Claims:WE CLAIM:
1. A stable pharmaceutical formulation comprising phenylephrine or a salt thereof and chlorpheniramine maleate wherein phenylephrine or salt thereof and chlorpheniramine maleate are in not in close contact with each other
2. The stable pharmaceutical formulation as claimed in claim 1, wherein phenylephrine or salt thereof and chlorpheniramine maleate are present in separate layers in a bilayer or multilayer formulation
3. The stable pharmaceutical formulation as claimed in claim 1, wherein comprising one or more pH adjusting agent in one or more layers
4. A stable pharmaceutical formulation comprising phenylephrine or a salt thereof, chlorpheniramine maleate and one or more pH adjusting agent wherein phenylephrine or salt thereof and chlorpheniramine maleate are present in close contact with each other.
5. The stable pharmaceutical formulation as claimed in claim 4, wherein phenylephrine or salt thereof and chlorpheniramine maleate are present in a single layer formulation.
6. The stable pharmaceutical formulation as claimed in claim 3 and claim 4, wherein pH adjusting agent selected from the group consisting of citric acid, fumaric acid, malic acid, lactic acid, glycolic acid and tartaric acid and the like as claimed in a proportion of 0.01 to 10% by weight of the pharmaceutical formulation
7. The stable pharmaceutical formulation as claimed in any of the above claims is a tablet
8. The stable pharmaceutical formulation as claimed in any of the above claims comprising caffeine and paracetamol
9. The stable pharmaceutical formulation as claimed in any of the above claims comprising one or more pharmaceutically acceptable excipient selected from the group consisting of diluents, binders, disintegrants, lubricants and glidants.
10. The stable pharmaceutical formulation and process of preparing thereof as described and illustrated in the examples herein.
, Description:The following specification describes the invention and the manner in which it is to be performed::
STABLE PHARMACEUTICAL FORMULATION OF PHENYLEPHRINE OR SALT THEREOF AND CHLORPHENIRAMINE MALEATE
INTRODUCTION
The present invention relates to stable pharmaceutical formulation comprising phenylephrine or salt thereof, chlorpheniramine maleate and one or more pharmaceutically acceptable excipients; and process for preparing such stable pharmaceutical formulation.
BACKGROUND OF THE INVENTION
Upper respiratory mucosal congestion caused by infections such as the common cold and influenza can produce number of unpleasant symptoms. These include congestion of nasal passages, excessive sinus secretions, headache, muscle ache, fever and malaise.
Phenylephrine or salt thereof is used in pharmaceutical formulations as a nasal decongestant. Phenylephrine or salt thereof is used as alternative for pseudoephedrine due to illicit use of pseudoephedrine for manufacture of methamphetamine. Combinations containing phenylephrine and chlorpheniramine maleate are known in the art. For example, RINZA®, marketed in Russia is a tablet having Phenylephrine Hydrochloride (5mg), Chlorpheniramine Maleate Tablets (2mg) paracetamol (500mg) and Caffeine (30mg). However, phenylephrine or salt thereof is unstable in the presence of chlorpheniramine maleate or other maleate containing drugs like dexbrompheniramine maleate, which causes the formation of phenylephrine-maleate adducts.
US Patent Application no. 2006/0127473 discloses stabilized phenylephrine compositions comprising silicified microcrystalline cellulose.
European Patent no. 2246045 discloses an invention related to process for stabilizing phenylephrine where phenylephrine or salt thereof and acid is dissolved in aqueous solution followed by drying of said aqueous solution.
However, there still remains a need in the art for improved stabilized pharmaceutical formulation of phenylephrine or salt thereof and chlorpheniramine maleate.
SUMMARY OF INVENTION
The present invention relates to stable pharmaceutical formulation of phenylephrine or salt thereof and chlorpheniramine maleate.
An aspect relates to a stable pharmaceutical formulation comprising phenylephrine or a salt thereof and chlorpheniramine maleate wherein phenylephrine or salt thereof and chlorpheniramine maleate are not in close contact with each other.
A further aspect relates to a stable pharmaceutical formulation comprising phenylephrine or a salt thereof, chlorpheniramine maleate and one or more pH adjusting agent wherein phenylephrine or salt thereof and chlorpheniramine maleate are not in close contact with each other
A further aspect relates to a stable pharmaceutical formulation comprising phenylephrine or a salt thereof, chlorpheniramine maleate and one or more pH adjusting agent wherein phenylephrine or salt thereof and chlorpheniramine maleate are present in close contact with each other.
A further aspect relates to a stable pharmaceutical formulation mentioned in any of the above, may additionally contain one or more pharmaceutically acceptable excipients
A further aspect relates to a stable pharmaceutical formulation mentioned in any of the above, additionally contain caffeine and paracetamol.
DETAILED DESCRIPTION
As used herein, the term “stable” means that the amount of phenylephrine-maleate adduct impurity in the pharmaceutical formulation is not more than 0.2 % w/w after storage at about 40°C and 75% relative humidity in open condition for 21 days.
As used herein, the term “not in close contact” means, phenylephrine or salt thereof and chlorpheniramine maleate must be kept physically separated. This may be achieved by any of the ways known in the art, i) separate granulations for each of the drugs followed by compression into a bi-layer or multi-layer tablet ii) Coating a layer of chlorpheniramine maleate on to core tablet of phenylephrine.
As used herein, the term “pH adjusting agent” may include organic acid and inorganic acid. Organic acid selected from the group comprising of citric acid, fumaric acid, malic acid, lactic acid, glycolic acid, tartaric acid, succinic acid, ascorbic acid, aspartic acid, acetic acid, formic acid, oxalic acid, gallic acid, malonic acid, methane sulfonic acid, proprionic acid, pthalic acid, thioacetic acid, thioglycolic acid, thiobromoacetic acid, thiochloroacetic acid, trichloroacetic acid, trifluoro acetic acid and the like. Inorganic acid selected from the group comprising of hydrobromic acid, chlorous acid, hypobromous acid, hydrochloric acid, hypochlorous acid, nitric acid, nitrous acid, pernitric acid, sulfuric acid, sulfurous acid, hyposulfurous acid, chloric acid, bromous acid, bromic acid, persulfuric acid, pyrosulfuric acid, disulfurous acid, dithionous acid, peroxydisulfuric acid, hydrosulfuric acid, perchloric acid, phosphoric acid, phosphorous acid, hypophosphous acid, perchromic acid, boric acid, arsenic acid and the like.
In the stable pharmaceutical formulation of present invention, pH adjusting agent may be contained in a proportion of 0.01 to 10 % by weight of the pharmaceutical formulation. In particular, pH adjusting agent may be contained in a proportion of 0.1 to 1 % by weight of the pharmaceutical formulation.
As used herein, the term “granulating solvent” may include aqueous and non- aqueous solvents. Non aqueous solvents may include ethanol, methanol, isopropyl alcohol, acetone, Dimethylsulfoxide, hexane, propylene glycol, polyethylene glycol and the like.
In the stable pharmaceutical formulation of present invention, phenylephrine or salt thereof may be contained in an amount of 1 mg to 60 mg. Suitable salt forms include, but are not limited to, phenylephrine hydrochloride, hydrobromide, bitartarate and tannate salts. In particular, dose of phenylephrine hydrochloride may be contained in an amount of 2 mg to 20mg.
In the stable pharmaceutical formulation of present invention, chlorpheniramine maleate may be contained in an amount of 0.1 mg to 30 mg. In particular, dose of chlorpheniramine maleate may be contained in an amount of 0.5 mg to 10 mg.
In the stable pharmaceutical formulation of present invention, caffeine may be contained in an amount of 10 mg to 50 mg. In particular, dose of caffeine may be contained in an amount of 20 mg to 40 mg.
In the stable pharmaceutical formulation of present invention, paracetamol may be contained in an amount of 250 mg to 1000 mg.
As used herein, the term “pharmaceutical formulation” may include solid dosage forms suitable for oral administration such as tablets, capsules, pills, films, caplets, granules, pellets and the like. In particular, tablets provide advantages including convenience of administration, masking effect on bitter taste. The tablet may be an immediate release tablet, a delayed release tablet, a modified release tablet, a chewable tablet, a confectionary tablet, an oral disintegrating tablet. These solid dosage forms may be coated with sugar coating or film coating with the aim of, for example, preventing abrasion wear, masking bitterness and improving stability.
As used herein, the term “pharmaceutically acceptable excipient” include any such materials known in the art that are nontoxic and do not interact with other components of a pharmaceutical formulation in a deleterious manner. According to the present invention “pharmaceutical acceptable excipient” include, for example, diluent, binder, disintegrant, lubricant and glidant that are useful in preparation of pharmaceutical formulation. Pharmaceutically acceptable excipients can be used as intra granular or extra granular excipients.
Pharmaceutical diluent include, but are not limited to, pregelatinized starch, crystalline cellulose, powdered cellulose, lactose monohydrate, lactose anhydrous, mannitol, maize starch, corn starch, sorbitol, xylitol, precipitated calcium carbonate, magnesium carbonate, dibasic calcium phosphate, tribasic calcium phosphate and the like.
Pharmaceutical binder include, but are not limited to, polyvinylpyrrolidone or povidone, hydroxypropylcellulose, hydroxypropyl methylcellulose, copovidone, powdered acacia, gelatin, guar gum, carbomers, methylcellulose, polymethacrylates, starches and the like.
Pharmaceutical disintegrant include, but are not limited to, sodium starch glycolate, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidones, low-substituted hydroxypropylcelluloses, colloidal silicon dioxide, starches and the like.
Pharmaceutical lubricant include, but are not limited to magnesium stearate, sodiumstearyl fumarate, glyceryl monostearate, palmitic acid, talc, carnauba wax, calcium stearate, sodium stearate, zinc stearate, polyoxyethylene monostearate, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid and the like.
Pharmaceutical glidant include, but are not limited to, silicon dioxide, talc and the like.
An embodiment of the present invention relates to to a stable pharmaceutical formulation comprising phenylephrine or a salt thereof and chlorpheniramine maleate wherein phenylephrine or salt thereof and chlorpheniramine maleate are not in close contact with each other.
An embodiment relates to a stable pharmaceutical formulation comprising phenylephrine or salt thereof and chlorpheniramine maleate wherein phenylephrine or salt thereof and chlorpheniramine maleate are present in separate layers.
An embodiment relates to a stable pharmaceutical formulation comprising phenylephrine or salt thereof and chlorpheniramine maleate wherein phenylephrine or salt thereof and chlorpheniramine maleate are present in separate layers in a bi-layer tablet.
An embodiment relates to a stable pharmaceutical formulation comprising phenylephrine or a salt thereof, chlorpheniramine maleate and one or more pH adjusting agent wherein phenylephrine or salt thereof and chlorpheniramine maleate are not in close contact with each other.
An embodiment relates to a stable pharmaceutical formulation comprising phenylephrine or salt thereof, chlorpheniramine maleate and one or more pH adjusting agent wherein phenylephrine or salt thereof and chlorpheniramine maleate are present in separate layers, one or more pH adjusting agent may present in either or each of the layers.
An embodiment relates to a stable pharmaceutical formulation comprising phenylephrine or salt thereof, chlorpheniramine maleate and one or more pH adjusting agent wherein phenylephrine or salt thereof and chlorpheniramine maleate are present in separate layers, one or more pH adjusting agent may present in either or each of the layers in a bi-layer tablet.
An embodiment relates to a stable pharmaceutical formulation comprising phenylephrine or a salt thereof, chlorpheniramine maleate and one or more pH adjusting agent wherein phenylephrine or salt thereof and chlorpheniramine maleate are present in close contact with each other.
An embodiment relates to a stable pharmaceutical formulation comprising phenylephrine or a salt thereof, chlorpheniramine maleate and one or more pH adjusting agent wherein phenylephrine or salt thereof and chlorpheniramine maleate are present in a single layer tablet.
An embodiment relates to a stable pharmaceutical formulation mentioned in any of the above, additionally contain caffeine and paracetamol.
An embodiment relates to a stable pharmaceutical formulation mentioned in any of the above; additionally contain one or more pharmaceutically acceptable excipients.
Tablets may be manufactured by mixing phenylephrine or salt thereof, chlorpheniramine maleate, one or more pharmaceutically acceptable excipient followed by compression as in the case of direct compression. Granules of phenylephrine or salt thereof and chlorpheniramine can be prepared by any one of known methods such as wet granulation, dry granulation, layering granulation, hot melt-granulation and the like. Then to the compression molding after adding extra granular excipients, if needed
The tableting machine capable of compressing multilayered, particular bi-layered, tablets can be used. For a bi-layered tablet, granules or powders of the first layer and second layer are sequentially placed in an appropriately sized die with an intermediate compression step being applied to the first layer, followed by final compression step after the second layer is added to the die to form the bi-layered tablet.
Tablet formulations may be film coated with non-functional polymer or sugar coated for the purpose of preventing abrasion wear, masking bitterness, improving stability, and the like.
The present invention relates to preparation of a stable pharmaceutical formulation by wet granulation or spray granulation, wherein the process comprises the steps of:
a) Blending phenylephrine or salt thereof, and one or more intra granular pharmaceutically acceptable excipients;
b) Granulating the blend using granulating solvent (in which optionally one or more pH adjusting agent is dissolved);
c) Drying and sifting the granules;
d) Blending the granules with extra granular excipients;
e) Blending Chlorpheniramine maleate, at least one pH adjusting agent and one or more intra granular pharmaceutically acceptable excipients;
f) Granulating the blend using granulating solvent (in which optionally one or more pH adjusting agent is dissolved);
g) Drying and sifting the granules;
h) Blending the granules with extra granular excipients;
i) Step (d) and step (h) were compressed into bi-layer tablets or blended and compressed into single layer tablets
The present invention relates to a dry granulation process of preparation of a stable pharmaceutical formulation, wherein the process comprises the steps of:
a) Blending phenylephrine or salt thereof, one or more pH adjusting agent and one or more intra granular pharmaceutically acceptable excipients;
b) Granulating the blend of using roll compactor, an oscillating granulator etc.
c) Blending the granules of with extra granular excipients;
d) Blending Chlorpheniramine maleate, optionally one or more pH adjusting agent and one or more intra granular pharmaceutically acceptable excipients;
e) Granulating the blend of using roll compactor, an oscillating granulator etc.
f) Blending the granules of with extra granular excipients
i) Step (c) and step (f) were compressed into bi-layer tablets or blended and compressed into single layer tablets
The present invention relates to preparation of a stable pharmaceutical formulation by wet granulation or spray granulation, wherein the process comprises the steps of:
a) Blending phenylephrine or salt thereof, chlorpheniramine maleate, and one or more intra granular pharmaceutically acceptable excipients;
b) Granulating the blend using granulating solvent (in which one or more pH adjusting agent is dissolved);
c) Drying and sifting the granules;
d) Blending the granules with extra granular excipients;
e) Compressing the blend of into tablets
The present invention relates to preparation of a stable pharmaceutical formulation by dry granulation, wherein the process comprises the steps of:
a) Blending phenylephrine or salt thereof, chlorpheniramine maleate, one or more pH adjusting agent and one or more intra granular pharmaceutically acceptable excipients;
b) Granulating the blend using roll compactor, an oscillating granulator etc.
c) Blending the granules with extra granular excipients;
d) Compressing the blend into tablets
A further embodiment of present invention, may additionally contain caffeine and paracetamol in any of the above inventions related to process
While this invention has been described with reference to specific embodiments, the scope of the invention is not limited to these embodiments alone. Further some of the embodiments are illustrated as working examples below and are meant to be representative only. The invention may be construed in any other forms and embodiments which may be understood and applied by a person skilled in the art within the scope of the present invention.
Working Examples:
Example 1 Example 2 Example 3
Phenylephrine portion
Ingredients (mg/tablet) (mg/tablet) (mg/tablet)
Intra granular
1 Phenylephrine hydrochloride 10.00 10.00 10.00
2 Paracetamol 250.00 250.00 250.00
3 Caffeine 15.00 15.00 15.00
4 Sodium starch glycolate 9.00 9.00 9.00
5 Pregelatinized starch 20.00 20.00 21.50
Binder solution
6 Povidone K-30 5.50 5.50 5.50
7 Citric acid monohydrate 1.50 1.50 -
8 Water Qs Qs Qs
Extra granular
9 Talc 5.00 5.00 5.00
10 Sodium starch glycolate 6.00 6.00 6.00
11 Pregelatinized starch 12.50 12.50 12.50
12 Iron oxide yellow 0.50 0.50 0.50
13 Magnesium stearate 2.50 2.50 2.50
Total weight 337.50 337.50 337.50

Chlorpheniramine maleate portion Example 1 Example 2 Example 3
Ingredients (mg/tablet) (mg/tablet) (mg/tablet)
Intra granular
1 Chlorpheniramine maleate 2.00 2.00 2.00
2 Paracetamol 250.00 250.00 250.00
3 Caffeine 15.00 15.00 15.00
4 Sodium starch glycolate 9.00 9.00 9.00
5 Pregelatinized starch 29.50 28.50 29.50
Binder solution
6 Povidone K-30 5.50 5.50 5.50
7 Citric acid monohydrate - 1.00 -
8 Water Qs Qs Qs
Extra granular
9 Talc 5.00 5.00 5.00
10 Sodium starch glycolate 6.00 6.00 6.00
11 Pregelatinized starch 12.50 12.50 12.50
12 Iron oxide yellow 0.50 0.50 0.50
13 Magnesium stearate 2.50 2.50 2.50
Total weight 337.50 337.50 337.50
Phenylephrine portion process:
1. All the materials were dispensed
2. Phenylephrine hydrochloride, paracetamol, caffeine, pregelatinized starch and sodium starch glycolate were milled through suitable screen.
3. Milled materials of step 2 were mixed in a Rapid mixer granulator for suitable time
4. Step 3 dry mix was granulated with solution of povidone (citric acid was also dissolved in example 1 and 2) in water
5. Wet mass was milled through suitable screen.
6. Granules were dried until desired LOD is achieved
7. Dried granules were milled through suitable screen.
8. Extra granular material talc, sodium starch glycolate, Iron oxide yellow, magnesium stearate and pregelatinized starch were sifted through suitable mesh.
9. Granules of step 7 were mixed with talc, sodium starch glycolate, pregelatinized starch and Iron oxide yellow in blender for suitable time.
10. Step 9 blend was mixed with magnesium stearate in a blender for suitable time.
Chlorpheniramine maleate portion process:
1. All the materials were dispensed
2. Chlorpheniramine maleate, paracetamol, caffeine, pregelatinized starch and sodium starch glycolate were milled through suitable screen.
3. Milled materials of step 2 were mixed in a Rapid mixer granulator for suitable time
4. Step 3 dry mix was granulated with solution of povidone (citric acid was also dissolved in example 2) in water
5. Wet mass was milled through suitable screen.
6. Granules were dried until desired LOD is achieved
7. Mill the dried granules through specified screen.
8. Extra granular material talc, sodium starch glycolate, Iron oxide yellow, magnesium stearate and pregelatinized starch were sifted through suitable mesh.
9. Granules of step 7 with talc, sodium starch glycolate, pregelatinized starch and Iron oxide yellow were mixed in blender for suitable time.
10. Step 9 blend was mixed with magnesium stearate in a blender for specified time.
Bi-layer tablets were compressed using round shape punches using bi-layer tablet compression machine
Example 4 : Single layer tablet with citric acid
S.No. Ingredients Example 4 (mg/tablet)
Intra granular
1 Phenylephrine Hydrochloride 10.00
2 Chlorpheniramine Maleate 2.00
3 Caffeine 30.00
4 Paracetamol 500.00
5 Sodium starch glycolate 12.00
6 Pregelatinized Starch 54.00
Binder solution
7 PVP K-30 11.00
8 Citric acid monohydrate 3.00
9 Water qs
Extra granular
Talc 10.00
10 Sodium starch glycolate 12.00
11 Iron oxide Yellow 1.00
12 Pregelatinized Starch 25.00
12 Magnesium stearate 5.00
Total weight 675.00

Process:
1. All the materials were dispensed.
2. Phenylephrine hydrochloride, chlorpheniramine Maleate, paracetamol, caffeine, pregelatinized starch and sodium starch glycolate were milled through suitable screen.
3. Milled materials of step 2 were mixed in a rapid mixer granulator for suitable time
4. Step 3 dry mix was granulated with solution of povidone and citric acid in water
5. Wet mass was milled through suitable screen.
6. Granules were dried until desired LOD is achieved
7. Dried granules were milled through suitable screen.
8. Extra granular material talc, sodium starch glycolate, iron oxide yellow, magnesium stearate and pregelatinized starch were sifted through suitable mesh.
9. Granules of step 7 were mixed with talc, sodium starch glycolate, pregelatinized starch and iron oxide yellow in blender for specified time.
10. Step 9 blend was mixed with magnesium stearate in a blender for specified time.
11. Tablets were compressed using round shape punches

Comparative Example 1: Single layer tablet without citric acid
S.No. Ingredients mg/tablet
Intra granular
1 Phenylephrine HCl 10.00
2 Chlorpheniramine Maleate 2.00
3 Caffeine 30.00
4 Paracetamol 500.00
5 Sodium starch glycolate 0.00
6 Pregelatinized Starch 69.05
Binder solution
7 PVP K-30 11.00
9 Water qs
Extra granular
Talc 10.00
10 Sodium starch glycolate 11.95
11 Iron oxide yellow 1.00
12 Pregelatinized Starch 25.00
12 Magnesium stearate 5.00
Total weight 675.00
Process:
1. All the materials were dispensed.
2. Phenylephrine Hydrochloride, chlorpheniramine maleate, paracetamol, caffeine, pregelatinized starch and sodium starch glycolate were milled through suitable screen.
3. Milled materials of step 2 in were mixed with Rapid mixer granulator for suitable time
4. Step 3 dry mix with was granulated with solution of povidone in water
5. Wet mass was milled through suitable screen.
6. Granules were dried until desired LOD is achieved
7. Dried granules were milled through suitable screen.
8. Extra granular material talc, sodium starch glycolate, iron oxide yellow, magnesium stearate and pregelatinized starch were sifted through suitable mesh.
9. Granules of step 7 with were mixed with talc, sodium starch glycolate, and pregelatinized starch in blender for suitable time.
10. Step 9 blend was mixed with magnesium stearate in a blender for suitable time.
11. Tablets were compressed using suitable punches
Comparative Example 2: Single layer tablet with different granulations
Phenylephrine portion
S.No. Ingredients (mg/tablet)
Intra granular
1 Phenylephrine Hydrochloride 10.00
2 Caffeine 15.00
3 Paracetamol 250.00
4 Sodium starch glycolate 9.00
5 Pregelatinized Starch 21.50
Binder solution
6 Povidone K-30 5.50
7 Water qs

Chlorpheniramine Maleate portion
S.No. Ingredients (mg/tablet)
Intra granular
1 Chlorpheniramine Maleate 2.00
2 Caffeine 15.00
3 Paracetamol 250.00
4 Sodium starch glycolate 9.00
5 Pregelatinized Starch 29.50
Binder solution
6 Povidone K-30 5.50
7 Water qs

Final blending
1 Phenylephrine Hydrochloride portion 311.00
2 Chlorpheniramine Maleate portion 311.00
3 Talc 10.00
4 Sodium starch glycolate 12.00
5 Pregelatinized Starch 25.00
6 Iron oxide Yellow 1.00
7 Magnesium stearate 5.00
Total weight 675.00

Phenylephrine composition process:
1. All the materials were dispensed
2. Phenylephrine hydrochloride, paracetamol, caffeine, pregelatinized starch and sodium starch glycolate were milled through specified screen.
3. Milled materials of step 2 were mixed in a rapid mixer granulator for specified time
4. Step 3 dry mix was granulated with solution of povidone in water
5. Wet mass was milled through specified screen.
6. Granules were dried until desired LOD is achieved
7. Dried granules were milled through specified screen.

Chlorpheniramine Maleate composition process:
1. All the materials were dispensed
2. Paracetamol, caffeine, chlorpheniramine maleate, pregelatinized starch and sodium starch glycolate were milled through specified screen.
3. Milled materials of step 2 were mixed in a Rapid mixer granulator for specified time
4. Step 3 dry mix was granulated with solution of povidone in water
5. Wet mass was milled through specified screen.
6. Granules were dried until desired LOD is achieved
7. Dried granules were milled through suitable screen.

Blending and lubrication
8. Extra granular material talc, sodium starch glycolate, iron oxide yellow, magnesium stearate and pregelatinized starch were sifted through suitable mesh.
9. Phenylephrine hydrochloride portion and chlorpheniramine maleate portion were mixed with talc, sodium starch glycolate, pregelatinized starch and iron oxide yellow in blender for suitable time.
10. Step 9 blend was mixed with magnesium stearate in a blender for suitable time.
11. Bi-layer tablets were compressed using round punches using bi-layer tablet compression machine.
Stability studies:
Formulations were subjected to 40°C / 75% RH, 60°C & 80°C in open exposure condition for different time periods. Chlorpheniramine-maleate adduct impurity and phenylephrine Hydrochloride assay was estimated using HPLC analysis.
Examples Storage Time point impurity

Example 1
Initial Initial ND
40°C/75%RH 7 days ND
14 days ND
21 days ND
Example 2 Initial Initial ND
40°C/75%RH 3 days ND
7 days ND
14 days ND
21 days ND

Example 3
Initial Initial ND
40°C/75%RH 3 days ND
7 days ND
14 days 0.1
21 days 0.15

Example 4 Initial Initial ND
3 days 0.07
7 days 0.08
40°C/75%RH 14 days 0.11
21 days 0.16

Comparative example 1 Initial Initial -
40°C/75%RH 3 days 0.27
7 days 0.5
14 days 0.75
21 days 1
Comparative example 2 Initial Initial -
40°C/75%RH 3 days 0.2
7 days 0.4
14 days 0.7
21 days 1

From the above results it is evident that single layer tablets with citric acid (Example 4) are stable than single layer tablets without citric acid (Comparative example 1 and comparative example 2). Further bi-layer tablets (with or without citric acid) (Example 1, Example 2 & Example 3)are stable than all other formulations.