EP2262758A2

EP2262758A2 - O-desmethylvenlafaxine salts

Info

Publication number: EP2262758A2
Application number: EP09720254A
Authority: EP
Inventors: Srinivas Reddy Gade; Vijayawrdhan Chitta
Original assignee: Dr Reddys Laboratories Ltd; Dr Reddys Laboratories Inc
Current assignee: Dr Reddys Laboratories Ltd; Dr Reddys Laboratories Inc
Priority date: 2008-03-12
Filing date: 2009-03-12
Publication date: 2010-12-22
Also published as: WO2009114685A3; EP2262758A4; WO2009114685A2

Abstract

Salts of O-desmethylvenlafaxine, their polymorphic forms, and processes for their preparation.

Description

O-DESMETHYLVENLAF AXINE SALTS

INTRODUCTION

Aspects of the present patent application relate to O-desmethylvenlafaxine and its salts and processes for their preparation, and also to polymorphic forms of O-desmethylvenlafaxine salts.

O-desmethylvenlafaxine, or "desvenlafaxine," are adopted names for a drug compound having the chemical names 1-[2-dimethylamine-(4- hydroxyphenyl)ethyl]cyclohexanol, or RS-4-[2-dimethylamino-1-(1- hydroxycyclohexyl)ethyl]phenol, the formula C₁₆H_2SNO₂, and represented by structural Formula I.

Formula I

O-desmethylvenlafaxine is used for the treatment of major depressive disorder. O-desmethylvenlafaxine, the major pharmacologically active metabolite of the drug compound venlafaxine, selectively blocks the reuptake of serotonin and norepinephrine and is currently being sold in the form of its succinic acid salt monohydrate, in products using the trademark PRISTIQ that are orally administered extended-release tablets containing amounts of desvenlafaxine succinate monohydrate that are equivalent to 50 mg or 100 mg of desvenlafaxine.

U.S. Patent No. 4,535,186 describes O-desmethylvenlafaxine and its pharmaceutically acceptable salts. It also discloses the process for the preparation of O-desmethylvenlafaxine fumarate salt.

U.S. Patent No. 6,673,838 describes a succinate salt of O- desmethylvenlafaxine.

International Application Publication No. WO 00/32556 discloses various salts of O-desmethylvenlafaxine.

Chinese Patent Application No. 101081815 discloses O- desmethylvenlafaxine citric acid salts or their mixtures, wherein the ratio of O- desmethylvenlafaxine and citric acid is 1 :1 , 1 :2, 2:1 or 3:1. Chinese Patent Application No. 101081816 discloses O- desmethylvenlafaxine tartaric acid salts or their mixtures, wherein the ratio of O- desmethylvenlafaxine and tartaric acid is 1 :1 , 1 :2, or 2:1 .

Chinese Patent Application No. 101081817 discloses O- desmethylvenlafaxine maleic acid salts or their mixtures, wherein the ratio of O- desmethylvenlafaxine and maleic acid is 1 :1 , 1 :2, or 2: 1.

Although the known O-desmethylvenlafaxine salts and their polymorphic forms may address some of the deficiencies in pharmaceutical product formulations and their manufacturability, there remains a need for yet further improvement in these properties as well as improvements in other properties such as flowability, vapor impermeability and solubility. Further, the discovery of new salts and polymorphic forms of a drug enlarges the repertoire of materials that a formulation scientist has with which to design a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristics. There is a continuing need to provide O-desmethylvenlafaxine, and its salts, polymorphs, and preparation processes, which are commercially viable.

SUMMARY

Aspects of the present application relate to O-desmethylvenlafaxine, its salts, and processes for preparation thereof. Embodiments also relate to polymorphic forms of O-desmethylvenlafaxine salts.

In an aspect, there are provided processes for the preparation of salts of O- desmethylvenlafaxine, an embodiment of a process including:

(a) providing a solution of O-desmethylvenlafaxine in a suitable solvent; (b) adding an acid to the solution of (a); and

(c) isolating a salt of O-desmethylvenlafaxine.

In an aspect, there are provided processes for the preparation of crystalline salts of O-desmethylvenlafaxine, an embodiment of a process including:

(a) providing a solution of O-desmethylvenlafaxine in dichloromethane; (b) adding an acid to the solution of (a); and

(c) isolating a crystalline salt of O-desmethylvenlafaxine. In an embodiment, there is provided the compound O- desmethylvenlafaxine oxalate. In an embodiment, there is provided a crystalline compound O- desmethylvenlafaxine oxalate.

In an embodiment, there is provided crystalline O-desmethylvenlafaxine oxalate having polymorphic Form A. In an embodiment, there is provided a crystalline compound O- desmethylvenlafaxine tartrate.

In an embodiment, there is provided crystalline O-desmethylvenlafaxine tartrate having polymorphic Form B.

In an embodiment, there is provided a crystalline compound O- desmethylvenlafaxine citrate.

In an embodiment, there is provided crystalline O-desmethylvenlafaxine citrate having polymorphic Form C.

In an embodiment, there is provided crystalline O-desmethylvenlafaxine oxalate having polymorphic Form D. In an embodiment, there is provided crystalline O-desmethylvenlafaxine citrate having polymorphic Form E.

In another embodiment, there is provided an amorphous form of O- desmethylvenlafaxine maleate.

In another embodiment, there is provided an amorphous form of O- desmethylvenlafaxine tartrate.

In another embodiment, there is provided an amorphous form of O- desmethylvenlafaxine citrate.

The present patent application also provides pharmaceutical compositions that include O-desmethylvenlafaxine or a salt thereof, and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a powder X-ray diffraction ("PXRD") pattern of crystalline O- desmethylvenlafaxine oxalate Form A, prepared according to Example 1. Fig. 2 is a differential scanning calorimetry ("DSC") curve of crystalline O- desmethylvenlafaxine oxalate Form A, prepared according to Example 1.

Fig. 3 is a thermogravimetric analysis (TGA") curve of crystalline O- desmethylvenlafaxine oxalate Form A, prepared according to Example 1. Fig. 4 is a PXRD pattern of crystalline O-desmethylvenlafaxine tartrate Form B, prepared according to Example 3.

Fig. 5 is a DSC curve of crystalline O-desmethylvenlafaxine tartrate Form B, prepared according to Example 3. Fig. 6 is a TGA curve of crystalline O-desmethylvenlafaxine tartrate Form

B, prepared according to Example 3.

Fig. 7 is a PXRD pattern of amorphous O-desmethylvenlafaxine maleate, prepared according to Example 9.

Fig. 8 is a PXRD pattern of crystalline O-desmethylvenlafaxine citrate Form C, prepared according to Example 5.

Fig. 9 is a TGA curve of crystalline O-desmethylvenlafaxine citrate Form C, prepared according to Example 5.

Fig. 10 is a PXRD pattern of crystalline O-desmethylvenlafaxine oxalate Form D, prepared according to Example 2. Fig. 1 1 is a PXRD pattern of amorphous O-desmethylvenlafaxine tartrate, prepared according to Example 4.

Fig. 12 is a PXRD pattern of amorphous O-desmethylvenlafaxine citrate, prepared according to Example 6.

Fig. 13 is a PXRD pattern of amorphous O-desmethylvenlafaxine citrate, prepared according to Example 7.

Fig. 14 is a PXRD pattern of crystalline O-desmethylvenlafaxine citrate Form E, prepared according to Example 8.

Fig. 15 is a PXRD pattern of amorphous O-desmethylvenlafaxine maleate, prepared according to Example 10.

DETAILED DESCRIPTION

All percentages and ratios used herein are expressed by weight and all measurements made are at 25°C and atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, "comprising" is an open ended term including the elements recited, or their equivalents 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 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, but does not read on the prior art. 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 the very least, the degree of expected experimental error, technique error, and instrument error for a given technique that is used to measure a value.

Note that while the specification and claims may refer to a final formulated product such as, for example, a tablet or other dosage form of the invention as, for example, containing particles having a certain particle size or distribution, or a certain type of, for example, a specific form of an excipient, it may be difficult to tell from the final dosage form that the recitation is satisfied. However, such a recitation may be satisfied if the materials used prior to final production (in the case of a tablet for example, blending and tablet formulation), for example, meet that recitation. Indeed, as to any property or characteristic of a final product which cannot be ascertained from the dosage form directly, it is sufficient if that property resides in the components recited just prior to final production steps.

Where this document refers to a material, such as in this instance, O- desmethylvenlafaxine, and the unique solid forms, salts, solvates and/or optical isomers thereof by reference to patterns, spectra or other graphical data, it may do so by qualifying that they are "substantially" 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 slightly shifted in their positions, relative intensities, or other values due to a number of factors known to those of 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 drawings herein with a pattern or curve generated from an unknown form of, in this case, an O-desmethylvenlafaxine salt, and confirm its identity as one of the forms 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 drawing, 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, etc., within any associated and recited margin of error, for purposes of identification. A reference to a molecule such as, in this case, O-desmethylvenlafaxine, unless otherwise specified or inconsistent with the disclosure in general, refers to any salt, amorphous form, optical isomer and/or solvate form thereof.

There is a general need for solids of pharmaceutically active compounds that can be produced by processes giving products suitable for pharmaceutical preparations. It is desirable for such products to have the following properties: easy to handle, good dissolution rate, excellent bioavailability and good storage stability.

Pharmaceutical stability is believed to depend on a simultaneous influence of a variety of factors, of which some important factors are the sizes of crystals, shapes of crystals, water content, residual solvents, and impurities. One or more of these factors can be uniquely addressed by the isolation processes of the crystalline forms of O-desmethylvenlafaxine salts.

Toward this end, it has been the endeavor of pharmaceutical scientists to provide novel salts and stable forms of drug substances, which would have the strengths of crystalline forms, viz. thermodynamic stability, and those of amorphous forms, viz. enhanced solubility, rapid onset of action and an enhanced bioavailability.

The present application relates to salts of O-desmethylvenlafaxine and processes for their preparation. Embodiments also relate to polymorphic forms of O-desmethylvenlafaxine salts. The polymorphic forms obtained in the present application, unless stated otherwise, have been characterized by their powder X-ray diffraction (PXRD) patterns, differential scanning calorimetry (DSC) curves, and thermogravimetric analysis (TGA) curves. PXRD data reported herein were obtained using copper Ka radiation, having the wavelength 1.5418 A, and were obtained using a Bruker AXS D8 Advance Powder X-ray Diffractometer.

Differential scanning calorimetric analysis was carried out with a DSC Q1000 instrument from TA Instruments with a ramp of 10⁰C/ minute with a modulation time of 60 seconds and a modulation temperature of ±1 °C. The starting temperature was 0⁰C and ending temperature was 200⁰C.

TGA analysis was carried out in a TGA Q500 instrument with a ramp of 10°C/minute, up to 250⁰C.

In an aspect, there are provided processes for the preparation of salts of O- desmethylvenlafaxine, an embodiment including:

(a) providing a solution of O-desmethylvenlafaxine in a suitable solvent;

(b) adding an acid to the solution of (a); and

(c) isolating the salt of O-desmethylvenlafaxine.

Step (a) involves providing a solution of O-desmethylvenlafaxine in a suitable solvent.

The solution of O-desmethylvenlafaxine in (a) may be obtained, for example, by dissolving O-desmethylvenlafaxine of any physical form in a suitable solvent. Alternatively it may also be obtained directly from a reaction mixture containing O-desmethylvenlafaxine that is obtained during the course of its synthesis.

Suitable solvents that may be used in (a) include, but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, isobutanol, 2-methyl-2-pentanol, t-amyl alcohol, and the like; halogenated hydrocarbons such as dichioromethane, ethylene dichloride, chloroform, chlorobenzene, and the like; hydrocarbon solvents, such as hexanes, heptanes, pentanes, cyclohexane, toluene, xylenes 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, methyl t-butyl ether, diisopropyl ether, tetrahydrofuran, dioxane, and the like; polar aprotic solvents such as N,N-dimethylformamide, N₁N- dimethylacetamide, dimethylsulphoxide, sulpholane, N-methylpyrrolidone, and the like; nitriles such as acetonitrile, propionitrile, and the like; water; and mixtures thereof. The solutions can be formed at ambient or elevated temperatures, the higher temperatures enabling higher concentration solutions.

Step (b) involves adding an acid to the solution of step (a).

An acid may be directly added to the solution or mixture comprising O- desmethylvenlafaxine, or a solution of an acid in a suitable solvent may be added to the solution or mixture comprising O-desmethylvenlafaxine obtained in (a).

Optionally, both O-desmethylvenlafaxine and the acid may be together added into a solvent to obtain a reaction mixture. The sequence of addition of various reagents and raw materials is not limited.

Suitable acids that may be used in (b) include, but are not limited to, oxalic acid, tartaric acid, citric acid, maleic acid, acetic acid, sulfuric acid, phosphoric acid, and the like.

Suitable solvents that may be used for providing a solution of an acid include but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, isobutanol, 2-methyl-2-pentanol, t-amyl alcohol, and the like; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene, and the like; hydrocarbon solvents, such as hexanes, heptane, pentane, cyclohexane, toluene, xylenes 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, methyl t-butyl ether, diisopropyl ether, tetrahydrofuran, dioxane, and the like; polar aprotic solvents such as N₁N- dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, sulpholane, N- methylpyrrolidone, and the like; nitriles such as acetonitrile, propionitrile, and the like; water; and mixtures thereof. The solvent is not required to be the same as the solvent used in (a) for preparing a solution of desvenlafaxine.

Suitable temperatures for conducting (b) may be less than about 100°C, less than about 80⁰C, less than about 60⁰C, less than about 40°C, less than about 20⁰C, or any other suitable temperatures. Suitable times for salt formation in (b) depend on the temperature and other conditions, and may be generally less than about 30 hours, or less than about 20 hours, or less than about 10 hours, less than about 5 hours, less than about 2 hours, less than about 1 hour, or any other suitable times. Step (c) involves isolating the salt of O-desmethylvenlafaxine.

The product formed in (b) may be isolated by conventional techniques known in the art. For example, useful techniques include but are not limited to: decantation, centrifugation, gravity filtration, suction filtration, concentrating, cooling, stirring, shaking, adding an anti-solvent, adding seed crystals, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, and the like. The isolation may be optionally carried out at atmospheric pressure or under reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor. The solid so obtained may be in the form of a crystalline compound, a solvate, an amorphous compound or a combination thereof, depending on the requirement. The resulting solid may be optionally further dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100⁰C, less than about 60⁰C, less than about 4O⁰C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time period to achieve a desired purity of the product, such as, for example, about 1 to about 15 hours, or longer.

In an aspect, there are provided processes for the preparation of crystalline salts of O-desmethylvenlafaxine, an embodiment including:

(c) isolating a crystalline salt of O-desmethylvenlafaxine. Step (a) involves providing a solution of O-desmethylvenlafaxine in dichloromethane. The solution of O-desmethylvenlafaxine in (a) may be obtained, for example, by dissolving O-desmethylvenlafaxine of any physical form in dichloromethane. Alternatively it may also be obtained directly from a reaction mixture containing O-desmethylvenlafaxine in dichloromethane that is obtained during the course of its synthesis.

Step (b) involves adding an acid to the solution of step (a).

An acid may be directly added to the solution or mixture comprising O- desmethylvenlafaxine, or a solution of an acid in a suitable solvent may be added to the solution comprising O-desmethylvenlafaxine obtained in (a). Optionally, both O-desmethylvenlafaxine and the acid may be together added into the solvent to obtain a reaction mixture. The sequence of addition of various reagents and raw materials is not limited.

Suitable solvents that may be used for providing a solution of an acid include, but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, isobutanol, 2-methyl-2-pentanol, t-amyl alcohol, and the like; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene, and the like; hydrocarbon solvents, such as hexanes, heptane, pentane, cyclohexane, toluene, xylenes 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, methyl t-butyl ether, diisopropyl ether, tetrahydrofuran, dioxane, and the like; polar aprotic solvents such as N₁N- dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, sulpholane, N- methylpyrrolidone, and the like; nitriles such as acetonitrile, propionitrile, and the like; water; and mixtures thereof.

Suitable temperatures for conducting (b) may be less than about 100⁰C, less than about 80⁰C, less than about 60°C, less than about 40°C, less than about 20°C, or any other suitable temperatures.

Suitable times for completing the salt formation in (b) depend on the temperature and other conditions, and may be generally less than about 30 hours, less than about 20 hours, less than about 10 hours, less than about 5 hours, less than about 2 hours, less than about 1 hour, or any other suitable times.

Step (c) involves isolating the crystalline salt of O-desmethylvenlafaxine. The product formed in (b) may be isolated by techniques that include, but are not limited to: decantation, centrifugation, gravity filtration, suction filtration, concentrating, cooling, stirring, shaking, adding an anti-solvent, adding seed crystals, evaporation, flash evaporation and the like. Isolation can include precipitating a solid by cooling the solution. On cooling, solid comes out of solution as a crystalline salt of O-desmethylvenlafaxine. If desired, the solution may be concentrated by conventional methods such as evaporation or distillation, before cooling the solution. The exact cooling temperatures and times required for a desired extent of crystallization can be readily determined by a person skilled in the art, and will also depend on parameters such as concentrations and temperatures of the solution or slurry. The isolation in (c) may be optionally carried out at atmospheric pressure or under reduced pressure. Stirring or other alternate methods such as shaking, agitation and the like that mix the contents may also be employed for crystallization to occur. The suspension may be maintained for times required to achieve the desired product yield and purity, varying from about 15 minutes to about 20 hours, or longer. The resulting crystalline salt may then be recovered from the final mixture using any of techniques known in the art, such as filtration by gravity or by suction, centrifugation, slow evaporation, and the like. The crystals so obtained may carry a small proportion of occluded mother liquor containing a higher percentage of impurities and, If desired, the crystals may be washed with a solvent to wash out the mother liquor. The resulting solid may be optionally further dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100⁰C, less than about 60⁰C, less than about 4O⁰C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve the desired purity of the product, such as, for example, about 15 minutes to about 20 hours, or longer. In an embodiment, there is provided O-desmethylvenlafaxine oxalate. In an embodiment, there is provided crystalline O-desmethylvenlafaxine oxalate.

In an embodiment, there is provided crystalline O-desmethylvenlafaxine oxalate having polymorphic Form A and characterized by any one or more of:

A powder X-ray diffraction pattern having peaks at about 5.2, 10.4, 1 1.6, 13.2, 14.1 , 15.6, 15.9, 16.5, 17.9, 20.4, 22.4, 24.5, 26.3, and 26.6, ± 0.2 degrees 2-theta.

A powder X-ray diffraction pattern having peak locations substantially in accordance with Fig. 1 .

A DSC curve showing an endotherm onset at about 85°C. A DSC curve substantially in accordance with Fig. 2. A weight loss about 4% by weight from TGA. A TGA curve substantially in accordance with Fig. 3. In another embodiment, there is provided crystalline O- desmethylvenlafaxine oxalate having polymorphic Form D and characterized by either or both of:

A powder X-ray diffraction pattern having peaks at about 5.2, 10.4, 1 1.6, 14.4, 16.6, 19.1 , and 26.4, ± 0.2 degrees 2-theta. A powder X-ray diffraction pattern having peak locations substantially in accordance with Fig. 10. In another embodiment, there is provided crystalline O- desmethylvenlafaxine tartrate.

In another embodiment, there is provided crystalline O- desmethylvenlafaxine tartrate having polymorphic Form B and characterized by any one or more of:

A powder X-ray diffraction pattern having peaks at about 1 1.6, 13.2, 16.1 , 20.6, 23.3, 29.7, 32.0, 35.3, and 37.4, ± 0.2 degrees 2-theta.

A powder X-ray diffraction pattern having peak locations substantially in accordance with Fig. 4.

A DSC curve showing an endotherm onset at about 156°C. A DSC curve substantially in accordance with Fig. 5. A weight loss about 1 % by weight from TGA. A TGA curve substantially in accordance with Fig. 6. In an embodiment, there is provided an amorphous form of O- desmethylvenlafaxine tartrate.

In another embodiment, there is provided an amorphous form of O- desmethylvenlafaxine tartrate characterized by a powder X-ray diffraction pattern substantially in accordance with Fig. 1 1.

In an embodiment, there is provided crystalline O-desmethylvenlafaxine citrate.

In an embodiment, there is provided crystalline O-desmethylvenlafaxine citrate having polymorphic Form C and characterized by any one or more of: A powder X-ray diffraction pattern having peaks at about 13.1 , 15.6,

15.9, 19.5, and 26.1 , ± 0.2 degrees 2-theta.

A powder X-ray diffraction pattern having peak locations substantially in accordance with Fig. 8.

A weight loss about 1 % by weight from TGA. A TGA curve substantially in accordance with Fig. 9.

In an embodiment, there is provided crystalline O-desmethylvenlafaxine citrate having polymorphic Form E and characterized by either or both of:

A powder X-ray diffraction pattern having peaks at about 13.2, 14.1 , 15.6, 15.9, 16.1 , 16.5, 17.7, 19.4, 20.4, 24.9, 25.9, 31 .2, 33.4, and 36.2, ± 0.2 degrees 2-theta.

A powder X-ray diffraction pattern having peak locations substantially in accordance with Fig. 14. In an embodiment, there is provided an amorphous form of O- desmethylvenlafaxine citrate. In another embodiment, there is provided an amorphous form of O- desmethylvenlafaxine citrate, characterized by a powder X-ray diffraction pattern substantially in accordance with Fig. 12.

In an embodiment, there is provided an amorphous form of O- desmethylvenlafaxine maleate. In another embodiment, there is provided an amorphous form of O- desmethylvenlafaxine maleate characterized by a powder X-ray diffraction pattern substantially in accordance with Fig. 7. Also provided are pharmaceutical formulations containing a therapeutically effective amount of a polymorphic form of a salt of O-desmethylvenlafaxine, together with one or more pharmaceutically acceptable excipients.

The pharmaceutical formulations that include O-desmethylvenlafaxine salts with one or more pharmaceutically acceptable excipients 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 immediate-release, delayed-release, modified-release, or any combination of two or more thereof. Further, immediate-release formulations may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified-release formulations may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate-controlling substances, to form matrix or reservoir systems or combinations of matrix and reservoir systems. The formulations may be prepared using process steps such as direct blending, dry granulation, wet granulation or 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 are useful in the present invention include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered cellulosees, microcrystalline cellulosees, 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 dioxides 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, ethyl celluloses, methylcelluloses, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are useful in embodiments include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.

The processes of present invention are simple, cost-effective, ecologically friendly, reproducible, scalable, and robust, to produce O-desmethylvenlafaxine salts with high purity.

Certain specific aspects and embodiments of the present application are explained in greater 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.

EXAMPLE 1 : PREPARATION OF O-DESMETHYLVENLAFAXINE OXALATE.

A mixture of O-desmethylvenlafaxine (40 g), oxalic acid (19.2 g) and dichloromethane (400 mL) was heated to reflux and stirred for about 90 minutes. The reaction mixture was cooled to 25-30⁰C. The formed solid was filtered, washed with dichloromethane (40 mL) and dried at about 6O⁰C under vacuum for about 3 hours to afford the title compound (yield 53.4 g, HPLC purity: 99.87%).

The product is crystalline Form A, characterized by a powder X-ray diffraction pattern substantially in accordance with Fig. 1.

EXAMPLE 2: PREPARATION OF O-DESMETHYLVENLAFAXINE OXALATE.

A mixture of O-desmethylvenlafaxine (5.0 g), oxalic acid (2.4 g) and acetonitrile (50 mL) was heated to reflux and stirred for about 90 minutes. The mixture was cooled to 25-30⁰C. The formed solid was filtered, washed with acetonitrile (5 mL) and dried at about 60°C under vacuum for about 4.5 hours to afford the title compound (yield 6.4 g, HPLC purity 99.95%).

The product is crystalline Form D, characterized by a powder X-ray diffraction pattern substantially in accordance with Fig. 10.

EXAMPLE 3: PREPARATION OF O-DESMETHYLVENLAFAXINE TARTRATE. O-desmethylvenlafaxine (40 g), dichloromethane (400 mL) and L-tartaric acid (22.8 g) were charged into a round bottom flask and the mixture was stirred for about 10 minutes at 25-30⁰C. The mixture was heated to reflux and stirred for about 90 minutes. The mixture was cooled to 25-30⁰C. The formed solid was filtered, washed with dichloromethane (40 ml_) and dried at about 60⁰C under vacuum for about 3 hours to afford the title compound (yield 62.2 g, HPLC purity 99.9%). The product is crystalline Form B, characterized by a powder X-ray diffraction pattern substantially in accordance with Fig. 4.

EXAMPLE 4: PREPARATION OF O-DESMETHYLVENLAFAXINE TARTRATE. O-desmethylvenlafaxine (25 g) and methanol (250 mL) were charged into a round bottom flask and the mixture was stirred for about 10 minutes at 25-3O⁰C. L-tartaric acid (14.3 g) dissolved in methanol (70 mL) was added to the above solution over 20 minutes at 25-30⁰C. The solvent was evaporated at about 40- 45°C to afford the title compound as an amorphous solid (yield 9.3 g, HPLC purity 99.88%). The amorphous form obtained by this example is characterized by a powder X-ray diffraction pattern substantially in accordance with Fig.1 1.

EXAMPLE 5: PREPARATION OF O-DESMETHYLVENLAFAXINE CITRATE. O-desmethylvenlafaxine (40 g), dichloromethane (400 mL) and citric acid (29.2 g) were charged into a round bottom flask and the mixture was stirred for about 10 minutes. The mixture was heated to reflux and stirred for about 90 minutes. The mixture was cooled to 25-30⁰C. The formed solid was filtered, washed with dichloromethane (40 mL) and dried at about 60⁰C under vacuum for about 3 hours to afford the title compound (yield 69 g, HPLC purity 99.91 %). The product is crystalline Form C, characterized by a powder X-ray diffraction pattern substantially in accordance with Fig. 8.

EXAMPLE 6: PREPARATION OF O-DESMETHYLVENLAFAXINE CITRATE.

O-desmethylvenlafaxine (25 g) and acetone (250 mL) were charged into a round bottom flask and the mixture was stirred for about 10 minutes at 25-30⁰C. Citric acid (14.3 g) dissolved in water (70 mL) was added to the above solution over 20 minutes at 25-3O⁰C. The obtained solution was stirred for about 4 hours at 25-30⁰C. The solvent was evaporated at about 60⁰C to afford the title compound as an amorphous solid (yield 4.9 g, HPLC purity 99.92%).

The amorphous form obtained by this example is characterized by a powder X-ray diffraction pattern substantially in accordance with Fig. 12.

EXAMPLE 7: PREPARATION OF O-DESMETHYLVENLAFAXINE CITRATE.

O-desmethylvenlafaxine (5 g) and methanol (50 mL) were charged into a round bottom flask and the mixture was stirred for about 10 minutes at 25-30⁰C. The mixture was heated to reflux for about 10 minutes. Citric acid (3.6 g) dissolved in methanol (7 mL) was added to the above solution over 10 minutes under reflux. The obtained solution was cooled to room temperature. The solvent was evaporated at about 4O⁰C to afford the title compound as an amorphous solid (Yield: 8.5 g, HPLC purity: 99.93%).

The amorphous form obtained by this example is characterized by a powder X-ray diffraction pattern substantially in accordance with Fig. 13.

EXAMPLE 8: PREPARATION OF O-DESMETHYLVENLAFAXINE CITRATE.

O-desmethylvenlafaxine (5 g) and ethyl acetate (50 mL) were charged into a round bottom flask and the mixture was stirred for about 10 minutes at 25-3O⁰C. The mixture was heated to reflux for about 15 minutes. Citric acid (4.4 g) was added over 10 minutes, under reflux. The obtained solution was cooled to room temperature and stirred for about 30 minutes. The formed solid was filtered, washed with ethyl acetate (7 mL) and dried at about 74°C under vacuum for about 3 hours, 20 minutes to afford the title compound (yield 9.1 g, HPLC purity 99.93%).

The product is crystalline Form E, characterized by a powder X-ray diffraction pattern substantially in accordance with Fig. 14.

EXAMPLE 9: PREPARATION OF O-DESMETHYLVENLAFAXINE MALEATE. O-desmethylvenlafaxine (25 g) and methanol (125 mL) were charged into a flask and stirred for about 10 minutes. Maleic acid (1 1 g) dissolved in methanol (30 mL) was added and the mixture was stirred at 25-30⁰C to produce a clear solution. The solvent was distilled completely under reduced pressure at about 40°C. The obtained solid was dried under reduced pressure at 40°C to afford the title compound as an amorphous solid (yield 36.0 g, HPLC purity 99.88%).

The amorphous form obtained by this example is characterized by a powder X-ray diffraction pattern substantially in accordance with Fig. 7.

EXAMPLE 10: PREPARATION OF 0-DESMETHYLVENLAFAXINE MALEATE.

O-desmethylvenlafaxine (5.0 g) and methanol (50 mL) were charged into a flask and stirred for about 10 minutes. Maleic acid (2.2 g) dissolved in methanol (5 mL) was added and the mixture was stirred at about 25-30⁰C to produce a clear solution. The obtained solution was cooled to about 2°C and stirred for about 1 hour, 45 minutes. The solvent was evaporated at about 40⁰C to afford the title compound as an amorphous solid (yield 7.2 g, HPLC purity 99.93%).

The amorphous form obtained by this example is characterized by a powder X-ray diffraction pattern substantially in accordance with Fig. 15.

Claims

CLAIMS:

1. A process for preparing a salt of O-desmethylvenlafaxine, comprising:

(a) providing a solution of O-desmethylvenlafaxine in a solvent;

(b) adding an acid to the solution of (a); and

(c) isolating a salt of O-desmethylvenlafaxine.

2. The process of claim 1 , wherein a solvent comprises one or more of: an alcohol; a halogenated hydrocarbon; a ketone; an ester; an ether; a polar aprotic solvent; a nitrile; and water.

3. The process of claim 1 , wherein a solvent comprises one or more of methanol, acetone, dichloromethane, acetonitrile, and water.

4. The process of claim 1 , wherein an acid comprises oxalic acid, tartaric acid, citric acid, maleic acid, acetic acid, sulfuric acid, or phosphoric acid.

5. The process of claim 1 , wherein an acid comprises oxalic acid, tartaric acid, citric acid, or maleic acid.

6. A process for the preparation of a crystalline salt of O- desmethylvenlafaxine, comprising:

(a) providing a solution of O-desmethylvenlafaxine in dichloromethane;

(b) adding an acid to the solution of (a); and

(c) isolating a crystalline salt of O-desmethylvenlafaxine.

7. The process of claim 6, wherein an acid comprises oxalic acid, tartaric acid, or citric acid.

8. A compound O-desmethylvenlafaxine oxalate, in substantially crystalline form.

9. The compound of claim 8, characterized by a powder X-ray diffraction pattern having peaks at about 5.2, 10.4, 11.6, 13.2, 14.1 , 15.6, 15.9, 16.5, 17.9, 20.4, 22.4, 24.5, 26.3, and 26.6, ± 0.2 degrees 2-theta.

10. The compound of claim 8, characterized by a powder X-ray diffraction pattern having peak locations substantially in accordance with Fig. 1.

1 1. The compound of claim 8, characterized by a differential scanning calorimetry curve having an endothermic peak onset at about 85°C.

12. A crystalline O-desmethylvenlafaxine oxalate having crystalline Form A.

13. The crystalline O-desmethylvenlafaxine oxalate of claim 12, characterized by a differential scanning calorimetry curve substantially in accordance with Fig. 2.

14. The crystalline O-desmethylvenlafaxine oxalate of claim 12, characterized by a thermogravimetric analysis weight loss of about 4% by weight.

15. The crystalline O-desmethylvenlafaxine oxalate of claim 12, characterized by a thermogravimetric analysis curve substantially in accordance with Fig. 3.

16. A crystalline O-desmethylvenlafaxine oxalate having crystalline Form D.

17. The compound of claim 16, characterized by a powder X-ray diffraction pattern having peaks at about 5.2, 10.4, 1 1.6, 14.4, 16.6, 19.1 and 26.4, ± 0.2 degrees 2-theta.

18. The compound of claim 16, characterized by a powder X-ray diffraction pattern having peak locations substantially in accordance with Fig. 10.

19. A compound O-desmethylvenlafaxine tartrate, in crystalline form.

20. The compound of claim 19, having crystalline polymorphic Form B.

21. The compound of claim 19, characterized by a powder X-ray diffraction pattern having peaks at about 11.6, 13.2, 16.1 , 20.6, 23.3, 29.7, 32.0, 35.3, and 37.4, ± 0.2 degrees 2-theta.

22. The compound of claim 19, characterized by a powder X-ray diffraction pattern having peak locations substantially in accordance with Fig. 4.

23. The compound of claim 19, characterized by a differential scanning calorimetry curve having an endothermic peak onset at about 156°C.

24. The compound of claim 19, characterized by a differential scanning calorimetry curve substantially in accordance with Fig. 5.

25. The compound of claim 19, characterized by a thermogravimetric analysis weight loss about 1 % by weight.

26. The compound of claim 19, characterized by a thermogravimetric analysis curve substantially in accordance with Fig. 6.

27. The compound O-desmethylvenlafaxine tartrate, in amorphous form.

28. The compound of claim 27, characterized by a powder X-ray diffraction pattern having peak locations substantially in accordance with Fig. 1 1.

29. A compound O-desmethylvenlafaxine citrate, in crystalline form.

30. A crystalline O-desmethylvenlafaxine citrate having crystalline Form C.

31. The compound of claim 30, characterized by a powder X-ray diffraction pattern having peaks at about 13.1 , 15.6, 15.9, 19.5, and 26.1 , ± 0.2 degrees 2-theta.

32. The compound of claim 30, characterized by a powder X-ray diffraction pattern having peak locations substantially in accordance with Fig. 8.

33. The compound of claim 30, characterized by a thermogravimetric analysis weight loss about 1 % by weight.

34. The compound of claim 30, characterized by a thermo gravimetric analysis curve substantially in accordance with Fig. 9.

35. A crystalline O-desmethylvenlafaxine citrate having crystalline Form E.

36. The compound of claim 35, characterized by a powder X-ray diffraction pattern having peaks at about 13.2, 14.1 , 15.6, 15.9, 16.1 , 16.5, 17.7, 19.4, 20.4, 24.9, 25.9, 31.2, 33.4, and 36.2, ± 0.2 degrees 2-theta.

37. The compound of claim 35, characterized by a powder X-ray diffraction pattern having peak locations substantially in accordance with Fig. 14.

38. The compound O-desmethylvenlafaxine citrate, in amorphous form.

39. The compound of claim 38, characterized by a powder X-ray diffraction pattern having peak locations substantially in accordance with Fig. 12.

40. The compound O-desmethylvenlafaxine maleate, in amorphous form.

41. The compound of claim 40, characterized by a powder X-ray diffraction pattern having peak locations substantially in accordance with Fig. 7.

42. A pharmaceutical formulation, comprising a compound of any of claims 8-41 and at least one pharmaceutically acceptable excipient.