Stable pharmaceutical formulation of paroxetine hydrochloride and a process for preparation thereof

Abstract

Provided are formulations of a stable paroxetine hydrochloride tablet comprising paroxetine hydrochloride, povidone or copovidone as a binder, and an HCl free/non-hygroscopic filler, prepared by the wet granulation method. Preferably, the paroxetine hydrochloride is paroxetine hydrochloride hemihydrate.

1 . An oral pharmaceutical dosage form comprising paroxetine hydrochloride, a binder selected from the group consisting of povidone and copovidone, and a filler that is HCl free or non-hygroscopic, wherein the pharmaceutical dosage form is prepared by wet granulating paroxetine hydrochloride in the presence of a binder grade of povidone or copovidone, and the filler, to obtain an intra-granular portion of a granulate, and converting the granulate to the oral pharmaceutical dosage form. 
     
     
         2 . The oral pharmaceutical dosage form of  claim 1 , wherein the filler is non-hygroscopic. 
     
     
         3 . The oral pharmaceutical dosage for of  claim 1 , wherein the filler is HCl free. 
     
     
         4 . The oral pharmaceutical dosage for of  claim 3 , wherein the filler is non-hygroscopic. 
     
     
         5 . The oral pharmaceutical dosage form of  claim 4 , wherein the filler is a sugar. 
     
     
         6 . The oral pharmaceutical dosage form of  claim 5 , wherein the sugar is mannitol. 
     
     
         7 . The oral pharmaceutical dosage form of  claim 4 , wherein the filler is dibasic calcium phosphate anhydrous. 
     
     
         8 . The oral pharmaceutical dosage form of  claim 1 , wherein the paroxetine hydrochloride is paroxetine hydrochloride hemihydrate. 
     
     
         9 . The oral pharmaceutical dosage form of  claim 1 , wherein the binder is povidone. 
     
     
         10 . The oral pharmaceutical dosage form of  claim 1 , wherein the binder is co-povidone. 
     
     
         11 . The oral pharmaceutical dosage form of  claim 1 , wherein the ratio of povidone or copovidone to paroxetine hydrochloride is from about 20% to about 60% weight to weight of povidone or copovidone to paroxetine hydrochloride. 
     
     
         12 . The oral pharmaceutical dosage form of  claim 11 , wherein the ratio is from about 30% to about 40%. 
     
     
         13 . The oral pharmaceutical dosage form of  claim 12 , wherein the ratio is from about 35% to about 40%. 
     
     
         14 . The oral pharmaceutical dosage form of  claim 1 , wherein the ratio of povidone or copovidone to intra-granular portion is about 2% to about 9% weight to weight of povidone or copovidone to intra-granular portion, the intra-granular weight including the weight of povidone or copovidone. 
     
     
         15 . The oral pharmaceutical dosage form of  claim 14 , wherein the ratio is about 3% to about 7%. 
     
     
         16 . The oral pharmaceutical dosage form of  claim 15 , wherein the ratio is about 4% to about 7%. 
     
     
         17 . The oral pharmaceutical dosage form of  claim 1 , wherein the wet granulating is carried out with water as a processing solvent. 
     
     
         18 . The oral pharmaceutical dosage form of  claim 1 , wherein the wet granulating is carried out with a mixture of water and a water miscible ketone or alcohol, or mixtures thereof as a processing solvent. 
     
     
         19 . The oral pharmaceutical dosage form of  claim 1 , wherein the dosage form is selected from the group consisting of tablets, capsules, sachets, granules, suspension, effervescent tablets, chewable tablets and geltabs. 
     
     
         20 . The oral pharmaceutical dosage form of  claim 19 , wherein the dosage form is a tablet. 
     
     
         21 . A method of reducing serotonin re-uptake comprising administering the oral pharmaceutical dosage form of  claim 1  to a mammal. 
     
     
         22 . A process for preparing an oral pharmaceutical dosage form comprising the steps of:
 a) wet granulating paroxetine hydrochloride in the presence of a binder grade of a binder selected from the group consisting of povidone and copovidone, and a filler that is HCl free or non-hygroscopic, to obtain an intra-granular portion of a granulate;   b) preparing a final blend from the granulate; and   c) converting the final blend to an oral pharmaceutical dosage form.   
     
     
         23 . The process of  claim 22 , wherein the filler is HCl free. 
     
     
         24 . The process of  claim 22 , wherein the filler is non-hygroscopic. 
     
     
         25 . The process of  claim 24 , wherein the filler is HCl free. 
     
     
         26 . The process of  claim 22 , wherein the filler is a sugar. 
     
     
         27 . The process of  claim 26 , wherein the sugar is mannitol. 
     
     
         28 . The process of  claim 22 , wherein the filler is dibasic calcium phosphate anhydrous. 
     
     
         29 . The process of  claim 22 , wherein the paroxetine hydrochloride is paroxetine hydrochloride hemihydrate. 
     
     
         30 . The process of  claim 22 , wherein the binder is povidone. 
     
     
         31 . The process of  claim 22 , wherein the binder is copovidone. 
     
     
         32 . The process of  claim 22 , wherein the ratio of povidone or copovidone to paroxetine hydrochloride is from about 20% to about 60% weight to weight of povidone or copovidone to paroxetine hydrochloride. 
     
     
         33 . The process of  claim 32 , wherein the ratio is from about 30% to about 40%. 
     
     
         34 . The process of  claim 33 , wherein the ratio is from about 35% to about 40%. 
     
     
         35 . The process of  claim 22 , wherein the ratio of povidone or copovidone to the intra-granular portion is about 2% to about 9% weight to weight of povidone or copovidone to the intra-granular portion, the intra-granular weight including the weight of povidone or copovidone. 
     
     
         36 . The process of  claim 35 , wherein the ratio is about 3% to about 7%. 
     
     
         37 . The process of  claim 36 , wherein the ratio is about 4% to about 7%. 
     
     
         38 . The process of  claim 22 , wherein the wet granulating is carried out with water as a processing solvent. 
     
     
         39 . The process of  claim 22 , wherein the wet granulating is carried out with a mixture of water and a water miscible ketone or alcohol, or mixtures thereof as a processing solvent. 
     
     
         40 . The process of  claim 22 , wherein the oral pharmaceutical dosage form is selected from the group consisting of tablets, capsules, sachets, granules, suspension, effervescent tablets, chewable tablets and geltabs. 
     
     
         41 . The process of  claim 40 , wherein the oral pharmaceutical dosage form is a tablet prepared by compressing the final blend. 
     
     
         42 . The process of  claim 41 , further comprising a step of coating the tablet. 
     
     
         43 . The process of  claim 42 , wherein the coating is carried out by using a composition of about 30% titanium dioxide, about 30% hydroxypropyl methylcellulose, about 8% polyethylene glycol and about 1% polysorbate, respective weight to weight. 
     
     
         44 . A tablet comprising of the following active ingredient and excipients, in weight to weight percentages:
 a) about 10% to about 12.5% of paroxetine hydrochloride as an active ingredient;   b) about 70% to about 90% of dibasic calcium phosphate anhydrous;   c) about 1.5% to about 5% of sodium starch glycolate;   d) about 0.5% to about 3% of magnesium stearate; and   e) about 2.5% to about 7.5% of povidone,   
       wherein the tablet is prepared by wet granulating paroxetine hydrochloride in the presence of povidone, sodium starch glycolate and dibasic calcium phosphate anhydrous to obtain a granulate, and converting the granulate to a tablet. 
     
     
         45 . The tablet of  claim 44 , wherein the paroxetine hydrochloride is paroxetine hydrochloride hemihydrate. 
     
     
         46 . The tablet of  claim 44 , further comprising about 3 to about 12 mg of a coating composition of about 30% titanium dioxide, about 30% hydroxypropyl methylcellulose, about 8% polyethylene glycol and about 1% polysorbate, respective weight to weight. 
     
     
         47 . The tablet of  claim 44 , wherein the wet granulating is carried out with water as a processing solvent. 
     
     
         48 . The tablet of  claim 44 , wherein the wet granulating is carried out with a mixture of water and a water miscible ketone or alcohol, or mixtures thereof as a processing solvent. 
     
     
         49 . A method for inhibiting the re-uptake of serotonin comprising administering the tablet of  claim 44  to a mammal. 
     
     
         50 . A process for preparing a paroxetine hydrochloride tablet comprising the steps of:
 a) wet granulating with water as a processing solvent paroxetine hydrochloride in the presence of sodium starch glycolate, Grade 29 to Grade 32 povidone and dibasic calcium phosphate anhydrous;   b) milling the granulate;   c) mixing the granulate with an additional amount of sodium starch glycolate and calcium phosphate dibasic anhydrous;   d) adding magnesium stearate to obtain a final blend; and   e) compressing the final blend to obtain the tablet.   
     
     
         51 . The process of  claim 50 , wherein the paroxetine hydrochloride is paroxetine hydrochloride hemihydrate. 
     
     
         52 . A mechanically stable paroxetine hydrochloride tablet, wherein the tablet does not substantially lose its hardness after storage at a temperature of about 80° C. and a relative humidity of at least about 75% for at least about 24 hours. 
     
     
         53 . The tablet of  claim 52 , wherein the paroxetine hydrochloride is paroxetine hydrochloride hemihydrate. 
     
     
         54 . The tablet of  claim 52 , wherein the hardness is at least about 10 SCU after about 24 hours. 
     
     
         55 . The tablet of  claim 54 , wherein the hardness is at least about 14 SCU after about 24 hours. 
     
     
         56 . The tablet of  claim 55 , wherein the hardness is at least about 16 SCU after about 24 hours. 
     
     
         57 . A method of inhibiting serotonin re-uptake comprising administering the tablet of  claim 52  to a mammal.