O-DESMETHYL VENLAFAXINE SACCHARINATE

RELATED APPLICATIONS

This application claims priority of U.S. provisional application Serial No. 60/963,244, filed August 2, 2007, the contents of which are incorporated herein in their entirety.

FIELD OF THE INVENTION

[0001] The present invention is directed to

4-[2-(dimethylamino)-l-(l-hydroxycyclohexyl)ethyl]phenol saccharin, referred to as O-desmethyl venlafaxine saccharinate, and a polymorph thereof, processes for the preparation thereof, and formulations containing the same.

BACKGROUND OF THE DWENTION

[0002] Venlafaxine, (±)- 1 -[2-(Dimethylamino)- 1 -(4-methoxyphenyl) ethyl] cyclohexanol, having the following formula

is the first of a class of anti-depressants. Venlafaxine acts by inhibiting re-uptake of norepinephrine and serotonin, and is an alternative to the tricyclic antidepressants and selective re-uptake inhibitors.

[0003] O-Desmethyl venlafaxine, referred to herein as ODV, is

4-[2-(dimethylamino)-l-(l-hydroxycyclohexyl)ethyl]phenol and has the following formula:

Composite Parameter to the Pharmacokinetics of Venlafaxine and its Active

O-Desmethyl Metabolite", J. Clin. Pharmacol. 32:716-724 (1992).

[0004] O-Desmethyl venlafaxine and processes for the preparation thereof are described in US patent numbers 6,197,828 and 6,689,912, and in US publication No. 2005/0197392, which are incorporated herein by reference.

[0005] Venlafaxine base can be used as a starting material in the preparation of O-desmethyl venlafaxine, as demonstrated in US 6,689,912,

US 6,197,828, WO 03/048104 and US 2005/0197392.

[0006] The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.

[0007] One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubilities.

[0008] The discovery of polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.

[0009] There is a need in the art for additional solid state forms of

O-desmethyl venlafaxine and processes for the preparation thereof.

SUMMARY OF THE INVENTION

[00010] In one embodiment, the present invention encompasses crystalline

O-desmethyl venlafaxine saccharinate characterized by data selected from the group consisting of: a powder XRD pattern with peaks at about 13.2, 14.5 and

17.6 _. ± 0.2 degrees two-theta, and a powder XRD pattern substantially as shown in figure 1.

[00011] In another embodiment the present invention provides a process for preparing O-desmethyl venlafaxine saccharinate, comprising reacting ODV with saccharin.

[00012] In yet another embodiment, the present invention provides pharmaceutical compositions comprising the above O-desmethyl venlafaxine saccharinate and a pharmaceutically acceptable excipient.

[00013] In another embodiment, the present invention provides a process for preparing the above pharmaceutical compositions, comprising combining the

O-desmethyl venlafaxine saccharinate of the present invention and a pharmaceutically acceptable excipient.

[0014] In another embodiment, the present invention provides a method of inhibiting re-uptake of norepinephrine and serotonin in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of

O-desmethyl venlafaxine saccharinate.

BRIEF DESCRIPTION OF THE FIGURES

[00015] Figure 1 shows a PXRD pattern of crystalline O-desmethyl venlafaxine saccharinate

DETAILED DESCRIPTION OF THE INVENTION

[00016] "ODV" and "ODV base", as used herein, refer to O-desmethyl venlafaxine base. "ODV saccharin" and "ODV saccharinate" refer to the saccharin salt of O desmethyl venlafaxine.

[00017] In one embodiment, the present invention provides O-desmethyl venlafaxine saccharinate (ODV saccharinate). The ODV saccharinate is preferably in isolated form, more preferably in a solid form, and most preferably in

crystalline form. As used herein, "isolated" means that the ODV saccharinate has been separated from the reaction mixture or solvent in which it was formed, at least to the extent that it contains no more than about 30% of any other substance by weight.

[00018] The O-desmethyl venlafaxine saccharinate may be characterized by data selected from the group consisting of: a powder XRD pattern with peaks at about 13.2, 14.5 and 17.6_± 0.2 degrees two-theta, and a powder XRD pattern demonstrated in figure 1.

[00019] hi another embodiment, the described O-desmethyl venlafaxine saccharinate can be further characterized by a powder XRD pattern having two or more additional peaks selected from: about 9.4, 12.3, 20.6 and 22.0 ± 0.2 degrees two-theta.

[00020] In another embodiment the present invention provides a process for preparing O-desmethyl venlafaxine saccharinate, comprising reacting ODV with saccharin. Preferably the process comprises: providing a mixture of succinic acid in water; admixing ODV base; admixing saccharin, and removing the solvent to obtain O-desmethyl venlafaxine saccharinate.

[00021] In another embodiment the present invention provides a process for preparing O-desmethyl venlafaxine saccharinate, comprising reacting ODV with saccharin, preferably in a solvent. Preferably the process comprises admixing

ODV and saccharin and removing the solvent to obtain O-desmethyl venlafaxine saccharinate. The solvent may be any organic solvent capable of dissolving the saccharin and the ODV, such as methanol, ethanol, acetone, or ethyl acetate.

Water, and more preferably water heated to at least 50°C, is preferred.

[00022] hi a preferred embodiment, a solution of succinic acid in water is prepared in a water bath. More preferably, the water bath is at a temperature of about 40°C-80°C.

[00023] Preferably, ODV base is admixed with the succinic acid by adding

ODV base to the solution of succinic acid in a solvent, preferably water. After adding the ODV base, mixing is carried out until all the ODV base is dissolved, preferably for at least 10 minutes.

[00024] A saccharin solution is preferably prepared by mixing saccharin and water. Preferably, the mixing is done at a temperature of about 40°C-80°C .

[00025] Preferably saccharin and ODV are admixed by adding the saccharin solution to the described ODV succinate solution to produce ODV-saccharinate. [00026] Preferably, obtaining the ODV-saccharinate is by methods such as evaporation, cooling, or addition of an anti-solvent, in order to precipitate the ODV saccharinate. An anti-solvent is a solvent in which the ODV saccharinate is not significantly soluble, and which will cause the ODV succinate to precipitate when added to a saturated solution of ODV succinate in a different solvent. This may be followed by an isolation step, such as filtration or centrifugation to remove remaining solvent and succinic acid, and by drying in air, in vacuum, in an oven etc. More preferably the removing of the solvent from the solution of ODV saccharinate is by evaporation. The evaporation is preferably done for about 16 hours. Preferably the solvent is only partially evaporated. Typically, the removing of the solvent provides a solid material, which is the described O-desmethyl venlafaxine saccharinate.

[00027] In another embodiment, the present invention provides pharmaceutical compositions comprising the above O-desmethyl venlafaxine saccharinate and a pharmaceutically acceptable excipient. [00028] In another embodiment, the present invention provides pharmaceutical compositions comprising O-desmethyl venlafaxine saccharinate and at least one pharmaceutical excipient that enables control of the drug release according to predetermined time period.

[00029] In another embodiment, the present invention provides a process for preparing the above pharmaceutical composition comprising combining the O-desmethyl venlafaxine saccharinate of the present invention and a pharmaceutically acceptable excipient.

[00030] In another embodiment, the present invention provides a method of inhibiting re-uptake of norepinephrine and serotonin in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of the above O-desmethyl venlafaxine saccharinate.

[00031 ] Pharmaceutical compositions may be prepared as medicaments to be administered orally, parenterally, rectally, transdermally, bucally, or nasally. Suitable forms for oral administration include tablets, compressed or coated pills, dragees, sachets, hard or gelatin capsules, sub-lingual tablets, syrups, and suspensions. Suitable forms for parenteral administration include aqueous or non-

aqueous solutions or emulsions, while for rectal administration, suitable forms for administration include suppositories with hydrophilic or hydrophobic vehicles. For topical administration, the invention provides suitable transdermal delivery systems known in the art, and for nasal delivery, there are provided suitable aerosol delivery systems known in the art.

[00032] In addition to the active ingredient(s), the pharmaceutical compositions of the present invention may contain one or more excipients or adjuvants. Selection of excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.

[00033] The mentioned "pharmaceutical excipient that enables control of the drug release according to predetermined time period" may be cellulose polymer, methacrylate polymer, acrylic acid polymer, block copolymer, gum, polyethylene oxide and waxes. The cellulose polymer may be one or more of hydroxypropylmethyl cellulose, methylcellulose, hydroxypropylethylcellulose, ethyl cellulose and hydroxypropyl cellulose. The gum can be one or more of xanthan gum, alginic acid and sodium alginate. The pharmaceutical excipient that enables control of the drug release according to predetermined time period may be between about 10% and about 95% W/W of the monolithic tablet, more prefarebly between about 20% and about 80% W/W of the monolithic tablet. [00034] Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. 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, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit ^® ), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[00035] Solid pharmaceutical compositions that are compacted into 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), carboxymethylcellulose sodium, dextrin,

ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel ^® ), hydroxypropyl methyl cellulose (e.g. Methocel ^® ), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon ^® , Plasdone ^® ), pregelatinized starch, sodium alginate, and starch. [00036] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di- Sol ^® , Primellose ^® ), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon ^® , Polyplasdone ^® ), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab ^® ), and starch.

[00037] Glidants can be added to improve the flowability of a non- compacted solid composition and to improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate. [00038] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and die. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and die, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the die. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.

[00039] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[00040] Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.

[00041] In liquid pharmaceutical compositions of the present invention, the active ingredient and any other solid excipients are suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin. In such suspension the solid excipients may be either in solution or suspended in the liquid carrier. The active ingredient retains its crystalline structure in such liquid pharmaceutical compositions.

[00042] Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that maybe useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol. [00043] Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, 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, starch tragacanth, and xanthan gum.

[00044] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve the taste.

[00045] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.

[00046] 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.

[00047] Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.

[00048] The solid compositions of the present invention include powders, granulates, aggregates, and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. The pharmaceutical compositions of the present invention include immediate or controlled release formulations. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages may be conveniently presented in unit dosage form and prepared by any of the methods well known in the pharmaceutical arts.

[00049] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, patches and elixirs.

[00050] The dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell. The shell may be made from gelatin, and, optionally, contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.

[00051] The active ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art. [00052] A composition for tableting or capsule filling may be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended, and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and/or milled, dried, and then screened and/or milled to the desired particle size. The granulate may then be tableted or other excipients may be added prior to tableting, such as a glidant and/or a lubricant. [00053] A tableting composition may be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients may be compacted into a slug or a sheet, and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.

[00054] As an alternative to dry granulation, a blended composition may be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.

[00055] A capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step. [00056] In another embodiment, the present invention provides a method of treating a patient comprising administering to a patient in need thereof a therapeutically effective amount of the above crystalline form of O-desmethyl venlafaxine saccharinate. Preferably, the patient suffers from a condition which may be treated with a norepinephrine or a serotonin re-uptake inhibitor. Such patient may, for example, be suffering from depression.

[00057] Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The disclosures of the references referred to in this patent application are incorporated herein by reference. The invention is further defined by reference to the following examples describing in detail the process and compositions of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES

[00058] Exemplary methods for preparing a crystalline form of

O-desmethyl venlafaxine saccharinate, characterized by a powder XRD pattern with peaks at about 13.2, 14.5 and 17.6_ ± 0.2 degrees 2-theta, are as follows: Example 1

Step 1: Succcinic acid (650.3 mg) was added to water (70 ml) and mixed in a water bath at 50°C. After a clear solution was obtained, ODV base (1449.9 mg) was added and mixed for 15 min, and the solution was filtered through a 0.2μ filter.

Step 2: Saccharin (183.18 mg) was added to purified water (53 ml) and mixed at 50°C until dissolved.

Step 3: The ODV succinate solution prepared in step 1 (12.7 ml) was mixed with all the solution prepared in step 2. The resulting solution was evaporated to dryness over about 16 hours in a water bath at 50°C. The XRD pattern of the resulting solid material is shown in Figure 1.

Example 2:

Step 1 : Saccharin (183.2 mg) was added to water (20 ml) and mixed in a water bath at 70 -80 °C. After a clear solution was obtained, ODV base (263.4 mg) was added and mixed until dissolved.

Step 2: The water from the resulting solution was partially evaporated using a hot water bath at 50-80°C until sedimentation was observed. The resulting solid material was separated by vaccum filtration, and dried in an oven at 45°C for about 1 hour.

Example 3:

Step 1: Saccharin (183.2 mg) was added to water (10 ml) and mixed in a water bath at 70 -80°C. After a clear solution was obtained, ODV base (263.4 mg) was added and mixed until dissolved.

Step 2: The water from the resulting solution was partially evaporated using a hot water bath at 50-80°C until sedimentation was observed. The resulting solid material was separated by vaccum filtration, and dried in an oven at 45 °C for about 1 hour.