MX2007016172A - Substantially pure o-desmethylvenlafaxine and processes for preparing it. - Google Patents

Abstract

Methods for preparing substantially pure O-desmethylvenlafaxine are described.

Description

SUBSTANTIALLY PURE O-DESMETILVENLAFAXINA AND PROCESSES TO PREPARE FIELD OF THE INVENTION The invention comprises substantially pure O-demethylvenlafaxine.

BACKGROUND OF THE INVENTION Venlafaxine, (±) -1- [2- (dimethylamino) -1- (4-ethoxyphenyl) ethyl] cyclohexanol, is the first of a class of antidepressants. Venlafaxine acts by inhibiting the reuptake of norepinephrine and serotonin, and is an alternative for tricyclic antidepressants and selective resorption inhibitors. Venlafaxine has the following chemical formula, Formula I: Formula I O-desmethylvenlafaxine, which has the chemical name 4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenol, is the main metabolite of venlafaxine and has been shown to inhibit the absorption of norepinephrine and serotonin. See Klamerus, K.J. et al, "Introduction of the Composite Parameter to the Pharmacokinetics of Venlafaxine and its Active O-Desmetil Metabolite", J. Clin. Pharmacol. 32: 716-724 (1992). 0-desmethylvenlafaxine has the following chemical formula, Formula II: Molecular Weight: 263.38 Formula II Processes for the synthesis of O-demethylvenlafaxine, comprising the step of demethylation of the phenol group of venlafaxine, are described in US Patent Nos. 7,026,608 and 6,689,912 and in the US publication. No. 2005/0197392, which are incorporated herein by reference.

The synthesis revealed in the preceding references is carried out according to the following scheme: MBC CMBS BBMV Methylation-ri amine Ves-lafaxii-a ODV VRL "MCB" refers to methyl benzyl cyanide, "CMBC" refers to cyclohexyl methylbenzyl cyanide, "DDMV" refers to didesmethyl venlafaxine, and "ODV" refers to 0 -desmetilvenlafaxina.

Like any synthetic compound, O-desmtilvenlafaxina may contain foreign compounds or impurities that may have many origins. They may be unreacted starting materials, byproducts of the reaction, products of side reactions, or degradation products. Impurities of 0-desmethylvenlafaxine or any active pharmaceutical ingredient (API) are undesirable and, in extreme cases, may still be harmful to a patient who is being treated with a dosage form containing the API.

It is also known in art that impurities in an API can come from the degradation of the API itself, which is related to the stability of the pure API during storage, and the manufacturing processes, which include chemical synthesis. Process impurities include unreacted starting materials, chemical derivatives of impurities contained in initial materials, synthetic by-products, and degradation products.

In addition to the stability, which is an important factor in the duration of the API, the purity of the API produced in the commercial manufacturing process is clearly a necessary condition for commercialization. Impurities introduced during commercial manufacturing processes should be limited to very small amounts, and preferably are substantially absent. For example, the ICH Q7A guide for API manufacturers requires process impurities to be kept below established limits by specifying the quality of the raw materials, controlling the parameters of the process, such as temperature, pressure, time, and the stoichiometric ratios, and including purification steps, such as crystallization, distillation and extraction of liquid liquids, in the manufacturing process.

The product mixture of a chemical reaction is rarely a single compound with a purity sufficient to meet pharmaceutical standards. The collateral products and reaction by-products and additional reagents used in the reaction, in most cases, are also present in the product mix. At certain stages during the processing of an API, such as O-desmtilvenlafaxina, its purity must be analyzed, generally, by HPLC, NMR or TLC analysis, to determine if it is suitable for continuous processing, for use in a pharmaceutical product. The API does not need to be absolutely pure, since absolute purity is a theoretical ideal that is generally unattainable. In contrast, purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and therefore, as safe as possible for clinical use. As discussed above, guidelines from the US Food and Drug Administration recommend that the amounts of some impurities be limited to less than 0.1 percent.

Generally, collateral products, byproducts and additional reagents (collectively "impurities") are identified spectroscopically and / or with another physical method, and then associated with a peak position, such as that of a chromatogram, or a dot on a plate of TLC. (Strobel p.953, Strobel, H.A., Heineman, W.R., Chemical Instrumentation: A Systematic Approach, 3rd dd. (Wiley &Sons: New York 1989)). Then, the impurity can be identified, for example, by its relative position in the chromatogram, where the position in a chromatogram is conventionally measured in minutes between the injection of the sample into the column and the elution of the particular component through the detector. The relative position of the chromatogram is called the "retention time".

Therefore, due to its medical uses, it is desirable to obtain substantially pure 0-desmethylvenlafaxine.

Extract of the invention In one embodiment the present invention provides substantially pure O-demethylvenlafaxine containing less than 5% area by HPLC, more preferably less than 3% area by HPLC, even more preferably less than 1% area by HPLC of total impurities.

Preferably, O-demethylvenlafaxine contains less than 0.7% area by HPLC of total impurities. More preferably, less than 0.2% area by HPLC of total impurities and more preferably, O-demethylvenlafaxine contains less than 0.07% area by HPLC of total impurities.

In another embodiment, the present invention provides a process for preparing substantially pure O-demethylvenlafaxine comprising: combining under pressure venlafaxine, an organic solvent and a reagent selected from the group consisting of: thiophenol, sodium sulfide and alkyl thioalate of C? C8, to form a mixture, heat the mixture to a temperature of 30 ° C to 220 ° C, and recover O-desmetilvenlafaxina.

In another embodiment, the present invention provides a process for preparing substantially pure O-demethylvenlafaxine comprising: combining venlafaxine, an organic solvent and C?-C8 alkyl thiolate or sodium sulfide to form a mixture, heating the mixture at a temperature from 100 ° C to 210 ° C, and recover O-desmethylvenlafaxine.

In another embodiment, the present invention provides a process for preparing substantially pure O-demethylvenlafaxine comprising: combining venlafaxine and thiophenol to form a mixture, heating the mixture at a temperature of 100 ° C to 210 ° C and recovering O-desmethylvenlafaxine.

In yet another embodiment, the present invention provides the use of C-C8 alkyl thiolate and sodium sulfide for the demethylation of venlafaxine.

In yet another embodiment, the present invention provides a process for preparing substantially pure O-demethylvenlafaxine comprising: preparing tridemethyl venlafaxine as described in co-pending patent application 60/849216 (which is incorporated herein by reference); converting said tridemethyl venlafaxine to O-desmethylvenlafaxine; and recover O-desmetilvenlafaxina.

In another embodiment, the invention relates to an analytical method for testing the chemical purity of O-demethylvenlafaxine.

In another embodiment, the present invention provides a pharmaceutical composition comprising substantially pure O-demethylvenlafaxine and a pharmaceutically acceptable excipient.

In yet another embodiment, the present invention provides a process for preparing a pharmaceutical formulation comprising mixing substantially pure O-demethylvenlafaxine and a pharmaceutically acceptable carrier.

Detailed description of the invention As used herein, the term "substantially pure" refers to O-demethylvenlafaxine having a purity, measured as% area by HPLC, of 95% or more. Preferably, substantially pure O-demethylvenlafaxine has a purity of 97% area by HPLC, more preferably 99% area by HPLC, still more preferably 99.3% by HPLC, more preferably 99.8% by area. area by HPLC.

The present invention provides O-demethylvenlafaxine (ODV) which contains less than 5% area by HPLC, preferably less than 3% area by HPLC, more preferably less than 1% area by HPLC, of total impurities. The term "% area by HPLC" as used herein refers to the area in an HPLC chromatogram of one or more peaks compared to the total area of all peaks in the HPLC chromatogram expressed as a percentage of the total area. In addition, the purity of 0-desmethyl venlafaxine can be expressed herein as the purity of "HPLC". As such, the "HPLC purity" is a calculation of the area under the peak of O-desmethyl venlafaxine divided by the total area under the curve in an HPLC chromatogram.

Preferably, O-demethylvenlafaxine contains less than 0.7% area by HPLC of total impurities. More preferably, less than 0.2% area by HPLC of total impurities and more preferably, O-demethylvenlafaxine contains less than 0.07% area by HPLC of total impurities.

The O-demethylvenlafaxine established by the present invention is obtained as a racemate or as optically pure O-demethylvenlafaxine.

It will be apparent to one skilled in the art that the novel crystallization of crude O-demethylvenlafaxine can produce a higher purity.

In another embodiment, the present invention provides a process for preparing substantially pure O-demethylvenlafaxine comprising: combining, preferably under reduced pressure, venlafaxine (VNL), an organic solvent and a reagent selected from the group consisting of: thiophenol, sodium sulfide and an alkyl C 1 -C 8 thiolate, to form a mixture, preferably to heat the mixture at a temperature of 30 ° C to 220 ° C, preferably 30 ° C to 100 ° C and recover substantially pure 0-desmethylvenlafaxine.

As used herein, the term "reduced pressure" refers to a pressure of less than 1 atmosphere, preferably at a pressure of less than 0.5 atmosphere, more preferably at a pressure of less than 0.1 atmosphere.

The organic solvent can be selected from the group consisting of: C3-C7 ketones, C3-C7 esters, C5-C8 aliphatic hydrocarbons, chlorinated hydrocarbons, C2-C8 alcohols. More preferably, the solvent is selected from the group consisting of: acetone, ethyl acetate, toluene, DMF, NMP, DMA, THF and ethanol.

As used herein, the term "high boiling solvent" refers to a solvent that has a boiling point higher than 100 ° C. Preferably, the solvent with high boiling point is selected from the group consisting of: toluene, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyridone, N-methyl-2-pyrrolidone, 1-methyl- 2-pyrrolidinone (NMP) and dimethylacetamide (DMA). More preferably, the solvent with a high boiling point is DMA, DMF or NMP.

Whenever NMP is used, the ratio of NMP to venlafaxine is preferably 1 to 20 (by volume), more preferably 2 to 4 (by volume).

Whenever DMA or DMF is used, the ratio of DMA and DMF to venlafaxine is preferably at least 1 volume, more preferably, 1 to 10 (by volume), more preferably, 2.5 volumes.

Whenever thiophenol is used in the process, preferably a catalyst is used in the reaction mixture. More preferably, the catalyst is an alkaline base, such as potassium carbonate.

Preferably, substantially pure O-demethylvenlafaxine obtained by the preceding process contains less than 0.7% area by HPLC of total impurities. More preferably, less than 0.2% area by HPLC of total impurities and more preferably, the substantially pure O-demethylvenlafaxine obtained by the preceding process contains less than 0.07% area by HPLC of total impurities.

O-demethylvenlafaxine can be recovered from the mixture by any method known to those skilled in the art.

Preferably, the O-demethylvenlafaxine thus obtained is in a crystalline form, characterized by X-ray powder diffraction reflections at: 12.1, 13.2, 15.9 and 20.4 degrees two theta ± 0.2 degrees two theta.

In another embodiment, the present invention provides a process for preparing substantially pure O-demethylvenlafaxine comprising: combining venlafaxine, an organic solvent and a C 1 -C 8 alkyl thiolate or sodium sulfide to form a mixture, heating the mixture to a temperature from 100 ° C to 210 ° C, preferably from 100 ° C to 190 ° C, more preferably from 135 ° C to 190 ° C, and recovering substantially pure O-desmethylvenlafaxine.

The organic solvent used is that described above.

Whenever NMP is used, the ratio of NMP to venlafaxine is preferably 1 to 20 (by volume), more preferably 2 to 4 (by volume).

Whenever DMA or DMF is used, the ratio of DMA and DMF to venlafaxine is preferably at least 1 volume, more preferably 1 to 10 (by volume), more preferably 2.5 volumes.

Preferably, the substantially pure O-demethylvenlafaxine obtained by the preceding process contains less than 0.7% area by HPLC of total impurities. More preferably, less than 0.2% area by HPLC of total impurities and more preferably the O-demethylvenlafaxine obtained by the preceding process contains less than 0.07% area by HPLC of total impurities.

The O-demethylvenlafaxine can be recovered from the mixture by any method known to the person skilled in the art.

Preferably, the O-demethylvenlafaxine thus obtained is in a crystalline form, characterized by X-ray powder reflections at: 12.1, 13.2, 15.9 and 20.4 degrees two theta ± 0.2 degrees two theta.

In another embodiment, the present invention provides a process for preparing substantially pure O-demethylvenlafaxine comprising: combining venlafaxine and thiophenol to form a mixture, heating the mixture at a temperature of 100 ° C to 210 ° C, preferably 100 ° C to 190 ° C, more preferably 135 ° C to 190 ° C, and recovering substantially pure O-desmethylvenlafaxine.

Optionally, the foregoing process can be carried out in the presence of a non-hydroxylic or non-ether solvent. The solvent can be selected from the group consisting of: NMP, DMSO, DMF, DMA, carbocera, marlotherm and silicon oil. Preferably, the solvent is NMP.

Whenever NMP is used, the ratio of NMP to venlafaxine is preferably 1 to 20 (by volume), more preferably 2 to 4 (by volume).

Preferably, a catalyst is used in the reaction mixture of venlafaxine and thiophenol. More preferably, the catalyst is a base. More preferably, the catalyst is an alkali metal base, such as potassium carbonate.

Preferably, the substantially pure O-demethylvenlafaxine obtained by the preceding process contains less than 0.7% area by HPLC of total impurities. More preferably, less than 0.2% area by HPLC of total impurities and more preferably, the O-demethylvenlafaxine obtained by the preceding process contains less than 0.07% area by HPLC of total impurities.

O-demethylvenlafaxine can be recovered from the mixture by any method known to those skilled in the art.

Preferably, the O-demethylvenlafaxine thus obtained is in a crystalline form, characterized by X-ray powder diffraction reflections at: 12.1, 13.2, 15.9 and 20.4 degrees two theta ± 0.2 degrees two theta.

All the processes for preparing substantially pure O-desmethylvenlafaxine described above, can be continued by suspending the O-desmethylvenlafaxine obtained in a mixture of an organic solvent and water, to reduce impurities. The Substantially pure O-demethylvenlafaxine obtained by the suspension has a test purity of at least 95%, more preferably, a test purity of 99%. Preferably, the mixture of organic solvent and water can be a mixture of alcohol and water or a mixture of water and acetonitrile, more preferably the mixture of alcohol and water is a mixture of C-C4 alcohol and water, more preferably the mixture of Alcohol and water is a mixture of isopropanol and water.

As used herein, the term "test purity" refers to a purity determined by a method known in the art that calculates the mass of O-desmethyl venlafaxine by comparing the percentage of sample area to the percentage of area of a standard.

Optionally, O-demethylvenlafaxine is suspended in a mixture of water and IPA. Preferably, the mixture of water and IPA is in a ratio of 15:25 to 80:20 (by volume), more preferably the ratio is 80:20 (by volume).

The suspension can be maintained for 5 minutes to 5 hours, preferably for 30 minutes to 4 hours, more preferably for 1 hour to 3 hours, more preferably for 2 hours, at a temperature of 20 ° C to 70 ° C, preferably to a temperature of 20 ° C to 40 ° C, more preferably at room temperature, to obtain substantially pure O-demethylvenlafaxine having a test purity of 95%, preferably 99%. Substantially pure O-demethylvenlafaxine can be recovered from the suspension by any method known to those skilled in the art. Preferably, the recovery comprises the precipitation of O-desmethyl venlafaxine from an aqueous solution or suspension in water and IPA wherein the pH is adjusted to 7.5-13.5, preferably from 7.5 to 10, more preferably at a pH of 8. The pH adjustment comprises adding an acid, preferably the acid is selected from HCl and an organic acid, more preferably the acid is citric acid or succinic acid, more preferably the acid is succinic acid.

In yet another embodiment, the present invention provides the use of C-C8 alkyl thiolate and sodium sulfide for the demethylation of venlafaxine.

In yet another embodiment, the present invention provides a process for preparing substantially pure O-demethylvenlafaxine comprising: preparing tridemethyl venlafaxine (TDMV) as described in co-pending patent application No. 60/849216, which is incorporated herein by reference reference; converting said tridemethyl venlafaxine to O-desmethylvenlafaxine, and recovering substantially pure 0-desmethylvenlafaxine from the reaction mixture.

A process for preparing tridesmethyl venlafaxine comprises: combining didesmethylvenlafaxine, a high-boiling solvent, and a thiolate to form a mixture, heating the mixture at a temperature of 100 ° C to 220 ° C, preferably 140 ° C to 210 ° C C, more preferably at a temperature of 155 ° C to 210 ° C, and optionally recover tridemethyl venlafaxine from the mixture.

The tridemethyl venlafaxine obtained by the preceding process preferably contains less than 5% area by HPLC of total impurities.

Preferably, the solvent with high boiling point is that described above.

Preferably, the thiolate is a high molecular weight thiolate or areal thiolate. More preferably, the thiolate is sodium dodecanthiolate or thiophenol. The sodium dodecanthnolate can be obtained by any method known to those skilled in the art, such as combining sodium methoxide, methanol and dodecanethiol.

Whenever thiophenol is used, a catalyst is preferably used in the reaction mixture. More preferably, the catalyst is a base. More preferably, the catalyst is an alkali metal base, such as potassium carbonate is the catalyst.

Preferably, the mixture is heated to a temperature of 155 ° C to 210 ° C.

Tridemethyl venlafaxine can be recovered from the mixture by any method known to those skilled in the art.

The conversion of tridesmethyl venlafaxine to O-demethylvenlafaxine can also be carried out as described in co-pending patent application No. 60/849216, which is incorporated herein by reference. This process comprises: combining a solution of tridesmethyl venlafaxine and a formaldehyde source with sodium borohydride or sodium triacetoxy borohydride to obtain a suspension and optionally recovering O-desmethylvenlafaxine from the suspension.

Optionally, the initial tridesmethyl venlafaxine material is in a solution with an organic solvent such as a C? -4 alcohol.

Optionally, the process is carried out in acidic conditions. Preferably, the acid source is an organic acid, such as formic acid or an acetic acid.

Preferably, before combining sodium borohydride or triacetoxy sodium borohydride, the solution is cooled to a temperature of less than 10 ° C, more preferably less than 5 ° C.

The substantially pure O-demethylvenlafaxine can also be recovered from the reaction mixture by any method known to those skilled in the art. Preferably, the recovery of substantially pure O-demethylvenlafaxine comprises adjusting the pH of a suspension containing crude 0-demethylvenlafaxine, for example the reaction mixture from the conversion step, to a pH of 7.5-13.5, obtaining Substantially pure 0-desmethylvenlafaxine. Adjusting the pH of the suspension containing crude O-demethylvenlafaxine can derive or allow the precipitation of substantially pure O-demethylvenlafaxine from the suspension. The suspension containing O-demethylvenlafaxine may be the suspension from the reaction mixture of the conversion of tridemethylvenlafaxine to O-demethylvenlafaxine or a suspension in a mixture of water and a C -C alcohol. The pH can be adjusted with any suitable organic or inorganic acid, preferably the pH is adjusted with citric acid or succinic acid. Upon substantially substantially recovering substantially pure O-demethylvenlafaxine the pH is preferably adjusted to a pH of 7.5-10, more preferably at pH 8. Recovery of substantially pure O-demethylvenlafaxine may also comprise filtering the substantially pure O-desmethylvenlafaxine obtained. Optionally, an antisolvent is added to the adjusted pH suspension, where the antisolvent is a solvent miscible with water. Preferably, the antisolvent is a C 1 -C 4 alcohol, more preferably isopropanol (IPA).

Preferably, the substantially pure O-demethylvenlafaxine obtained by the preceding process contains less than 0.7% area by HPLC of total impurities. More preferably, less than 0.2% area by HPLC of total impurities and more preferably the O-demethylvenlafaxine obtained by the preceding process contains less than 0.07% area by HPLC of total impurities.

O-demethylvenlafaxine can be recovered from the suspension by any method known to those skilled in the art.

In another embodiment, the invention relates to an analytical method for treating the chemical purity of O-demethylvenlafaxine which comprises combining a sample of O-demethylvenlafaxine with a mixture of acetonitrile and buffer in a ratio of 3: 7, to obtain a solution; inject the solution onto a C-18 column, for example a Zorbax SB C-18 4.6 * 250mm Part No. 28105-020 column or a similar column, then the sample is eluted from the column at 55 minutes using a mixture of acetonitrile and buffer (3: 7) (named eluent A) and a mixture of acetonitrile: buffer: trifluoroacetic acid: triethylamine (designated eluent B) as eluent, and measuring the chemical purity of the relevant sample with an ultraviolet radiation detector . The eluent B is preferably prepared by adding to a mixture of 700 parts of acetonitrile and 300 parts of buffer, 1.6 parts of trifluoroacetic acid and 2.9 parts of triethylamine and adjusting the resulting mixture to pH 3.0, more preferably the eluent B is preferably prepared by combining 700 ml of acetanitrile, 300 ml of buffer, 1.6 ml of trifluoroacetic acid, and 2.9 ml of triethylamine and adjusting to a pH of 3.0.

Preferably, the buffer contains 0.4% trifluoroacetic acid, 0.7% triethylamine and 98.9% water having a pH of 3.0. Preferably, the eluent used can be a mixture of the eluent A and the eluent B, wherein their ratio varies with time, i.e., a gradient eluent. At 0 minutes, the eluent contains 100% of eluent A and 0% of eluent B. At 21 minutes, the eluent preferably contains 100% of eluent A and 0% of eluent B. At 55 minutes, the eluent preferably contains 45% of the eluent A and 55% of the eluent B.

In another embodiment, the present invention provides a composition comprising O-demethylvenlafaxine and a pharmaceutically acceptable excipient.

In yet another embodiment, the present invention provides a process for preparing a pharmaceutical formulation comprising mixing substantially pure O-demethylvenlafaxine and a pharmaceutically acceptable carrier.

The pharmaceutical compositions can be prepared as medicaments to be administered orally, parenterally, rectally, transdermally, buccally or nasally. Suitable forms for oral administration include tablets, compressed or coated tablets, dragees, sachets, hard or gelatin capsules, sublingual tablets, syrups, and suspensions. Suitable forms of parenteral administration include an aqueous or non-aqueous solution or emulsion, while for rectal administration, suitable forms include suppositories with a hydrophilic or hydrophobic vehicle. For topical administration, the invention provides transdermal delivery systems known in the art, and for nasal administration, aerosol delivery systems known in the art are provided.

In addition to the active ingredient (s), the pharmaceutical compositions of the present invention may contain one or more excipients or adjuvants. The selection of excipients and the amounts to be used can be easily determined based on the experience and analysis of normal reference procedures and works in the field.

The diluents increase the volume of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier to handle for the patient and caregiver. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., AVICEL®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, calcium phosphate dibasic dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (for example, EUDRAGIT®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compacted in a dosage form, such as a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g., carbopol), sodium carboxymethylcellulose, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., KLUCEL®) , hydroxypropyl methyl cellulose (eg, METHOCEL®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (eg, KOLLIDON®, PLASDONE®), pregelatinized starch, sodium alginate and starch.

The dissolution rate of a solid pharmaceutical composition compacted in the stomach of the patient can be increased by adding a disintegrator to the composition. Disintegrators include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (eg, Ac-Di-Sol®, PRIMELLOSE®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (for example, KOLLIDON®, POLYPLASDONE®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (for example, EXPLO ®) and starch.

Slides can be added to improve the flow properties of a non-compacted solid composition and to improve dosing precision. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

When a dosage form such as a tablet is made by compaction of a powder composition, the composition is pressurized by a punch and die. Some excipients and active ingredients have a tendency to adhere to punch and die surfaces, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and facilitate the release of the product from the die. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmito-stearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc fumarate.

Flavoring and flavoring agents make the dosage form more palatable to the patient. Flavoring and flavoring agents common for pharmaceuticals that can be included in the composition of the present invention include maltol, vanilla, ethyl vanilla, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

The solid and liquid compositions can also be stained using any pharmaceutically acceptable dye to improve their appearance and / or facilitate the identification of the product and the unit dosage level by the patient.

In the liquid pharmaceutical compositions of the present invention, the active ingredient and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin. In said suspension the solid excipients may be in solution or suspended in the liquid carrier. The active ingredient maintains its structure in said liquid pharmaceutical compositions.

The liquid pharmaceutical compositions may contain emulsifying agents to uniformly disperse throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that may be useful in the liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetoestaryl alcohol, and cetyl alcohol.

The liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouthfeel of the product and / or coat the gastrointestinal tract lining. These agents include acacia, alginic acid bentonite, carbomer, calcium or sodium of carboxymethylcellulose, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, tragacanth starch, and xanthan gum. Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve flavor.

Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.

According to the present invention, a liquid composition may also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate.

The selection of the excipients and the amounts used can be easily determined by the scientist formulator based on experience and on the analysis of normal procedures and reference works in the field.

The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. Dosages include suitable dosages for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalation, and ophthalmic administration. Although the most appropriate administration in any given case depends on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages can conveniently be presented in a unit dosage form and prepared by any of the methods known in the pharmaceutical art.

Dosage forms include solid dosage forms such as tablets, powders, capsules, suppositories, sachets, chips and capsules, as well as liquid syrups, suspensions and elixirs.

The dosage form of the present invention may be a capsule containing the composition, preferably a solid powder or granule composition of the invention, within a hard or soft capsule. The capsule can be made of gelatin, and optionally it can contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or a dye.

The active ingredient and the excipients can be formulated into compositions and dosage forms according to methods known in the art.

A composition for the manufacture of tablets or for the filling of capsules can be prepared by wet granulation. In wet granulation, some or all of the ingredients and excipients in powder form are mixed and then further mixed in the presence of a liquid, generally water, which causes the powders to clump together into granules. The granulate is screened and / or milled, dried and then sieved and / or milled to the desired particle size. With the granulate tablets can then be made or other excipients, such as a glidant and / or a lubricant, can be added prior to the manufacture of tablets.

A composition for making tablets can be prepared conventionally by dry blending. For example, the mixed composition of the active ingredients and excipients can be compacted into a piece or a sheet and then comminuted into compacted granules. The compacted granules can then be compressed into a tablet.

As an alternative for dry granulation, a blended composition can be directly compressed into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. The excipients that are particularly well suited for the manufacture of tablets by direct compression include microcrystalline cellulose, spray-dried lactose, dicalcium phosphate dihydrate and colloidal silica. The correct use of these and other excipients in the manufacture of tablets by direct compression is known to those who belong to the art and have experience and expertise in the challenge of particular formulation of the manufacture of tablets by direct compression.

A capsule filler of the present invention may comprise any of the mixtures and granulates that were described with reference to the manufacture of tablets, although they do not undergo the final step of tablet manufacture.

In another embodiment, the present invention provides a method for treating a patient, comprising administering to a patient in need thereof a therapeutically effective amount of the preceding substantially pure O-desmethylvenlafaxine. Preferably, the method is to treat a patient suffering from a condition who can be treated with a norepinephrine or serotonin reuptake inhibitor. Said patient may be suffering from depression.

Having thus described the present invention with reference to certain preferred embodiments, other embodiments will become apparent to those skilled in the art from the analysis of the specification. The invention is also defined by reference to the following examples which describe in detail the synthesis of the novel tridamethyl venlafaxine compound and also its conversion into O-demethylvenlafaxine. It will be apparent to those skilled in the art that many modifications can be made, both of materials and methods, without departing from the scope of the invention.

EXAMPLES XRD diffraction was performed on the Scintag X-ray powder diffractometer, model X'TRA with a solid-state detector. Copper radiation of 1.548 A was used. The sample holder was a circular common aluminum sample holder with a scratch-free bottom. The exploration parameters were in the range of: 2-40 degrees two theta; exploration mode: continuous exploration; Step size: 0.05 degree; and speed of 5 degrees / minute.

HPLC method to measure the chemical purity: Column: Zorbax SB C-18 4,6 * 250 mm Part No. 28105-020 or equivalent column Buffer: 0.4% trifluoroacetic acid, 0.7% triethylamine, 98.9% water (adjusted to pH 3.0 ). Eluent A: 30% acetonitrile 70% Buffer Eluent B: Prepared by adding to a mixture of 700 ml of acetonitrile and 300 ml of buffer, 1.6 ml of trifluoroacetic acid and 2.9 ml of triethylamine (adjusted to pH 3.0) . Stop time: 55 minutes Gradient of Time (min) ^ to A Eluent B Eluent: (%) (%) 0 100 0 21 100 0 55 45 55 Balancing time: 10 minutes Flow: 1.0 mL / minute Detector: 230 nm Injection volume: 10 μL Diluent: Eluent A Column temperature: 25 ° C Example 1; Preparation of O-demethylvenlafaxine in NMP Venlafaxine (50 g, 180 mmol), thiophenol (20 mL, 295 mmol), K2C03 (1 g, 6 mmol) and NMP (90 mL) were loaded into a 500 ml 3 neck flask equipped with stir bar, condenser and thermometer. The mixture was heated to 190 ° C. After 5 hours at 190 ° C, the heating bath was removed (less than 1.5% VNL). IPA (300 ml) was added at 80 ° C. The solution was cooled to 0 ° C-5 ° C overnight. The solid was filtered under reduced pressure and washed with IPA and water. The solid was then dried overnight at 50 ° C under vacuum and gave pure OVD base. OVD was obtained with a purity of 97% and a trial of 93.55.

Example 2. Preparation of O-demethylvenlafaxine in NMP To a one neck flask equipped with magnetic stirring bar, deán stark, condenser and thermometer were added at room temperature under nitrogen flow, VNL (5 g, 18.2 mmol), Na 2 S Hydrated (1.58 g, 12 mmol , assay> 60%) and NMP (12 ml). The reaction mixture was heated to 150 ° C in 1 hour and maintained at this temperature for 7.5 hours. Then the reaction mixture was cooled to room temperature and stirred overnight at this temperature. Na2S hydrate (0.71 g, 5.4 mmol, assay> 60%) was then added. The mixture was heated to 165 ° C in 1 hour and kept at this temperature for 5 hours. After this time the reaction was cooled to 40 ° C, IPA (30 ml) and a 10% aqueous solution of citric acid (20 ml) were added slowly through a dropping funnel until light precipitation was observed (pH 10). The suspension was stirred over the weekend at room temperature and the solid was filtered under reduced pressure and washed with IPA (20 ml). The solid was dried overnight in a vacuum oven at 50 ° C and dry OVD was obtained (assay 55.2%, purity of HPLC 99.11%).

Example 3; Preparation of O-demethylvenlafaxine under pressure A 250 ml autoclave is charged with 5 g of VNL (0.0182 mol), 3.81 g of sodium ethanothiolate (0.0458 mol, 2.5 equivalents) and? MP (10 ml). The reaction mixture is stirred at a temperature of 30 ° C to 220 ° C and at 1-20 bar pressure for 4 hours. The mixture is then cooled to room temperature. At room temperature, IPA (10 ml) and water (10 ml) are added. To this mixture a 10% aqueous solution of citric acid is added to reach pH 12. A solid begins to precipitate and is stirred at room temperature for 2.5 hours. The solid is then filtered under reduced pressure and washed with solvent. The wet cake is dried in a vacuum oven at 50 ° C and pure OVD is obtained.

Example 4. Preparation of O-demethylvenlafaxine in DMA To a 100 ml three neck flask equipped with a mechanical stir bar, thermometer and condenser was added 5 g of V? L (0.0182 mol), 3.81 g of sodium ethanothiolate (0.0458 mol, 2.5 equivalents) and dimethylacetamide (10 ml). The mixture was heated at 135 ° C for 4 hours, and then cooled to room temperature. At room temperature, IPA (10 ml) and water were added (10 ml). The reaction mixture was clear. To this mix (pH 13) a 10% aqueous solution of citric acid was added to reach pH 12.4. A solid started to precipitate and was stirred at room temperature for 2.5 hours. The solid was then filtered under reduced pressure and washed with IPA. The wet cake was dried in a vacuum oven at 50 ° C and crude OVD was obtained (78% assay, HPLC 99.84%).

Example 5: Preparation of O-desmetilvenlaf xine in DMA To a 100 ml three neck flask equipped with a mechanical stir bar, a thermometer and a condenser were added 10 g of VNL (0.0364 mol), 7.62 g of sodium ethanethiolate (0.091 mol, 2.5 equivalents) and dimethylacetamide (20 ml). The mixture was heated at 110 ° C for 9 hours and then cooled to room temperature. At this temperature IPA (25 ml) and water (15 ml) were added. The reaction mixture was clear. At this temperature (pH 12.43) 32% HCl was added and reached pH 10. A solid started to precipitate and was stirred at room temperature during 2.5 hours. The solid was then filtered and washed with IPA. The wet cake was dried in a vacuum oven at 50 ° C and crude ODV was obtained (assay 77.8%, HPLC 94.98%).

Example 6. Preparation of O-demethylvenlafaxine in DMF To a 100 ml three-necked flask equipped with a mechanical stir bar, a thermometer and a condenser was added 5 g of VNL (0.0364 mol), 3.81 g of sodium ethanethiolate (0.0454 mol, 2 g). , 5 equivalents) and dimethylformamide (10 ml). The mixture was heated at 135 ° C for 3 hours and 20 minutes. The solution was then cooled to room temperature.

At this temperature ethyl acetate (10 ml) was added and some material precipitated. The mixture was again heated to 70 ° C and then cooled slowly to room temperature. The mixture was stirred overnight at this temperature. Then, IPA, saline and citric acid 10% at pH 9-10 were added to the mixture. The suspension was stirred at room temperature for five minutes and filtered under reduced pressure. The wet cake was washed with IPA and dried in a vacuum oven overnight at 50 ° C and ODV was obtained (76.3% assay, 99.29% HPLC).

Example 7. Preparation of O-demethylvenlafaxine by suspension in water and IPA 1 Gram ODV (GS 1652) was stirred for 2 hours at room temperature in 5 ml of a mixture of water: IPA (80:20). The suspension was stirred for 2 hours at room temperature and the solid was filtered under reduced pressure and washed with 2 ml of water: IPA (80:20). The solid was dried in a vacuum oven overnight at 50 ° C and dry pure ODV was obtained (98.7% assay, HPLC 99.93%).

Example 8: Preparation of O-demethylvenlafaxine by suspension in water To a 100 ml flask equipped with a magnetic stir bar were added at a wet temperature, ODV (5.65 g) which was previously produced and water (40 ml). The suspension was stirred at room temperature for 2.5 hours. The suspension was then filtered under reduced pressure and washed with water (10 ml). The solid was dried in a vacuum oven overnight at 50 ° C and pure white solid ODV was obtained (95% assay, 99% HPLC purity).

Example 9s Preparation of O-demethylvenlaf xine in NMP To a three-necked flask equipped with a mechanical stir bar, a condenser and a thermometer were added at room temperature under nitrogen flow, VNL (12 g, 43.26 mmol), hydrated? A2S (6.2 g, 47 , 69 mmol, assay> 60%) and? MP (24 mL). The reaction mixture was heated to 175 ° C in 1 hour and kept at this temperature for 3 hours. Then the reaction mixture was cooled to 90 ° C. Water (26 ml) and succinic acid (5 g, 42.34 mmol) were added and light precipitation was observed (pH 8.0). Diethyl carbonate (24 ml) was added to the solution and the suspension was stirred at 60 ° C for 0.5 hour. The reaction mixture was then cooled to room temperature and the solid was filtered under reduced pressure and washed with H20 (2X20 ml). The solid was dried overnight in a vacuum oven at 50 ° C and 9.26 g (yield = 79.43%) of a dry pure ODV base were obtained (assay 97.7% purity 99.34%) .

Example 11; Preparation of O-demethylvenlafaxine in NMP To a three neck flask with a mechanical stirring bar, a condenser and a thermometer were added at room temperature under nitrogen flow, VNL (12 g, 43.26 mmol), Na2S hydrated (6.2 g, 47.69 g). mmol, assay> 60%) and NMP (24 mL). The reaction mixture was heated to 175 ° C in 1 hour and kept at this temperature for 3 hours. Then the reaction mixture was cooled to 90 ° C. Water (36 ml) and succinic acid (6 g, 50.8 mmol) were added and light precipitation was observed (pH 8.0). Acetonitrile (24 ml) was added and the suspension was stirred at 60 ° C for 0.5 hour. Then the reaction mixture was cooled to room temperature, the solid was filtered under reduced pressure and washed with H20 (2X20 ml). The solid was dried overnight in a vacuum oven at 50 ° C and a pure dry ODV base was obtained (assay 95.8%, HPLC purity 99.47%).

Example 11: Preparation of O-demethylvenlafaxine in NMP To a three-necked flask equipped with a mechanical stirring bar, a condenser and a thermometer were added at room temperature under nitrogen flow, VNL (12 g, 43.26 mmol), Na2S hydrate (6.2 g, 47, 69 mmol, assay> 60%) and NMP (24 mL). The reaction mixture was heated to 175 ° C in 1.5 hours and kept at this temperature for 4 hours. Then the reaction mixture was cooled to room temperature. Water (60 ml) and succinic acid (5 g, 42.34 mmol) were added and precipitation was observed (pH 8.0). The suspension was heated to 95 ° C and stirred at 95 ° C for 1 hour. Then the reaction mixture was cooled to room temperature, the solid was filtered under reduced pressure and washed with H20 (2X20 ml). The solid was dried overnight in a vacuum oven at 50 ° C and 11.34 g of ODV base were obtained (yield = 95.38%, assay 95.8%, HPLC purity 98.07%).

Example 12. Preparation of tridesmethyl venlafaxine DDMV xHCl (10 g, 40 mmol), K2C03 (6 g, 44 mmol), thiophenol (8 mL, 60 mmol) and NMP (40 mL) were loaded into a 250 mL flask equipped with a magnetic stir bar, a condenser and a nitrogen inlet and heated in a sand bath. The bath temperature was maintained at 210 ° C for 5.5 hours. HPLC analysis confirmed that DDMV was completely consumed. TDMV was obtained with a purity of 95%.

Example 13: Preparation of substantially pure O-desmethylvenlaf xine TDMV (0.2 g, 0.85 mmol) was dissolved in methanol. A solution of formalin (0.4 ml, 5 mmol) was added and the resulting solution was cooled in an ice bath. To the cold solution, NaBH4 (65 mg, 1.7 mmol) was added. After 15 minutes a sample was analyzed by HPLC, and determined to contain 85% ODV in the reaction mixture.

Then IPA and 10% citric acid was added to the mixture at pH 9-10. The suspension was stirred at room temperature for five minutes and filtered under reduced pressure. The wet cake was washed with IPA and dried in a vacuum oven overnight at 50 ° C and pure ODV was obtained.

Comparative example with WO 03/048104 - example 4 NaOMe (1.3 g, 24 mmol) dissolved in methanol (3 ml) and dodecanethiol (5.83 ml = 4.92 g, 24 mmol) were mixed together and placed in a rotary evaporator under reduced pressure at 90 ° C. Venlafaxine (5.12 g, 18 mmol) and PEG 400 (3.7 g, 0.75 volumes) were added to this residue. The mixture was then heated to 200 ° C (Flash = 190 ° C). After 3 hours IPA (18 ml) was added and the pH adjusted to 9.5 with aqueous HCl. The solid was filtered under reduced pressure and washed with IPA and water. The wet ODV was dried under reduced pressure and ODV was obtained. ODV was obtained with a purity of 73.5% and a test of 74.2%.

Comparative example with WO 03/048104 - example 2 Venlafaxine (2.8 g, 10.1 mmol), sodium salt of benzothiolate (3.45 g, 26 mmol) and PEG 400 (12.5 g, 4.5 volumes) were charged into a 100 ml flask with a magnetic stir bar The mixture was heated in a sand bath at 160 ° C. At 90 ° C a complete solution was observed. After 5 hours, at 160 ° C the bath was removed and water (30 ml) was added. The pH was adjusted with 85% H3P04 at pH = 3.5. The mixture was extracted with 25 ml of hexane to remove the organic by-products, and the pH of the aqueous phase was readjusted to pH 9.5 with aqueous ammonia. A solid precipitated from the reaction mixture. The solid was filtered, resuspended in water (40 ml) and filtered under reduced pressure. The solid thus obtained was dried under reduced pressure and ODV was obtained. ODV was obtained with a purity of 95.6% and a test of 78.5%.

Claims (74)

1. Substantially pure O-desmethylvenlafaxine.

2. The substantially pure O-desmethylvenlafaxine according to claim 1, wherein the amount of total impurities is less than 5% area by HPLC.

3. The substantially pure O-desmethylvenlafaxine according to claim 2, wherein the amount of total impurities is less than 3% area by HPLC.

4. The substantially pure O-desmethylvenlafaxine according to claim 3, wherein the amount of total impurities is less than 1% area by HPLC.

5. The substantially pure O-demethylvenlafaxine according to claim 4, wherein the amount of total impurities is less than 0.7% area by HPLC.

6. The substantially pure O-demethylvenlafaxine according to claim 5, wherein the amount of total impurities is less than 0.2% area by HPLC.

7. The substantially pure O-desmethylvenlafaxine according to claim 6, wherein the amount of total impurities is less than 0.7% area by HPLC.

8. A process for preparing a substantially pure O-demethylvenlafaxine comprising: a) combining venlafaxine, an organic solvent and a reagent selected from the group consisting of thiophenol, sodium sulfide and an alkyl thiolate of C-C6 to form a mixture; b) heating the mixture; and c) recovering substantially pure O-desmethylvenlafaxine.

9. The process for preparing a substantially pure O-demethylvenlafaxine according to claim 8, wherein the organic solvent is selected from the group consisting of C3-C7 ketone, a C3-C7 ester, a C5-C8 aliphatic hydrocarbon, an C6-C12 aromatic hydrocarbon, a high-boiling solvent, a C2-C8 ether, a chlorinated hydrocarbon and a C2-CB alcohol.

10. The process for preparing a substantially pure O-demethylvenlafaxine according to claim 8, wherein the high-boiling solvent is selected from the group consisting of toluene, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl- 2-pyridone, N-methyl-2-pyrrolidone, 1-methyl-2-pyrrolidinone (NMP) and dimethylacetamide (DMA).

11. The process for preparing a substantially pure O-demethylvenlafaxine according to claim 10, wherein the high-boiling solvent is DMA, DMF or NMP.

12. The process for preparing a substantially pure O-demethylvenlafaxine according to claim 9, wherein the organic solvent is selected from the group consisting of acetone, ethyl acetate, toluene, DMF, NMP, DMA, THF and ethanol.

13. The process for preparing a substantially pure O-demethylvenlafaxine according to claim 12, wherein NMP is the organic solvent and venlafaxine and NMP in the mixture are in a ratio of venlafaxine: NMP between 1: 1 and 1:20 by volume.

14. The process for preparing a substantially pure O-desmethylvenlafaxine according to claim 12, wherein the organic solvent is DMF or DMA and venlafaxine and the organic solvent are in a ratio of venlafaxine: organic solvent of between 1: 1 and 1:10 in volume.

15. The process for preparing a substantially pure O-desmethylvenlafaxine according to any of claims 8 to 14, wherein when the reagent is thiophenol a catalyst is added to the mixture of step (a).

16. The process for preparing a substantially pure O-desmethylvenlafaxine according to claim 15, wherein the catalyst is a base.

17. The process for preparing a substantially pure O-desmethylvenlafaxine according to claim 16, wherein the base is an alkali metal carbonate.

18. The process for preparing a substantially pure O-demethylvenlafaxine according to claim 17, wherein the alkali metal carbonate is potassium carbonate.

19. The process for preparing a substantially pure O-desmethylvenlafaxine according to any of claims 8 to 18, wherein the mixture is heated in step (b) at a temperature of 100 ° C to 210 ° C for a period of 1 to 12 hours .

20. The process for preparing a substantially pure O-desmethylvenlafaxine according to claim 19, wherein the mixture is heated to a temperature of 110 ° C to 190 ° C.

21. The process for preparing an O-demethylvenlafaxine according to any of claims 19 to 20, wherein the period is from 3 hours to 10 hours.

22. The process for preparing a O-desmethylvenlafaxine substantially pure according to any of claims 8 to 21, wherein venlafaxine, the organic solvent and the reagent are combined under reduced pressure, and the mixture is heated in step (b) to a temperature from 30 ° C to 220 ° C.

23. The process for preparing a substantially pure O-demethylvenlafaxine according to claim 22, wherein the pressure is less than 1 atmosphere.

24. The process for preparing a substantially pure O-desmethylvenlafaxine according to any of claims 8 to 23, wherein the recovery of 0-desmethylvenlafaxine comprises crystallization.

25. The process for preparing a substantially pure O-desmethylvenlafaxine according to claim 24, wherein crystalline O-desmethylvenlafaxine is characterized by a diffraction pattern of X-ray powder having peak reflections at 12.1, 13.2, 15 , 9 and 20.4 degrees two theta ± 0.2 degrees two theta.

26. The process for preparing a O-desmethylvenlafaxine substantially pure according to any of claims 8 to 23, further comprising, before recovering the O-desmethylvenlafaxine substantially pure, suspending the mixture in a solvent selected from the group consisting of water, a mixture of water and alcohol and a mixture of water and acetonitrile.

27. The process for preparing a substantially pure O-desmethylvenlafaxine according to claim 26, wherein the mixture of water and IPA is in a ratio of 15:25 to 80:20 (by volume).

28. The process for preparing a substantially pure O-desmethylvenlafaxine according to claim 27, wherein the mixture of water and IPA has a ratio of 80:20 (by volume).

29. The process for preparing a substantially pure O-demethylvenlafaxine according to any of claims 26 to 28, wherein the suspension is carried out at a temperature of 20 ° C to 70 ° C for a period of 5 minutes to 5 hours.

30. The process for preparing a substantially pure O-desmethylvenlafaxine according to claim 28, wherein the suspension is carried out at room temperature for a period of 2 hours.

31. The process for preparing a O-desmethylvenlafaxine substantially pure according to any of claims 26 to 30, wherein the recovery of O-desmethylvenlafaxine comprising the precipitation of 0-desmethylvenlafaxine from an aqueous solution or suspension in water / IPA adjusting the pH to 7.5-13.5.

32. The process for preparing a substantially pure O-demethylvenlafaxine according to claim 31, wherein the pH is adjusted to pH 7.5 to 10.

33. The process for preparing a substantially pure O-demethylvenlafaxine according to claim 32, wherein the pH is adjusted to pH 8.

34. The process for preparing a substantially pure O-desmethylvenlafaxine according to any of claims 31 to 33, wherein the adjustment of the pH comprises adding an acid.

35. The process for preparing a substantially pure O-desmethylvenlafaxine according to claim 34, wherein the acid is selected from the group consisting of inorganic acids and organic acids.

36. The process for preparing an O-demethylvenlafaxine according to claim 35, wherein the organic acid is succinic acid.

37. A substantially pure O-demethylvenlafaxine produced by the process according to any of claims 26 to 36.

38. The substantially pure O-demethylvenlafaxine according to claim 37, which has a test purity of at least 95%.

39. The substantially pure O-demethylvenlafaxine according to claim 38, which has a test purity of at least 99%.

40. A process for preparing a substantially pure O-demethylvenlafaxine, comprising: a) combining venlafaxine and thiophenol to form a mixture; b) heating the mixture to a temperature of 100 ° C to 210 ° C and c) recovering substantially pure O-desmethylvenlafaxine.

41. The process for preparing substantially pure O-desmethylvenlafaxine according to claim 40, wherein a catalyst is added to the mixture of step (a).

42. The process for preparing a substantially pure O-demethylvenlafaxine according to claim 41, wherein the catalyst is a base.

43. The process for preparing a substantially pure O-demethylvenlafaxine according to claim 42, wherein the base is an alkali metal carbonate.

44. The process for preparing a substantially pure O-desmethylvenlafaxine according to any of claims 40 to 43, wherein the mixture of step (a) also comprises a solvent that is a non-hydroxylic or non-ether solvent.

45. The process for preparing a substantially pure O-demethylvenlafaxine according to claim 44, wherein the solvent is selected from the group consisting of NMP, DMSO, DMF, DMA, carbocera, marlotherm and silicon oil.

46. The process for preparing an O-demethylvenlafaxine according to claim 45, wherein the solvent is NMP.

47. The process for preparing an O-desmethylvenlafaxine according to any of claims 40 to 46, wherein the recovery of substantially pure O-desmethylvenlafaxine comprises crystallization.

48. The process for preparing a substantially pure O-demethylvenlafaxine according to claim 47, wherein the crystalline O-demethylvenlafaxine obtained is characterized by a powder X-ray diffraction pattern having peak reflections at 12.1, 13.2, 15.9 and 20.4 degrees two theta ± 0.2 degrees two theta.

49. The process for preparing a substantially pure O-desmethylvenlafaxine according to any of claims 40 to 48, which also comprises suspending, before recovering the O-desmethylvenlafaxine, in a solvent mixture selected from the group consisting of water, water mixtures and alcohol, and a mixture of water and acetonitrile.

50. The process for preparing a substantially pure O-desmethylvenlafaxine according to claim 49, wherein the solvent mixture is a water / IPA mixture having a ratio of 80:20 by volume.

51. The process for preparing a substantially pure O-desmethylvenlafaxine according to claim 50, and wherein the suspension is carried out at a temperature of 20 ° C to 70 ° C for a period of 5 minutes to 5 hours.

52. The process for preparing a substantially pure O-demethylvenlafaxine according to claim 51, wherein the suspension is carried out at room temperature for a period of 2 hours.

53. The process for preparing a substantially pure O-demethylvenlafaxine according to any of claims 49 to 52, wherein the recovery of substantially pure O-demethylvenlafaxine comprises the precipitation of O-demethylvenlafaxine from an aqueous solution or suspension in water / IPA by adjusting the pH at 7.5-13.5.

54. The process for preparing a substantially pure O-desmethylvenlafaxine according to claim 53, wherein the pH is adjusted to pH 8.

55. A substantially pure O-demethylvenlafaxine produced by the process according to any of claims 40 to 54.

56. The substantially pure O-desmethylvenlafaxine according to claim 55, which has a test purity of at least 99%.

57. A method for demethylating venlafaxine comprising reacting venlafaxine with a C-C8 alkyl thiolate and sodium sulfide.

58. A process for preparing a substantially pure O-demethylvenlafaxine comprising: a) combining dedesmethylvenlafaxine, a high-boiling solvent and a thiolate to form a mixture; b) heat the mixture at a temperature of 100 ° C to 220 ° C, and form tridemethyl venlafaxine; and c) converting tridemethyl venlafaxine to O-desmethylvenlafaxine; and d) recovering substantially pure O-desmethylvenlafaxine.

59. The process for preparing a substantially pure O-desmethylvenlafaxine according to claim 58, wherein the thiolate is sodium dodecanthiolate or thiophenol.

60. The process for preparing a substantially pure O-desmethylvenlafaxine according to claim 59, wherein the conversion of tridesmethyl venlafaxine to O-desmethylvenlafaxine comprises combining a solution of tridesmethyl venlafaxine and a formaldehyde source with sodium borohydride or sodium triacetoxy borohydride for obtain a suspension, and recover O-desmetilvenlafaxina.

61. The process for preparing a substantially pure O-demethylvenlafaxine according to claim 60, wherein the solution of tridesmethyl venlafaxine and a formaldehyde source is cooled to a temperature below 10 ° C before combining with sodium borohydride or triacetoxy borohydride. sodium.

62. The process for preparing an essentially pure O-desmethylvenlafaxine according to any of claims 58 to 61, wherein the recovery of substantially pure O-demethylvenlafaxine com-pends to adjust the pH of a suspension of the substantially pure O-desmethylvenlafaxine in step c) at pH 7.5-13.5 and also filter the suspension.

63. The process for preparing a substantially pure O-desmethylvenlafaxine according to claim 62, wherein the pH is adjusted to pH 7.5-10.

64. The process for preparing a substantially pure O-demethylvenlafaxine according to claim 63, wherein the pH is adjusted to 8.

65. The process for preparing a substantially pure O-desmethylvenlafaxine according to any of claims 62 to 64, wherein the pH is adjusted with an acid.

66. The process for preparing a substantially pure O-desmethylvenlafaxine according to claim 65, wherein the acid is an organic acid.

67. The process for preparing a substantially pure O-desmethylvenlafaxine according to claim 66, wherein the acid is citric acid or succinic acid.

68. The process for preparing a substantially pure O-desmethylvenlafaxine according to any of claims 62 to 67, which also comprises adding a water-miscible anti-solvent to the suspension at the adjusted pH.

69. The process for preparing a substantially pure O-desmethylvenlafaxine according to claim 68, wherein the antisolvent is isopropanol (IPA).

70. An analytical method for testing the chemical purity of 0-desmethylvenlafaxine comprising: a) combining a sample of O-desmethylvenlafaxine with a mixture of acetonitrile: buffer in a ratio of 3: 7 (eluent A) to obtain a solution; b) inject the solution into a C-18 column; c) eluting the sample from the column at 55 minutes by stirring a mixture of eluent A and eluent B (a mixture of 700 parts of acetonitrile: 300 parts of buffer: 1.6 parts of trifluoroacetic acid: and 2.9 parts of triethylamine, adjusted to pH 3.0) as an eluent; and d) measuring the chemical purity of the sample with ultraviolet radiation detection.

71. The analytical method according to claim 70, wherein the buffer contains 0.4% trifluoroacetic acid, 0.7% triethylamine, and 98.9% water and has a pH of 3.0.

72. The analytical method according to any of claims 70 and 71, wherein the eluent is a gradient eluent that at 0 minutes, contains 100% of the eluent A and 0% of the eluent B, at 21 minutes it contains 100% of the eluent A and 0% of eluent B and at 55 minutes, contains 45% of eluent A and 55% of eluent B.

73. A pharmaceutical composition comprising substantially pure 0-demethylvenlafaxine and a pharmaceutically acceptable excipient.

74. A process for preparing a pharmaceutical formulation comprising combining substantially pure O-demethylvenlafaxine and a pharmaceutically acceptable carrier.