NAPROXCINOD PROCESS AND SOLID DISPERSION

INTRODUCTION

Aspects of the present invention relate to processes for the preparation of naproxcinod, including its purification, to crystalline 2-(S)-(4-chlorobutyl)-2-(6- methoxy-2-naphthyl)-propanoate, and to solid dispersions of naproxcinod with a pharmaceutically acceptable carrier, and processes for making them.

The drug compound having the adopted name "naproxcinod" has a chemical name 4-nitrooxybutyl (2S)-2-(6-methoxynaphthylen-2-yl)-propanoate, represented by the chemical structure of formula I.

Naproxcinod (also called NO-naproxen; AZD-3582; HCT-3012; and nitronaproxen) is a cycloxygenase-inhibiting, nitric oxide (NO)-donating, derivative of the NSAID naproxen, under development by NicOx for the potential treatment of pain and inflammation in osteoarthritis.

U.S. Patent No. 5,700,947 discloses nitric esters of derivatives of propionic acid, i.e., a nitric ester of of 4-hydroxybutyl-2-(6-methoxy-2-naphthyl) propionate. The patent also describes a process for the preparation of a nitric ester of 4- hydroxybutyl-2-(6-methoxy-2-naphthyl) propionate by reacting a sodium salt of 2- (6-methoxy-2-naphthyl) propionic acid with 1 -bromo-4-chlorobutane in dimethylformamide to give 4-chlorobutyl-2-(6-methoxy-2-naphthyl) propionate, followed by reacting with silver nitrate in acetonitrile. After completion of the reaction, the reaction mixture is filtered and the solvent is evaporated under reduced pressure. The obtained residue is mixed with dichloromethane and the reaction mixture is filtered. The filtrate is washed with water and then made anhydrous with sodium sulfate. The solvent is evaporated under reduced pressure to afford a dry residue, which is purified by chromatography on silica gel, utilizing an eluting mixture of hexane and ether. The fractions containing the product are collected and the solvent is evaporated under reduced pressure to give a nitric ester of 4-hydroxybutyl-2-(6-methoxy-2-naphthyl) propionate.

U. S. Patent No. 6,700,01 1 discloses a process for the preparation of nitroxy alkyl esters of the 2(S)-(6-methoxy-2-naphthyl)-propanoic acid having an enantiomeric excess higher than or equal to 97%, by reacting an acid halide of 2- (S)-(6-methoxy-2-naphthyl)-propanoic acid with 4-nitroxybutan-1 -ol in an inert solvent and in the presence of an inorganic base to give a 4-nitroxybutyl ester of 2(S)-(6-methoxy-2-naphthyl)-propanoic acid, in the form of an oil.

U.S. Patent No. 7,199,258 discloses a process for the preparation of naproxcinod by reacting naproxen with 4-bromobutyl nitrate to give a yellow oily compound of naproxcinod. This patent also discloses a process for the preparation of naproxcinod by reacting naproxen with 4-nitroxybutyl-4- methylbenzenesulphonate to give naproxcinod.

U.S. Patent Application Publication No. 2005/0234123 discloses a process for the preparation of naproxcinod by reacting (S)-naproxen 4- (methanesulfonyloxy) butyl ester with sodium nitrate to give naproxcinod as a yellow oil.

Naproxcinod obtained from the above methods is an oil or residue.

NO-donating NSAIDs are lipophilic drugs with poor aqueous solubility. They may be classified in to class 2 according to the Biopharmaceutical Classification System proposed by Amidon et al. (Pharm. Res.12 (1995), pp. 413- 420). Compounds of this class are characterized by their low aqueous solubility but reasonably good permeability.

Many of the NO-donating NSAIDs are obtained in the form of an oily compound. Therefore, the conventional methods for making pharmaceutical formulations, such as tableting, are not applicable for these compounds. It has been the endeavor of pharmaceutical scientists to provide solid forms of drug substances, which are easy to handle and have good storage stability especially in the case of drugs, which are oils, in this particular case naproxcinod. Further, there remains a need to provide an improved process for the preparation of naproxcinod, which is easily scaleable, cost effective and environment-friendly.

SUMMARY

In an aspect, the present invention provides processes for the preparation of a compound of formula I, embodiments of which includes one or more of the following steps, individually or in the sequence recited:

a) reacting the compound of formula Il or a pharmaceutically acceptable salt thereof,

with a compound of formula III, wherein X ₁ is a OH or a halogen such as Cl, Br, or I, and X is a halogen such as Cl, Br, or I, to give a compound of formula IV;

wherein X is as described previously; b) optionally, purifying the compound of formula IV; c) reacting a compound of formula IV with a nitrating agent to give a compound of formula I; and

d) optionally, purifying the compound of formula I. In an embodiment, the present invention provides a compound of formula

IV having a chemical purity greater than about 93%, or greater than about 95%, or greater than about 97%, by weight, as determined using high performance liquid chromatography (HPLC).

In an embodiment, the present invention provides a compound of formula IV having an optical purity greater than about 97%, or greater than about 98%, or greater than about 99%, or greater than about 99.5%, enantiomeric excess (e.e.) as determined using HPLC.

In an embodiment, the present invention provides a compound of formula I having a chemical purity greater than about 93%, or greater than about 95%, or

greater than about 97%, or greater than about 98%, or greater than about 99%, or greater than about 99.5%, by weight, as determined using HPLC.

In an embodiment, the present invention provides a compound of formula I having an optical purity greater than about 99%, or greater than about 99.5%, or greater than about 99.7%, or greater than about 99.8%, or greater than about 99.9%, enantiomeric excess (e.e.) as determined using HPLC.

In an embodiment, the present invention provides crystalline 2-(S)-(4- chlorobutyl)-2-(6-methoxy-2-naphthyl)-propanoate.

In an embodiment, the present invention provides crystalline 2-(S)-(4- chlorobutyl)-2-(6-methoxy-2-naphthyl)-propanoate characterized by a powder X- ray diffraction (PXRD) pattern having peaks located substantially at about 4.9, 9.8, 1 1 .1 , 13.1 , 18.6, 18.8, 19.3, 19.5, 20.1 , 20.4, 22.3, 23.0, 24.8, 25.5, 27.1 , and 29.8, ± 0.2 degrees 2-theta.

In an embodiment, the present invention provides 2-(S)-(4-chlorobutyl)-2- (6-methoxy-2-naphthyl)-propanoate characterized by one or both of a PXRD pattern and an infrared (IR) absorption spectrum substantially as illustrated by Fig. 1 and Fig. 2, respectively.

In an embodiment, the present invention provides solid dispersions of naproxcinod that include naproxcinod and a pharmaceutically acceptable carrier. In an embodiment, the present invention provides solid dispersions of naproxcinod for use in preparing pharmaceutical formulations comprising naproxcinod, a solid dispersion comprising an admixture of naproxcinod with one or more pharmaceutically acceptable carriers.

In an embodiment, the present invention provides processes for preparing solid dispersions of naproxcinod, including physically mixing naproxcinod with one or more pharmaceutically acceptable carriers.

In an embodiment, the present invention provides processes for preparing solid dispersions of naproxcinod, including one or more of the following steps: a) providing a solution or suspension of naproxcinod optionally in combination with one or more pharmaceutically acceptable carriers in an organic solvent; and b) removing the solvent, and optionally combining the resulting solid with one or more pharmaceutically acceptable carriers.

In an embodiment, the present invention provides solid dispersions of naproxcinod with one or more pharmaceutically acceptable carriers, characterized by a PXRD pattern substantially as illustrated by any of Fig. 3 through Fig. 6.

In an embodiment, the present invention provides pharmaceutical formulations comprising a solid dispersion of naproxcinod with one or more pharmaceutically acceptable carriers, optionally in combination with one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is an illustration of powder a powder X-ray diffraction (PXRD) pattern of crystalline 2-(S)-(4-chlorobutyl)-2-(6-methoxy-2-naphthyl)-propanoate prepared according to Example 3.

Fig. 2 is an illustration of an infrared (IR) absorption spectrum of crystalline 2-(S)-(4-Chlorobutyl)-2-(6-Methoxy-2-Naphthyl)-propanoate prepared according to Example 3.

Fig. 3 is an illustration of a PXRD pattern of a solid dispersion of naproxcinod prepared according to Example 22, method A.

Fig. 4 is an illustration of a PXRD pattern of a solid dispersion of naproxcinod prepared according to Example 22, method B. Fig. 5 is an illustration of PXRD patterns of lactose monohydrate (D), microcrystalline cellulose (C) and solid dispersions of naproxcinod prepared according to Example 22, methods A and B.

Fig. 6 is an illustration of a PXRD pattern of a solid dispersion of naproxcinod with microcrystalline cellulose prepared according to Example 22, methods D and E.

DETAILED DESCRIPTION

All percentages and ratios used herein are by weight of the total composition and all measurements made are at 25°C and normal pressure unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. The present invention can comprise (open ended) or consist essentially of the components of the present invention as well as other ingredients or elements described herein. As used herein, "comprising" means the elements recited, or their equivalent in structure or function, plus any other element or

elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise. As used herein, "consisting essentially of means that the invention may include ingredients in addition to those recited in the claim, but only if the additional ingredients do not materially alter the basic and novel characteristics of the claimed invention. Typically, such additives will not be present at all, or will be present only in trace amounts. However, it may be possible to include up to about 10% by weight of materials that could materially alter the basic and novel characteristics of the invention as long as the utility of the compounds (as opposed to the degree of utility) is maintained. All ranges recited herein include the endpoints, including those that recite a range "between" two values. Terms such as "about," "generally," "substantially," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

References to a material, such as in this instance naproxcinod or its intermediates, and the solid forms, salts, solvates and/or optical isomers thereof by reference to patterns, spectra or other graphical data, may be done by qualifying that they are "substantially" as shown or depicted in a figure, or by one or more data points. By "substantially" used in such a context, it will be appreciated that patterns, spectra and other graphical data can be shifted somewhat in their positions, relative intensities, or other values due to a number of factors known to those having skill in the art. For example, in the crystallographic and powder X-ray diffraction arts, shifts in peak positions or the relative intensities of one or more peaks of a pattern can occur because of, without limitation, the equipment used, the sample preparation protocol, preferred packing and orientations, the radiation source, operator error, method and length of data collection, and the like. However, those of ordinary skill in the art will be able to compare the figures herein with a pattern generated of an unknown form of, in this case, naproxcinod or its intermediates, and confirm its identity with a form disclosed and claimed herein. The same holds true for other techniques which may be reported herein as well as for distinguishing between amorphous forms.

In addition, where a reference is made to a figure, it is permissible to, and this document includes and contemplates, the selection of any number of data points illustrated in the figure which uniquely define that solid form, salt, solvate, and/or enantiomer within any associated and recited margin of error, for purposes of identification.

A reference to a molecule such as, in this case, naproxcinod or its intermediates, unless otherwise specified or inconsistent with the disclosure in general, refers to any salt, amorphous form, enantiomer and/or solvate form thereof. When a molecule or other material is identified herein as "pure", it generally means, unless specified otherwise, that the material is about 99% pure or more. In general, this refers to purity with regard to unwanted residual solvents, reaction by-products, impurities and unreacted starting materials. In the case of solid forms such as an amorphous form, "pure" also means about 99% or more of an amorphous form free from crystalline forms, as appropriate or in the case of crystalline solids, "pure" also means about 99% or more of one crystal form free from amorphous forms and other crystal forms. "Substantially" pure means, the same as "pure" except that the lower limit is about 98% pure or greater and likewise, "essentially" pure means the same as "pure" except that a lower limit is about 95% pure.

In an aspect, the present invention provides processes for the preparation of a compound of formula I, embodiments of which include one or more of the following steps, individually or in the sequence recited: a) reacting the compound of formula Il or a pharmaceutically acceptable salt thereof,

with a compound of formula wherein X ₁ is a OH or a halogen such as Cl, Br, or I, and X is a halogen such as Cl, Br, or I, to give a compound of formula IV;

wherein X is as described previously; b) optionally, purifying a compound of formula (IV); c) reacting a compound of formula IV with a nitrating agent to give a compound of formula I; and

d) optionally, purifying the compound of Formula I.

Step a) involves reacting the compound of Formula Il or a pharmaceutically acceptable salt thereof with a compound of Formula III to give a compound of Formula IV.

The compound of Formula Il or a pharmaceutically acceptable salt thereof of the present invention may be prepared by a suitable method known in the art. For example, an embodiment of a process for the preparation of the compound of Formula Il includes one or more of the following steps, individually or in the sequence recited: i. preparing an ester of chloroacetic acid by reacting chloroacetic acid or its derivative such as acid halide with an alcohol, optionally in the presence of a suitable catalyst and a suitable solvent; ii. reacting the ester of chloroacetic acid with 2-acetyl-6- methoxynaphthalene, optionally in the presence of a suitable base and a suitable solvent, to provide 3-(6-methoxy-2-naphthyl)-2,3-epoxy butanoic acid ester; iii. reacting the 3-(6-methoxy-2-naphthyl)-2,3-epoxy butanoic acid ester with a suitable base, optionally in a suitable solvent, to provide 2-(6-methoxy-2- naphthyl)-propionaldehyde; iv. reacting the 2-(6-methoxy-2-naphthyl)-propionaldehyde with hydroxyl amine or its acid addition salt, optionally in a suitable solvent, to provide the corresponding oxime;

v. converting the oxime to 2-(6-methoxy-2-naphthyl) propionic acid or its base addition salt; vi. resolving the 2-(6-methoxy-2-naphthyl) propionic acid or its base addition salt with a resolving agent to obtain a diastereomeric salt of (2S)-2-(6- methoxy-2-naphthyl) propionic acid; vii. optionally, purifying the diastereomeric salt of (2S)-2-(6-methoxy-2- naphthyl) propionic acid; viii. converting the diastereomeric salt of (2S)-2-(6-methoxy-2-naphthyl) propionic acid into (2S)-2-(6-methoxy-2-naphthyl) propionic acid or its base addition salt; ix. optionally, purifying the (2S)-2-(6-methoxy-2-naphthyl) propionic acid or its base addition salt; and x. optionally, converting the resultant (2S)-2-(6-methoxy-2-naphthyl) propionic acid into a pharmaceutically acceptable salt. Step a) may be optionally carried out in the presence of a suitable reagent.

Suitable reagents that may be used in step a) include, but are not limited to: organic bases such as thethylamine, thbutylamine, N-methylmorpholine, N ₁ N- diisopropylethylamine, N-methylpyrrolidine, pipehdine, pyrrolidine, pyridine, 4- (N,N-dimethylamino)pyhdine, N-methylmorpholine, morpholine, imidazole, 2- methyl imidazole, 4-methylimidazole, and the like; inorganic bases including alkali metal hydrides such as lithium hydride, sodium hydride and the like, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide, alkaline metal hydroxides such as aluminium hydroxide, magnesium hydroxide, calcium hydroxide and the like, alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like, alkaline earth metal carbonates such as magnesium carbonate, calcium carbonate and the like, bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; ion exchange resins including resins bound to ions such as sodium, potassium, lithium, calcium, magnesium, substituted or unsubstituted ammonium and the like; mixtures of AI2O3 and methanesulfonic acid; and any other suitable reagent.

The quantity of reagent used in step a) ranges from less than about 5 molar equivalents, or less than about 3 molar equivalents, or less than about 2 molar equivalents, or less than about 1.5 molar equivalents, or less than about 1 molar

equivalent, or less than about 0.5 molar equivalents, or any other suitable quantity, per mole of the compound of formula II.

Step a) may be optionally carried out in a suitable solvent. Suitable solvents that may be used in step a) include, but are not limited to: water; alcohols such as methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2-butanol, t- butanol, and the like; ketones such as acetone, butanone, methyl butyl ketone, methyl isobutyl ketone, and the like; esters such as ethyl acetate, isopropyl acetate, t-butyl acetate, iso-butyl acetate, and the like; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, 1 ,4-dioxane, and the like; aliphatic or alicyclic hydrocarbons such as hexanes, n-heptane, cyclohexane, and the like; halogenated hydrocarbons such as dichloromethane, chloroform, 1 ,1 ,2-thchloroethane, 1 ,2-dichloroethene, chlorobenzene, and the like; aromatic hydrocarbons such as toluene, xylenes, tetralin, and the like; nitriles such as acetonitrile, propionitrile and the like; polar aprotic solvents such as N, N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, and the like; ionic liquids, which are emerging as green reaction media for a variety of organic transformations and may comprise organic cations such as tetraalkylammonium, thalkylsulphonium, tetraalkylphosphonium, 1 ,3-dialkylimidazolium, N-alkyl-pyhdinum, N ₁ N- dialkylpyrrolidinium, N-alkylthiazolium, N,N-dialkylthazolium, N,N-dialkyloxazolium, and N,N-dialkylpyrazolium; anions which lead to neutral and stoichiometric ionic liquids such as BF ₄ ^" , PF ₆ ^" , SbF ₆ ^" , ZnCI ₃ ^" , CuCI ₂ ^" , SnCI ₃ ^" , MeSO ₃ ^" , N(CF ₃ SO ₂ ) ₂ ^" , N(C ₂ F ₅ SO ₂ );? ^" , N(FSO ₂ ) ₂ ^" , C(CF ₃ SO ₂ ) ₃ ^" , CF ₃ CO ₂ ^" , and CF ₃ SO ₃ ^" ; imidazolium-based ionic liquids such as 1 -alkyl-3-methylimidazolium tetrafluoroborates like 1- methyl imidazolium tetrafluoroborate ([HmIm][BF ₄ ]); 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF ₄ ]) and 1 -alkyl-3-methylimidazolium hexafluorophosphates like 1 -butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF ₆ ]), 1 -butyl-2,3-dimethylimidazolium hexafluorophosphate ([bdmim][PF ₆ ], 1-butyl-3-methylimidazolium bis (thfluoromethanesulphonyl) imide ([bmim][N(Tf)2], 1 -butyl-2,3-dimethylimidazolium bis (thfluoromethanesulphonyl) imide ([bm2im][N(Tf)2], 1 -butyl-1 -methyl-pyrrolidinium bis (thfluoromethanesulphonyl) imide ([bmpy][N(Tf)2]; and mixtures thereof.

The quantity of solvent used in step a) may range from less than about 30 times, or less than about 20 times, or less than about 10 times, or any other suitable quantity, the quantity of the compound of formula II.

Suitable temperatures that may be used in step a) may be less than about 150 ⁰ C, less than about 100 ⁰ C, less than about 80°C, less than about 60 ⁰ C, less than about 40°C, less than about 30°C, less than about 20 ⁰ C, less than about 10°C, or any other suitable temperatures.

It has surprisingly been found that the quantity of compound of formula III used in step a) can affect the concentration of dimer impurity of formula Ia, to a level less than about 2%, or less than about 1 %, or less than about 0.5% by weight, as determined by high performance liquid chromatography (hereinafter referred as HPLC). Also it has been observed that as the molar equivalents of a compound of formula III with respect to the compound of formula Il increase, the formation of dimer impurity of formula Ia is at a minimum value less than about 2%, or less than about 1 %, or less than about 0.5% by weight, as determined by HPLC.

The quantity of a compound of formula III that is used generally is greater than 1 molar equivalent, and may be up to about 10 molar equivalents, up to about 8 molar equivalents, up to about 6 molar equivalents, up to about 5 molar equivalents, up to about 3 molar equivalents, up to about 2 molar equivalents, or any other suitable quantity, per mole of compound of formula II. The reaction yield is optimized, in some embodiments, when a molar ratio of compound of formula III to compound of formula Il is between about 1 :1.5 and about 1 :5, or about 1 :1.5 and about 1 :3. However, dimer impurity formation is reduced at higher ratios, such as about 8:1 to about 3:1 , about 8:1 to about 4:1 , or about 8:1 to about 5:1.

Optionally, the mixture containing a compound of formula IV obtained in step a) before or after conventional work-up may be carried forward to step c) without isolation or without further purification in step b).

Step b) involves optionally purifying a compound of formula IV.

Purification of a compound of formula IV may be effected by removing, without limitation, any of unwanted starting materials, dimer impurity of formula Ia, and any other corresponding impurity, such as by using conventional methods known to a person having ordinary skill in the art. In one variant, purification of a compound of formula IV involves removal of the excess quantity of a compound of formula III used in step a) by conventional methods known to a person having ordinary skill in the art.

Suitable techniques that may be used for removing unwanted starting materials include using a rotational distillation device such as Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization) and the like, or any other suitable techniques, under reduced pressure or at atmospheric pressure.

The temperatures at which the said unwanted starting materials or impurities may be removed are less than about 200 ⁰ C, less than about 150 ⁰ C, less than about 100°C, less than about 60 ⁰ C, less than about 40°C, less than about 20°C, or any other suitable temperatures.

Step c) involves reacting a compound of formula IV with a nitrating agent to give the compound of formula I.

Step c) may be optionally carried out in a suitable solvent. Suitable solvents that may be used in step c) include, but are not limited to: water; alcohols such as methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2-butanol, t-butyl alcohol, 1 - pentanol, 2-pentanol, neopentyl alcohol, amyl alcohol, 2-methoxyethanol, 2- ethoxyethanol, ethylene glycol, glycerol, and the like; ketones such as acetone, butanone, methyl iso-butyl ketone, and the like; esters such as ethyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, and the like; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,4-dioxane, and the like; aliphatic or alicyclic hydrocarbons such as hexanes, n- heptane, n-pentane, cyclohexane, and the like; halogenated hydrocarbons such as dichloromethane, chloroform, 1 ,1 ,2-trichloroethane, 1 ,2-dichloroethene, and the like; aromatic hydrocarbons such as toluene, xylenes, and the like; nithles such as acetonitrile, propionitrile and the like; polar aprotic solvents such as N ₁ N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, and the like; organic acids such as acetic acid, formic acid, trifluoroacetic acid, chloroacetic acid, propionic acid, butanoic acid,

isobutyric acid, valeric acid, isovaleric acid, benzoic acid, salicylic acid, phthalic acid, p-toluenesulphonic acid, o-toluenesulphonic acid, benzenesulphonic acid, methanesulphonic acid, ethanesulphonic acid and the like; and mixtures thereof.

The quantity of solvent that is used in step c) can affect conversion of a compound of formula IV to the compound of formula I, generally by prolonging the reaction times as the quantity of solvent increases. The quantity of solvent used in step c) may range from less than about 10 ml_, less than about 7 ml_, less about 5 ml_, less than about 3 ml_, less than about 2 ml_, or less than about 1 ml_, per gram of a compound of formula IV. Suitable nitrating agents used in step c) include, but are not limited to: metal nitrates such as lithium nitrate, sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, iron nitrate, zinc nitrate, and silver nitrate; quaternary ammonium nitrates such as tetraalkylammonium nitrate sources; and any other suitable nitrating agents including mixtures thereof. The quantity of nitrating agent used in step c) may range from less than about 7 molar equivalents, less than about 5 molar equivalents, less than about 3 molar equivalents, less than about 2 molar equivalents, or less than about 1 molar equivalent, per mole of a compound of formula IV.

Step c) may be optionally carried out in the presence of a phase-transfer catalyst. Suitable phase-transfer catalysts that may be used in step c) include, but are not limited to: tetraalkylammonium salts, aryalkylammonium salts, tetraalkylphosphonium salts, arylalkylphosphonium salts, crown ethers, ethylene glycols such as polyethylene glycol, and any other suitable phase transfer catalysts including mixtures thereof. Suitable temperatures used in step c) may be less than about 200 ⁰ C, less than about 150 ⁰ C, less than about 100°C, less than about 80 ⁰ C, less than about 60°C, less than about 40°C, less than about 30 ⁰ C, less than about 20°C, or any other suitable temperatures.

Step b) and step d) involve optional purification of a compound of formula IV and the compound of formula I, respectively.

One of the unique features of NO-releasing NSAIDs is that many of these compounds are in the form of oils or thermosoftening semisolids. Hence, the purification of bulk compound of formula I to meet regulatory quality standards by

conventional physical methods such as crystallization, precipitation and the like are not applicable.

Optional purification of a compound of formula IV and the compound of formula I can include one or more of the following steps, individually or in the sequence recited: i) optionally, providing a solution of a compound of formula IV or the compound of formula I in a suitable solvent; ii) treating the resultant solution of step i) or a crude sample of a compound of formula IV or a crude sample of the compound of formula I with a solid adsorbent; and iii) recovering a purified compound of formula IV or the purified compound of formula I.

Step i) involves providing a solution in a solvent.

Providing a solution in step i) includes: A. direct use of a reaction mixture containing a compound of formula IV or the compound of formula I that is obtained in the course of manufacturing the compound; or

B. dissolving a compound of formula IV or the compound of formula I in a suitable solvent. Suitable solvents that may be used in step i) include, but are not limited to: water; alcohols such as methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2- butanol, t-butanol, ethylene glycol, glycerol and the like; ketones such as acetone, butanone, methyl isobutyl ketone and the like; esters such as ethyl acetate, isopropyl acetate, t-butyl acetate, and the like; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,4-dioxane, and the like; aliphatic or alicyclic hydrocarbons such as hexanes, n-heptane, cyclohexane, and the like; halogenated hydrocarbons such as dichloromethane, chloroform, 1 ,1 ,2-thchloroethane, 1 ,2-dichloroethane, and the like; aromatic hydrocarbons such as toluene, xylenes, and the like; nitriles such as acetonitrile, propionithle, and the like; polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, and the like; and any other suitable solvent including mixtures thereof.

Step ii) involves treating the solution of step i); or crude sample of a compound of formula IV or the compound of formula I without providing a solution, with a solid adsorbent.

Suitable solid adsorbents which may be used in step ii) include, but are not limited to: polymers such as cross-linked copolymers of styrene-divinylbenzene or halogenated, cross-linked copolymers of styrene-divinylbenzene such as Sepabeads™ SP207 (a brominated styrene-divinylbenzene copolymer), Sepabeads FP-BU, FP-OD, Sepabeads EB-BU, EB-OD, Sepabeads-825, 850, Sepabeads SP-70, SP-700, SP-207; Diaion™ HP-2MG, HP-20, HP-21 polymers; Amberlite™ XAD-2 , XAD-4, XAD-7HP, Amberlite XAD-16, Amberlite XAD-1180; ADS-550, ADS-551 , ADS-400, ADS-600, ADS-800 and Duolite™ XAD-761 ; ion exchange resins such as anion or cation exchange resins; and any other suitable solid adsorbents.

SP207 is a high porous, styrene based adsorbent resin with bromine groups chemically bonded to the crosslinked polystyrene matrix. The bromination provides greater hydrophobicity (greater selectivity for non-polar molecules) than pure styrenic polymers. SP207 has a higher specific gravity (approximately 1.18 g/cc) than styrenic adsorbent resins. SP207 is recommended for upflow fluidized bed contact (EBA) applications. SP207SS resin is a macroporous, chemically modified brominated styrenic polymeric bead type resin offered in a 75-150 μm particle distribution. SP207SS is designed for reversed phase chromatographic applications. The bromination of the aromatic ring provides increased hydrophobicity versus classical styrenic polymers or Ci ₈ bonded silica. The brominated polymeric matrix provides unique selectivity, full pH operating range and long operating life versus conventional bonded silica packing materials used in preparative and industrial applications.

The quantity of solid adsorbent used in step ii) may range from less than about 50 times, less than about 40 times, less than about 30 times, less than about 20 times, less than about 10 times, less than about 5 times, less than about 1 time, or any other suitable multiple or fraction of the weight of a compound of formula IV or the compound of formula I.

Step ii) optionally involves pretreatment of solid adsorbent with a solvent, before treating the solution of step i) or the crude compound with solid adsorbent.

Suitable solvents that may be used in step ii) for pretreatment of solid adsorbent include, but are not limited to: water; alcohols such as methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2-butanol, t-butanol, ethylene glycol, glycerol, and the like; ketones such as acetone, butanone, methyl isobutyl ketone, and the like; esters such as ethyl acetate, isopropyl acetate, t-butyl acetate, and the like; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,4-dioxane, and the like; aliphatic or alicyclic hydrocarbons such as hexanes, n-heptane, cyclohexane, and the like; halogenated hydrocarbons such as dichloromethane, chloroform, 1 ,1 ,2- trichloroethane, 1 ,2-dichloroethane, and the like; aromatic hydrocarbons such as toluene, xylenes, and the like; nitriles such as acetonitrile, propionithle, and the like; polar aprotic solvents such as N,N-dimethylformamide, N ₁ N- dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, and the like; and any other suitable solvent including mixtures thereof. In one variant, treating the solution of step i) with solid adsorbent includes the conventional methods such as column chromatography techniques or batch mode methods, and any other suitable methods including a combination thereof. Suitable columns that may be used in a chromatography technique of the present invention include but are not limited to, glass columns, stainless steel columns, any Teflon-coated column, and the like, and any other suitable column. The diameters of the column used in step ii) may range from about 1 cm to about 90 cm, or any other suitable diameter. An end-capped column may be fixed to a vertical support and the solid adsorbents may be loaded through the top, open end of the column. The elution may be carried out employing eluant or mobile phase passed through the column by gravity or by the application of pressure. Suitable solvents that may be used as eluants include, but are not limited to: alcohols such as methanol, ethanol and the like; ketones such as acetone, methyl isobutyl ketone and the like; esters such as ethyl acetate, t-butyl acetate and the like; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, and the like; aliphatic or alicyclic hydrocarbons such as hexanes, n-heptane, and the like; halogenated hydrocarbons such as dichloromethane, chloroform, and the like; aromatic hydrocarbons such as toluene, and the like;

nitriles such as acetonitrile, propionitrile and the like; and any other suitable solvents including mixtures thereof.

A faster flow rate of the eluant minimizes the time required to elute a column and thereby minimizes diffusion, resulting in a better separation; see Van Deemter's equation. A simple laboratory column runs by gravity flow. The flow rate of such a column can be increased by extending the head of fresh eluant above the top of the stationary phase, or can be decreased using valve controls. Better flow rates can be achieved using a pump or by using compressed gas (e.g. air, nitrogen, or argon) pressure to push the solvent through the column ("flash column chromatography").

Treating the solution of step i), or a crude sample of a compound of formula IV or the compound of formula I without providing a solution, with solid adsorbent in a batch mode method involves conventional techniques such as stirring, shaking, mixing, agitating, and the like, including any combination thereof. Optionally, the solid adsorbent after treatment of a compound of formula IV) or the compound of formula I in step b) and step d), respectively, may be recovered and the recovered solid adsorbent may be washed or treated with a suitable solvent. Such recovered solid adsorbent may be reused for any number of cycles in steps b) and d) for the purification of a compound of formula IV or the compound of formula I, respectively.

Step iii) involves isolating a purified compound of formula IV or the purified compound of formula I.

Isolation of purified compound in step iii) may involve methods including removal of solvent, cooling, adding an anti-solvent, extraction with a solvent, and the like. Stirring or other alternate methods such as shaking, agitation, and the like that mix the contents may also be employed for isolation.

Suitable techniques that may be used for the removal of solvent include but are not limited to rotational distillation using a device such as Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization) and the like, optionally under reduced pressure.

Suitable temperatures that may be used for removal of solvent may be less than about 200 ⁰ C, less than about 150 ⁰ C, less than about 100°C, less than about 60 ⁰ C, less than about 40°C, less than about 20°C, or any other suitable temperatures.

In an embodiment, the present invention provides a compound of formula IV having a chemical purity greater than about 93%, greater than about 95%, greater than about 97%, greater than about 98%, or greater than about 99%, by weight, as determined using HPLC. In an embodiment, the present invention provides a compound of formula

IV having an optical purity greater than about 97%, greater than about 98%, greater than about 99%, or greater than about 99.5% enantiomeric excess (e.e.), as determined using HPLC.

It is surprisingly found that a compound of formula IV of the present invention is stable even when exposed to high temperatures, such as less than about 150 ⁰ C, or less than about 100 ⁰ C, for prolonged times.

In an embodiment, the present invention provides the compound of formula I having a chemical purity greater than about 93%, greater than about 95%, greater than about 97%, greater than about 98%, greater than about 99%, or greater than about 99.5%, by weight, as determined using HPLC.

In an embodiment, the present invention provides the compound of formula I having an optical purity greater than about 99%, greater than about 99.5%, greater than about 99.7%, greater than about 99.8%, or greater than about 99.9% enantiomeric excess (e.e.), as determined using HPLC. A compound of formula IV or the compound of formula I obtained according to the present invention can be, and desirably is, substantially free of one or more of the corresponding impurities as determined using HPLC.

"Substantially free" of one or more of the corresponding impurities as used herein, unless otherwise defined, refers to the compound that may contain less than about 7%, less than about 5%, less than about 3%, less than about 2%, less than about 1 %, less than about 0.5%, less than about 0.3%, less than about 0.1 %, or less than about 0.05% by weight, of each impurity including, without limitation, the dimer impurity of formula Ia, a chloronaproxcinod impurity of formula IVa, a bromonaproxcinod impurity of formula IVb, unwanted enantiomers, or any other corresponding impurity, as determined using HPLC. The total amount of impurities should also be less than about 7%, less than about 5%, less than about 3%, less than about 2%, less than about 1 %, or less than about 0.5%, by weight.

Previously known processes are inferior to provide compounds of formulae IV and I with respect to all of the characteristics defined above.

A HPLC method for measuring the chemical purity of a compound of Formula IV or a compound of Formula I of the present application involves the use of a Symmetry shield RP-18, 100x4.6x3.5 μm or equivalent column. Other parameters of the method are as shown in Table 1.

Table 1

A HPLC method useful for measuring the enantiomeric purity of a compound of formula IV or the compound of formula I of the present application involves the use of (S,S)-Whelk-O 1 , 250x4.6^5 μm (Regis Technologies. Inc.) or equivalent column. Other parameters of the method are as shown in Table 2.

Table 2

In an embodiment, the present invention provides crystalline 2-(S)-(4- chlorobutyl)-2-(6-methoxy-2-naphthyl)-propanoate.

In an embodiment, the present invention provides crystalline 2-(S)-(4- chlorobutyl)-2-(6-methoxy-2-naphthyl)-propanoate characterized by a powder X- ray diffraction (PXRD) pattern having peaks located substantially at about 4.9, 9.8, 11.1 , 13.1 , 18.6, 18.8, 19.3, 19.5, 20.1 , 20.4, 22.3, 23.0, 24.8, 25.5, 27.1 , and 29.8, ± 0.2 degrees 2-theta.

In an embodiment, the present invention provides 2-(S)-(4-chlorobutyl)-2- (6-methoxy-2-naphthyl)-propanoate characterized by one or both of a PXRD pattern and an IR absorption spectrum, substantially as illustrated in Figs. 1 and 2, respectively.

The crystalline 2-(S)-(4-chlorobutyl)-2-(6-methoxy-2-naphthyl)-propanoate can be stored under ambient conditions and is easy to handle on a commercial

scale. The prior processes do not disclose a crystalline 2-(S)-(4-chlorobutyl)-2-(6- methoxy-2-naphthyl)-propanoate.

In an embodiment, the present invention provides a solid dispersion of naproxcinod and a pharmaceutically acceptable carrier. As used herein, the term "solid dispersion" refers to a group of solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. The matrix may be either crystalline or amorphous. The drug may be dispersed molecularly, in amorphous particles (clusters), or in crystalline particles. In an embodiment, the present invention provides a solid dispersion of naproxcinod for use in preparing pharmaceutical formulations comprising naproxcinod, a solid dispersion comprising an admixture of naproxcinod with one or more pharmaceutically acceptable carriers.

In an embodiment, the present invention provides processes for preparing solid dispersions of naproxcinod, including a physical mixing of naproxcinod with one or more pharmaceutically acceptable carriers.

Physical mixing of naproxcinod with one or more pharmaceutically acceptable carriers may be performed by methods known in the art.

In an embodiment, the present invention provides processes for preparing a solid dispersion of naproxcinod, including one or more of the following steps: a) providing a solution or suspension of naproxcinod, optionally in combination with one or more pharmaceutically acceptable carriers, in an organic solvent; and b) removing the solvent, then optionally combining the resulting solid with one or more pharmaceutically acceptable carriers.

Step a) involves providing a solution or suspension of naproxcinod in combination with one or more pharmaceutically acceptable carriers.

Step a) may involve forming a solution or suspension of naproxcinod together with one or more pharmaceutically acceptable carriers. Providing a solution or suspension of nNaproxcinod in a suitable solvent includes:

(i) direct use of reaction mixture containing naproxcinod that is obtained in the course of its manufacture, if desired, after addition of one or more pharmaceutically acceptable carriers; or

(ii) forming a solution or suspension of naproxcinod in a suitable solvent, either alone or in combination with one or more pharmaceutically acceptable carriers.

Solvents which may be used in step (ii) for forming a solution or suspension of naproxcinod, either alone or in combination with one or more pharmaceutically acceptable carriers, include, but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, 1 -propanol, 2-propanol, 1 -butanol, 2-butanol, t-butyl alcohol, and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2- dichloroethane, chloroform, carbon tetrachloride, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, and the like; ethers such as diethyl ether, dimethyl ether, diisopropyl ether, methyl t-butyl ether, 1 ,4- dioxane, and the like; nitriles such as acetonitrile, propionitrile, and the like; water; and any mixtures thereof. The temperatures for forming a solution or a suspension may range from about 20 ⁰ C to about 100 ⁰ C, depending on the solvent used for dissolution. Any other temperatures also are acceptable as long as a clear solution of naproxcinod is obtained without affecting its quality. In embodiments, step (ii) is carried out at about 20°C to about 60 ⁰ C, or about 20°C to about 40°C. The quantity of solvent used in step (ii) depends on the solvent and the temperature chosen for the process. The concentration of naproxcinod in the solution or suspension may generally range from about 0.1 to about 10 g/mL.

When the solution or suspension of naproxcinod is prepared together with a pharmaceutically acceptable carrier, the order of charging different materials to the solution is not critical for obtaining the desired solid dispersion. A specific order may be preferred with respect to the equipment being used and will be easily determined by a person skilled in the art. Naproxcinod or pharmaceutically acceptable carrier may be completely soluble in the solvent or they may form a suspension. In embodiments, naproxcinod and the pharmaceutically acceptable carrier may be separately dissolved either in the same solvent or in different solvents, and then combined to form a mixture.

Pharmaceutically acceptable carriers that may be used for the preparation of solid dispersions of naproxcinod of the present invention include, but are not limited to: water soluble sugar derivatives including any pharmaceutically

acceptable water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodexthn, dextrates, dextrins, lactitol, and the like; pharmaceutical hydrophilic carriers such as polyvinylpyrrolidones (homopolymers or copolymers of N-vinyl pyrrolidone), gums, cellulose derivatives (including hydroxypropyl methylcelluloses, hydroxypropyl celluloses, microcrystalline celluloses and others), polymers of carboxymethyl celluloses, cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydhc alcohols, polyethylene glycols, polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives, and the like; and organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives. The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this application. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation.

Step b) involves removal of the solvent from the solution or suspension obtained from step a), using a suitable technique, and optionally combining the resulting solid with one or more pharmaceutically acceptable carriers.

The solvent may be removed by techniques known in art, which include but are not limited to: distillation, evaporation, oven drying, tray drying, rotational drying (such as using a Buchi Rotavapor), spray drying, freeze-drying, fluidized bed drying, flash drying, spin flash drying, agitated thin film drying, and the like. The solvent may be removed by distillation, optionally under reduced pressure, and the distillation may be carried out to a minimum concentration or to completion at temperatures ranging from about 20 ⁰ C to about 100 ⁰ C.

These techniques are applicable to both aqueous and non-aqueous solutions and suspensions. Step b) may optionally further involve combining the resulting solid with one or more pharmaceutically acceptable carriers.

The solid dispersion obtained from step b) may be collected from the equipment using techniques such as by scraping, by shaking the container, or by other techniques specific to the equipment used.

Optionally, the product obtained from step b) can be dried. Drying may be suitably carried out in a tray dryer, rotary dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like with or without application of a vacuum. The drying may be carried out at temperatures of about 35°C to about 100 ⁰ C. The drying may be carried out for any time periods necessary for obtaining a desired quality, such as from about 5 minutes to several hours, or longer.

Certain solid dispersions of naproxcinod and a pharmaceutically acceptable carrier obtained using the above process may be characterized by PXRD patterns substantially as illustrated by Figs. 3-6. In an embodiment, the present invention provides pharmaceutical formulations comprising the compound of Formula I, together with one or more pharmaceutically acceptable excipients.

In an embodiment, the present invention provides pharmaceutical formulations comprising a solid dispersion of naproxcinod together with one or more pharmaceutically acceptable excipients.

The pharmaceutical formulations may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using techniques such as direct blending, dry granulation or wet granulation, or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Pharmaceutically acceptable excipients that find use in the present invention include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones,

hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches, and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, and the like; glidants such as colloidal silicon dioxide, and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate-controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.

All X-ray data reported herein were obtained using a Bruker Axs D8 Advance Powder X-ray Diffractometer with copper Ka radiation. Infrared absorption spectra were obtained using a Perkin Elmer System Spectrum 1 model spectrophotometer or Thermo Nexus 470 spectrometer, the samples being in a paraffin oil.

Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.

COMPARATIVE EXAMPLE: Preparation of 2-(S)-(4-chlorobutyl)-2-(6-methoxy-2- naphthyl)-propanoate according to U.S. Patent No. 5,700,947.

Naproxen (15 g) and ethanol (150 ml_) are charged into a round bottom flask and stirred for 5-10 minutes. A solution of sodium ethoxide (4.43 g) in ethanol (75 ml_) is added at 25-35°C. The mixture is stirred at 25-35°C for 5-10 minutes. The solvent is evaporated at 50-60 ⁰ C to afford 16.4 g of the sodium salt of naproxen.

N, N-Dimethylformamide (300 ml_) and the sodium salt of naproxen (16.4 g) are charged into a round bottom flask and stirred for 5-10 minutes. A solution of 1 -bromo-4-chlorobutane (11.1 g) in dimethylformamide (225 ml_) is added and the mixture is maintained at 25-35°C for 12 hours. Water (450 ml_) and

dichloromethane (300 mL) are charged to the mixture and stirred for 10-20 minutes. The layers are separated and the aqueous layer is extracted with dichloromethane (300 mL). Sodium sulfate (10 g) is added to the organic layer and the solvent from the organic layer is evaporated at 40-45 ⁰ C to afford 15.2 g of the title compound. Purity by HPLC: 72%; naproxen of formula (II) 22%; dimer impurity of formula Ia 0.35%.

EXAMPLE 1 : Preparation of naproxen.

Secondary-butanol (1100 L) and toluene (400 L) are charged into a reactor and stirred for 5-10 minutes. Monochloroacetic acid (960 kg) and then p-toluene- sulphonic acid (9.6 kg) are charged to the mixture and the mixture is heated to 92±5°C, or reflux temperature. Nitrogen gas is purged into the mixture and the nitrogen pressure is maintained in a range of 0.5-1 kg/cm ² . The mixture is maintained at reflux temperature and water is collected azeotropically at 108.5+21.5 ⁰ C. The mixture is cooled to below 45°C and is transferred into another reactor. Secondary-butanol (50 L) is charged into the reactor. The mixture is cooled to 17.5±2.5°C and 2-acetyl-6-methoxy-naphthalene (1200 kg) is added. Potassium secondary-butoxide (1200 kg) is added to the mixture at 20±5°C and the mixture is maintained at 25±5°C for 4 hours. The mixture is transferred into another reactor and a solution of sodium hydroxide (720 kg) in water (1000 L) is added at 30±5°C over 4+1 hours. The mixture is maintained at 30±5°C for 150+30 minutes. Water (3600 L) is added and the mixture is heated to reflux temperature and maintained at 82+6°C for 6 hours. Hydroxylamine sulphate solution (500 kg) is added at 82+6°C over 45 minutes to 2 hours, and the mixture is maintained at 82+6°C for 5 hours. The mixture is cooled to 35+5°C, the lower aqueous layer is separated, and the organic layer containing 2-(6-methoxy-2-naphthyl)- propionaldoxime is collected.

A solution of 40% sodium hydroxide (1800 L) is charged into the reactor and is heated to 97.5+2.5°C. The above organic layer containing 2-(6-methoxy-2- naphthyl)-propionaldoxime is charged through a rising film evaporator with simultaneous solvent distillation. The mixture is heated to 112.5+2.5°C with simultaneous solvent distillation and water (130 L) is added. The mixture is heated to 125+5°C with simultaneous solvent distillation and maintained at reflux

temperature for 9+1 hours. The mixture is cooled to 90±5°C and water (500 L) and toluene (2000 L) are added. The mixture is stirred for 45 minutes and the aqueous layer is separated at 80±5°C. Water (3000 L) is added and the mixture is heated to 90±5°C and maintained for 30 minutes. The layers are separated and water (2000 L) is added to the aqueous layer. The pH of the aqueous layer is adjusted to 8-8.5 with sulphuric acid at 60+10 ⁰ C. Toluene (2 ^χ 1750 L) is added and the mixture is heated to 60+5 ⁰ C. The mixture is stirred for 30 minutes and allowed to settle for not less than 30 minutes at 60+5 ⁰ C. The aqueous layer is separated at 60+5 ⁰ C. The aqueous layer, containing sodium 2-(6-methoxy-2-naphthyl) propionate, (1200 kg) and toluene (10800 L) are charged into another reactor and the mixture is heated to 65+5°C. The pH of the n mixture is adjusted to below 4 with sulphuric acid at a temperature of 65+5°C and the mixture is heated to 75+5°C and maintained for 30-45 minutes. The bottom aqueous layer is separated. Toluene (1200 L) and water (1100 L) are added to the organic layer and stirred at 75+5°C for 30 minutes. The bottom aqueous layer is separated. N- octyl-D-Glucamine (802 kg) is charged to the organic layer and the mass is heated to 85+5°C. Water is distilled azeotropically at 98+18°C. The mass is cooled to 70+5 ⁰ C and N-octyl-D-glucamine is added. The mixture is heated to reflux temperature and maintained for 15-30 minutes. The mixture is cooled to 32.5+7.5°C and maintained for 15-30 minutes. The mass is filtered and the filter washed with toluene (3*3000 L) to afford naproxen-N-octyl-D-glucamine salt.

Water (6000 L) and the wet naproxen-N-octyl-D-glucamine salt (3400 kg) are charged into a reactor and the pH of the mass is adjusted to below 4 with sulphuric acid. Toluene is distilled azeotropically at 80-105 ⁰ C. Water (2400 L) is added to the mass and the mass is cooled to 70+5 ⁰ C. The mass is filtered and the filter washed with water (100 L) to afford crude naproxen. lsopropyl alcohol (3900 L) and wet crude naproxen (650 kg) are charged into a reactor. The mass is heated to 70+5°C and maintained for 20+10 minutes. Carbon (2 kg) is added and the mass is stirred for 15-30 minutes at 70+5°C. The r mass is filtered and the filter washed with hot isopropyl alcohol (150 L). The filtrate is cooled to 2.5+2.5°C and maintained for 90+30 minutes. The obtained

solid is filtered and washed with isopropyl alcohol (8x100 L) and the solid is dried at 65±5°C to afford 500 kg of the title compound.

EXAMPLE 2: Preparation of naproxen sodium. Methanol (2630 L) and sodium hydroxide (86 kg) are charged into a reactor and stirred for 15-30 minutes. Naproxen (500 kg) is added and the mixture is heated to 55±5°C and maintained for 15-30 minutes. Carbon (10 kg) is added and the mass is stirred for 15-30 minutes, then the mass is cooled to below 40 ⁰ C. The mass is filtered and the filter washed with methanol (140 L), then the solvent from the filtrate is evaporated under reduced pressure at 50+10 ⁰ C to 50-60% of the initial volume. The mass is cooled to 7.5±7.5°C and isopropyl alcohol (2500 L) is added over 150+60 minutes. The mass is cooled to 5+5°C and maintained for 45- 60 minutes. The formed solid is filtered and washed with isopropyl alcohol (100 liters) and dried at 65+5°C to afford 450 kg of the title compound.

EXAMPLE 3: Preparation of 2-(S)-(4-chlorobutyl)-2-(6-methoxy-2-naphthyl)- propanoate.

Naproxen (20 g) and acetonithle (300 mL) are charged into a round bottom flask and heated to 50 ⁰ C to dissolve naproxen completely, then the solution is cooled to 25-35°C and potassium carbonate (14.3 g) is added. The mixture is heated to 55-60 ⁰ C and aged for about 2 hours. The mixture is cooled to 25-35°C, 1 -bromo-4-chlorobutane (17.8 g) is added, and the mixture is stirred for 5-10 minutes. The mixture is heated to 60 ⁰ C and maintained for 7-8 hours. The mixture is filtered at 25-35°C and the filtrate is distilled completely under vacuum at 48- 52°C. The residue (30 g) is dissolved in toluene (100 mL). 10% NaOH solution (50 mL) is added and the mixture is stirred for 10-20 minutes. The organic layer is separated and washed with water (2*100 mL). The organic layer is distilled completely under vacuum at 58°C and the residue is cooled to 25-35°C to afford 25.6 g of the title compound. Purity by HPLC 96.26%; powder X-ray diffraction pattern illustrated in Fig. 1 ; infrared absorption spectrum illustrated in Fig. 2.

EXAMPLE 4: Preparation of 2-(S)-(4-chlorobutyl)-2-(6-methoxy-2-naphthyl)- propanoate.

AI ₂ O ₃ (2.19 g) and methanesulfonic acid (2.08 g) are charged into a round bottom flask and stirred for 5-10 minutes. 4-chlorobutanol (3.05 g) and naproxen (5 g) are added and the mixture is stirred for 5-10 minutes. The mixture is heated to 45-50 ⁰ C and maintained for 1 -2 hours. The mixture is cooled to 25-35°C and water (25 ml_) and ethyl acetate (50 ml_) are added. The mixture is stirred for 10- 20 minutes and the organic layer is separated. The aqueous layer is extracted with ethyl acetate (50 ml_) and the ethyl acetate layer is washed with water (2*100 ml_). The ethyl acetate layer is distilled completely at 40 ⁰ C to afford 4.1 g of the title compound. Purity by HPLC 94.66%.

EXAMPLE 5: Preparation of 2-(S)-(4-chlorobutyl)-2-(6-methoxy-2-naphthyl)- propanoate. Naproxen (1 g) and 4-chlorobutanol (0.46 g) are combined and stirred for

5-10 minutes, then 1 -methylimidazoliumtetrafluoroborate (20 mL) is added. The mixture is heated to 60 ⁰ C and maintained for 3-4 hours. The mixture is cooled to 25-35°C and extracted with ethyl acetate (2*25 mL), then the combined ethyl acetate layer is dried over sodium sulphate (2 g). The solvent is distilled completely under vacuum at 50°C to afford 1.2 g of the title compound.

EXAMPLE 6: Preparation of 2-(S)-(4-Chlorobutyl)-2-(6-methoxy-2-naphthyl)- propanoate.

Naproxen (15 g) and acetonithle (300 mL) are charged into a round bottom flask and the mixture is stirred at 25-35°C for 5-10 minutes. K ₂ CO ₃ (10.8 g) is added and the mixture is stirred at 25-35°C for 30-45 minutes. 1-bromo-4- chlorobutane (33.4 g) is added and the mixture is heated to 55-60 ⁰ C and maintained for 2-3 hours. The mixture is cooled to 25-35°C, and then is filtered and the filter washed with acetonitrile (30 mL). Solvent from the filtrate is evaporated at 50-55 ⁰ C under reduced pressure. Toluene (150 mL) and water (150 mL) are charged to the residue at 25-35°C and stirred for 5-10 minutes. The layers are separated and the organic layer is washed with water (2*150 mL). The solvent from the organic layer is evaporated at 50-55 ⁰ C under reduced pressure

to afford 19.6 g of the title compound. Purity by HPLC 94.56%; dinner impurity of formula Ia 1.55%.

EXAMPLE 7: Preparation of 2-(S)-(4-Chlorobutyl)-2-(6-methoxy-2-naphthyl)- propanoate.

Naproxen (30.0 g) and acetonitrile (600 mL) are charged into a round bottom flask and the mixture is stirred at 25-35°C for 5-10 minutes. K ₂ CO ₃ (21.5 g) is added and the mixture is stirred at 25-35°C for 30-45 minutes. 1 -bromo-4- chlorobutane (111.5 g) is added and the mixture is heated to 55-65°C and maintained for 2-3 hours. The mixture is cooled to 25-35°C, and then filtered and the filter washed with acetonitrile (60 mL). The solvent from the filtrate is evaporated at 50-55 ⁰ C under reduced pressure. Toluene (300 mL) and water (300 mL) are charged to the residue at 25-35°C and stirred for 5-10 minutes. The layers are separated and the organic layer is washed with water (2*300 mL). The solvent from the organic layer is evaporated at 50-55 ⁰ C under reduced pressure to afford 52.0 g of residue. 1 -bromo-4-chlorobutane is evaporated from the residue under high vacuum at 90 ⁰ C, then the mass is distilled completely at 110°C for 3 hours to afford 38.0 g of the title compound. Chemical purity by HPLC 97.01 %; dimer impurity of Formula Ia 0.56%; chiral purity by HPLC 99.58% e.e.

EXAMPLE 8: Preparation of 2-(S)-(4-Chlorobutyl)-2-(6-methoxy-2-naphthyl)- propanoate.

Naproxen (50.0 g) and acetonitrile (1000 mL) are charged into a round bottom flask and the mixture is stirred at 25-35°C for 5-10 minutes. K ₂ CO ₃ (35.9 g) is added and the mixture is stirred at 25-35°C for 30-45 minutes. 1 -bromo-4- chlorobutane (297.3 g) is added and the mixture is heated to 55-65°C and maintained for 2-3 hours. The mixture is cooled to 25-35°C, and then filtered and the filter washed with acetonitrile (100 mL). The solvent from the filtrate is evaporated at 50-55 ⁰ C under reduced pressure to afford 281 g of residue. The residue is distilled completely at 80 ⁰ C to afford 100 g of residue. Toluene (500 mL) and water (500 mL) are charged to the residue at 25-35°C and stirred for 5-10 minutes. The layers are separated and the organic layer is washed with water (2 ^χ 500 mL). The solvent from the organic layer is evaporated at 60 ⁰ C to afford

52.4 g of residue. Chemical purity by HPLC 96.28%; dinner impurity of formula Ia 0.36%.

EXAMPLE 9: Preparation of 2-(S)-(4-Chlorobutyl)-2-(6-methoxy-2-naphthyl)- propanoate.

Naproxen (3 kg) and acetonithle (60 L) are charged into a reactor and stirred at 25-35°C for 10 minutes. K ₂ CO ₃ (2.16 kg) is added and the mixture is stirred at 25-35°C for 35 minutes. 1 -bromo-4-chlorobutane (12.27 kg) is added and the mixture is heated to 55-60 ⁰ C and maintained for 4 hours. The mixture is cooled to 25-35°C, and then is filtered and the filter washed with acetonitrile (15 L). The solvent from the filtrate is evaporated at 50-55 ⁰ C under reduced pressure. Toluene (9 L) is charged to the residue and the solvent is evaporated completely at 50-55 ⁰ C under reduced pressure. The residue is cooled to 25-35°C. Toluene (30 L) is charged to the residue and stirred for 10 minutes. 50% sodium hydroxide solution (2 ^χ 15 L) is added and the mixture is stirred at 25-35°C for 20 minutes. The layers are separated. The organic layer is washed with water (2 ^χ 30 L) and the layers are separated. The solvent from the organic layer is evaporated below 70-75 ⁰ C under reduced pressure. Toluene (2 ^χ 15 L) is charged to the residue and the solvent is evaporated completely below 70-75°C under reduced pressure. The residue is maintained at 70-75°C under reduced pressure for 6 hours to remove excess 1-bromo-4-chlorobutane. The residue is cooled to 25-35°C to afford 2.88 kg of the title compound. Chemical purity by HPLC 96.9%; dimer impurity of formula Ia 0.53%.

EXAMPLE 10: Preparation of naproxcinod.

2-(S)-(4-chlorobutyl)-2-(6-methoxy-2-naphthyl)-propanoate (3 g), silver nitrate (2.4 g), and acetonitrile (150 mL) are charged into a round bottom flask and heated to 95°C. The mixture is maintained under 2-4 kg/cm ² nitrogen pressure at 95°C for 13-14 hours. The mixture is filtered through a Hyflow (flux-calcined diatomaceous earth) bed and the filtrate is evaporated completely in a Buchi Rotavapor under reduced pressure at 45-55°C. Dichloromethane (75 mL) is charged to the residue at room temperature and the unwanted solid is filtered. The filtrate is washed with water (2 ^χ 25 mL). The solvent is evaporated completely in a

Rotavapor at 45°C to afford 2.4 g of the title compound. Chemical purity by HPLC 88.99%.

EXAMPLE 11 : Preparation of naproxcinod. 2-(S)-(4-chlorobutyl)-2-(6-methoxy-2-naphthyl)-propanoate (2 g) and acetonitrile (10 mL) are combined and stirred for 10-15 minutes. AgNO3 (2.1 g) is added and stirred for 5-10 minutes. The mixture is heated to 55-65°C, maintained at 65°C for 27 hours, and then is heated to 80 ⁰ C and maintained for 48 hours. The mixture is filtered and the filtrate is distilled completely at 45°C. The residue is purified by chromatography on silica gel, with an eluent mixture of petroleum ether and ethyl acetate (9:1 by volume). The fractions containing the product are collected and the solvent is evaporated completely at 40-45 ⁰ C to afford 0.5 g of the title compound. Chemical purity by HPLC 98.84%.

EXAMPLE 12: Preparation of naproxcinod.

2-(S)-(4-chlorobutyl)-2-(6-methoxy-2-naphthyl)-propanoate (1 g), silver nitrate (1.06 g) and acetonitrile (2 mL) are combined in a round bottom flask and stirred for 15-20 minutes at 25-35°C. The mixture is heated to 80-85 ⁰ C and maintained for 6 hours, then is filtered through a Hyflow bed and the solution is evaporated completely in a Rotavapor under reduced pressure at 45-55°C to afford the title compound.

EXAMPLE 13: Preparation of naproxcinod.

2-(S)-(4-chlorobutyl)-2-(6-methoxy-2-naphthyl)-propanoate (10 g) and acetonitrile (20 mL) are charged into a round bottom flask and stirred for 5-10 minutes. Silver nitrate (7.96 g) is added and the mixture is heated to 80-85 ⁰ C. The mixture is maintained at 80-85°C for 18-19 hours and then is cooled to 25-35°C. Dichloromethane (100 mL) is added, followed by cooling to 0-5 ⁰ C and maintaining for 25-30 minutes. The mixture is filtered through a Hyflow bed and the filter washed with dichloromethane (20 mL). Water (100 mL) is added to the filtrate and stirred for 5-10 minutes. The layers are separated and the organic layer is washed with water (2*100 mL). The solvent from the organic layer is evaporated completely at 50-55°C to afford 8.1 g of the title compound. Chemical purity by HPLC 94.65%; dimer impurity of formula Ia 4.62%.

EXAMPLE 14: Preparation of naproxcinod.

2-(S)-(4-chlorobutyl)-2-(6-methoxy-2-naphthyl)-propanoate (10 g) and acetonitrile (20 ml_) are charged into a round bottom flask and stirred for 5-10 minutes. Silver nitrate (10.62 g) is added and the mixture is heated to 80-85 ⁰ C. The mixture is maintained at 80-85 ⁰ C for 15-16 hours and then is cooled to 25- 35°C. Dichloromethane (100 ml_) is added, followed by cooling to 0-5 ⁰ C and maintaining for 25-30 minutes. The mixture is filtered through a Hyflow bed and washed with dichloromethane (20 ml_). Water (100 ml_) is added to the filtrate and stirred for 5-10 minutes. The layers are separated and the organic layer is washed with water (2*100 ml_). The solvent from the organic layer is evaporated completely at 50-55°C to afford 8.2 g of the title compound. Chemical purity by HPLC 92.63%; dimer impurity of formula Ia 6.34%.

EXAMPLE 15: Preparation of naproxcinod.

2-(S)-(4-chlorobutyl)-2-(6-methoxy-2-naphthyl)-propanoate (40 g) and acetonitrile (120 mL) are charged into a round bottom flask and stirred for 5-10 minutes. Silver nitrate (42.5 g) is added to the mixture and the mixture is heated to 80-85°C. The mixture is maintained at 80-85 ⁰ C for a period of 35-36 hours. The mixture is filtered at 25-35°C and washed with acetonitrile (80 mL). The solvent from the filtrate is evaporated completely at 50-55°C and then dichloromethane (400 mL) is added to the residue. The mixture is cooled to 0-5 ⁰ C and maintained for 30-45 minutes. The mixture is filtered and the filter washed with dichloromethane (80 mL). Water (400 mL) is charged to the filtrate and stirred for 10-20 minutes. The layers are separated and the organic layer is washed with water (2*400 mL). The solvent from the organic layer is evaporated completely at 50-55°C to afford 36.2 g of the title compound. Purity by HPLC 96.08%; dimer impurity of formula Ia 3.25%.

EXAMPLE 6: Preparation of naproxcinod.

2-(S)-(4-chlorobutyl)-2-(6-methoxy-2-naphthyl)-propanoate (10 g) and acetonitrile (50 mL) are charged into a round bottom flask and stirred for 5-10 minutes. Silver nitrate (10.6 g) is added and the mixture is heated to 80-85°C. The mixture is maintained at 80-85 ⁰ C for 54-55 hours. The mixture is filtered and the

filter washed with acetonitrile (20 mL). The solvent from the filtrate is evaporated completely at 50 ⁰ C and then dichloromethane (100 mL) is charged to the residue. The mixture is cooled to 0-5 ⁰ C and maintained for 30-45 minutes. The mixture is filtered and the solid washed with dichloromethane (20 mL). Water (100 mL) is added to the filtrate and stirred for 10-20 minutes. The layers are separated and the organic layer is washed with water (2*100 ml). The solvent from the organic layer is evaporated completely at 50-55°C to afford 7.8 g of the title compound. Chemical purity by HPLC 96.2%; dimer impurity of formula Ia 3.17%.

EXAMPLE 17: Preparation of naproxcinod.

2-(S)-(4-chlorobutyl)-2-(6-methoxy-2-naphthyl)-propanoate (10 g) and acetonitrile (100 mL) are charged into a round bottom flask and stirred for 5-10 minutes. Silver nitrate (10.6 g) is added and the mixture is heated to 80-85 ⁰ C. The reaction mixture is maintained at 80-85°C for 60-65 hours. The mixture is filtered and washed with acetonitrile (20 mL). The solvent from the filtrate is evaporated completely at 50°C and then dichloromethane (100 mL) is added to the residue. The mixture is cooled to 0-5 ⁰ C and maintained for 30-45 minutes. The mixture is filtered and the filter washed with dichloromethane (20 mL). Water (100 mL) is added to the filtrate and stirred for 10-20 minutes. The layers are separated and the organic layer is washed with water (2*100 mL). The solvent from the organic layer is evaporated completely at 50-55°C to afford 7.8 g of the title compound. Chemical purity by HPLC 96.2%; dimer impurity of formula Ia 3.06%.

EXAMPLE 18: Preparation of naproxcinod. 2-(S)-(4-chlorobutyl)-2-(6-methoxy-2-naphthyl)-propanoate (2.4 kg) and acetonitrile (4.8 L) are charged into a reactor and stirred at 25-35°C for 10 minutes. Silver nitrate (2.8 kg) is added and the mixture is heated to 80-85 ⁰ C. The mixture is maintained at 80-85°C for 16-17 hours. The mixture is cooled to 25- 35°C. Acetonitrile (12 L) is added and stirred for 10 minutes. The mixture is filtered and washed with acetonitrile (7.2 L). The solvent from the filtrate is evaporated completely under reduced pressure at 50-55 ⁰ C. The residue is cooled to 25-35°C and then dichloromethane (24 L) is added to the residue. The mixture is cooled to 0-5°C and maintained for 45 minutes. The mixture is filtered and the filter washed with dichloromethane (7.2 L). Water (12 L) is added to the filtrate and stirred for 20

minutes. The layers are separated and the aqueous layer is extracted with dichloromethane (2*12 L). The organic layer is washed with water (3*12 L). The solvent from the organic layer is evaporated completely below 55-60 ⁰ C under reduced pressure to afford 2.0 kg of the title compound. Chemical purity by HPLC 98.9%; dimer impurity of formula Ia 0.496%.

EXAMPLE 19: Purification of naproxcinod using column chromatography.

ADS-551 resin (95 mL, 72 g) is loaded into a stainless steel column. A solution of naproxcinod (10 g) in methanol (50 mL) is passed through the resin adsorbent column and, after completion of sample loading, an additional 250 mL of methanol is passed through the column at a linear flow rate of 47.3 cm/hour. Fractions are collected at the outlet of the column as soon as sample loading is started and the collected fractions are a void volume and fractions 1 -7, measuring 35, 25, 25, 50, 50, 50, 50, and 100 mL, respectively. Fractions containing naproxcinod, with dimer impurity and other polar impurities less than 0.1 area percent by HPLC, are pooled (fractions 3-6). The pooled fractions are evaporated at 25-40 ⁰ C under reduced pressure to afford 8.0 g of the title compound. Resin is regenerated by passing dichloromethane (300 mL) through the column, after collecting fraction 7 at the same flow rate. Chemical purity by HPLC 99.38%; dimer impurity of formula Ia not detected.

Starting material purity by HPLC was 98.87%; dimer impurity of formula Ia in the starting material 0.37%.

EXAMPLE 20: Purification of naproxcinod using column chromatography. Mobile phase: a mixture of methanol and dichloromethane in the volume ratio of 9:1 .

SP-207 resin (60 g) is charged into a beaker and washed with mobile phase. The resin is soaked in mobile phase (100 mL) for 1 -2 hours. A slurry of soaked resin in mobile phase (100 mL) is packed into a stainless steel column (2.2 ^χ 25 cm) and equilibration is started with a 4 ml/minute flow rate. A solution of naproxcinod (2.5 g) in mobile phase (20 mL) is loaded onto the column and collection of void volume and fractions of 50 mL size is commenced. Fractions with dimer impurity and other polar impurity below 0.1 are pooled (fractions 2-6). The pooled fractions are evaporated at 25-40°C under reduced pressure to afford

2.15 g of the title compound. Chemical purity by HPLC 99.68%; dimer impurity of formula Ia not detected

EXAMPLE 21 : Purification of naproxcinod using a batch method. A slurry of SP207SS resin (5.0 g) in methanol (25 mL) is prepared and sonicated for 10-15 minutes, then the resin is filtered. A solvent mixture is prepared by combining methanol (36 mL) and dichloromethane (4 mL) and sonicated for 3-5 minutes, then naproxcinod (1.0 g) is dissolved in the solvent mixture. The resin is added to the solution and stirred for 90 minutes, then the suspension is filtered to remove resin and the solvent from the filtrate is evaporated at 25-40 ⁰ C under reduced pressure to afford 600 mg of the title compound. Chemical purity by HPLC 93.4%; dimer impurity of formula Ia 0.42%.

Starting material purity by HPLC 90.65%; dimer impurity of formula Ia 3.4%. The content of dimer impurity of formula Ia in naproxcinod after treatment with different adsorbents, using the above procedure, is summarized in the following table.

ND= Not detected; MeOH= = methanol; DCM= dichloromethane; OD silica= Octadecylsilica; Reuse= Recycle of packed resin column.

EXAMPLE 22: Preparation of solid dispersion of naproxcinod.

Method A

Naproxcinod (0.6 g) and dichloromethane (25 ml_) are combined and stirred for 10-15 minutes to dissolve naproxcinod completely. Lactose (0.6 g) and microcrystalline cellulose (0.6 g) are added and stirred for 30-45 minutes at room temperature. The mixture is distilled completely under reduced pressure below 50 ⁰ C to afford 1.8 g of dispersion.

Method B

Naproxcinod (0.5 g), lactose (0.5 g) and dichloromethane (25 ml_) are combined and stirred for 15-20 minutes. The mixture is distilled completely in a Buchi Rotavapor below 40 ⁰ C. The residue and microcrystalline cellulose (0.5 g) are mixed thoroughly in the Rotavapor for about of 30-45 minutes at room temperature to afford 1 .45 g of dispersion.

Method C

Naproxcinod (1 .8 g), lactose (1 .8 g) and microcrystalline cellulose (1 .8 g) are combined and mixed thoroughly for about 30-45 minutes to afford 5.4 g of dispersion.

Method D

Naproxcinod (1 .0 g), microcrystalline cellulose (1 .0 g) and dichloromethane (100 ml_) are combined and stirred at room temperature for 20-30 minutes. The solvent is evaporated completely under vacuum at 45°C and the solid is dried at 45°C to afford 2.0 g of dispersion.

Method E

Naproxcinod (0.5 g) and microcrystalline cellulose (1 .0 g) are combined and mixed thoroughly at room temperature for 45-50 minutes. The solid is dried at 45°C to afford 1 .35 g of dispersion. Fig. 3 shows a PXRD pattern of a solid dispersion of naproxcinod, prepared according to method A.

Fig. 4 shows a PXRD pattern of a solid dispersion of naproxcinod, prepared according to method B.

Fig. 5 shows PXRD patterns of solid dispersions of naproxcinod prepared according to method A (pattern "A"), and method B (pattern "B"), microcrystalline cellulose (pattern "C"), and lactose monohydrate (pattern "D").

Fig. 6 shows a PXRD pattern of a solid dispersion of naproxcinod with microcrystalline cellulose, prepared according to either of methods D and E.