are combined into are combined and the Solvent removed by rotary evapora a suitable flask and stirred for 60 minutes. The resulting tion. The product is dried under vacuum overnight. Solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4x90 mL). The organic EXAMPLE 125 layers are combined and the Solvent removed by rotary evaporation. The product is dried under vacuum overnight. Preparation of Levorphanol Suprofenate from Levorphanol Tartrate Dihydrate and Suprofen EXAMPLE 122 0227 Levorphanol Suprofenate may be prepared using Preparation of Levorphanol Etodolate from the following synthetic scheme. Suprofen (0.2603 g, 1.00 Levorphanol Tartrate Dihydrate and Etodolac mmol) dissolved in a minimal volume of ethanol is com bined with potassium hydroxide (0.05611 g, 1.00 mmol) 0224 Levorphanol etodolate may be prepared using the dissolved in a minimal volume of ethanol and stirred for 1 following synthetic scheme. Etodolac (0.2874g, 1.00 mmol) hour. Levorphanol tartrate dihydrate (0.4435 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with is dissolved in a minimal volume of water and combined potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a with the ethanolic Suprofenate Solution. The resulting Solu minimal volume of ethanol and stirred for 1 hour. Levor tion is stirred and the total Volume reduced to approximately phanol tartrate dihydrate (0.4435 g, 1.00 mmol) is dissolved 30 mL. The concentrated Solution is transferred to a sepa in a minimal volume of water and combined with the ratory funnel and the desired product extracted with diethyl ethanolic etodolate Solution. The resulting Solution is stirred ether (4x90 mL). The organic layers are combined and the and the total volume reduced to approximately 30 mL. The solvent removed by rotary evaporation. The product is dried concentrated Solution is transferred to a separatory funnel under Vacuum overnight. and the desired product extracted with diethyl ether (4x90 mL). The organic layers are combined and the Solvent EXAMPLE 126 removed by rotary evaporation. The product is dried under Vacuum overnight. Preparation of Levorphanol (S)-Flurbiprofenate from Levorphanol Tartrate Dihydrate and EXAMPLE 123 (S)-Flurbiprofen Preparation of Levorphanol Sulindate from 0228) Levorphanol (S)-flurbiprofenate may be prepared Levorphanol Tartrate Dihydrate and Sulindac using the following synthetic scheme. (S)-Flurbiprofen (0.2443 g, 1.00 mmol) dissolved in a minimal volume of 0225 Levorphanol Sulindate may be prepared using the ethanol is combined with potassium hydroxide (0.05611 g, following synthetic scheme. Sulindac (0.3564g, 1.00 mmol) 1.00 mmol) dissolved in a minimal volume of ethanol and dissolved in a minimal volume of ethanol is combined with stirred for 1 hour. Levorphanol tartrate dihydrate (0.4435 g, potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a 1.00 mmol) is dissolved in a minimal volume of water and minimal volume of ethanol and stirred for 1 hour. Levor combined with the ethanolic flurbiprofenate solution. The phanol tartrate dihydrate (0.4435 g, 1.00 mmol) is dissolved resulting Solution is stirred and the total volume reduced to in a minimal volume of water and combined with the approximately 30 mL. The concentrated Solution is trans ethanolic Sulindate Solution. The resulting Solution is stirred ferred to a separatory funnel and the desired product and the total volume reduced to approximately 30 mL. The extracted with diethyl ether (4x90 mL). The organic layers concentrated Solution is transferred to a separatory funnel are combined and the Solvent removed by rotary evapora and the desired product extracted with diethyl ether (4x90 tion. The product is dried under vacuum overnight. US 2005/0203115 A1 Sep. 15, 2005 37

EXAMPLE 127 tion is stirred and the total Volume reduced to approximately 30 mL. The concentrated Solution is transferred to a sepa Preparation of Levorphanol Tolimetinate from ratory funnel and the desired product extracted with diethyl Levorphanol Tartrate Dihydrate and Tolimetin ether (4x90 mL). The organic layers are combined and the Sodium Dihydrate solvent removed by rotary evaporation. The product is dried 0229) Levorphanol tolmetinate may be prepared using under Vacuum overnight. the following Synthetic Scheme. Aqueous Solutions of tol EXAMPLE 1.31 metin sodium dihydrate (0.3153 g, 1.00 mmol) and of levorphanol tartrate dihydrate (0.4435 g, 1.00 mmol) are Preparation of Levorphanol Loxoprofenate from combined into a Suitable flask and stirred for 60 minutes. Levorphanol Tartrate Dihydrate and Loxoprofen The resulting Solution is transferred to a separatory funnel 0233 Levorphanol loxoprofenate may be prepared using and the desired product extracted with diethyl ether (4x90 the following synthetic scheme. Loxoprofen (0.2463 g, 1.00 mL). The organic layers are combined and the Solvent mmol) dissolved in a minimal volume of ethanol is com removed by rotary evaporation. The product is dried under bined with potassium hydroxide (0.05611 g, 1.00 mmol) Vacuum overnight. dissolved in a minimal volume of ethanol and stirred for 1 hour. Levorphanol tartrate dihydrate (0.4435 g, 1.00 mmol) EXAMPLE 128 is dissolved in a minimal volume of water and combined with the ethanolic loxoprofenate Solution. The resulting Preparation of Levorphanol Fenoprofenate from Solution is stirred and the total volume is reduced to approxi Levorphanol Tartrate Dihydrate and Fenoprofen mately 30 mL. The concentrated solution is transferred to a Calcium Trihydrate Separatory funnel and the desired product extracted with 0230 Levorphanol fenoprofenate may be prepared using diethyl ether (4x90 mL). The organic layers are combined the following Synthetic Scheme. Aqueous Solutions of feno and the Solvent removed by rotary evaporation. The product profen calcium trihydrate (0.2884 g., 0.50 mmol) and of is dried under vacuum overnight. levorphanol tartrate dihydrate (0.4435 g, 1.00 mmol) are EXAMPLE 132 combined into a Suitable flask and stirred for 60 minutes. Preparation of Levorphanol Diclofenate from The resulting Solution is transferred to a separatory funnel Levorphanol Tartrate Dihydrate and Sodium and the desired product extracted with diethyl ether (4x90 Diclofenac mL). The organic layers are combined and the Solvent removed by rotary evaporation. The product is dried under 0234 Levorphanol diclofenate may be prepared using the Vacuum overnight. following Synthetic Scheme. Aqueous Solutions of Sodium diclofenac (0.3181 g, 1.00 mmol) and of levorphanol tartrate EXAMPLE 129 dihydrate (0.4435 g, 1.00 mmol) are combined into a suit able flask and stirred for 60 minutes. The resulting solution Preparation of Levorphanol Oxaprozinate from is transferred to a separatory funnel and the desired product Levorphanol Tartrate Dihydrate and Oxaprozin extracted with diethyl ether (4x90 mL). The organic layers are combined and the Solvent removed by rotary evapora 0231 Levorphanol oxaprozinate may be prepared using tion. The product is dried under vacuum overnight. the following synthetic scheme. Oxaprozin (0.2933 g, 1.00 mmol) dissolved in a minimal volume of ethanol is com EXAMPLE 1.33 bined with potassium hydroxide (0.05611 g, 1.00 mmol) Preparation of 5R.9R,13R,14S-Oxycodone dissolved in a minimal volume of ethanol and stirred for 1 Ibuprofenate from 5R,9R,13R,14S-Oxycodone hour. Levorphanol tartrate dihydrate (0.4435 g, 1.00 mmol) Hydrochloride and Ibuprofen is dissolved in a minimal volume of water and combined 0235 5R.9R,13R,14S-Oxycodone ibuprofenate may be with the ethanolic oxaprozinate Solution. The resulting Solu prepared using the following Synthetic Scheme. Ibuprofen tion is stirred and the total Volume reduced to approximately (0.2063 g, 1.00 mmol) dissolved in a minimal volume of 30 mL. The concentrated Solution is transferred to a sepa ethanol is combined with potassium hydroxide (0.05611 g, ratory funnel and the desired product extracted with diethyl 1.00 mmol) dissolved in a minimal volume of ethanol and ether (4x90 mL). The organic layers are combined and the stirred for 1 hour. Oxycodone hydrochloride (0.3518 g, 1.00 solvent removed by rotary evaporation. The product is dried mmol) is dissolved in a minimal volume of water and under Vacuum overnight. combined with the ethanolic ibuprofenate solution. The resulting Solution is stirred and the total Volume is reduced EXAMPLE 130 to approximately 30 mL. The concentrated Solution is trans ferred to a separatory funnel and the desired product Preparation of Levorphanol Difunisalate from extracted with diethyl ether (4x90 mL). The organic layers Levorphanol Tartrate Dihydrate and Difunisal are combined and the Solvent removed by rotary evapora 0232 Levorphanol difunisalate may be prepared using tion. The product is dried under vacuum overnight. the following synthetic scheme. Difunisal (0.2502 g, 1.00 EXAMPLE 134 mmol) dissolved in a minimal volume of ethanol is com bined with potassium hydroxide (0.05611 g, 1.00 mmol) Preparation of 5R.9R,13R,14S-Oxycodone dissolved in a minimal volume of ethanol and stirred for 1 Acetylsalicylate from 5R,9R,13R,14S-Oxycodone hour. Levorphanol tartrate dihydrate (0.4435 g, 1.00 mmol) Hydrochloride and Acetylsalicylic Acid is dissolved in a minimal volume of water and combined 0236 R.9R,13R,14S-Oxycodone acetylsalicylate may be with the ethanolic difunisalate Solution. The resulting Solu prepared using the following Synthetic Scheme. Acetylsali US 2005/0203115 A1 Sep. 15, 2005 38 cylic acid (0.3003 g, 1.00 mmol) dissolved in a minimal EXAMPLE 1.37 volume of ethanol is combined with potassium hydroxide Preparation of 5R.9R,13R,14S-Oxycodone (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. Oxycodone hydrochloride Etodolate from 5R,9R,13R,14S-Oxycodone (0.3518 g, 1.00 mmol) is dissolved in a minimal volume of Hydrochloride and Etodolac water and combined with the ethanolic acetylsalicylate 0240 5R.9R,13R,14S-Oxycodone etodolate may be pre Solution. The resulting Solution is stirred and the total pared using the following Synthetic Scheme. Etodolac Volume reduced to approximately 30 mL. The concentrated (0.2874 g, 1.00 mmol) dissolved in a minimal volume of Solution is transferred to a separatory funnel and the desired ethanol is combined with potassium hydroxide (0.05611 g, product extracted with diethyl ether (4x90 mL). The organic 1.00 mmol) dissolved in a minimal volume of ethanol and layers are combined and the Solvent removed by rotary stirred for 1 hour. Oxycodone hydrochloride (0.3518 g, 1.00 evaporation. The product is dried under vacuum overnight. mmol) is dissolved in a minimal volume of water and combined with the ethanolic etodolate Solution. The result EXAMPLE 135 ing Solution is stirred and the total Volume reduced to approximately 30 mL. The concentrated Solution is trans Preparation of 5R.9R,13R,14S-Oxycodone ferred to a separatory funnel and the desired product Salicylate from 5R.9R,13R,14S-Oxycodone extracted with diethyl ether (4x90 mL). The organic layers Hydrochloride and Sodium Salicylate are combined and the Solvent removed by rotary evapora 0237) 5R.9R,13R,14S-Oxycodone salicylate may be pre tion. The product is dried under vacuum overnight. pared using the following Synthetic Scheme. Aqueous Solu EXAMPLE 1.38 tions of sodium salicylate (0.1601 g, 1.00 mmol) and of oxycodone hydrochloride (0.3518 g, 1.00 mmol) are com Preparation of 5R.9R,13R,14S-Oxycodone bined into a Suitable flask and stirred for 60 minutes. The Sulindate from 5R.9R,13R,14S-Oxycodone resulting Solution is transferred to a separatory funnel and Hydrochloride and Sulindac the desired product extracted with diethyl ether (4x90 mL). 0241 5R,9R,13R,14S-Oxycodone Sulindate may be pre The organic layers are combined and the Solvent removed by pared using the following Synthetic Scheme. Sulindac rotary evaporation. The product is dried under vacuum (0.3564 g, 1.00 mmol) dissolved in a minimal volume of overnight. ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and EXAMPLE 1.36 stirred for 1 hour. Oxycodone hydrochloride (0.3518 g, 1.00 mol) is dissolved in a minimal volume of water and com Preparation of 5R.9R,13R,14S-Oxycodone bined with the ethanolic Sulindate solution. The resulting Indomethacinate from 5R,9R,13R,14S-Oxycodone Solution is Stirred and the total Volume reduced to approxi Hydrochloride and Indomethacin mately 30 mL. The concentrated solution is transferred to a 0238 5R.9R,13R,14S-Oxycodone indomethacinate may Separatory funnel and the desired product extracted with be prepared using the following Synthetic Scheme. diethyl ether (4x90 mL). The organic layers are combined Indomethacin (0.3578 g, 1.00 mmol) dissolved in a minimal and the Solvent removed by rotary evaporation. The product volume of ethanol and combined with potassium hydroxide is dried under vacuum overnight. (0.05611 g, 1.00 mmol) dissolved in a minimal volume of EXAMPLE 139 ethanol and stirred for 1 hour. Oxycodone hydrochloride (0.3518 g, 1.00 mmol) is dissolved in a minimal volume of Preparation of 5R.9R,13R,14S-Oxycodone water and combined with the ethanolic indomethacinate (S)-Ketoprofenate from 5R,9R,13R,14S-Oxycodone Solution. The resulting Solution is stirred and the total Hydrochloride and (S)-Ketoprofen volume is reduced to approximately 30 mL. The solution is 0242 5R.9R,13R,14S-Oxycodone (S)-ketoprofenate transferred to a separatory funnel and the desired product may be prepared using the following Synthetic Scheme. extracted with diethyl ether (4x90 mL). The organic layers (S)-Ketoprofen (0.2543 g, 1.00 mmol) dissolved in a mini are combined and the Solvent removed by rotary evapora mal volume of ethanol is combined with potassium hydrox tion. The product is dried under vacuum overnight. ide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. Oxycodone hydrochloride EXAMPLE 1.37 (0.3518 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic ketoprofenate Solu Preparation of 5R.9R,13R,14S-Oxycodone tion. The resulting Solution is stirred and the total volume Naproxenate from 5R,9R,13R,14S-Oxycodone reduced to approximately 30 mL. The concentrated Solution Hydrochloride and Naproxen Sodium is transferred to a separatory funnel and the desired product 0239 5R.9R,13R,14S-Oxycodone naproxenate may be extracted with diethyl ether (4x90 mL). The organic layers prepared using the following Synthetic Scheme. Aqueous are combined and the Solvent removed by rotary evapora solutions of naproxen sodium (0.2522g, 1.00 mmol) and of tion. The product is dried under vacuum overnight. oxycodone hydrochloride (0.3518 g, 1.00 mmol) are com EXAMPLE 140 bined into a Suitable flask and stirred for 60 minutes. The resulting Solution is transferred to a separatory funnel and Preparation of 5R.9R,13R,14S-Oxycodone the desired product extracted with diethyl ether (4x90 mL). Suprofenate from 5R,9R,13R,14S-Oxycodone The organic layers are combined and the Solvent removed by Hydrochloride and Suprofen rotary evaporation. The product is dried under vacuum 0243 5R,9R,13R,14S-Oxycodone suprofenate may be overnight. prepared using the following Synthetic Scheme. Suprofen US 2005/0203115 A1 Sep. 15, 2005 39

(0.2603 g, 1.00 mmol) dissolved in a minimal volume of (4x90 mL). The organic layers are combined and the solvent ethanol is combined with potassium hydroxide (0.05611 g, removed by rotary evaporation. The product is dried under 1.00 mmol) dissolved in a minimal volume of ethanol and Vacuum overnight. stirred for 1 hour. Oxycodone hydrochloride (0.3518 g, 1.00 mol) is dissolved in a minimal volume of water and com EXAMPLE 1.44 bined with the ethanolic Suprofenate Solution. The resulting Solution is Stirred and the total Volume reduced to approxi Preparation of 5R.9R,13R,14S-Oxycodone mately 30 mL. The concentrated Solution is transferred to a Oxaprozinate from 5R,9R,13R,14S-Oxycodone Separatory funnel and the desired product extracted with Hydrochloride and Oxaprozin diethyl ether (4x90 mL). The organic layers are combined 0247 5R,9R,13R,14S-Oxycodone oxaprozinate may be and the Solvent removed by rotary evaporation. The product prepared using the following Synthetic Scheme. Oxaprozin is dried under vacuum overnight. (0.2933 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, EXAMPLE 141 1.00 mmol) dissolved in a minimal volume of ethanol and Preparation of 5R.9R,13R,14S-Oxycodone stirred for 1 hour. Oxycodone hydrochloride (0.3518 g, 1.00 (S)-Flurbiprofenate from mmol) is dissolved in a minimal volume of water and 5R,9R,13R,14S-Oxycodone Hydrochloride and combined with the ethanolic oxaprozinate Solution. The (S)-Flurbiprofen resulting Solution is stirred and the total volume reduced to approximately 30 mL. The concentrated Solution is trans 0244 5R.9R,13R,14S-Oxycodone (S)-flurbiprofenate ferred to a separatory funnel and the desired product may be prepared using the following Synthetic Scheme. extracted with diethyl ether (4x90 mL). The organic layers (S)-Flurbiprofen (0.2443 g, 1.00 mmol) dissolved in a are combined and the Solvent removed by rotary evapora minimal volume of ethanol is combined with potassium tion. The product is dried under vacuum overnight. hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. Oxycodone hydro EXAMPLE 1.45 chloride (0.3518 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic flurbi Preparation of 5R.9R,13R,14S-Oxycodone profenate Solution. The resulting Solution is stirred and the Difunisalate from 5R,9R,13R,14S-Oxycodone total volume reduced to approximately 30 mL. The concen Hydrochloride and Difunisal trated Solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4x90 mL). The 0248 5R.9R,13R,14S-Oxycodone difunisalate may be organic layers are combined and the Solvent removed by prepared using the following Synthetic Scheme. Difunisal rotary evaporation. The product is dried under vacuum (0.2502 g, 1.00 mmol) dissolved in a minimal volume of overnight. ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and EXAMPLE 142 stirred for 1 hour. Oxycodone hydrochloride (0.3518 g, 1.00 mmol) is dissolved in a minimal volume of water and Preparation of 5R.9R,13R,14S-Oxycodone combined with the ethanolic difunisalate Solution. The Tolmetinate from 5R,9R,13R,14S-Oxycodone resulting Solution is stirred and the total volume reduced to Hydrochloride and Tolmetin Sodium Dihydrate approximately 30 mL. The concentrated Solution is trans ferred to a separatory funnel and the desired product 0245) 5R.9R,13R,14S-Oxycodone tolmetinate may be extracted with diethyl ether (4x90 mL). The organic layers prepared using the following Synthetic Scheme. Aqueous are combined and the Solvent removed by rotary evapora solutions of tolmetin sodium dihydrate (0.3153 g, 1.00 tion. The product is dried under vacuum overnight. mmol) and of oxycodone hydrochloride (0.3518 g, 1.00 mmol) are combined into a suitable flask and stirred for 60 EXAMPLE 1.46 minutes. The resulting Solution is transferred to a separatory funnel and the desired product extracted with diethyl ether Preparation of 5R.9R,13R,14S-Oxycodone (4x90 mL). The organic layers are combined and the solvent Loxoprofenate from 5R,9R,13R,14S-Oxycodone removed by rotary evaporation. The product is dried under Hydrochloride and Loxoprofen Vacuum overnight. 0249 5R.9R,13R,14S-Oxycodone loxoprofenate may be EXAMPLE 1.43 prepared using the following Synthetic Scheme. Loxoprofen (0.2463 g, 1.00 mmol) is dissolved in a minimal volume of Preparation of 5R.9R,13R,14S-Oxycodone ethanol and combined with potassium hydroxide (0.05611 g, Fenoprofenate from 5R,9R,13R,14S-Oxycodone 1.00 mmol) dissolved in a minimal volume of ethanol and Hydrochloride and Fenoprofen Calcium Trihydrate stirred for 1 hour. Oxycodone hydrochloride (0.3518 g, 1.00 mmol) is dissolved in a minimal volume of water and 0246 5R,9R,13R,14S-Oxycodone fenoprofenate may be combined with the ethanolic loxoprofenate solution. The prepared using the following Synthetic Scheme. Aqueous resulting Solution is stirred and the total volume reduced to solutions of fenoprofen calcium trihydrate (0.2884 g., 0.50 approximately 30 mL. The concentrated Solution is trans mmol) and of oxycodone hydrochloride (0.3518 g, 1.00 ferred to a separatory funnel and the desired product mmol) are combined into a suitable flask and stirred for 60 extracted with diethyl ether (4x90 mL). The organic layers minutes. The resulting Solution is transferred to a separatory are combined and the Solvent removed by rotary evapora funnel and the desired product extracted with diethyl ether tion. The product is dried under vacuum overnight. US 2005/0203115 A1 Sep. 15, 2005 40

EXAMPLE 1.47 EXAMPLE 49 Particle Size Resulting When a Propoxyphene Particle Size Resulting When A Propoxyphene Diclofenate Solution is Added to Hydrochloric Acid Diclofenate Formulation is Added to Hydrochloric Acid 0250 Particle size of a methanolic solution of pro 0253) A propoxyphene diclofenate solution was prepared poxyphene diclofenate (61 mg/mL, 0.096 mmol/mL, 25 mL) by adding propoxyphene diclofenate (25 mg, 0.039 mmol) was monitored for 2.5 hours by adding this solution to HCl to the contents of a placebo 50 mg capsule containing a (0.1 N, 25 mL). Measurements were obtained using a dispersant and a Solubilizer. The particle size of this Solution Sympatec HELOS model KF particle sizer with SUCELL was monitored for about 2 hours by adding the solution of and R5 lens (0.5-875 um), pump, and stirrer speeds set to propoxyphene diclofenate to HCl (0.1 N, 25 mL). Measure 50% of the maximum value. The SUCELL was filled with ments were obtained using a Sympatec HELOS model KF water and reference measurements were acquired before particle sizer with SUCELL and R5 lens (0.5-875 um), adding an appropriate amount of propoxyphene diclofenate pump, and Stirrer Speeds Set to 50% of the maximum value. Solution for an approximate optical concentration of 10% at The SUCELL was filled with water and reference measure timepoints of 15, 45, 75, 120, and 150 minutes. The results ments were acquired before adding an appropriate amount of are tabulated in Table 15. Propoxyphene Diclofenate Solution for an approximate opti cal concentration of 10% at timepoints of 5, 10, 20, 30, 40, TABLE 1.5 60, 80, and 100 minutes. The data are shown in Table 17.

Results for Propoxyphene Diclofenate (61 mg/mL) in MeOH TABLE 1.7 Timepoint Particle Size Results for Propoxyphene Diclofenate Formulation (minutes) Mean (um) s50% (um) s90% (um) 15 152.4 141.2 287.9 Timepoint 45 155.5 143.O 293.9 (minutes) Mean (um) s50% (um) s90% (um) 75 161.7 140.5 3O8.6 5 8.8 6.9 17.5 12O 1492 135.4 286.3 1O 8.0 6.5 15.1 150 124.2 110.2 238.4 2O 7.4 6.1 13.8 30 7.5 6.O 13.5 40 7.1 5.9 12.9 60 6.9 5.8 12.4 EXAMPLE 1.48 8O 7.1 5.7 12.3 1OO 6.8 5.7 12.1 0251 Particle Size Resulting when a Propoxyphene Diclofenate Formulation is Added to Hydrochloric Acid 0252) A propoxyphene diclofenate Solution was prepared EXAMPLE 150 by adding propoxyphene diclofenate (12.5 mg, 0.020 mmol) Particle Size Resulting when a Propoxyphene to the contents of a placebo 50 mg capsule containing a Diclofenate Formulation is Added to Hydrochloric dispersant and a Solubilizer. The particle size of this Solution Acid was monitored for about 2 hours by adding the solution of propoxyphene diclofenate to HCl (0.1 N, 25 mL). Measure 0254. A propoxyphene diclofenate solution was prepared ments were obtained using a Sympatec HELOS model KF by adding propoxyphene diclofenate (40 mg, 0.063 mmol) particle sizer with SUCELL and R5 lens (0.5-875um), pump to the contents of a placebo 50 mg capsule containing a and stirrer speeds set to 50% of the maximum value. The dispersant and a Solubilizer. The particle size of this Solution SUCELL was filled with water and reference measurements was monitored for about 2 hours by adding the solution of were acquired before adding an appropriate amount of propoxyphene diclofenate to HCl (0.1 N, 25 mL). Measure propoxyphene diclofenate Solution for an approximate opti ments were obtained using a Sympatec HELOS model KF cal concentration of 10% at timepoints of 5, 10, 20, 30, 40, particle sizer with SUCELL and R5 lens (0.5-875 mm), 60, 80, and 100 minutes. The data are shown in Table 16. pump, and Stirrer Speeds Set to 50% of the maximum value. The SUCELL was filled with water and reference measure TABLE 16 ments were acquired before adding an appropriate amount of propoxyphene diclofenate Solution for an approximate opti Particle Size Results for Propoxyphene Diclofenate Formulation cal concentration of 10% at timepoints of 20, 40, 60,90, and Timepoint 120 minutes. The data are shown in Table 18. (minutes) Mean (um) s50% (um) s90% (um) TABLE 1.8 5 6.6 5.7 11.7 1O 6.6 5.6 11.6 Particle Size Results for Propoxyphene Diclofenate Formulation 2O 6.2 5.6 11.2 3O 6.6 5.6 11.4 Timepoint 40 6.1 5.5 10.9 (minutes) Mean (um) s50% (um) s90% (um) 60 6.1 5.5 10.9 8O 6.O 5.4 10.7 2O 9.1 7.0 18.0 1OO 6.8 5.6 11.4 40 8.8 6.7 17.3 60 8.5 6.4 16.0 US 2005/0203115 A1 Sep. 15, 2005 41

from the linearity curve generated from the Standard data. TABLE 18-continued The data are shown in Table 20.

Particle Size Results for Propoxyphene Diclofenate Formulation TABLE 2.0 Timepoint Solubility Results for Propoxyphene (minutes) Mean (um) s50% (um) s90% (um) Diclofenate as a Function of pH 90 7.9 6.1 14.8 12O 7.8 6.O 14.4 mg Dissolved from pH 48 mg Solution mg/mL. Dissolved % Dissolved 3 OOO)4 1.0528 x 10 O.OO9 5 36.005 O.09 74878 EXAMPLE 1.51 7 36.644 O.O916 75.677 9 34.018 O.O8504 71.168 Particle Size Resulting when a Propoxyphene 11 18.7OO O.O4676 39.395 Diclofenate Formulation is Added to Hydrochloric Acid EXAMPLE 153 0255. A propoxyphene diclofenate solution was prepared Solubility of Propoxyphene Diclofenate in by adding propoxyphene diclofenate (50 mg, 0.079 mmol) Polyethylene Glycol to the contents of a placebo 50 mg capsule containing a dispersant and a Solubilizer. The particle size of this Solution 0257 The total solubility of propoxyphene diclofenate in was monitored for about 2 hours by adding the solution of polyethylene glycol 400 was determined to exceed 670 propoxyphene diclofenate to HCl (0.1 N, 25 mL). Measure mg/mL. The solubility was determined by UV detection ments were obtained using a Sympatec HELOS model KF using a standard solution (0.049 mmol/L). particle sizer with SUCELL and R5 lens (0.5-875 mm), EXAMPLE 1.54 pump, and Stirrer Speeds Set to 50% of the maximum value. The SUCELL was filled with water and reference measure Preparation of (2S,3R)-(+)-4-(Dimethylamino)-3- ments were acquired before adding an appropriate amount of methyl-1,2-diphenyl-2-butanol Propionate propoxyphene diclofenate Solution for an approximate opti Diclofenate from Sodium Diclofenac and (2S,3R)- cal concentration of 10% at timepoints of 5, 10, 20, 30, 40, (+)-4-(Dimethylamino)-3-methyl-1,2-diphenyl-2- 60, 80, and 120 minutes. The data are shown in Table 19. butanol Propionate (Propoxyphene) Hydrochloride 0258 Sodium diclofenac (133.7 g., 0.4203 mol) was TABLE 1.9 dissolved in water (2500 mL) at about 50° C. with mechani cal stirring. To this a 50° C. solution of (2S,3R)-(+)-4- Particle Size Results for ProDOXVphene Diclofenate Formulation (dimethylamino)-3-methyl-1,2-diphenyl-2-butanol propi Timepoint onate hydrochloride (158.6 g., 0.4219 mol) in water (600 (minutes) Mean (um) s50% (um) s90% (um) mL) was slowly added while vigorously stirring the mixture with a mechanical Stirrer and maintaining the temperature at 5 9.1 7.0 17.9 1O 9.4 6.9 18.4 about 50 C. A thick sticky white precipitate formed as the 2O 9.1 6.6 17.4 mixture was stirred. The reaction was monitored by HPLC 3O 8.6 6.3 16.1 to calculate the amount of propoxyphene remaining in 40 8.3 6.1 15.4 60 8.5 5.9 15.1 Solution. When the reaction was considered complete, as 8O 8.O 5.8 14.3 evidence by the disappearance of propoxyphene from Solu 12O 7.8 5.7 14.2 tion, the Solution was decanted, and the Solid product washed with multiple aliquots of water (about 2000 mL) at 50° C. with mechanical stirring until HPLC confirmed only low levels of unreacted sodium diclofenac present. The solid EXAMPLE 1.52 material was then dissolved in a minimal amount of acetone and the acetone Subsequently removed by rotary evaporation Solubility when Propoxyphene Diclofenate is under vacuum to yield a white solid. The white solid was Added to Water at Various pH Values then removed from the flask and spread over the bottom of 0256 Propoxyphene diclofenate solutions were prepared a crystallizing dish which is placed in a vacuum oven for by adding propoxyphene diclofenate (approx. 48 mg, 0.076 prolonged drying at 30° C. to remove any odor of residual mmol) to dissolution vessels containing water (400 mL) at acetone. Yield of the title compound was 239.2 g (0.3763 pH of 2, 3, 5, 7, 9 and 11 and equilibrated at 36.8° C. The mol; 89.5%). solutions were stirred by paddles at 150 RPM for approxi EXAMPLE 155 mately 12 hours. Final Sample Solutions were prepared by diluting 12.5 mL of the propoxyphene diclofenate Solution Preparation of (2S,3R)-(+)-4-(Dimethylamino)-3- from each vessel filtered through a 0.45 um Nylon filter to methyl-1,2-diphenyl-2-butanol Propionate 50.0 mL with methanol. Five standard solutions of pro Diclofenate from Sodium Diclofenac and (2S,3R)- poxyphene diclofenate were prepared at concentrations (+)-4-(Dimethylamino)-3-methyl-1,2-diphenyl-2- ranging from 0.00091 to 0.02914 mg/mL. The standards and butanol Propionate (Propoxyphene) Hydrochloride Sample preparations were measured at 282 nm in a 1 cm cell 0259 Propoxyphene hydrochloride (117.0g, 0.3112 mol) using a UV spectrophotometer. The results were determined was dissolved in water (1500 mL) at about 50° C. with US 2005/0203115 A1 Sep. 15, 2005 42 mechanical stirring. To this a 50° C. solution of sodium water to remove excess diclofenac (Sodium or potassium). diclofenac (108.2 g, 0.34 mol) in water (2000 mL) was The levels of diclofenac salts were monitored to determine Slowly added while Vigorously stirring the mixture with a the reaction end point by HPLC according to the following mechanical Stirrer and maintaining the temperature at about procedure. 50° C. A thick sticky white precipitate formed as the solution was stirred. Completeness of reaction was confirmed by 0262 HPLC was performed with the HP1100 system HPLC to determine the amount of unreacted propoxyphene (Hewlett Packard, Palo Alto, Calif.). The method utilized a hydrochloride remaining in Solution (about 1 mg/mL 4.6x150 mm Cs column (Waters Corporation, Milford, remained). The reaction was considered complete, the Solu Mass.) maintained at room temperature. The mobile phase tion was decanted, and the Solid product washed with was gradient controlled, consisting of Mobile Phase A numerous aliquots of water (about 300 mL for each wash (MPA), a 90:10 mixture of water (4 drops trifluoroacetic acid ing) at about 50° C. with mechanical stirring until HPLC (TFA) per 900 mL); and Mobile Phase B (MP), a 70:30 confirmed only low levels of unreacted sodium diclofenate mixture of acetonitril: water. The gradient program was Set as remained (about 0.2 mg/mL). The solid material was then follows: dissolved in a minimal amount of acetone and the acetone Subsequently removed by rotary evaporation to yield a white Solid. The white Solid was then removed from the flask and Spread over the bottom of a crystallizing dish which was Time (min) % MP % MP placed in a vacuum oven for prolonged drying at 30° C. to O.O 95.0 95.0 remove residual acetone. Acetone removal was considered 3O.O 5.0 95.0 complete when no odor of residual acetone remained. Yield 31.0 5.0 95.0 of the title compound was 150.9 g (0.2374 mol; 76.3%). 32.O 95.0 5.0 EXAMPLE 1.56 Preparation of (2S,3R)-(+)-4-(Dimethylamino)-3- 0263. The flow rate was maintained at 1.0 mL/minute. methyl-1,2-diphenyl-2-butanol Propionate Standards and Sample Solutions were prepared in water at Diclofenate from Potassium Diclofenac and (2S, concentrations of 0.3, 0.6, and 1.0 mM. Injection volume for 3R)-(+)-4-(Dimethylamino)-3-methyl-1,2-diphenyl Sample and Standard preparations (diclofenac potassium 2-butanol Propionate (Propoxyphene) Hydrochlo (Yung Zip); propoxyphene HCl (Mallinckrodt)) was 10 ul, ride and run time was about 32 minutes. UV detection was 0260 Potassium diclofenac (335.2 g, 1.003 mol) was performed at 217 nm. The chromatographic data peak areas dissolved in water (2000 mL) at about 50° C. with mechani were collected and analyzed using Millenium chromatog cal stirring. To this a 50° C. solution of (2S,3R)-(+)-4- raphy software (Waters Corporation, Milford, Mass.) to (dimethylamino)-3-methyl-1,2-diphenyl-2-butanol propi generate the % W/w assay values for the Samples. onate hydrochloride (376.6 g., 1.002 mol) in water (700 mL) was slowly added while Vigorously Stirring the mixture with EXAMPLE 158 a mechanical Stirrer and maintaining the temperature at about 50 C. A thick sticky white precipitate formed as the Analysis of the Aqueous Mother Liquor and Solution was stirred over Several hours. Completeness of Subsequent Washings During Propoxyphene reaction was confirmed by HPLC to determine the amount of unreacted propoxyphene hydrochloride remaining in Diclofenate Synthesis Using High Pressure Liquid Solution (about 1 mg/mL remained). The reaction was con Chromatography sidered complete when about 1 mg/mL propoxyphene 0264. During the synthesis of propoxyphene diclofenate hydrochloride remained in solution. The solvent was as described in the foregoing examples the reaction was decanted, and the Solid product washed with numerous aliquots of water (about 500 mL for each washing) at about considered complete once the reaction mixture contained an 50° C. with mechanical stirring until HPLC confirmed only acceptably low level of propoxyphene as determined by low levels of unreacted Sodium diclofenate remained (about HPLC. When the reaction was complete, the aqueous 0.2 mg/mL). The solid material was then dissolved in a mother liquor was decanted and the product washed with minimal amount of acetone and the acetone Subsequently numerous aqueous rinses to remove exceSS diclofenac removed by rotary evaporation to yield a white solid. The (Sodium or potassium). Using an HPLC analysis according white solid was then removed from the flask and spread over to the following procedure, the propoxyphene and the bottom of a crystallizing dish which was placed in a diclofenac levels were monitored during the reaction to vacuum oven for prolonged drying at 30° C. to remove determine the end point of the reaction, and the point when residual acetone. Acetone removal was considered complete Sufficient washing had been accomplished. when no odor of residual acetone remained. Yield of the title 0265 For each of the procedures above, HPLC was compound was 613.2 g (0.9647 mol; 96.3%). performed with the HP 1100 system (Hewlett Packard, Palo EXAMPLE 1.57 Alto, Calif.). The method utilized a 4.6x150 mm Cs column (Waters Corporation, Milford, Mass.) maintained at room Analysis of Washings of Propoxyphene Diclofenate temperature. The mobile phase was gradient controlled, Synthesis Using High Pressure Liquid consisting of Mobile Phase A, a 90:10 mixture of water (4 Chromatography (HPLC) drops trifluoroacetic acid (TFA) per 900 mL):acetonitrile, 0261 During the synthesis of propoxyphene diclofenate and Mobile Phase B; a 70:30 mixture of acetonitrile:Water. in the foregoing examples, the product was washed with The gradient program was set as follows: US 2005/0203115 A1 Sep. 15, 2005 43

13. The ion pair compound according to claim 10, wherein said NSAID is a COX-LOX inhibitor. 14. The ion pair compound according to claim 10, Time (min) % MP % MP wherein said NSAID is a PLA inhibitor. O.O 95.0 95.0 15. The ion pair compound according to claim 2, wherein 3O.O 5.0 95.0 A in A is selected from the group consisting of nonse 31.0 5.0 95.0 lective COX inhibitors, selective COX-2 inhibitors, COX 32.O 95.0 5.0 LOX inhibitors, PLA inhibitors, and combinations thereof. 16. The ion pair compound according to claim 15, 0266 The flow rate was maintained at 1.0 mL/minute. wherein said NSAID is a nonselective COX inhibitor. Standard and Sample Solutions were prepared in water at 17. The ion pair compound according to claim 15, concentrations of 0.3, 0.6, and 1.0 mM. Injection volume for wherein said NSAID is a selective COX-2 inhibitor. the sample and Standard preparations (diclofenac potassium 18. The ion pair compound according to claim 15, (Yung Zip); propoxyphene HCl (Mallinckrodt)) was 10 uL wherein said NSAID is a COX-LOX inhibitor. and runtime of the analysis was about 32 minutes. UV 19. The ion pair compound according to claim 15, detection was performed at 217 nm. The chromatographic wherein said NSAID is a PLA inhibitor. data peak areas were collected and analyzed using Millen 20. The ion pair compound according to claim 1, wherein nium chromatography software (Waters Corporation, Mil the NSAID is selected from the group consisting of ford, Mass.) to generate the 96 w/w values for the samples. diclofenac, etodolac, Sulindac, alclofenac, fenclofenac, diflunisal, benorylate, fosfosal, Salicylic acid, acetylsalicylic What is claimed is: acid, ibuprofen, ketoprofen, naproxen, carprofen, fenbufen, 1. An ion pair compound according to general formula I: flurbiprofen, oxaprozin, Suprofen, triaprofenic acid, feno narcotic"A (I) profen, indoprofen, piroprofen, flufenamic, mefenamic, meclofenamic, niflumic, Salsalate, rolmerin, fentiazac, tilo wherein misole, oxyphenbutaZone, phenylbutaZone, apaZone, fepra narcotic represents at least one cation of at least one Zone, Sudoxicam, isoxicam, tenoxicam, piroXicam, narcotic agent or one or more Stereochemical isomers indomethacin, meloxicam, nabumetone, tolmetin, lumira thereof, and coxib, and parecoxib. 21. The ion pair compound according to claim 20, A represents an anion of at least one NSAID or one or wherein the NSAID is selected from the group consisting of more Stereochemical isomers thereof, diclofenac, etodolac, Sulindac, Salicylic acid, acetylsalicylic or a pharmaceutically acceptable Solvate, hydrate, poly acid, ibuprofen, ketoprofen, naproxen, lumiracoxib, and morph, isotopically labeled version, or combination parecoxib. thereof. 22. The ion pair compound according to claim 20, 2. The ion pair compound according to claim 1, wherein wherein the NSAID is diclofenac. the narcotic in narcotic is selected from the group con 23. The ion pair compound according to claim 20, Sisting of ketamine, oxycodone, propoxyphene, methadone, wherein the NSAID is lumiracoxib. hydrocodone, morphine, codeine, fentanyl, meperidine, 24. The ion pair compound according to claim 2, wherein hydromorphone, oxymorphone, dihydrocodeine, nalbu the NSAID is selected from the group consisting of phine, and buprenorphine. diclofenac, etodolac, Sulindac, alclofenac, fenclofenac, 3. The ion pair compound according to claim 2, wherein diflunisal, benorylate, fosfosal, Salicylic acid, acetylsalicylic the narcotic in narcotic is selected from the group con acid, ibuprofen, ketoprofen, naproxen, carprofen, fenbufen, Sisting of ketamine, oxycodone, propoxyphene, methadone, flurbiprofen, oxaprozin, Suprofen, triaprofenic acid, feno hydrocodone, morphine, and codeine. profen, indoprofen, piroprofen, flufenamic, mefenamic, 4. The ion pair compound according to claim 3, wherein meclofenamic, niflumic, Salsalate, rolmerin, fentiazac, tilo the narcotic is propoxyphene. misole, oxyphenbutaZone, phenylbutaZone, apaZone, fepra 5. The ion pair compound according to claim 3, wherein Zone, Sudoxicam, isoxicam, tenoxicam, piroXicam, the narcotic is codeine. indomethacin, meloxicam, nabumetone, tolmetin, lumira 6. The ion pair compound according to claim 3, wherein coxib, and parecoxib. the narcotic is hydrocodone. 25. The ion pair compound according to claim 24, 7. The ion pair compound according to claim 3, wherein wherein the NSAID is selected from the group consisting of the narcotic is Oxycodone. diclofenac, etodolac, Sulindac, Salicylic acid, acetylsalicylic 8. The ion pair compound according to claim 3, wherein acid, ibuprofen, ketoprofen, naproxen, lumiracoxib, and the narcotic is morphine. parecoxib. 9. The ion pair compound according to claim 3, wherein 26. The ion pair compound according to claim 1, wherein the narcotic is methadone. the compound is Selected from the group consisting of 10. The ion pair compound according to claim 1, wherein propoxyphene diclofenate, ketamine diclofenate, methadone A in A is selected from the group consisting of nonse diclofenate, hydrocodone diclofenate, codeine diclofenate, lective COX inhibitors, selective COX-2 inhibitors, COX propoxyphene Salicylate, propoxyphene acetylsalicylate, LOX inhibitors, PLA inhibitors, and combinations thereof. propoxyphene ibuprofenate, morphine diclofenate, and oxy 11. The ion pair compound according to claim 10, wherein codone diclofenate. said NSAID is a nonselective COX inhibitor. 27. The ion pair compound according to claim 24, 12. The ion pair compound according to claim 10, wherein the compound is Selected from the group consisting wherein said NSAID is a selective COX-2 inhibitor. of propoxyphene diclofenate, ketamine diclofenate, metha US 2005/0203115 A1 Sep. 15, 2005 44 done diclofenate, hydrocodone diclofenate, codeine phine flurbiprofenate, morphine tolmetinate, morphine diclofenate, morphine diclofenate, and oxycodone fenoprofenate, morphine oxaprozinate, morphine diclofenate. difunisalate, morphine loxoprofenate, 28. The ion pair compound according to claim 24, levorphanol ibuprofenate, levorphanol acetylsalicylate, wherein the compound is Selected from the group consisting levorphanol Salicylate, levorphanol indomethacinate, of propoxyphene Salicylate, propoxyphene acetylsalicylate, levorphanol naproxenate, levorphanol etodolate, levor and propoxyphene ibuprofenate. phanol Sulindate, levorphanol ketoprofenate, levorpha 29. The ion pair compound according to claim 1, wherein nol Suprofenate, levorphanol flurbiprofenate, levorpha the compound is Selected from the group consisting of nol tolmetinate, levorphanol fenoprofenate, propoxyphene lumiracoxibate, ketamine lumiracoxibate, levorphanol oxaprozinate, levorphanol difunisalate, methadone lumiracoxibate, hydrocodone lumiracoxibate, levorphanol loxoprofenate, codeine lumiracoxibate, morphine lumiracoxibate, and oxy codone lumiracoxibate. Oxycodone ibuprofenate, Oxycodone acetylsalicylate, 30. The ion pair compound according to claim 1, wherein Oxycodone Salicylate, oxycodone indomethacinate, the compound is Selected from the group consisting of Oxycodone naproxenate, Oxycodone etodolate, oxyc propoxyphene parecoxibate, ketamine parecoxibate, metha Odone Sulindate, Oxycodone ketoprofenate, oxycodone done parecoxibate, hydrocodone parecoxibate, codeine Suprofenate, oxycodone flurbiprofenate, oxycodone parecoxibate, morphine parecoxibate, and oxycodone pare tolmetinate, oxycodone fenoprofenate, oxycodone coXibate. Oxaprozinate, Oxycodone difunisalate, oxycodone 31. The ion pair compound according to claim 1, wherein loxoprofenate, the compound is Selected from the group consisting of propoxyphene naproxenate, propoxyphene etodolate, pro fentanyl naproXenate, fentanyl etodolate, fentanyl keto poxyphene ketoprofenate, propoxyphene Sulindate, pro profenate, fentanyl Sulindate, fentanyl Suprofenate, fen poxyphene Suprofenate, propoxyphene flurbiprofenate, pro tanyl flurbiprofenate, fentanyl tolmetinate, fentanyl poxyphene tolmetinate, propoxyphene fenoprofenate, fenoprofenate, fentanyl oxaprozinate, fentanyl difinis propoxyphene oxaprozinate, propoxyphene difunisalate, alate, fentanyl loxoprofenate, propoxyphene loxoprofenate, meperidine naproxenate, meperidine etodolate, meperi dine ketoprofenate, meperidine Sulindate, meperidine ketamine ibuprofenate, ketamine acetylsalicylate, ket Suprofenate, meperidine flurbiprofenate, meperidine amine indomethacinate, ketamine naproXenate, ket tolmetinate, meperidine fenoprofenate, meperidine amine etodolate, ketamine Sulindate, ketamine ketopro Oxaprozinate, meperidine difunisalate, meperidine fenate, ketamine Suprofenate, ketamine flurbiprofenate, loxoprofenate, ketamine tolmetinate, ketamine fenoprofenate, ket amine oxaprozinate, ketamine difunisalate, ketamine hydromorphone naproxenate, hydromorphone etodolate, loxoprofenate, ketamine Salicylate, ketamine hydromorphone ketoprofenate, hydromorphone Sulin diclofenate, date, hydromorphone Suprofenate, hydromorphone flurbiprofenate, hydromorphone tolmetinate, hydro methadone ibuprofenate, methadone acetylsalicylate, morphone fenoprofenate, hydromorphone methadone Salicylate, methadone indomethacinate, Oxaprozinate, hydromorphone difunisalate, hydromor methadone naproxenate, methadone etodolate, metha phone loxoprofenate, done Sulinate, methadone ketoprofenate, methadone Suprofenate, methadone flurbiprofenate, methadone Oxymorphone naproXenate, oxymorphone etodolate, Oxy tolmetinate, methadone fenoprofenate, methadone morphone ketoprofenate, oxymorphone Sulindate, Oxy Oxaprozinate, methadone difunisalate, methadone morphone Suprofenate, Oxymorphone flurbiprofenate, loxoprofenate, Oxymorphone tolmetinate, Oxymorphone fenopro hydrocodone ibuprofenate, hydrocodone acetylsalicylate, fenate, oxymorphone oxaprozinate, oxymorphone hydrocodone Salicylate, hydrocodone indomethacinate, difunisalate, oxymorphone loxoprofenate, hydrocodone naproxenate, hydrocodone etodolate, dihydrocodeine naproxenate, dihydrocodeine etodolate, hydrocodone Sulindate, hydrocodone ketoprofenate, dihydrocodeine ketoprofenate, dihydrocodeine Sulin hydrocodone Suprofenate, hydrocodone flurbipro date, dihydrocodeine Suprofenate, dihydrocodeine flur fenate, hydrocodone tolmetinate, hydrocodone feno biprofenate, dihydrocodeine tolmetinate, dihydroco profenate, hydrocodone oxaprozinate, hydrocodone deine fenoprofenate, dihydrocodeine Oxaprozinate, difunisalate, hydrocodone loxoprofenate, dihydrocodeine difunisalate, and dihydrocodeine loXo profenate. codeine ibuprofenate, codeine acetylsalicylate, codeine 32. The ion pair compound according to claim 1, wherein Salicylate, codeine indomethacinate, codeine naproX the compound is propoxyphene diclofenate. enate, codeine etodolate, codeine Sulindate, codeine 33. A pharmaceutical composition comprising a therapeu ketoprofenate, codeine Suprofenate, codeine flurbipro tically effective amount of the ion pair compound according fenate, codeine tolmetinate, codeine fenoprofenate, to claim 1 and a pharmaceutically acceptable carrier, diluent, codeine oxaprozinate, codeine difunisalate, codeine excipient, Stimulant, or combination thereof. loxoprofenate, 34. The pharmaceutical composition according to claim morphine ibuprofenate, morphine acetylsalicylate, mor 33, wherein the composition further comprises a therapeu phine Salicylate, morphine indomethacinate, morphine tically effective amount of an additional NSAID. naproxenate, morphine etodolate, morphine Sulindate, 35. The pharmaceutical composition according to claim morphine ketoprofenate, morphine Suprofenate, mor 34, wherein the additional NSAID is the same as A, or a US 2005/0203115 A1 Sep. 15, 2005 45 pharmaceutically acceptable Salt, Solvate, hydrate, poly profenate, hydrocodone oxaprozinate, hydrocodone morph, isotopically labeled version, or combination thereof. difunisalate, hydrocodone loxoprofenate, 36. The pharmaceutical composition according to claim codeine ibuprofenate, codeine acetylsalicylate, codeine 35, wherein the ion pair compound is propoxyphene Salicylate, codeine indomethacinate, codeine naproX diclofenate. enate, codeine etodolate, codeine Sulindate, codeine 37. The pharmaceutical composition according to claim ketoprofenate, codeine Suprofenate, codeine flurbipro 36, wherein the additional NSAID is selected from the group fenate, codeine tolmetinate, codeine fenoprofenate, consisting of diclofenac free acid and pharmaceutically codeine oxaprozinate, codeine difunisalate, codeine acceptable Salts thereof. loxoprofenate, 38. The pharmaceutical composition according to claim 37, wherein the pharmaceutically acceptable Salts are morphine ibuprofenate, morphine acetylsalicylate, mor Selected from Sodium and potassium Salts. phine Salicylate, morphine indomethacinate, morphine 39. The pharmaceutical composition according to claim naproxenate, morphine etodolate, morphine Sulindate, 34, wherein the additional NSAID is different from A. morphine ketoprofenate, morphine Suprofenate, mor 40. The pharmaceutical composition according to claim phine flurbiprofenate, morphine tolmetinate, morphine 33, wherein the composition further comprises a therapeu fenoprofenate, morphine oxaprozinate, morphine tically effective amount of an additional narcotic, difunisalate, morphine loxoprofenate, 41. The pharmaceutical composition according to claim levorphanol ibuprofenate, levorphanol acetylsalicylate, 40, wherein the additional narcotic is the same as the levorphanol Salicylate, levorphanol indomethacinate, narcotic in narcotic", or a pharmaceutically acceptable Salt, levorphanol naproxenate, levorphanol etodolate, levor Solvate, hydrate, polymorph, isotopically labeled version, or phanol Sulindate, levorphanol ketoprofenate, levorpha combination thereof. nol Suprofenate, levorphanol flurbiprofenate, levorpha 42. The pharmaceutical composition according to claim nol tolmetinate, levorphanol fenoprofenate, 41, wherein the additional narcotic is different from the levorphanol oxaprozinate, levorphanol difunisalate, narcotic in narcotic". levorphanol loxoprofenate, 43. The pharmaceutical composition according to claim Oxycodone ibuprofenate, Oxycodone acetylsalicylate, 33, wherein the ion pair compound is Selected from the Oxycodone Salicylate, oxycodone indomethacinate, group consisting of propoxyphene diclofenate, ketamine Oxycodone naproxenate, Oxycodone etodolate, oxyc diclofenate, methadone diclofenate, hydrocodone Odone Sulindate, Oxycodone ketoprofenate, oxycodone diclofenate, codeine diclofenate, propoxyphene Salicylate, Suprofenate, oxycodone flurbiprofenate, oxycodone propoxyphene acetylsalicylate propoxyphene ibuprofenate, tolmetinate, oxycodone fenoprofenate, oxycodone morphine diclofenate, and oxycodone diclofenate. Oxaprozinate, Oxycodone difunisalate, oxycodone 44. The pharmaceutical composition according to claim loxoprofenate, 33, wherein the compound is Selected from the group consisting of propoxyphene naproxenate, propoxyphene fentanyl naproXenate, fentanyl etodolate, fentanyl keto etodolate, propoxyphene ketoprofenate, propoxyphene profenate, fentanyl Sulindate, fentanyl Suprofenate, fen Sulindate, propoxyphene Suprofenate, propoxyphene flurbi tanyl flurbiprofenate, fentanyl tolmetinate, fentanyl profenate, propoxyphene tolmetinate, propoxyphene feno fenoprofenate, fentanyl oxaprozinate, fentanyl difunis profenate, propoxyphene Oxaprozinate, propoxyphene alate, fentanyl loxoprofenate, difunisalate, propoxyphene loxoprofenate, meperidine naproxenate, meperidine etodolate, meperi ketamine ibuprofenate, ketamine acetylsalicylate, ket dine ketoprofenate, meperidine Sulindate, meperidine amine indomethacinate, ketamine naproxenate, ket Suprofenate, meperidine flurbiprofenate, meperidine amine etodolate, ketamine Sulindate, ketamine ketopro tolmetinate, meperidine fenoprofenate, meperidine fenate, ketamine Suprofenate, ketamine flurbiprofenate, Oxaprozinate, meperidine difunisalate, meperidine ketamine tolmetinate, ketamine fenoprofenate, ket loxoprofenate, amine oxaprozinate, ketamine difunisalate, ketamine hydromorphone naproxenate, hydromorphone etodolate, loxoprofenate, ketamine Salicylate, ketamine hydromorphone ketoprofenate, hydromorphone Sulin diclofenate, date, hydromorphone Suprofenate, hydromorphone flurbiprofenate, hydromorphone tolmetinate, hydro methadone ibuprofenate, methadone acetylsalicylate, morphone fenoprofenate, hydromorphone methadone Salicylate, methadone indomethacinate, Oxaprozinate, hydromorphone difunisalate, hydromor methadone naproxenate, methadone etodolate, metha phone loxoprofenate, done Sulinate, methadone ketoprofenate, methadone Suprofenate, methadone flurbiprofenate, methadone Oxymorphone naproXenate, oxymorphone etodolate, Oxy tolmetinate, methadone fenoprofenate, methadone morphone ketoprofenate, oxymorphone Sulindate, Oxy Oxaprozinate, methadone difunisalate, methadone morphone Suprofenate, Oxymorphone flurbiprofenate, loxoprofenate, Oxymorphone tolmetinate, Oxymorphone fenopro hydrocodone ibuprofenate, hydrocodone acetylsalicylate, fenate, oxymorphone oxaprozinate, oxymorphone hydrocodone Salicylate, hydrocodone indomethacinate, difunisalate, oxymorphone loxoprofenate, hydrocodone naproxenate, hydrocodone etodolate, dihydrocodeine naproxenate, dihydrocodeine etodolate, hydrocodone Sulindate, hydrocodone ketoprofenate, dihydrocodeine ketoprofenate, dihydrocodeine Sulin hydrocodone Suprofenate, hydrocodone flurbipro date, dihydrocodeine Suprofenate, dihydrocodeine flur fenate, hydrocodone tolmetinate, hydrocodone feno biprofenate, dihydrocodeine tolmetinate, dihydroco US 2005/0203115 A1 Sep. 15, 2005 46

deine fenoprofenate, dihydrocodeine Oxaprozinate, tering to an animal in need of treatment a therapeutically dihydrocodeine difunisalate, and dihydrocodeine loXo effective amount of the ion pair compound according to profenate. claim 1. 45. The pharmaceutical composition according to claim 61. A method of treating a condition for which is indicated 40, wherein the ion pair compound is propoxyphene an analgesic and an anti-inflammatory agent in animals diclofenate. comprising administering to an animal in need of treatment 46. The pharmaceutical composition according to claim a therapeutically effective amount of the ion pair compound 33, further comprising: according to claim 1. 62. The method according to claim 59 wherein the animal at least one dispersing agent Selected from the group is a mammal. consisting of polymer-based dispersing agents and car 63. The method according to claim 62 wherein the mam bohydrate-based dispersing agents, mal is a human. wherein the ratio of the ion pair compound to the 64. The method according to claim 60 wherein the animal polymer-based dispersing agent is from about 3:1 is a mammal. (w/w) to about 1:50 (w/w), and 65. The method according to claim 64 wherein the mam mal is a human wherein the ratio of the ion pair compound to the 66. The method according to claim 61 wherein the animal carbohydrate-based dispersing agent is from about is a mammal. 3:1 (w/w) to about 1:20 (w/w); and 67. The method according to claim 66 wherein the mam at least one Solubilizing agent; and, optionally, mal is a human. 68. A method of treating a condition for which is indicated at least one Surfactant; and, further optionally, an analgesic in animals comprising administering to an at least one plasticizing agent. animal in need of treatment a therapeutically effective 47. The pharmaceutical composition according to claim amount of the pharmaceutical composition according to 46, wherein at least one dispersing agent is a polymer-based claim 33. dispersing agent. 69. A method of treating a condition for which is indicated 48. The pharmaceutical composition according to claim an anti-inflammatory agent in animals comprising adminis 47, wherein the polymer-based dispersing agent is polyvi tering to an animal in need of treatment a therapeutically nylpyrrollidone. effective amount of the pharmaceutical composition accord 49. The pharmaceutical composition according to claim ing to claim 33. 48, wherein the polyvinylpyrrollidone is polyvinylpyrroli 70. A method of treating a condition for which is indicated done K29-32. an analgesic and an anti-inflammatory agent in animals 50. The pharmaceutical composition according to claim comprising administering to an animal in need of treatment 46, wherein at least one dispersing agent is a carbohydrate a therapeutically effective amount of the pharmaceutical based dispersing agent. composition according to claim 33. 51. The pharmaceutical composition according to claim 71. The method according to claim 68 wherein the animal 50, wherein the carbohydrate-based dispersing agent is is a mammal. Selected from the group consisting of hydroxypropylcellu 72. The method according to claim 71 wherein the mam lose, hydroxymethylcellulose, and cyclodextrin. mal is a human. 52. The pharmaceutical composition according to claim 73. The method according to claim 69 wherein the animal 46, wherein the composition comprises a Solubilizing agent. is a mammal. 53. The pharmaceutical composition according to claim 74. The method according to claim 73 wherein the mam 52, wherein the Solubilizing agent is Selected from the group mal is a human. consisting of water and polyethylene glycol. 75. The method according to claim 70 wherein the animal 54. The pharmaceutical composition according to claim is a mammal. 53, wherein the molecular weight of the polyethylene glycol 76. The method according to claim 75 wherein the mam is from about 200 g/mol to about 8,000 g/mol. mal is a human. 55. The pharmaceutical composition according to claim 77. The method according to claim 59, wherein the 53, wherein the concentration of the polyethylene glycol is condition is Selected from the group consisting of arthritic from about 20 percent (w/w) to about 99 percent (w/w) disorders, gastrointestinal conditions, inflammatory condi based on the total weight of the composition. tions, pulmonary inflammation, opthalmic diseases, central 56. The pharmaceutical composition according to claim nervous Systems disorders, pain, fever, inflammation-related 46, wherein the composition comprises a plasticizing agent. cardiovascular disorders, angiogenesis-related disorders, 57. The pharmaceutical composition according to claim benign and malignant tumors, adenomatous polyps, fibrosis 56, wherein the plasticizing agent is Selected from the group which occurs with radiation treatment, endometriosis, consisting of glycerin, propylene glycol, and Sorbitol. Osteoporosis, dysmenorrhea, premature labor, asthma, eosi 58. The pharmaceutical composition according to claim nophil-related disorders, pyrexia, bone resorption, nephro 46, wherein the composition comprises a Surfactant. toxicity, hypotension, arthrosis, joint Stiffness, kidney dis 59. A method of treating a condition for which is indicated ease, liver disease, acute mastitis, diarrhea, colonic an analgesic in animals comprising administering to an adenomas, bronchitis, allergic neuritis, cytomegalovirus animal in need of treatment a therapeutically effective infectivity, apoptosis, HIV-induced apoptosis, lumbago, pSo amount of the ion pair compound according to claim 1. riasis, eczema, acne, burns, dermatitis, ultraViolet radiation 60. A method of treating a condition for which is indicated damage, allergic rhinitis, respiratory distress Syndrome, and an anti-inflammatory agent in animals comprising adminis endotoxin shock Syndrome. US 2005/0203115 A1 Sep. 15, 2005 47

78. The method according to claim 77, wherein the 98. The method according to claim 59, wherein the condition is an arthritic disorder. narcotic is propoxyphene. 79. The method according to claim 78, wherein the 99. The method according to claim 59, wherein the arthritic disorder is Selected from the group consisting of compound is Selected from the group consisting of pro rheumatoid arthritis and osteoarthritis. poxyphene diclofenate, ketamine diclofenate, methadone 80. The method according to claim 59, wherein the diclofenate, hydrocodone diclofenate, codeine diclofenate, condition is primary dySmenorrhea. propoxyphene Salicylate, propoxyphene acetylsalicylate 81. The method according to claim 59, wherein the propoxyphene ibuprofenate, morphine diclofenate, and oxy condition is ankylosing spondylitis. codone diclofenate. 82. The method according to claim 77, wherein the 100. The method according to claim 59, wherein the condition is an inflammatory disorder. compound is Selected from the group consisting of pro 83. The method according to claim 82, wherein the poxyphene naproxenate, propoxyphene etodolate, pro inflammatory disorder is Selected from the group consisting poxyphene ketoprofenate, propoxyphene Sulindate, pro of tendinitis and bursitis. poxyphene Suprofenate, propoxyphene flurbiprofenate, 84. The method according to claim 77, wherein the propoxyphene tolmetinate, propoxyphene fenoprofenate, condition is acute gouty arthritis. propoxyphene oxaprozinate, propoxyphene difunisalate, 85. The method according to claim 77, wherein the propoxyphene loxoprofenate, condition is pain. ketamine acetylsalicylate, ketamine naproxenate, ket 86. The method according to claim 85, wherein the type amine etodolate, ketamine Sulindate, ketamine ketopro of pain treated is anogenital, minor arthritic, dental, topical, fenate, ketamine Suprofenate, ketamine flurbiprofenate, asSociated with an upper respiratory infection, general, joint, ketamine tolmetinate, ketamine fenoprofenate, ket menstrual, mild, mild to moderate, acute musculo-skeletal, amine oxaprozinate, ketamine difunisalate, ketamine moderate to moderately Severe, moderate to Severe, muscu loxoprofenate, ketamine ibuprofenate, ketamine Salicy lar, neurogenic, obstetrical, ocular, oral mucosal and gingi late, ketamine indomethacinate, ketamine diclofenate, val, post operative, pre-operative, pre- and post-operative, methadone ibuprofenate, methadone acetylsalicylate, Severe, short term, urinary tract, or associated with gastric methadone Salicylate, methadone indomethacinate, hyperacidity. methadone naproxenate, methadone etodolate, metha 87. The method according to claim 85 wherein the type of done Sulinate, methadone ketoprofenate, methadone pain is mild to moderate. Suprofenate, methadone flurbiprofenate, methadone 88. The method according to claim 85 wherein the type of tolmetinate, methadone fenoprofenate, methadone pain is moderate to moderately Severe. Oxaprozinate, methadone difunisalate, methadone 89. The method according to claim 85 wherein the type of loxoprofenate, pain is moderate to Severe. hydrocodone ibuprofenate, hydrocodone acetylsalicylate, 90. The method according to claim 85 wherein the type of hydrocodone Salicylate, hydrocodone indomethacinate, pain is Severe. hydrocodone naproxenate, hydrocodone etodolate, 91. The method according to claim 85 wherein the type of hydrocodone Sulindate, hydrocodone ketoprofenate, pain is Selected from the group consisting of pre-operative, hydrocodone Suprofenate, hydrocodone flurbipro post operative, and pre- and post-operative. fenate, hydrocodone tolmetinate, hydrocodone feno 92. The method according to claim 59, wherein the profenate, hydrocodone oxaprozinate, hydrocodone NSAID is selected from the group consisting of diclofenac, difunisalate, hydrocodone loxoprofenate, etodolac, Sulindac, alclofenac, fenclofenac, diflunisal, beno rylate, fosfosal, aspirin, Salicylic acid, acetylsalicylic acid, codeine ibuprofenate, codeine acetylsalicylate, codeine ibuprofen, ketoprofen, naproxen, carprofen, fenbufen, flur Salicylate, codeine indomethacinate, codeine naproX biprofen, oxaprozin, Suprofen, triaprofenic acid, fenoprofen, enate, codeine etodolate, codeine Sulindate, codeine indoprofen, piroprofen, flufenamic, mefenamic, meclofe ketoprofenate, codeine Suprofenate, codeine flurbipro namic, niflumic, Salsalate, rolmerin, fentiazac, tilomisole, fenate, codeine tolmetinate, codeine fenoprofenate, OxyphenbutaZone, phenylbutaZone, apaZone, feprazone, codeine oxaprozinate, codeine difunisalate, codeine Sudoxicam, isoxicam, tenoxicam, piroXicam, indomethacin, loxoprofenate, meloxicam, nabumetone, tolmetin, lumiracoxib, and pare morphine ibuprofenate, morphine acetylsalicylate, mor coxib. phine Salicylate, morphine indomethacinate, morphine 93. The method according to claim 92, wherein the naproxenate, morphine etodolate, morphine Sulindate, NSAID is selected from the group consisting of diclofenac, morphine ketoprofenate, morphine Suprofenate, mor etodolac, Sulindac, Salicylic acid, acetylsalicylic acid, ibu phine flurbiprofenate, morphine tolmetinate, morphine profen, ketoprofen, naproxen, lumiracoxib, and parecoxib. fenoprofenate, morphine oxaprozinate, morphine 94. The method according to claim 59, wherein the difunisalate, morphine loxoprofenate, NSAID is a COX-2 selective inhibitor. levorphanol ibuprofenate, levorphanol acetylsalicylate, 95. The method according to claim 94, wherein the levorphanol Salicylate, levorphanol indomethacinate, COX-2 selective inhibitor is selected from the group con levorphanol naproxenate, levorphanol etodolate, levor Sisting of etoricoxib, rofecoxib, celecoxib, Valdecoxib. phanol Sulindate, levorphanol ketoprofenate, levorpha 96. The method according to claim 59, wherein the nol Suprofenate, levorphanol flurbiprofenate, levorpha NSAID is a COX-LOX inhibitor. nol tolmetinate, levorphanol fenoprofenate, 97. The method according to claim 59, wherein the levorphanol oxaprozinate, levorphanol difunisalate, NSAID is a PLA inhibitor. levorphanol loxoprofenate, US 2005/0203115 A1 Sep. 15, 2005 48

Oxycodone ibuprofenate, Oxycodone acetylsalicylate, 105. The method according to claim 60, wherein the Oxycodone Salicylate, oxycodone indomethacinate, condition is primary dysmenorrhea. Oxycodone naproxenate, oxycodone etodolate, oxyc 106. The method according to claim 60, wherein the odone Sulindate, oxycodone ketoprofenate, oxycodone condition is ankylosing spondylitis. Suprofenate, oxycodone flurbiprofenate, oxycodone 107. The method according to claim 102, wherein the tolmetinate, oxycodone fenoprofenate, oxycodone condition is an inflammatory disorder. Oxaprozinate, Oxycodone difunisalate, oxycodone 108. The method according to claim 107, wherein the loxoprofenate inflammatory disorder is Selected from the group consisting fentanyl naproxenate, fentanyl etodolate, fentanyl keto of tendinitis and bursitis. profenate, fentanyl Sulindate, fentanyl Suprofenate, fen 109. The method according to claim 102, wherein the tanyl flurbiprofenate, fentanyl tolmetinate, fentanyl condition is acute gouty arthritis. fenoprofenate, fentanyl oxaprozinate, fentanyl difunis 110. The method according to claim 102, wherein the alate, fentanylloxoprofenate, condition is pain. 111. The method according to claim 110, wherein the type meperidine naproxenate, meperidine etodolate, meperi of pain treated is anogenital, minor arthritic, dental, topical, dine ketoprofenate, meperidine Sulindate, meperidine asSociated with an upper respiratory infection, general, joint, Suprofenate, meperidine flurbiprofenate, meperidine menstrual, mild, mild to moderate, acute musculo-skeletal, tolmetinate, meperidine fenoprofenate, meperidine moderate to moderately Severe, moderate to Severe, muscu Oxaprozinate, meperidine difunisalate, meperidine lar, neurogenic, obstetrical, ocular, oral mucosal and gingi loxoprofenate, val, post operative, pre-operative, pre- and post-operative, hydromorphone naproxenate, hydromorphone etodolate, Severe, short term, urinary tract, or associated with gastric hydromorphone ketoprofenate, hydromorphone Sulin hyperacidity. date, hydromorphone Suprofenate, hydromorphone 112. The method according to claim 110 wherein the type flurbiprofenate, hydromorphone tolmetinate, hydro of pain is mild to moderate. morphone fenoprofenate, hydromorphone 113. The method according to claim 110 wherein the type Oxaprozinate, hydromorphone difunisalate, hydromor of pain is moderate to moderately Severe. phone loxoprofenate, 114. The method according to claim 110 wherein the type Oxymorphone naproxenate, oxymorphone etodolate, Oxy of pain is moderate to Severe. morphone ketoprofenate, Oxymorphone Sulindate, Oxy 115. The method according to claim 110 wherein the type morphone Suprofenate, Oxymorphone flurbiprofenate, of pain is Severe. Oxymorphone tolmetinate, oxymorphone fenopro 116. The method according to claim 110 wherein the type fenate, oxymorphone oxaprozinate, oxymorphone of pain is Selected from the group consisting of pre-opera difunisalate, oxymorphone loxoprofenate, tive, post operative, and pre- and post-operative. dihydrocodeine naproxenate, dihydrocodeine etodolate, 117. The method according to claim 60, wherein the dihydrocodeine ketoprofenate, dihydrocodeine Sulin NSAID is selected from the group consisting of diclofenac, date, dihydrocodeine Suprofenate, dihydrocodeine flur etodolac, Sulindac, alclofenac, fenclofenac, diflunisal, beno biprofenate, dihydrocodeine tolmetinate, dihydroco rylate, fosfosal, aspirin, Salicylic acid, acetylsalicylic acid, deine fenoprofenate, dihydrocodeine Oxaprozinate, ibuprofen, ketoprofen, naproxen, carprofen, fenbufen, flur dihydrocodeine difunisalate, and dihydrocodeine loXo biprofen, Oxaprozin, Suprofen, triaprofenic acid, fenoprofen, profenate. indoprofen, piroprofen, flufenamic, mefenamic, meclofe 101. The method according to claim 99, wherein the namic, niflumic, Salsalate, rolmerin, fentiazac, tilomisole, compound is propoxyphene diclofenate. OxyphenbutaZone, phenylbutaZone, apaZone, feprazone, 102. The method according to claim 60, wherein the Sudoxicam, isoxicam, tenoxicam, piroXicam, indomethacin, condition is Selected from the group consisting of arthritic meloxicam, nabumetone, tolmetin, lumiracoxib, and pare disorders, gastrointestinal conditions, inflammatory condi coxib. tions, pulmonary inflammation, opthalmic diseases, central 118. The method according to claim 117, wherein the nervous Systems disorders, pain, fever, inflammation-related NSAID is selected from the group consisting of diclofenac, cardiovascular disorders, angiogenesis-related disorders, etodolac, Sulindac, Salicylic acid, acetylsalicylic acid, ibu benign and malignant tumors, adenomatous polyps, fibrosis profen, ketoprofen, naproxen, lumiracoxib, and parecoxib. which occurs with radiation treatment, endometriosis, 119. The method according to claim 60, wherein the Osteoporosis, dysmenorrhea, premature labor, asthma, eosi NSAID is a COX-2 selective inhibitor. nophil-related disorders, pyrexia, bone resorption, nephro 120. The method according to claim 119, wherein the toxicity, hypotension, arthrosis, joint Stiffness, kidney dis COX-2 selective inhibitor is selected from the group con ease, liver disease, acute mastitis, diarrhea, colonic Sisting of etoricoxib, rofecoxib, celecoxib, Valdecoxib. adenomas, bronchitis, allergic neuritis, cytomegalovirus 121. The method according to claim 60, wherein the infectivity, apoptosis, HIV-induced apoptosis, lumbago, pSo NSAID is a COX-LOX inhibitor. riasis, eczema, acne, burns, dermatitis, ultraViolet radiation 122. The method according to claim 60, wherein the damage, allergic rhinitis, respiratory distreSS Syndrome, and NSAID is a PLA inhibitor. endotoxin shock Syndrome. 123. The method according to claim 60, wherein the 103. The method according to claim 102, wherein the narcotic is propoxyphene. condition is an arthritic disorder. 124. The method according to claim 60, wherein the 104. The method according to claim 103, wherein the compound is Selected from the group consisting of pro arthritic disorder is Selected from the group consisting of poxyphene diclofenate, ketamine diclofenate, methadone rheumatoid arthritis and osteoarthritis. diclofenate, hydrocodone diclofenate, codeine diclofenate, US 2005/0203115 A1 Sep. 15, 2005 49 propoxyphene Salicylate, propoxyphene acetylsalicylate tolmetinate, oxycodone fenoprofenate, oxycodone propoxyphene ibuprofenate, morphine diclofenate, and oxy Oxaprozinate, Oxycodone difunisalate, oxycodone codone diclofenate. loxoprofenate 125. The method according to claim 60, wherein the compound is Selected from the group consisting of pro fentanyl naproXenate, fentanyl etodolate, fentanyl keto poxyphene naproxenate, propoxyphene etodolate, pro profenate, fentanyl Sulindate, fentanyl Suprofenate, fen poxyphene ketoprofenate, propoxyphene Sulindate, pro tanyl flurbiprofenate, fentanyl tolmetinate, fentanyl poxyphene Suprofenate, propoxyphene flurbiprofenate, fenoprofenate, fentanyl oxaprozinate, fentanyl difunis propoxyphene tolmetinate, propoxyphene fenoprofenate, alate, fentanyl loxoprofenate, propoxyphene oxaprozinate, propoxyphene difunisalate, meperidine naproxenate, meperidine etodolate, meperi propoxyphene loxoprofenate, dine ketoprofenate, meperidine Sulindate, meperidine Suprofenate, meperidine flurbiprofenate, meperidine ketamine acetylsalicylate, ketamine naproxenate, ket tolmetinate, meperidine fenoprofenate, meperidine amine etodolate, ketamine Sulindate, ketamine ketopro fenate, ketamine Suprofenate, ketamine flurbiprofenate, Oxaprozinate, meperidine difunisalate, meperidine ketamine tolmetinate, ketamine fenoprofenate, ket loxoprofenate, amine oxaprozinate, ketamine difunisalate, ketamine hydromorphone naproxenate, hydromorphone etodolate, loxoprofenate, ketamine ibuprofenate, ketamine Salicy hydromorphone ketoprofenate, hydromorphone Sulin late, ketamine indomethacinate, ketamine diclofenate, date, hydromorphone Suprofenate, hydromorphone flurbiprofenate, hydromorphone tolmetinate, hydro methadone ibuprofenate, methadone acetylsalicylate, morphone fenoprofenate, hydromorphone methadone Salicylate, methadone indomethacinate, Oxaprozinate, hydromorphone difunisalate, hydromor methadone naproxenate, methadone etodolate, metha phone loxoprofenate, done Sulinate, methadone ketoprofenate, methadone Suprofenate, methadone flurbiprofenate, methadone Oxymorphone naproXenate, oxymorphone etodolate, Oxy tolmetinate, methadone fenoprofenate, methadone morphone ketoprofenate, oxymorphone Sulindate, Oxy Oxaprozinate, methadone difunisalate, methadone morphone Suprofenate, Oxymorphone flurbiprofenate, loxoprofenate, Oxymorphone tolmetinate, Oxymorphone fenopro hydrocodone ibuprofenate, hydrocodone acetylsalicylate, fenate, oxymorphone oxaprozinate, oxymorphone hydrocodone Salicylate, hydrocodone indomethacinate, difunisalate, oxymorphone loxoprofenate, hydrocodone naproxenate, hydrocodone etodolate, dihydrocodeine naproxenate, dihydrocodeine etodolate, hydrocodone Sulindate, hydrocodone ketoprofenate, dihydrocodeine ketoprofenate, dihydrocodeine Sulin hydrocodone Suprofenate, hydrocodone flurbipro date, dihydrocodeine Suprofenate, dihydrocodeine flur fenate, hydrocodone tolmetinate, hydrocodone feno biprofenate, dihydrocodeine tolmetinate, dihydroco profenate, hydrocodone oxaprozinate, hydrocodone deine fenoprofenate, dihydrocodeine Oxaprozinate, difunisalate, hydrocodone loxoprofenate, dihydrocodeine difunisalate, and dihydrocodeine loXo codeine ibuprofenate, codeine acetylsalicylate, codeine profenate. Salicylate, codeine indomethacinate, codeine naproX 126. The method according to claim 124, wherein the enate, codeine etodolate, codeine Sulindate, codeine compound is propoxyphene diclofenate. ketoprofenate, codeine Suprofenate, codeine flurbipro 127. The method according to claim 61, wherein the fenate, codeine tolmetinate, codeine fenoprofenate, condition is Selected from the group consisting of arthritic codeine oxaprozinate, codeine difunisalate, codeine disorders, gastrointestinal conditions, inflammatory condi loxoprofenate, tions, pulmonary inflammation, opthalmic diseases, central nervous Systems disorders, pain, fever, inflammation-related morphine ibuprofenate, morphine acetylsalicylate, mor cardiovascular disorders, angiogenesis-related disorders, phine Salicylate, morphine indomethacinate, morphine benign and malignant tumors, adenomatous polyps, fibrosis naproxenate, morphine etodolate, morphine Sulindate, which occurs with radiation treatment, endometriosis, morphine ketoprofenate, morphine Suprofenate, mor Osteoporosis, dysmenorrhea, premature labor, asthma, eosi phine flurbiprofenate, morphine tolmetinate, morphine nophil-related disorders, pyrexia, bone resorption, nephro fenoprofenate, morphine oxaprozinate, morphine toxicity, hypotension, arthrosis, joint Stiffness, kidney dis difunisalate, morphine loxoprofenate, ease, liver disease, acute mastitis, diarrhea, colonic adenomas, bronchitis, allergic neuritis, cytomegalovirus levorphanol ibuprofenate, levorphanol acetylsalicylate, infectivity, apoptosis, HIV-induced apoptosis, lumbago, pSo levorphanol Salicylate, levorphanol indomethacinate, riasis, eczema, acne, burns, dermatitis, ultraViolet radiation levorphanol naproxenate, levorphanol etodolate, levor damage, allergic rhinitis, respiratory distress Syndrome, and phanol Sulindate, levorphanol ketoprofenate, levorpha endotoxin shock Syndrome. nol Suprofenate, leVorphanol flurbiprofenate, levorpha 128. The method according to claim 127, wherein the nol tolimetinate, levorphanol fenoprofenate, condition is an arthritic disorder. levorphanol oxaprozinate, levorphanol difunisalate, 129. The method according to claim 128, wherein the levorphanol loxoprofenate, arthritic disorder is Selected from the group consisting of Oxycodone ibuprofenate, Oxycodone acetylsalicylate, rheumatoid arthritis and osteoarthritis. Oxycodone Salicylate, oxycodone indomethacinate, 130. The method according to claim 61, wherein the Oxycodone naproxenate, oxycodone etodolate, oxyc condition is primary dysmenorrhea. odone Sulindate, oxycodone ketoprofenate, oxycodone 131. The method according to claim 61, wherein the Suprofenate, oxycodone flurbiprofenate, oxycodone condition is ankylosing spondylitis. US 2005/0203115 A1 Sep. 15, 2005 50

132. The method according to claim 127, wherein the 150. The method according to claim 61, wherein the condition is an inflammatory disorder. compound is Selected from the group consisting of pro 133. The method according to claim 132, wherein the poxyphene naproxenate, propoxyphene etodolate, pro inflammatory disorder is Selected from the group consisting poxyphene ketoprofenate, propoxyphene Sulindate, pro of tendinitis and bursitis. poxyphene Suprofenate, propoxyphene flurbiprofenate, 134. The method according to claim 127, wherein the propoxyphene tolmetinate, propoxyphene fenoprofenate, condition is acute gouty arthritis. propoxyphene oxaprozinate, propoxyphene difinisalate, pro 135. The method according to claim 127, wherein the poxyphene loxoprofenate, condition is pain. ketamine acetylsalicylate, ketamine naproxenate, ket 136. The method according to claim 135, wherein the type amine etodolate, ketamine Sulindate, ketamine ketopro of pain treated is anogenital, minor arthritic, dental, topical, fenate, ketamine Suprofenate, ketamine flurbiprofenate, asSociated with an upper respiratory infection, general, joint, ketamine tolmetinate, ketamine fenoprofenate, ket menstrual, mild, mild to moderate, acute musculo-skeletal, amine oxaprozinate, ketamine difunisalate, ketamine moderate to moderately Severe, moderate to Severe, muscu loxoprofenate, ketamine ibuprofenate, ketamine Salicy lar, neurogenic, obstetrical, ocular, oral mucosal and gingi late, ketamine indomethacinate, ketamine diclofenate, val, post operative, pre-operative, pre- and post-operative, Severe, short term, urinary tract, or associated with gastric methadone ibuprofenate, methadone acetylsalicylate, hyperacidity. methadone Salicylate, methadone indomethacinate, methadone naproxenate, methadone etodolate, metha 137. The method according to claim 136 wherein the type done Sulinate, methadone ketoprofenate, methadone of pain is mild to moderate. Suprofenate, methadone flurbiprofenate, methadone 138. The method according to claim 136 wherein the type tolmetinate, methadone fenoprofenate, methadone of pain is moderate to moderately Severe. Oxaprozinate, methadone difinisalate, methadone loXo 139. The method according to claim 136 wherein the type profenate, of pain is moderate to Severe. 140. The method according to claim 136 wherein the type hydrocodone ibuprofenate, hydrocodone acetylsalicylate, of pain is Severe. hydrocodone Salicylate, hydrocodone indomethacinate, 141. The method according to claim 136 wherein the type hydrocodone naproxenate, hydrocodone etodolate, of pain is Selected from the group consisting of pre-opera hydrocodone Sulindate, hydrocodone ketoprofenate, tive, post operative, and pre- and post-operative. hydrocodone Suprofenate, hydrocodone flurbipro 142. The method according to claim 61, wherein the fenate, hydrocodone tolmetinate, hydrocodone feno NSAID is selected from the group consisting of diclofenac, profenate, hydrocodone oxaprozinate, hydrocodone etodolac, Sulindac, alclofenac, fenclofenac, diflunisal, beno difunisalate, hydrocodone loxoprofenate, rylate, fosfosal, aspirin, Salicylic acid, acetylsalicylic acid, codeine ibuprofenate, codeine acetylsalicylate, codeine ibuprofen, ketoprofen, naproxen, carprofen, fenbufen, flur Salicylate, codeine indomethacinate, codeine naproX biprofen, oxaprozin, Suprofen, triaprofenic acid, fenoprofen, enate, codeine etodolate, codeine Sulindate, codeine indoprofen, piroprofen, flufenamic, mefenamic, meclofe ketoprofenate, codeine Suprofenate, codeine flurbipro namic, niflumic, Salsalate, rolmerin, fentiazac, tilomisole, fenate, codeine tolmetinate, codeine fenoprofenate, OxyphenbutaZone, phenylbutaZone, apaZone, feprazone, codeine oxaprozinate, codeine difunisalate, codeine Sudoxicam, isoxicam, tenoxicam, piroXicam, indomethacin, loxoprofenate, meloxicam, nabumetone, tolmetin, lumiracoxib, and pare morphine ibuprofenate, morphine acetylsalicylate, mor coxib. phine Salicylate, morphine indomethacinate, morphine 143. The method according to claim 142, wherein the naproxenate, morphine etodolate, morphine Sulindate, NSAID is selected from the group consisting of diclofenac, morphine ketoprofenate, morphine Suprofenate, mor etodolac, Sulindac, Salicylic acid, acetylsalicylic acid, ibu phine flurbiprofenate, morphine tolmetinate, morphine profen, ketoprofen, naproxen, lumiracoxib, and parecoxib. fenoprofenate, morphine oxaprozinate, morphine 144. The method according to claim 61, wherein the difunisalate, morphine loxoprofenate, NSAID is a COX-2 selective inhibitor. 145. The method according to claim 94, wherein the levorphanol ibuprofenate, levorphanol acetylsalicylate, COX-2 selective inhibitor is selected from the group con levorphanol Salicylate, levorphanol indomethacinate, Sisting of etoricoxib, rofecoxib, celecoxib, Valdecoxib. levorphanol naproxenate, levorphanol etodolate, levor 146. The method according to claim 61, wherein the phanol Sulindate, levorphanol ketoprofenate, levorpha NSAID is a COX-LOX inhibitor. nol Suprofenate, levorphanol flurbiprofenate, levorpha 147. The method according to claim 61, wherein the nol tolmetinate, levorphanol fenoprofenate, NSAID is a PLA inhibitor. levorphanol oxaprozinate, levorphanol difunisalate, 148. The method according to claim 61, wherein the levorphanol loxoprofenate, oxycodone ibuprofenate, narcotic is propoxyphene. Oxycodone acetylsalicylate, oxycodone Salicylate, 149. The method according to claim 61, wherein the Oxycodone indomethacinate, oxycodone naproxenate, compound is Selected from the group consisting of pro Oxycodone etodolate, oxycodone Sulindate, oxycodone poxyphene diclofenate, ketamine diclofenate, methadone ketoprofenate, oxycodone Suprofenate, oxycodone flur diclofenate, hydrocodone diclofenate, codeine diclofenate, biprofenate, oxycodone tolmetinate, oxycodone feno propoxyphene Salicylate, propoxyphene acetylsalicylate profenate, Oxycodone oxaprozinate, oxycodone propoxyphene ibuprofenate, morphine diclofenate, and oxy difunisalate, oxycodone loxoprofenate fentanyl codone diclofenate. naproxenate, fentanyl etodolate, fentanyl ketopro US 2005/0203115 A1 Sep. 15, 2005 51

fenate, fentanyl Sulindate, fentanyl Suprofenate, fenta wherein nyl flurbiprofenate, fentanyl tolmetinate, fentanyl fenoprofenate, fentanyl oxaprozinate, fentanyl X is 1.2, or 3; difunisalate, fentanyl loxoprofenate, meperidine X is an anion with a charge of -X, and naproxenate, meperidine etodolate, meperidine keto profenate, B" is a cation. meperidine Sulindate, meperidine Suprofenate, meperi 153. The process according to claim 152, further com dine flurbiprofenate, meperidine tolmetinate, meperi prising dissolving narcotic X and AB" in Separate dine fenoprofenate, meperidine Oxaprozinate, meperi volumes of the same solvent or different solvents prior to the dine difunisalate, meperidine loxoprofenate, contacting. hydromorphone naproxenate, hydromorphone etodolate, 154. The process according to claim 153, wherein the ion hydromorphone ketoprofenate, hydromorphone Sulin pair compound of general formula I is sparingly Soluble or date, hydromorphone Suprofenate, hydromorphone insoluble in the solvent or different solvents, such that the flurbiprofenate, hydromorphone tolmetinate, hydro contacting results in the precipitation of the ion pair com morphone fenoprofenate, hydromorphone pound. Oxaprozinate, hydromorphone difunisalate, hydromor 155. The process according to claim 152, wherein the ion phone loxoprofenate, pair compound of general formula I is Soluble in the Solvent Oxymorphone naproxenate, oxymorphone etodolate, Oxy or different solvents. morphone ketoprofenate, Oxymorphone Sulindate, Oxy 156. The process according to claim 155, further com morphone Suprofenate, Oxymorphone flurbiprofenate, prising removing Said Solvent or Solvents and isolating the Oxymorphone tolmetinate, oxymorphone fenopro ion pair compound of general formula I. fenate, oxymorphone oxaprozinate, oxymorphone 157. The process according to claim 153, further wherein difunisalate, oxymorphone loxoprofenate, the contacting occurs on a cation exchange medium. dihydrocodeine naproxenate, dihydrocodeine etodolate, 158. The process according to claim 157, wherein the dihydrocodeine ketoprofenate, dihydrocodeine Sulin cation exchange medium is a cation eXchange chromatog date, dihydrocodeine Suprofenate, dihydrocodeine flur raphy column. biprofenate, dihydrocodeine tolmetinate, dihydroco 159. The process according to claim 158, further com deine fenoprofenate, dihydrocodeine Oxaprozinate, prising eluting the ion pair compound of general formula I dihydrocodeine difunisalate, and dihydrocodeine loXo profenate. from the chromatography column. 151. The method according to claim 149, wherein the 160. A composition comprising a plurality of ion pair compound is propoxyphene diclofenate. compounds, their pharmaceutically acceptable Solvates, 152. A process for preparing the ion pair compound hydrates, polymorphs, and/or isotopically labeled versions according to claim 1, comprising the Steps of contacting a thereof according to claim 1. salt of the formula narcotic"X* with a salt of the formula AB",