STABLE COMPOSITIONS OF VARENICLINE

Abstract

The present invention relates to a pharmaceutical composition comprising Varenicline or its pharmaceutically acceptable salt with reduced amount of nitrosamine impurity and a process for preparing the same.

Claims

1. A stable pharmaceutical composition comprising therapeutically effective amount of Varenicline or its pharmaceutically acceptable salt, one or more stabilizing agents, and one or more pharmaceutically acceptable excipients selected for the group comprising diluent, binder, disintegrant, lubricant, or glidant.

2. The stable pharmaceutical composition according to claim 1, wherein the amount of nitrosamine impurity after exposure of the pharmaceutical composition to 40° C./75% RH for a period of six months is less than about 50 ppm.

3. The stable pharmaceutical composition according to claim 1, wherein the ratio of Varenicline or its pharmaceutically acceptable salt to the stabilizing agent is 1:1 to 1:25.

4. The stable pharmaceutical composition according to claim 1, wherein the stabilizing agent is selected from the group consisting of isomalt, meglumine, povidone, ascorbic acid, tocopherol, 2,5-dihydroxy benzoic acid, butylated hydroxytoluene, butylated hydroxyanisole, propyl gallates, pullulan, or a combination thereof.

5. The stable pharmaceutical composition according to claim 4, wherein the stabilizing agent is butylated hydroxyanisole.

6. The stable pharmaceutical composition according to claim 5, wherein the ratio of Varenicline or its pharmaceutically acceptable salt to butylated hydroxyanisole is 1:1 to 1:10.

7. The stable pharmaceutical composition according to claim 5, wherein the pharmaceutical composition has less than about 500 ppm of adduct impurity of formula A: ##STR00005## after exposure of the pharmaceutical composition to 40° C./75% RH for a period of six months.

8. The stable pharmaceutical composition according to claim 5, wherein the amount of nitrosamine impurity is less than about 25 ppm and the amount of adduct impurity of formula A: ##STR00006## is less than about 250 ppm, after exposure of the pharmaceutical composition to 40° C./75% RH for a period of six months.

9. The stable pharmaceutical composition according to claim 1, comprising: 0.5% w/w—1.0% w/w of Varenicline or its pharmaceutically acceptable salt; 1% w/w—20% w/w of the stabilizing agent selected from the group consisting of isomalt, meglumine, povidone, ascorbic acid, tocopherol, 2,5-dihydroxy benzoic acid, butylated hydroxytoluene, butylated hydroxyanisole, propyl gallates, pullulan, or a combination thereof; 10% w/w—80% w/w of the diluent selected from the group consisting of cellulose derivatives, microcrystalline cellulose, sugars and sugar alcohols, mannitol, sorbitol, xylitol, trehalose, sucrose, maltodextrin, pullulan, calcium hydrogen phosphate, dicalcium phosphate, or a combination thereof, 1% w/w—10% w/w of the disintegrant selected from the group consisting of carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, sodium starch glycolate, polacrillin potassium, low substituted hydroxypropyl cellulose, crosslinked polyvinyl pyrrolidine, carboxymethyl starch sodium, or a combination thereof; 1% w/w—10% w/w of the binder selected from the group consisting of microcrystalline cellulose, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), hydroxypropylmethyl cellulose, hydroxypropyl cellulose, copovidone, sugars and sugar alcohols, maltodextrin, sodium carboxymethylcellulose, gums, pregelatinized starch, or a combination thereof, or a combination thereof; and 0.1% w/w—5% w/w of the lubricant selected from the group consisting of zinc stearate, magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid, colloidal silica, sodium lauryl sulfate, aluminium silicate, calcium silicate, stearic acid, polyethylene glycol or a combination thereof; based on the total weight of the composition.

10. The stable pharmaceutical composition according to claim 9, wherein the stabilizing agent is butylated hydroxytoluene, butylated hydroxyanisole, or a combination thereof; the diluent is microcrystalline cellulose, dicalcium phosphate, or a combination thereof; the disintegrant is croscarmellose sodium, crosslinked polyvinyl pyrrolidine or a combination thereof; the binder is hydroxypropylmethyl cellulose, maltodextrin, polyvinylpyrrolidone; and the lubricant is magnesium stearate, colloidal silicon dioxide, or combination thereof, wherein the amount of nitrosamine impurity is less than about 25 ppm and adduct impurity is less than about 250 ppm after exposure of the pharmaceutical composition to 40° C./75% RH for a period of six months.

11. The stable pharmaceutical composition according to claim 10, comprising about 0.5 mg Varenicline free base or equivalent amount of pharmaceutically acceptable salt, about 2 mg of butylated hydroxyanisole, about 10 mg croscarmellose sodium, about 9 mg of maltodextrin, about 45 mg of microcrystalline cellulose, about 30 mg of dibasic calcium phosphate, about 0.5mg of colloidal silicon dioxide, about 1 mg of magnesium stearate.

12. The stable pharmaceutical composition according to claim 10, comprising about 1 mg Varenicline free base or equivalent amount of pharmaceutically acceptable salt, about 4 mg of butylated hydroxyanisole, about 20 mg croscarmellose sodium, about 18 mg of maltodextrin, about 90 mg of microcrystalline cellulose, about 60 mg of dibasic calcium phosphate, about 1 mg of colloidal silicon dioxide, about 2 mg of magnesium stearate.

13. A compound of formula A, ##STR00007##

14. A process for preparation of a stable pharmaceutical composition comprising Varenicline or its pharmaceutically acceptable salt, wherein the process comprises: (a) preparing suspension(s) or solution(s) of Varenicline or its pharmaceutically acceptable salt, one or more stabilizing agents, and optionally one or more pharmaceutically acceptable excipients in a solvent together or separately; (b) adding the suspension(s) or solution(s) of step (a) onto one or more pharmaceutical acceptable excipients to make granules; (c) compressing the granules to form tablets or filling the granules in capsules.

15. The process for preparation of a stable pharmaceutical composition according to claim 14, wherein step (a) comprises preparing a solution of Varenicline tartrate and maltodextrin in water and preparing a solution of butylated hydroxyanisole in isopropyl alcohol and step (b) comprises granulating a blend of microcrystalline cellulose, dicalcium phosphate, and croscarmellose sodium with the solution of Varenicline tartrate and maltodextrin in water and butylated hydroxyanisole in isopropyl alcohol, to make granules.

16. The process for preparation of a stable pharmaceutical composition according to claim 15, wherein the step (b) comprises granulating the blend in a rapid mixer granulator.

17. The process for preparation of a stable pharmaceutical composition according to claim 14, wherein step (a) comprises: i) preparing a solution of butylated hydroxyanisole in Isopropyl alcohol, and ii) preparing a solution of Varenicline Tartrate in water followed by addition of Maltodextrin to obtain a drug binder solution; wherein step (b) comprises: i) blending croscarmellose sodium, microcrystalline cellulose, dibasic calcium phosphate followed by granulating the blend with the solution of step i) and step ii) in a rapid mixer granulator to obtain granules, ii) drying the granules followed by milling to obtain dried and milled granules; c) lubricating the dried and milled granules followed by compressing to obtain tablets, and d) optionally coating the tablets.

18. The process for preparation of a stable pharmaceutical composition according to claim 14, wherein the pharmaceutical composition has less than about 50 ppm of nitrosamine impurity after exposure of the pharmaceutical composition to 40° C./75% RH for a period of six months and less than about 500 ppm of adduct impurity of Formula A: ##STR00008## after exposure of the pharmaceutical composition to 40° C./75% RH for a period of six months.

19. The process for preparation of a stable pharmaceutical composition according to claim 17, wherein the pharmaceutical composition has less than about 25 ppm of nitrosamine impurity after exposure of the pharmaceutical composition to 40° C./75% RH for a period of six months, and less than about 250 ppm of adduct impurity of Formula A: ##STR00009## after exposure of the pharmaceutical composition to 40° C./75% RH for a period of six months.

20. A stable pharmaceutical composition prepared by process according to claim 17.

Description

EXAMPLE 1

Pharmaceutical Composition of Varenicline with Maltodextrin

[0096]

TABLE-US-00001 Ingredient Quantity % w/w Varenicline Tartrate 0.814 Maltodextrin 8.143 Microcrystalline Cellulose 46.75 Anhydrous dibasic calcium phosphate 28.579 Croscarmellose sodium 9.524 Colloidal Silicon Dioxide 0.476 Magnesium stearate 0.952 Opadry coat 4.762

[0097] Process: [0098] (a) Microcrystalline cellulose, anhydrous dibasic calcium phosphate, and other ingredients were dispensed and sifted. [0099] (b) Maltodextrin was dissolved in purified water under continuous stirring. Varenicline Tartrate was added to the solution of maltodextrin in water and dissolved under continuous stirring to form solution of Varenicline Tartrate with maltodextrin in water. [0100] (c) Blend of step a) was granulated using the solution of step b) followed by blending the granules together with Croscarmellose sodium, Microcrystalline cellulose and Colloidal silicon dioxide. [0101] (d) Blend of step (c) was lubricated with Magnesium stearate. [0102] (e) Lubricated blend of step (d) was compressed using suitable punches and dies to form tablets. [0103] (f) Tablets of step (e) were coated with coating solution.

EXAMPLE 2

Pharmaceutical Composition of Varenicline with Pullulan

[0104]

TABLE-US-00002 Ingredient Quantity % w/w Varenicline Tartrate 0.814 Pullulan 8.143 Anhydrous dibasic calcium phosphate 75.805 Croscarmellose sodium 9.524 Magnesium stearate 0.952 Opadry coat 4.762

[0105] Process for preparation of composition of Example 2 is similar to the process followed in Example 1 except solution of Varenicline Tartrate with pullulan in water was prepared.

EXAMPLE 3

Pharmaceutical Composition of Varenicline with Meglumine and Hydroxypropyl Cellulose

[0106]

TABLE-US-00003 Ingredient Quantity % w/w Varenicline Tartrate 0.814 Hydroxypropyl cellulose 8.143 Meglumine 5.700 Microcrystalline Cellulose 41.057 Anhydrous dibasic calcium phosphate 28.572 Croscarmellose sodium 9.524 Colloidal Silicon Dioxide 0.476 Magnesium stearate 0.952 Opadry coat 4.762

[0107] Process for preparation of composition of Example 3 is similar to the process followed in Example 1 except Varenicline tartrate was added to the solution of Hydroxypropyl cellulose and Meglumine.

EXAMPLE 4

Pharmaceutical Composition of Varenicline with Ascorbic Acid and Hydroxypropyl Cellulose

[0108]

TABLE-US-00004 Ingredient Quantity % w/w Varenicline Tartrate 0.814 Hydroxypropyl cellulose 8.143 Ascorbic acid 4.286 Microcrystalline Cellulose 42.46 Anhydrous dibasic calcium phosphate 28.59 Croscarmellose sodium 9.52 Colloidal Silicon Dioxide 0.473 Magnesium stearate 0.952 Opadry coat 4.762

[0109] Process for preparation of composition of Example 3 is similar to the process followed in Example 1 except Varenicline tartrate was added to the solution of Hydroxypropyl cellulose and Ascorbic acid.

Example 5

Pharmaceutical Composition of Varenicline with Ascorbic Acid and Maltodextrin

[0110]

TABLE-US-00005 Ingredient Quantity % w/w Varenicline Tartrate 0.814 Maltodextrin 8.143 Ascorbic acid 4.071 Microcrystalline Cellulose 42.68 Anhydrous dibasic calcium phosphate 28.57 Croscarmellose sodium 9.52 Colloidal Silicon Dioxide 0.478 Magnesium stearate 0.962 Opadry coat 4.762

[0111] Process: [0112] (a) Croscarmellose sodium & microcrystalline cellulose and other ingredients were dispensed and sifted. [0113] (b) Maltodextrin and ascorbic were dissolved in purified water under continuous stirring. Varenicline Tartrate was added to the solution of maltodextrin in water and dissolved under continuous stirring to form solution of Varenicline Tartrate with maltodextrin in water. [0114] (c) Blend of step (a) was granulated using solution of step b) and c) followed by blending with croscarmellose sodium, microcrystalline cellulose, and colloidal silicon dioxide. [0115] (d) Blend of step (d) was lubricated using magnesium stearate. [0116] (e) Lubricated blend of step (e) was compressed using suitable punches and dies to form tablets. [0117] (f) Tablets of step (e) were coated with coating solution.

Example 6

Pharmaceutical Composition of Varenicline with Butylated Hydroxytoluene, Butylated hydroxyanisole and Maltodextrin

[0118]

TABLE-US-00006 Ingredient Quantity % w/w Varenicline Tartrate 0.814 Maltodextrin 8.143 Butylated hydroxytoluene 0.357 Butylated hydroxyanisole 1.904 Microcrystalline Cellulose 73.80 Croscarmellose sodium 9.32 Stearic acid 0.90 Opadry Pink 20A540023 4.762

[0119] Process: [0120] (a) Croscarmellose sodium & microcrystalline cellulose and other ingredients were dispensed and sifted. [0121] (b) Solution of butylated hydroxyanisole and butylated hydroxytoluene was prepared using isopropyl alcohol under continuous stirring. [0122] (c) Maltodextrin was dissolved in purified water under continuous stirring. Varenicline Tartrate was added to the solution of maltodextrin in water and dissolved under continuous stirring to form solution of Varenicline Tartrate with maltodextrin in water. [0123] (d) Blend of step (a) was granulated using solution of step b) and c) followed by blending with croscarmellosesodium & microcrystalline cellulose. [0124] (e) Blend of step (d) was lubricated using stearic acid. [0125] (f) Lubricated blend of step (e) was compressed using suitable punches and dies to form tablets. [0126] (g) Tablets of step (f) were coated with coating solution.

Example 7

Pharmaceutical Composition of Varenicline with Butylated Hydroxyanisole

[0127]

TABLE-US-00007 S. No Name of Ingredients 0.5 mg 1 mg % w/w Drug Binder Solution 1 Varenicline Tartrate 0.855 1.710 0.814 2 Maltodextrin 8.550 17.100 8.143 3 Purified water Q.s. Q.s. Butylated Hydroxyanisole (BHA) Solution 4 Butylated Hydroxyanisole 2.000 4.000 1.905 5 Isopropyl Alcohol Q.s. Q.s. Dry Mixing 6 Microcrystalline Cellulose 42.095 84.190 40.090 7 Anhydrous Dibasic Calcium 30.000 60.000 28.571 Phosphate 8 Croscarmellose Sodium 5.000 10.000 4.762 Pre-lubrication 9 Microcrystalline Cellulose 5.000 10.000 4.762 10 Colloidal Silicon Dioxide 0.500 1.000 0.476 11 Croscarmellose Sodium 5.000 10.000 4.762 Lubrication 12 Magnesium Stearate 1.000 2.000 0.952 Average weight of 100.000 200.000 core tablets (mg) Film coating 13 Opadry White 20A58900 5.000 — 14 Opadry pink 20A540023 — 10.000 4.762 15 Purified Water.sup.# Q.s. Q.s. Average weight of 105.000 210.000 coated tablets (mg)

[0128] Process:

[0129] 1. Sifting: Croscarmellose sodium & microcrystalline cellulose and other ingredients were dispensed and sifted.

[0130] 2. BHA solution preparation: Isopropyl alcohol was taken in a suitable vessel & Butylated Hydroxyanisole was slowly added under continuous stirring.

[0131] 3. Drug Binder Solution preparation: Varenicline Tartrate was added to purified water and dissolved under continuous stirring. Maltodextrin was added to step under continuous stirring.

[0132] 4. Blending: Croscarmellose sodium & Microcrystalline cellulose, Anhydrous Dibasic Calcium phosphate were loaded in Rapid Mixer Granulator (RMG) and blended for suitable time.

[0133] 5. Granulation: Blend of step 4 was granulated with a solution of step 2 & 3. for suitable time in rapid mixer granulator (RMG).

[0134] 6. Drying: Granules of step 5 were dried in a fluid bed dryer (FBD) at 45° C.±10° C. to achieve suitable LOD.

[0135] 7. Sifting/Milling: Dried granules of step 5 were sifted through a suitable sieve and retains/oversize granules were milled in a suitable mill to get uniform sized dried granules.

[0136] 8. Blending: Granules obtained from step 7 were loaded in a suitable blender and blended for suitable time with prelubrication blend of Croscarmellose sodium, microcrystalline cellulose, and colloidal silicon dioxide using suitable blender for suitable time.

[0137] 9. Lubrication: Blend from step 8 was lubricated with Magnesium stearate in a suitable blender for suitable time.

[0138] 10. Compression: Lubricated blend of step 9 was compressed using rotary compression machine with suitable punches and dies for respective strength.

[0139] 11. Coating: Opadry was dispersed in purified water under continuous stirring for suitable time. Dispersion was sifted. Tablets were coated with the dispersion.

[0140] Stability Studies: The pharmaceutical compositions of the Example 7 (0.5 mg and 1 mg) were tested for stability at 25° C./60% RH and 40° C./75% RH for a period of six months. The amount of nitrosamine impurity is provided in table 1 below.

TABLE-US-00008 TABLE 1 Test 25° C./60% RH 40° C./75% RH Parameters Specification Batch No. Initial 3 M 6 M 3 M 6 M 0.5 mg Varenicline N NMT 1.0% FNJKV001 BQL BQL 0.03 0.07 0.13 formyl Impurity Varenicline NMT 0.5% BQL BQL BQL 0.07 0.10 Adduct impurity at RRT 3.2 Any unspecified NMT 0.5% 0.12 0.14 0.13 0.06 0.12 degradation product Total degradation NMT 2.5% 0.27 0.28 0.21 0.38 0.61 products Nitrosamine NMT 18.5 BDL BDL BDL BDL BDL impurity ppm 1 mg Varenicline N NMT 1.0% FWJKV001 BQL BQL BQL 0.07 0.12 formyl Impurity Varenicline NMT 0.5% BQL BQL BQL 0.13 0.18 Adduct impurity at RRT 3.2 Any unspecified NMT 0.5% 0.11 0.14 0.12 0.07 0.05 degradation product Total degradation NMT2.5% 0.15 0.14 0.12 0.43 0.47 products Nitrosamine NMT 18.5 BDL BDL BDL BDL BDL impurity ppm BDL is Below Detection Limit of Nitrosamine impurity: 0.92 parts per million BQL is Below Quantification Limit of Nitrosamine impurity: 2.78 parts per million

Example 8

Preparation of Stable Solid Dispersion of Varenicline Tartrate with Maltodextrin

[0141] A mixture of Varenicline Tartrate (0.5 g) and maltodextrin (0.5 g) was dissolved in water (25 mL) at 25° C. and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50° C. to solid dispersion of Varenicline Tartrate.