DESC:TECHNICAL FIELD
The present subject matter relates to a solid oral pharmaceutical composition comprising combination of azilsartan medoxomil or a pharmaceutically acceptable salt thereof and chlorthalidone with at least one pharmaceutically acceptable excipient. The present subject matter also relates to a fixed dose pharmaceutical composition comprising azilsartan kamedoxomil and chlorthalidone with at least one pharmaceutically acceptable excipient. Furthermore, it also relates to methods for manufacturing such compositions and use thereof.

BACKGROUND
Azilsartan is a selective AT1 subtype angiotensin II receptor antagonist. Azilsartan medoxomil is a prodrug, which is hydrolysed to azilsartan in the gastrointestinal tract during absorption. The potassium salt of azilsartan medoxomil is azilsartan kamedoxomil. It is a white to nearly white powder with a molecular weight of 606.62. It is practically insoluble in water and freely soluble in methanol.

Azilsartan kamedoxomil, is chemically described as (5-Methyl-2-oxo- 1,3-dioxol-
4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-
yl] methyl}-1H-benzimidazole-7-carboxylate monopotassium salt and is reported to have the following chemical structure:

Chlorthalidone is a thiazide-like diuretic. It produces diuresis with increased excretion of sodium and chloride. It is chemically described as 2-chloro-5(1-hydroxy-3-oxo-1-isoindolinyl) benzenesulfonamide and is reported to have the following chemical structure:

Azilsartan Kamedoxomil and its combination with chlorthalidone are approved by USFDA and are commercially available under the trade names of EDARBI® and EDARBYCLOR® by Arbor Pharmaceuticals for the treatment of hypertension, to lower blood pressure.

U.S. Patent No. 5,583,141 discloses compound azilsartan. U.S. Patent No. 7,157,584 discloses azilsartan kamedoxomil. U.S. Patent No. 7,572,920 discloses process of preparation of the azilsartan kamedoxomil and method for treating hypertension in combination with a diuretic.

U.S. Patent No. 9,066,936 discloses a solid pharmaceutical composition comprising azilsartan kamedoxomil and a pH control agent, wherein the pH control agent provides a pH of 3 to 5 when dissolved or suspended in water at a concentration of 1% w/v at 25°C.

U.S. Patent No. 9,169,238 discloses a solid pharmaceutical composition comprising azilsartan kamedoxomil, chlorthalidone and a pH control agent, wherein the pH control agent provides a pH of 2 to 5 when dissolved or suspended in water at a concentration of 1% w/v at 25°C. The pH control agent is preferably monosodium fumarate or a combination of fumaric acid and sodium ion donor. In addition, fumaric acid and sodium hydroxide may be used in combination.

Indian Patent application 5882/CHE/2013 discloses tablet composition comprising azilsartan kamedoxomil and pH regulating agent having a pH not less than 5. It also discloses that composition optionally comprises second active agent.

Indian Patent application IN202041035039 discloses stable pharmaceutical compositions comprising azilsartan kamedoxomil and/or combination with chlorthalidone and a pH regulating agent magnesium aluminometasilicate having a pH in the range of 7 to 12 when dissolved or suspended in water at a concentration of 1% w/v at 25?.

There still remains a need to provide a stable pharmaceutical composition containing azilsartan medoxomil or a salt there of with desired dissolution and bioavailability parameters.

The present subject matter relates to a pharmaceutical composition comprising azilsartan kamedoxomil and/or combination with chlorthalidone and pH control agent with one or more suitable pharmaceutically acceptable excipients.

The pH control agent/s as per this disclosure typically exhibits a pH of more than 5.0, preferably about 5.0 to about 7.0, about 5.0 to about 6.0 and more preferably about 5.5 to 6.0.

As part of developmental efforts, it was surprisingly found out that, azilsartan kamedoxomil can be stabilized to prepare stable pharmaceutical compositions comprising azilsartan kamedoxomil and/or combination with chlorthalidone by utilizing a pH control agent such as: a strong acid such as hydrochloric acid, sulfuric acid, phosphoric acid and like; basic substance such as inorganic bases (e.g., sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, magnesium carbonate, calcium carbonate, magnesium oxide, ammonia, synthetic hydrotalcite), organic bases (e.g., basic amino acid such as lysine, arginine, etc., meglumine, and the like); methacrylic acid copolymer such as methacrylic acid and ethyl acrylate copolymer e.g. Eudragit L100-55 and the like. It was also surprisingly found out that the satisfactory stability can be achieved by employing a single pH control agent. This is in contrary to the existing prior art for example US9,066,936 and US9,169,238, which require combination of acid, such as fumaric acid and base, such as sodium hydroxide. Accordingly, the present subject matter relates to a stable pharmaceutical composition comprising azilsartan kamedoxomil and/or combination with chlorthalidone and such pH control agent as described above, with one more pharmaceutically acceptable excipient(s).

The present subject matter also provides a stable, economically and industrially feasible process for preparing pharmaceutical compositions comprising azilsartan kamedoxomil and/or combination with chlorthalidone and desired pH control agent with one or more suitable pharmaceutically acceptable excipients.

SUMMARY OF THE SUBJECT MATTER

The present subject matter relates to a solid oral pharmaceutical composition comprising combination of azilsartan and chlorthalidone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. Furthermore, it also relates to methods for manufacturing such compositions, and uses thereof.

An aspect of the present subject matter is to provide a solid oral pharmaceutical composition comprising combination of azilsartan kamedoxomil and chlorthalidone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. Furthermore, it also relates to methods for manufacturing such compositions, and uses thereof.

An aspect of the present subject matter is to provide a pharmaceutical composition with improved stability and dissolution of azilsartan kamedoxomil and chlorthalidone or pharmaceutically acceptable salt thereof and a process of manufacturing the pharmaceutical composition thereof.

An aspect of the present subject matter is to provide a stable pharmaceutical compositions comprising combination of azilsartan kamedoxomil with chlorthalidone and a pH control agent that provides a pH of more than 5.0, preferably about 5.0 to about 7.0, about 5.0 to about 6.0 and more preferably about 5.5 to 6.0 with one more pharmaceutically acceptable excipient(s).

Another aspect of the present subject matter is to provide a pharmaceutical composition with improved stability and dissolution of azilsartan kamedoxomil using a pH control agent that provides a pH of more than 5.0, preferably about 5.0 to about 7.0, about 5.0 to about 6.0 and more preferably about 5.5 to 6.0 with one more pharmaceutically acceptable excipient(s).

Another aspect of the present subject matter is to provide a pharmaceutical composition with improved stability and dissolution of azilsartan kamedoxomil using a strong acid as a pH control agent that provides a pH of more than 5.0, preferably about 5.0 to about 7.0, about 5.0 to about 6.0 and more preferably about 5.5 to 6.0 with one more pharmaceutically acceptable excipient(s). In an aspect, the acid is hydrochloric acid .

Another aspect of the present subject matter is to provide a pharmaceutical composition with improved stability and dissolution of azilsartan kamedoxomil and chlorthalidone or a pharmaceutically acceptable salt thereof using hydrochloric acid as a pH control agent, adjusted to provide a pH of more than 5.0, preferably about 5.0 to about 7.0, about 5.0 to about 6.0 and more preferably about 5.5 to 6.0 with one more pharmaceutically acceptable excipient(s).

In an embodiment of the present subject matter, a process to prepare the pharmaceutical compositions of the present subject matter involves wet granulation.

In an embodiment, the wet granulation process involves rapid mixer granulator. In another embodiment, the wet granulation process involves fluidized bed processor.

In an embodiment, the pharmaceutical composition of the present subject matter is prepared by separately granulating azilsartan kamedoxomil and chlorthalidone or a pharmaceutically acceptable salt thereof, and then blending both the granules, optionally with extragranular material to obtain final dosage form.

DETAILED DESCRIPTION OF THE SUBJECT MATTER:

An object of the present subject matter is to provide a solid pharmaceutical composition with improved stability and dissolution of azilsartan kamedoxomil and/or chlorthalidone or a pharmaceutically acceptable salt thereof.

Another object of the present subject matter is to provide a method of stabilizing azilsartan kamedoxomil and/or chlorthalidone or a pharmaceutically acceptable salt thereof and further, a method of improving dissolution thereof.

It was found out that, azilsartan kamedoxomil can be stabilized to prepare stable pharmaceutical compositions comprising azilsartan kamedoxomil and/or combination with chlorthalidone by utilizing a single pH control agent.

As used herein, "a" or "an" means one or more unless otherwise specified.

The term "composition" is intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

The pH control agent as per the present subject matter may be any pharmaceutically acceptable ingredient that provides the desired pH and simultaneously achieves desired stability and dissolution of active ingredient/s.

To be precise, the pH of the pH control agent refers to an observed pH obtained by dissolving or suspending a pH control agent in water at a concentration of 1% w/v at 25.degree. C.

The term “intra-granular or intra-granular portion” as used herein includes, but is not limited to, a part or component of composition mixed or blended to form granules.

The term “extra-granular or extra-granular portion” as used herein includes, but is not limited to, a part or component of composition mixed or blended with dry mix formed after granulation, lubricated, and which is further subjected to compression to form the tablets and coating the tablets.

In an embodiment, a composition of the present subject matter is prepared by separately granulating azilsartan part and chlorthalidone part and compressing both the granules to form the tablets.

In an embodiment, the composition containing azilsartan and chlorthalidone or pharmaceutically acceptable salt thereof is prepared by a process comprising following steps,
a) granulating a blend of azilsartan kamedoxomil and one or more pharmaceutically acceptable excipients by wet granulation process, using a granulation medium containing a pH control agent dissolved in a suitable solvent,
b) separately granulating intragranular excipients using a granulation medium containing chlorthalidone dissolved in a suitable solvent to prepare chlorthalidone granules,
d) blending azilsartan and chlorthalidone part granules with extragranular excipients to obtain final blend,
e) compressing the final blend to form a tablet and coating the tablet.

In one embodiment, a composition of the present subject matter is prepared by separately granulating azilsartan part, chlorthalidone part and placebo granules part and compressing all the granules to form tablets.

In an embodiment, a composition containing azilsartan and chlorthalidone or a pharmaceutically acceptable salt thereof is prepared by a process comprising following steps,
a) granulating a blend of azilsartan kamedoxomil and one or more pharmaceutically acceptable excipients by wet granulation process using a suitable solvent to prepare azilsartan granules,
b) preparing separate placebo granules by granulating intragranular excipients with a granulating medium containing a pH control agent, and
c) separately granulating intragranular excipients using a granulation medium containing chlorthalidone dissolved in a suitable solvent to prepare chlorthalidone granules,
d) blending azilsartan, chlorthalidone and placebo part granules with extragranular excipients to obtain final blend,
e) compressing the final blend to form tablet and coating the tablet.

In one embodiment, the composition of the present subject matter is stable for at least one month under packed condition. In embodiments, the composition of the present subject matter is stable for at least two months under packed condition. In embodiments, the composition of the present subject matter is stable for at least six months under packed condition.
Another aspect of the present subject matter provides a pharmaceutical composition comprising,
(a) azilsartan medoxomil or a pharmaceutically acceptable salt thereof,
(b) chlorthalidone,
(c) one or more pharmaceutically acceptable excipient.

Another aspect of the present subject matter provides a pharmaceutical composition comprising,
(a) azilsartan medoxomil or a pharmaceutically acceptable salt thereof,
(b) chlorthalidone,
(c) pharmaceutically acceptable pH control agent,
(d) one or more pharmaceutically acceptable excipient.

Another aspect of the present subject matter provides a pharmaceutical composition comprising,
(a) azilsartan medoxomil or a pharmaceutically acceptable salt thereof,
(b) chlorthalidone,
(c) pharmaceutically acceptable pH control agent,
(d) one or more pharmaceutically acceptable diluent,
(e) one or more pharmaceutically acceptable disintegrant,
(f) one or more pharmaceutically acceptable lubricant.

Another aspect of the present subject matter provides a pharmaceutical composition comprising,
(a) azilsartan kamedoxomil,
(b) chlorthalidone,
(c) pharmaceutically acceptable pH control agent,
(d) one or more pharmaceutically acceptable diluent,
(e) one or more pharmaceutically acceptable disintegrant,
(f) one or more pharmaceutically acceptable lubricant.

Another aspect of the present subject matter provides a pharmaceutical composition comprising,
(a) azilsartan medoxomil or a pharmaceutically acceptable salt thereof,
(b) chlorthalidone or a pharmaceutically acceptable salt thereof,
(c) one or more pharmaceutically acceptable excipient,
wherein a pharmaceutical composition is prepared by wet granulation.

Another aspect of the present subject matter provides a pharmaceutical composition comprising,
(a) azilsartan medoxomil or a pharmaceutically acceptable salt thereof,
(b) chlorthalidone,
(c) pharmaceutically acceptable pH control agent,
(d) one or more pharmaceutically acceptable diluent,
(e) one or more pharmaceutically acceptable disintegrant,
(f) one or more pharmaceutically acceptable lubricant.
wherein a pharmaceutical composition is prepared by a process involving wet granulation in rapid mixer granulator.

Another aspect of the present subject matter provides a pharmaceutical composition comprising,
(a) azilsartan kamedoxomil,
(b) chlorthalidone,
(c) pharmaceutically acceptable pH control agent,
(d) one or more pharmaceutically acceptable diluent,
(e) one or more pharmaceutically acceptable binder,
(f) one or more pharmaceutically acceptable disintegrant.
(g) one or more pharmaceutically acceptable lubricant.
wherein a pharmaceutical composition is prepared by a process involving wet granulation in fluidized bed granulator.

According to one embodiment, the excipients include one or more of pH control agents, diluents, binders, disintegrants and lubricants.

The term “pH control agent” is intended to be interpreted in the context of pharmaceutical formulation science. Suitable pH control agent can be selected from the group of, but not limited to strong acids such as hydrochloric acid, sulfuric acid, phosphoric acid and like; basic substances include inorganic bases (e.g., sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, magnesium carbonate, calcium carbonate, magnesium oxide, ammonia, synthetic hydrotalcite), organic bases (e.g., basic amino acid such as lysine, arginine, etc., meglumine, and the like); methacrylic acid copolymer such as methacrylic acid and ethyl acrylate copolymer e.g. Eudragit L100-55 and the like.

The term “diluent” is intended to be interpreted in the context of pharmaceutical formulation science. Suitable diluents can be selected from the group of, but not limited to microcrystalline cellulose (MCC), pregelatinized starch, sugar and sugar alcohol such as mannitol, lactose, fructose, isomalt, lactitol, maltitol, sorbitol, erythritol, maltose, polydextrose, sucrose, trehalose, xylitol, calcium carbonate, dicalcium phosphate, calcium sulfate, cellulose acetate, ethylcellulose, inulin, magnesium carbonate, magnesium oxide, maltodextrin, sodium bicarbonate, sodium carbonate and sodium chloride.

The term “binder” is intended to be interpreted in the context of pharmaceutical formulation science. Suitable binder can be selected from the group of, but not limited to povidone, copovidone pregelatinized starch, cellulose, methyl cellulose, ethyl cellulose, cellulose derivatives (e.g., hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC)), polyethylene glycol and hydroxypropyl methyl cellulose acetate succinate (HPMC-AS).

The terms “disintegrant” and “disintegrants” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable disintegrants according to the present subject matter can be selected from but not limited to crospovidone, croscarmellose sodium (CCS), sodium starch glycolate (SSG), pregelatinized starch, alginic acid, sodium alginate, carboxymethylcellulose calcium, chitosan, crospovidone, glycine, guar gum, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, povidone, sodium alginate, sodium carboxymethylcellulose and starch.

The terms “lubricant” and “lubricants” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable pharmaceutical lubricant according to the present subject matter can be selected from but not limited to magnesium, aluminium, zinc or calcium stearate, glyceryl behenate, glyceryl dibehenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of behenate esters of glycerine (e.g. a mixture of glyceryl behenate, tribehenin and glyceryl behenate), magnesium stearate, myristic acid, palmitic acid, stearic acid, talc, tribehenin, sodium stearyl fumarate (SSF) and sucrose stearate.

In an embodiment of the present subject matter, the organic solvent suitable for preparing a composition is selected from isopropyl alcohol, ethanol, methanol, acetone, dichloromethane, acetonitrile, petroleum ether or mixture thereof.

As used herein, the word “comprising” describes components that must be present, but leaves open the possibility that other unspecified components may also be present within the scope of the relevant term.

In one aspect there is provided a pharmaceutical tablet comprising the pharmaceutical composition as defined herein.

In one embodiment there is provided a pharmaceutical tablet comprising a pharmaceutical composition in the form of tablet core, wherein the tablet core is coated with a layer of coating. In one embodiment the coating is a film coating.

When the tablet has a film coating, the film coating may be applied using conventional methods. A coating can be used to provide protection against, for example, moisture ingress or degradation by light, to colour the formulation, or to modify or control the release of azilsartan and chlorthalidone from the formulation.

In one embodiment, a pharmaceutical composition is a pharmaceutical tablet.

In one embodiment, the pharmaceutical composition is a pharmaceutical tablet composition suitable for oral administration to a human.

In one embodiment, the pharmaceutical tablet comprises 40 mg of Azilsartan base which is equivalent to 42.68 mg of azilsartan kamedoxomil.

In one embodiment, the pharmaceutical tablet comprises 12.5 mg and 25 mg Chlorthalidone.

In one aspect, there is provided a pharmaceutical composition, as defined herein, for use as a medicament.

In one embodiment, there is provided a method of using pharmaceutical composition comprising an effective amount of azilsartan kamedoxomil, and chlorthalidone with one or more pharmaceutically acceptable excipient in the treatment of hypertension.

It is to be understood that each of the variously stated ranges is intended to be continuous so as to include each numerical parameter between the stated minimum and maximum value of each range.

Embodiments provided herein may be more fully understood by reference to the following examples. These examples are meant to be illustrative of pharmaceutical composition and dosage form provided herein, but is not in any way limiting.

Example 1:
Table 1-Pharmaceutical composition of Azilsartan and Chlorthalidone
Sr. No. Ingredients % of ingredient by weight of core tablet
(40/25 mg)
1 Azilsartan medoxomil or salt thereof 10-13
2 Chlorthalidone 5-7
3 Diluents (e.g. Mannitol, microcrystalline cellulose, lactose) 60 - 75
4 pH control agent (e.g. Hydrochloric acid, Methacrylic Acid and Ethyl Acrylate Copolymer) Q.S.
5 Disintegrant (e.g. Sodium starch glycolate, crospovidone, croscarmellose sodium, L-substituted hydroxypropyl cellulose) 4-12
6 Binder (e.g. Hydroxypropyl cellulose, Povidone , copovidone) 0.1-3
7 Lubricant(e.g. Magnesium stearate, stearic acid, sodium stearyl fumarate) 0.5 – 2
8 Optionally film coating 2-3

Example 2
Table 2 – Pharmaceutical composition of Azilsartan and Chlorthalidone
S. No Ingredient Name % (w/w)
Intra Granular Part-I (Azilsartan kamedoxomil granulation)
1 Azilsartan Medoxomil Monopotassium 11.5
2 Mannitol (Pearlitol® 200SD) 21.1
3 Microcrystalline cellulose (Avicel ® PH-101) 6.7
4 Hydroxypropyl cellulose (Klucel LF Pharm) 1.1
5 Hydrochloric acid q.s
6 Purified water q.s
7 Acetone q.s
Intra Granular Part-II (Chlorthalidone granulation)
8 Mannitol (Pearlitol® 200SD) 24.3
9 Microcrystalline cellulose (Avicel ® PH-102) 6.7
10 Crospovidone (Kollidon® CL-F) 2.7
Preparation of API and Binder solution
11 Chlorthalidone 6.7
12 Methanol q.s
Extra-granular material
13 Mannitol (Pearlitol® 200SD) 7.2
14 Microcrystalline cellulose (Avicel ® PH-112) 2.7
15 Crospovidone (Kollidon® CL-F) 5.4
16 Magnesium Stearate (LIGAMED MF-2-V) 1.0
Core Tablet weight 97.1
Film-Coating
17 OPADRY® II 85F550102 RED 2.9
18 Purified Water q.s
Coated Tablet weight 100.00

Procedure for Example 2
Azilsartan kamedoxomil granulation part
1. Azilsartan Medoxomil Monopotassium along with intragranular excipients mannitol, microcrystalline cellulose and hydroxypropyl cellulose were dispensed and sifted in quadro sifter.
2. Purified water was taken in container and added to 37% w/v hydrochloric acid. A pH of 1% w/w acidified water is 5.6-5.7.
3. Acetone was dispensed and mixed with acidified water of step 2 in the ratio of 95:5. A pH of 1% w/w of acidified acetone in water is 5.6-5.7.
4. Sifted material of step 1 was dry mixed in rapid mixer granulator for 10-15 minutes.
5. The dry mix material of step 4 was granulated with acidified acetone of step 3.
6. The granulated wet mass was dried in rapid dryer at 50-60°C and dried material was milled in quadro co-mill.
Chlorthalidone granulation part
1. Intragranular excipients mannitol, microcrystalline cellulose and crospovidone were dispensed and sifted in quadro sifter.
2. Chlorthalidone was dissolved in methanol.
3. Sifted material of step 1 was loaded in fluidized bed processor (FBP).
4. Material of step 3 was wet granulated in FBP with the drug solution of step 2.
5. The granulated wet mass was dried in rapid dryer at 50-60°C and dried material was milled in quadro co-mill.

Compression and coating
1. Extragranular material containing mannitol, microcrystalline cellulose, crospovidone and magnesium stearate were dispensed and sifted through quadro sifter.
2. The sifted material of step 1 was blended with Azilsartan and chlorthalidone granules in a bin blender for 10-15 minutes.
3. The lubricated blend was compressed using suitable punch tooling.
4. Opadry was dispersed in water under stirring.
5. The compressed tablets were film coated with aqueous dispersion of step 4 in a perforated coating pan.
Example 3
Table 3 – Pharmaceutical composition of Azilsartan and Chlorthalidone
S. No Ingredient Name % (w/w)
Intra Granular Part-I (Azilsartan kamedoxomil granulation)
1 Azilsartan Medoxomil Monopotassium 11.2
2 Mannitol (Pearlitol® 200SD) 12.7
3 Microcrystalline cellulose (Avicel ® PH-101) 3.8
4 Hydroxypropyl cellulose (Klucel LF Pharm) 1.1
5 Acetone q.s
Intra Granular Part-II Acidified Placebo granulation)
6 Mannitol (Pearlitol® 200SD) 22.3
7 Microcrystalline cellulose (Avicel ® PH-101) 6.6
8 Hydrochloric acid q.s
9 Purified water q.s
Intra Granular Part-III (Chlorthalidone granulation)
10 Mannitol (Pearlitol® 200SD) 19.6
11 Microcrystalline cellulose (Avicel ® PH-102) 5.3
12 Crospovidone (Kollidon® CL-F) 2.6
Preparation of API and Binder solution
13 Chlorthalidone 6.6
14 Methanol q.s
Extra-granular material
15 Crospovidone (Kollidon® CL-F) 4.4
16 Magnesium Stearate (LIGAMED MF-2-V) 0.9
Core Tablet weight 97.1
Film-Coating
17 OPADRY® II 85F550102 RED 2.90
18 Purified Water q.s
Coated Tablet weight 100.00

Procedure for Example 3
Azilsartan Medoxomil granulation part
1. Azilsartan Medoxomil Monopotassium along with intragranular excipients mannitol, microcrystalline cellulose and hydroxypropyl cellulose were dispensed and sifted in quadro sifter.
2. Sifted material of step 1 was dry mixed in rapid mixer granulator for 10-15 minutes.
3. The dry mix material of step 2 was granulated with acetone.
4. The granulated wet mass was dried in rapid dryer at 50-60°C and dried material was milled in quadro co-mill.

Placebo granulation part
1. Intragranular excipients mannitol and microcrystalline cellulose were dispensed and sifted in quadro sifter.
2. Purified water was taken in container and added to 37% w/v hydrochloric acid. A pH of 1% w/w acidified water is 5.6-5.7.
3. Sifted material of step 1 was dry mixed in rapid mixer granulator for 10-15 minutes.
4. The dry mix material of step 3 was granulated with acidified water of step 2.
5. The granulated wet mass was dried in rapid dryer at 50-60°C and dried material was milled in quadro co-mill.

Chlorthalidone granulation part
1. Intragranular excipients mannitol, microcrystalline cellulose and crospovidone were dispensed and sifted in quadro sifter.
2. Chlorthalidone was dissolved in methanol.
3. Sifted material of step 1 was loaded in fluidized bed processor (FBP).
4. Material of step 3 was wet granulated in FBP with the drug solution of step 2.
5. The granulated wet mass was dried in rapid dryer at 50-60°C and dried material was milled in quadro co-mill.

Compression and coating
1. Extragranular material containing crospovidone and magnesium stearate were dispensed and sifted through quadro sifter.
2. The sifted material of step 1 was blended with Azilsartan granules, chlorthalidone granules and placebo granules in a bin blender for 10-15 minutes.
3. The lubricated blend was compressed using suitable punch tooling.
4. Opadry was dispersed in water under stirring.
5. The compressed tablets were film coated with aqueous dispersion of step 4 in a perforated coating pan.

Example 4
Table 4 – Pharmaceutical composition of Azilsartan and Chlorthalidone
S. No Ingredient Name % (w/w)
Intra Granular Part-I (Azilsartan kamedoxomil granulation)
1 Azilsartan Medoxomil Monopotassium 11.5
2 Mannitol (Pearlitol® 200SD) 21.1
3 Microcrystalline cellulose (Avicel ® PH-101) 6.7
4 Hydroxypropyl cellulose (Klucel LF Pharm) 1.1
5 Hydrochloric acid q.s
6 Acetone q.s
Intra Granular Part-II (Chlorthalidone granulation)
7 Mannitol (Pearlitol® 200SD) 24.3
8 Microcrystalline cellulose (Avicel ® PH-102) 6.7
9 Crospovidone (Kollidon® CL-F) 2.7
Preparation of API and Binder solution
10 Chlorthalidone 6.7
11 Methanol q.s
Extra-granular material
12 Mannitol (Pearlitol® 200SD) 7.1
13 Microcrystalline cellulose (Avicel ® PH-112) 2.7
14 Crospovidone (Kollidon® CL-F) 5.4
15 Magnesium Stearate (LIGAMED MF-2-V) 1.0
Core Tablet weight 97.1
Film-Coating
16 OPADRY® II 85F550102 RED 2.9
17 Purified Water q.s
Coated Tablet weight 100.00
Procedure for Example 4
Azilsartan kamedoxomil granulation part
1. Azilsartan Medoxomil Monopotassium along with intragranular excipients mannitol, microcrystalline cellulose and hydroxypropyl cellulose were dispensed and sifted in quadro sifter.
2. Hydrochloric acid (37% w/v) was taken in container and added to acetone. A pH of 1% w/w acidified acetone is 5.8-6.1.
3. Sifted material of step 1 was dry mixed in rapid mixer granulator for 10-15 minutes.
4. The dry mix material of step 4 was granulated with acidified acetone of step 3.
5. The granulated wet mass was dried in rapid dryer at 50-60°C and dried material was milled in quadro co-mill.

Chlorthalidone granulation part
1. Intragranular excipients mannitol, microcrystalline cellulose and crospovidone were dispensed and sifted in quadro sifter.
2. Chlorthalidone was dissolved in methanol.
3. Sifted material of step 1 was loaded in fluidized bed processor (FBP).
4. Material of step 3 was wet granulated in FBP with the drug solution of step 2.
5. The granulated wet mass was dried in rapid dryer at 50-60°C and dried material was milled in quadro co-mill.

Compression and coating
1. Extragranular material containing mannitol, microcrystalline cellulose, crospovidone and magnesium stearate were dispensed and sifted through quadro sifter.
2. The sifted material of step 1 was blended with Azilsartan and chlorthalidone granules in a bin blender for 10-15 minutes.
3. The lubricated blend was compressed using suitable punch tooling.
4. Opadry was dispersed in water under stirring.
5. The compressed tablets were film coated with aqueous dispersion of step 4 in a perforated coating pan.

Example 5 – Dissolution study
Dissolution study was performed on the formulations obtained in example 2, 3 and 4 in comparison to that of Edarbyclor (azilsartan medoxomil and chlorthalidone) tablets 40mg/25mg in 900 mL pH 6.8 Phosphate Buffer with 1% Tween 80 at 50 RPM in USP Type 2 apparatus (Paddle). The results are presented in Table 5.
Table 5

Product EDARBYCLOR
(Azilsartan medoxomil and Chlorthalidone) Tablets
40mg / 25mg Example 2
Azilsartan medoxomil and Chlorthalidone Tablets 40mg / 25mg Example 3
Azilsartan medoxomil and Chlorthalidone Tablets 40mg / 25mg Example 4
Azilsartan medoxomil and Chlorthalidone Tablets 40mg / 25mg
Azilsartan Medoxomil
Time (min) Mean* % RSD Mean* % RSD Mean* % RSD Mean* % RSD
10 60 8.0 82 1.7 77 3.9 81 3.0
15 78 5.1 86 1.2 83 1.1 84 2.8
20 87 3.8 88 1.7 86 1.1 86 2.1
30 92 2.6 89 1.9 88 1.2 87 2.4
45 93 2.0 91 2.4 89 1.0 89 2.7
60 94 1.5 90 2.0 90 1.2 90 1.8
F2 Value - 50 55 51
Chlorthalidone
Time (min) Mean* % RSD Mean* % RSD Mean* % RSD Mean* % RSD
10 87 7.7 86 1.3 78 7.2 81 2.5
15 94 4.3 89 0.9 90 1.9 85 2.2
20 95 3.6 90 1.1 93 1.5 86 1.5
30 96 2.9 93 1.3 96 1.4 88
1.7
45 97 2.4 95 1.8 98 1.4 89
2.1
60 98 1.0 96 1.8 99 1.3 90 0.8
F2 Value - 73 67 55

* % drug release
Example 6 – Stability study
Organic impurities in azilsartan medoxomil and chlorthalidone tablets 40mg/25mg was determined by HPLC method and the results are presented in the Table 6, 7 & 8.

Table 6 – Stability study for Example 2:

Condition Initial 3M
40°C/75%RH 3M
25°C/60%RH
% Assay(Azilsartan) 96.9 90.3 91
% Assay(Chlorothalidone) 100.4 102.1 100.9
Impurities (CHLOROTHALIDONE) % w/w % w/w % w/w
Chlorothalidone RC-A/ EP imp-B 0.090 0.081 0.078
Max unknown(Chlorothalidone) 0.063 0.046 BQL
Total Impurities
(Chlorothalidone+unknown) 0.228 0.240 0.165
Impurities (AZILSARTAN) % w/w % w/w % w/w
Active Metabolite (Stage-III) 2.221 7.271 6.913
Max Unknown (Azilsartan) 0.146 0.172 0.228
Total Impurities (Azilsartan Excluding Active Metabolite) 0.334 1.309 1.240
Total Impurity_ Excluding Active Metabolite
(Azilsartan + Chlorothalidone) 0.562 1.549 1.405

Table 7– Stability study for Example 3:
Condition Initial 3M
40°C/75%RH 3M 25°C/60%RH
% Assay(Azilsartan) 95.8 92.4 93.6
% Assay(Chlorothalidone) 99.1 99.8 99.4
Impurities (CHLOROTHALIDONE) % w/w % w/w % w/w
Chlorothalidone RC-A/ EP imp-B 0.088 0.086 0.085
Max unknown(Chlorothalidone) 0.054 0.042 0.041
Total Impurities
(Chlorothalidone+unknown) 0.223 0.189 0.186
Impurities (AZILSARTAN) % w/w % w/w % w/w
Active Metabolite (Stage-III) 1.522 3.397 3.024
Max Unknown (Azilsartan) 0.083 0.088 0.121
Total Impurities (Azilsartan Excluding Active Metabolite) 0.240 0.769 0.381
Total Impurity_ Excluding Active Metabolite
(Azilsartan + Chlorothalidone) 0.463 0.958 0.567

Table 8– Stability study for Example 4:
Condition Initial 3M 40°C/75%RH 3M 25°C/60%RH
% Assay(Azilsartan) 97.5 96.6 97.7
% Assay(Chlorothalidone) 99 96.6 97.1
Impurities (CHLOROTHALIDONE) % w/w % w/w % w/w
Chlorothalidone RC-A/ EP imp-B 0.086 0.084 0.082
Max unknown(Chlorothalidone) 0.041 BQL BQL
Total mpurities (Chlorothalidone+unknown) 0.209 0.203 0.168
Impurities (AZILSARTAN) % w/w % w/w % w/w
Active Metabolite (Stage-III) 1.953 2.974 2.248
Max Unknown (Azilsartan) 0.096 0.072 0.092
Total Impurities (Azilsartan Excluding Active Metabolite) 0.30 0.357 0.238
Total Impurity_ Excluding Active Metabolite
(Azilsartan + Chlorothalidone) 0.509 0.560 0.406

Example 8 - Bioequivalence study:
An open label, balanced, randomized, single oral dose, crossover, oral bioequivalence study of Azilsartan medoxomil and Chlorthalidone Tablets 40/25 mg in comparison with EDARBYCLOR® (Azilsartan medoxomil and Chlorthalidone Tablets) 40/25 mg tablets (Marketed by Azurity Pharmaceuticals Inc) was performed in healthy, adult, human subjects under fasting and fed conditions.
The outcome of bioequivalence study for Azilsartan medoxomil and chlorthalidone compositions of the present invention under fed and fasting state complies with pre-defined bioequivalence criteria for Cmax,AUC0-t andAUC0-8.
,CLAIMS:1. A solid oral pharmaceutical composition comprising:
Azilsartan or a pharmaceutically acceptable salt thereof;
Chlorthalidone or a pharmaceutically acceptable salt thereof;
a pH control agent, which provide a pH of more than 5 and one or more pharmaceutically acceptable excipients.

2. The solid oral pharmaceutical composition according to claim 1, wherein the composition contains pH control agent which provides a pH of more than 5, preferably about 5.0 to about 7.0, preferably about 5.0 to about 6.0 and more preferably about 5.5 to 6.0 when dissolved or suspended in water at a concentration of 1% w/v at 25° C.

3. The solid oral pharmaceutical composition according to claim 1, wherein the pH control agent is selected from group comprising strong acid such as hydrochloric acid, sulfuric acid, phosphoric acid ; basic substance such as inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, magnesium carbonate, calcium carbonate, magnesium oxide, ammonia, synthetic hydrotalcite ; organic bases such as basic amino acid such as lysine, arginine, meglumine ; methacrylic acid copolymer such as methacrylic acid and ethyl acrylate copolymer.

4. The solid oral pharmaceutical composition according to claim 1, wherein the pH control agent comprising hydrochloric acid.

5. The solid oral pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipient is selected from a group comprising diluents, binders, disintegrants, lubricants.

6. The solid oral pharmaceutical composition according to claim 1 wherein the solid pharmaceutical composition is a tablet.

7. The solid oral pharmaceutical composition according to claim 1 can be prepared by wet granulation process such as using rapid mixer granulator or fluidized bed processor.