Field of the invention The present invention relates to a stabilized venlafaxine formulation wherein formulation is prepared by a dry process.
Background of the invention The physicochemical properties of pharmaceuticals, including solubility and dissolution rate, can be influenced by the degree of crystallinity, solvation state, and crystal form. For e.g. at room temperature, the anhydrate forms of ampicillin, theophylline, and glutethimide have a higher dissolution rate than their corresponding hydrates. This difference in dissolution rate can be attributed to the difference in the free energy of hydration and may lead to difference in bioavailability.
Although the physical form of a drug substance is carefully selected for dosage form manufacture, the processing conditions will determine the solid state of the drug in the final product. During tablet manufacture, processing steps may include milling, granulation, drying, and compression, which may lead to change in the solid state form.
Wet granulation is a commonly used unit operation in the pharmaceutical industry. Granulation is mainly performed to improve powder flow, decrease dustiness and prevent segregation. Wet granulation involves the steps of mixing in high shear mixer, addition of a binder solution, obtaining granules from wet mass, drying, and milling, if required and then compression. Many of these steps expose the material to harsh conditions, which may lead to processing induced transformations.
These processing induced transformations may lead to change in the solid state of the drug. One polymorph may differ from other polymorph in its stability, solubility that may lead to difference in bioavailability. In some cases it has been observed that one solid state differ from other in mechanical properties such as hardness, tensile strength, tabletting and even flow. Hydrate and anhydrous forms are also known to differ in their solubility. Even the regulatory authorities have recognized the importance of polymorphism and require polymorphism screening for new chemical drug substances (as per ICH guideline).
Venlafaxine is an anti-depressant and acts by inhibiting synaptosomal uptake of norepinephrine (3H-NE) and serotonin (14C-5HT). Processes for the preparation of Venlafaxine hydrochloride are described in EP-A-112,669 and in Yardley et al., J. Med. Chem., 1990, vol. 33, page 2899. This hydrochloride salt is desirable since it enables Venlafaxine to be conveniently formulated. There is still a need to produce Venlafaxine formulation in a reproducible, pure and crystalline form to enable formulations to meet pharmaceutical requirements and specifications.
Furthermore, it is economically desirable that the product is stable for extended periods of time without the need for specialized storage conditions. The processes in the above mentioned patent and publication result in the preparation of a crystalline form of Venlafaxine hydrochloride having a melting point between 215 and 217°C which is herein designated as Form C.
Several polymorph and hydrate of venlafaxine have been disclosed in the prior art. WO 02/036542 describe Form A, B and D of the venlafaxine hydrochloride. WO 02/045658 disclosed form I, II, III and IV of venlafaxine hydrochloride.
It was observed venlafaxine hydrochloride undergoes polymorphic conversion when wet granulation process was followed during the production of a solid dosage form. It was discovered that there was no such conversions when a dry process was followed.
Summary of the invention Hence, in one of the aspects, there is provided a stabilized formulation comprising venlafaxine or pharmaceutically acceptable salts thereof wherein formulation is prepared by a dry process.
In another aspect, there is provided a stabilized formulation comprising venlafaxine or pharmaceutically acceptable salts thereof wherein formulation is prepared by a direct compression, non aqueous granulation or dry granulation process.
In another aspect, there is provided a process for preparation of a stabilized formulation comprising venlafaxine or pharmaceutically acceptable salts thereof wherein formulation is prepared by a dry process.
In another aspect, there is provided a method of treating or preventing depression, general anxiety disorder, social anxiety disorder and post traumatic stress disorder in a mammal in need thereof comprising administering to the mammal effective amount of a stabilized formulation comprising venlafaxine or pharmaceutically acceptable salts thereof wherein formulation is prepared by a dry process.
In another aspect, there is provided a process for preparation of stabilized pharmaceutical composition comprising venlafaxine or pharmaceutically acceptable salts thereof comprising the steps of:
a) blending venlafaxine and one or more pharmaceutically acceptable excipients,
b) slugging the above mixture,
c) screening the slugged mixture to obtain granules,
d) optionally blending granules of step c) with one or more pharmaceutically acceptable excipients,
e) lubricating the blend of step d) or granules of step c), and
f) compressing into or filling into suitable size solid dosage form.
In another aspect, there is provided a process for preparation of stabilized pharmaceutical composition comprising venlafaxine or pharmaceutically acceptable salts thereof comprising the steps of:
a) blending venlafaxine and one or more pharmaceutically acceptable excipients,
b) compacting the above mixture in a roller compactor,
c) screening the compacted mixture to obtain granules,
d) optionally blending granules of step c) with one or more pharmaceutically acceptable excipients,
e) lubricating the blend of step d) or granules of step c), and
f) compressing into or filling into suitable size solid dosage form.
In another aspect, there is provided a process for preparation of stabilized pharmaceutical composition comprising venlafaxine or pharmaceutically acceptable salts thereof comprising the steps of:
a) blending venlafaxine and one or more pharmaceutically acceptable excipients,
b) lubricating the blend, and
c) compressing into or filling into suitable size solid dosage form.
In another aspect, there is provided a process for preparation of stabilized pharmaceutical composition comprising venlafaxine or pharmaceutically acceptable salts thereof comprising the steps of:
a) blending venlafaxine and one or more pharmaceutically acceptable excipients,
b) granulating the blend with non-aqueous solvent,
c) optionally blending granules of step b) with one or more pharmaceutically acceptable excipients,
d) lubricating the blend of step c) or granules of step b), and
e) compressing into or filling into suitable size solid dosage form.
Brief Description of Drawings Figure I indicates characteristic X-ray diffraction pattern of venlafaxine hydrochloride Form C. Figure II indicates X-ray diffraction pattern of venlafaxine hydrochloride after wet granulation and drying wherein in addition to Form C characteristic peaks of Form B and D were also observed.
Figure III indicates X-ray diffraction pattern of venlafaxine hydrochloride after dry granulation wherein no characteristic peaks of Form B and D were observed.
Detailed description The term venlafaxine as used herein referes to racemic mixture, of R and S-venlafaxine and their optically pure enantiomers. As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Suitable non-toxic acids include inorganic and organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic and the like. Particularly preferred are hydrochloric, hydrobromic, phosphoric, and sulfuric acids, and most particularly preferred is the hydrochloride salt.
Formulation as used herein includes tablets, capsules, pills, minitablets and the like. The formulation can be a conventional or extended release formulation.
The term "dry" means substantially "dry" as opposed to the large amount of addition of water employed in the wet granulation process. Hence, dry process includes dry granulation, direct compression and non-aqueous granulation.
In direct compression techniques, venlafaxine is admixed with pharmaceutically acceptable excipients and compressed into tablets.
In dry granulation, venlafaxine is admixed with pharmaceutically acceptable excipients and compressed into large slugs or roller compacted into ribbon-like strands. The slugged/compacted material is then suitably milled to produce a free flowing powder which is then compressed into tablets or filled into capsules.
In nonaqueous granulation venlafaxine is admixed with pharmaceutically acceptable excipients and granulated with non-aqueous solvent. The granules are then compressed into tablets or filled into capsules. In case of non-aqueous granulation, solvents such as methanol, acetone, isopropanol and ethanol (anhydrous) or mixtures thereof may be used, preferably methanol, acetone and isopropanol or mixtures thereof.
Additional excipients may be added and mixed with the free flowing powder before being compressed into tablets.
The pharmaceutical^ acceptable excipients may be selected from amongst the surfactant, diluents, binders, disintegrants, lubricants, glidants, solvents and coloring agents, which are chemically and physically compatible with venlafaxine. The excipients used may be in anhydrous or dry form as even excipients may contribute in hydrate formation.
Diluents may be selected from calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, cellulose-microcrystalline, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like.
Binders may be selected from any such pharmaceutically acceptable excipient, which have cohesive properties to act as binders. Preferably, those excipients are microcrystalline cellulose, cellulose powder, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
Disintegrants may be selected from starches or modified starches such as starch, modified starch, croscarmellose sodium, crospovidone and sodium starch glycolate.
Lubricants may be selected from colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated vegetable oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, glyceryl monostearate, PEG 4000 and the like.
Glidants may be selected from colloidal silicon dioxide and talc.
The surfactant may be selected from anionic, cationic or non-ionic surface-active agents or surfactants. Suitable anionic surfactants include those containing carboxylate, sulfonate, and sulfate ions such as sodium lauryl sulfate (SLS), sodium laurate, dialkyl sodium sulfosuccinates particularly bis-(2-ethylhexyl) sodium sulfosuccinate, sodium stearate, potassium stearate, sodium oleate and the like. Suitable cationic surfactants include those containing long chain cations, such as benzalkonium chloride, bis-2-hydroxyethyl oleyl amine or the like. Suitable non-ionic surfactants include polyoxyethylene sorbitan fatty acid esters, fatty alcohols such as lauryl, cetyl and stearyl alcohols; glyceryl esters such as the naturally occurring mono-, di-, and tri-glycerides; fatty acid esters of fatty alcohols; polyglycolized glycerides such as Gelucire; polyoxyethylene-polyoxypropylene block co-polymer such as Poloxamer and other alcohols such as propylene glycol, polyethylene glycol, sorbitan, sucrose, and cholesterol.
The tablets as described above may have an additional non-functional coating such as polyethylene glycol or Opadry or opadry AMB (aqueous moisture barrier).
Examples of coloring agents include any FDA approved colors for oral use. It may include Iron oxide, Lake of Tartrazine, Lake of Quinoline Yellow, Lake of Sunset Yellow and Lake of Erythrosine, Lack of Carmosine Ponceau, Allura Red.
Coating may be performed by applying one or more film forming polymers, with or without other pharmaceutically inert excipients, as a solution/suspension using any conventional coating technique known in the art, such as spray coating in a conventional coating pan or fluidized bed processor; or dip coating.
The following examples illustrate the invention but should not be construed as limiting the scope of the invention.
EXAMPLE 1 (Table Removed)
1. Venlafaxine HCI was sifted through sieve.
2. Intragranular Yellow and Red iron oxide were sifted along with small quantity of lactose monohydrate.
3. Intragranular microcrystalline cellulose, Sodium starch Glycolate and remaining quantity of lactose monohydrate were blended together.
4. Material of step 1, 2 & 3 were blended.
5. Blend of step 4 were granulated using water.
6. The granules of step-5 were dried in FBD and passed through sieve.

7. Extragranular yellow and red iron oxide were sifted alongwith small quantity of microcrystalline cellulose.
8. Extragranular Sodium starch glycolate, remaining quantity of microcrystalline cellulose & material of step-7 were sifted.
9. The material of step-6 and 8 were blended together.
10. Sifted magnesium stearate was blended with material of step-9.
11. The blend of step-10 was compressed.
When wet granulation was carried out using form C of venlafaxine hydrochloride, it was observed that a part of Form C was converted to a mixture of Form D and Form B (as indicated in Figure I and II). XRD of the tablets were obtained, after crushing the tablet as given in Figure II, wherein peaks of Form B (at 2 theta value of 18.24) and D (at 2 theta value of 7.44 and 8.58) were observed.
EXAMPLE 2 (Table Removed)
1. Venlafaxine HCI was sifted through sieve.
2. Intragranular Yellow and Red iron oxide were sifted along with small quantity of lactose.
3. Intragranular Sodium starch Glycolate and remaining quantity of lactose were blended together.
4. Material of step 1, 2 & 3 were blended.
5. Intragranular Magnesium stearate was sifted and blended with material of step-4.
6. The material of step-5 was roller compacted. The compacts were milled and passed through sieve.
7. The material of step-6 was sifted through sieve.
8. Extragranular yellow and red iron oxide were sifted along with small quantity of microcrystalline cellulose.
9. Extragranular Sodium starch glycolate, remaining quantity of microcrystalline cellulose & material of step - 8 were sifted.
10. The material of step-7 and 9 were blended together.
11. Sifted magnesium stearate was blended with material of step-10.
12. The blend of step-11 was compressed.
When dry granulation was carried out using Form C of venlafaxine hydrochloride, no conversion was observed. XRD of the tablets were obtained, after crushing the tablet as given in Figure III, wherein no polymorphic conversion was observed.
EXAMPLE 3 (Table Removed)
1. Weigh all the ingredients.
2. Sift Iron oxide yellow and red along with small quantity of microcrystalline cellulose.
3. Sift Venlafaxine HCI, remaining quantity of microcrystalline cellulose, Lactose anhydrous and Sodium Starch Glycolate through sieve.
4. Sift Magnesium stearate through sieve.
5. Blend material of step-2 and 3.
6. Add material of step-4 to step-5 and blend further.
7. Compress the blend of step-6 into suitable size tablets.
From figure I, II and III it is clear that there is no polymorphic conversion when a dry process is followed.

WE CLAIM:
1. A stabilized formulation comprising venlafaxine or pharmaceutically acceptable salts thereof wherein formulation is prepared by a dry process.
2. The stabilized formulation according to claim 1 wherein dry process includes direct compression, non aqueous granulation or dry granulation process.
3. The stabilized formulation according to claim 2 wherein dry granulation is by slugging.
4. The stabilized formulation according to claim 3 wherein process for preparation comprises the steps of:

a) blending venlafaxine and one or more pharmaceutically acceptable excipients,
b) slugging the above mixture,
c) screening the slugged mixture to obtain granules,
d) optionally blending granules of step c) with one or more pharmaceutically acceptable excipients,
e) lubricating the blend of step d) or granules of step c), and
f) compressing into or filling into suitable size solid dosage form.

5. The stabilized formulation according to claim 2 wherein dry granulation is by compaction.
6. The stabilized formulation according to claim 3 wherein process for preparation comprises the steps of:

a) blending venlafaxine and one or more pharmaceutically acceptable excipients,
b) compressing into compacts by roller compacter,
c) screening the compacts to obtain granules,
d) optionally blending granules of step c) with one or more pharmaceutically acceptable excipients,
e) lubricating the blend of step d) or granules of step e), and
f) compressing into or filling into suitable size solid dosage form.

7. The stabilized formulation according to claim 1 wherein pharmaceutically acceptable salt is hydrochloride.
8. The stabilized formulation according to claim 1 wherein formulation includes tablet, capsule, pills or minitablets.
9. The stabilized formulation according to claim 1 wherein formulation further comprises pharmaceutically acceptable excipients
10. The stabilized formulation according to claim 9 wherein pharmaceutical excipients are dry or anhydrous.
11. The stabilized formulation according to claim 9 wherein pharmaceutical excipients may be selected from amongst the surfactant, diluents, binders, disintegrants, lubricants, glidants, solvents and coloring agents.
12. The stabilized formulation according to claim 11 wherein diluent is lactose.
13. The stabilized formulation according to claim 11 wherein binder is microcrystalline cellulose.
14. The stabilized formulation according to claim 11 wherein disintegrants is sodium starch glycolate.
15. The stabilized formulation according to claim 11 wherein coloring agent is iron oxide.
16. The stabilized formulation according to claim 1 wherein process for preparation comprises the steps of:

a) blending venlafaxine and one or more pharmaceutically acceptable excipients,
b) granulating the blend by non-aqueous solvent,
c) optionally blending granules of step b) with one or more pharmaceutically acceptable excipients,
d) lubricating the blend of step c) or granules of step b), and
e) compressing into or filling into suitable size solid dosage form.

17. The stabilized formulation according to claim 16 non-aqueous solvent for granulation included methanol, acetone and isopropanol or mixtures thereof.
18. The stabilized formulation according to claim 1 wherein process for preparation comprises the steps of:

a) blending venlafaxine and one or more pharmaceutically acceptable excipients,
b) lubricating the blend, and
c) compressing into or filling into suitable size solid dosage form.
19. Use of the stabilized formulation as defined in any of the preceding claims for treatment
or prevention of depression, general anxiety disorder, social anxiety disorder and post
traumatic stress disorder.
20. A stabilized formulation of venlafaxine as herein described.