FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, Rule 13]
ORAL LIQUID COMPOSITION COMPRISING DIVALPROEX SODIUM AND PROCESS FOR
PREPARING THEREOF;
ABBOTT HEALTHCARE PRIVATE LIMITED, A COMPANY INCORPORATED UNDER THE PROVISION OF COMPANIES ACT, 1956, HAVING REGISTERED OFFICE AT 4, CORPORATE PARK, SION - TROMBAY ROAD, MUMBAI - 400 071, MAHARAHTRA, INDIA.
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF THE INVENTION
The present invention relates to oral liquid composition comprising divalproex sodium and process for preparing thereof. Particularly, the present invention relates to a stable oral liquid composition, such as solution comprising divalproex sodium and process for preparing thereof.
BACKGROUND OF THE INVENTION
Valproate is a broad spectrum antiepileptic with efficacy in a wide range of seizure types and epilepsy syndromes. Valproate is a drug of choice for children with newly diagnosed epilepsy (focal or generalized), idiopathic generalized epilepsy, epilepsies with prominent myoclonic seizures or with multiple seizure types, and photosensitive epilepsies. Most commonly used are valproic acid and its sodium salt. The acid is a liquid while the sodium salt is a hygroscopic solid characterized by poor stability. As a result, both have limited utility in the preparation of oral dosage forms.
Divalproex sodium also known as valproate semi sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar ratio and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. It is described as a stable crystalline solid and is designated as sodium hydrogen bis{2-propylpentanoate). Divalproex sodium is thought to work by increasing the levels of a brain neurotransmitter called gamma-aminobutyric acid (GABA). It is believed that increasing GABA's inhibitory action on brain neurons accounts for the ability of divalproex sodium to decrease seizures, curb manic behaviors, and decrease the frequency of migraine headaches. Divalproex is also an approved (USFDA) drug for prophylaxis of migraine and treatment of bipolar disorder. Clinically many physicians prefer divalproex for pediatric migraine. Childhood epilepsies are a heterogeneous group

of conditions that differ in diagnostic criteria and management and have dramatically different outcomes. The low potential for paradoxical seizure aggravation and the long term efficacy of the said drug are additional important factors that contribute to its excellent profile. Clinically it is the drug of choice of pediatricians or pediatric neurologists.
U.S. Patent No. 5009897 discloses granules, suitable for pressing into tablets, the granules comprising a core of divalproex sodium and a coating of a mixture of a polymer and microcrystalline cellulose.
U.S. Patent No. 5019398 discloses a sustained-release tablet of divalproex sodium in a matrix of hydroxypropyl methylcellulose and hydrated silica.
U.S. Patent No. 6419953 pertains to a hydrophilic matrix tablet suitable for the once-a-day administration of valproate compounds such as divalproex sodium comprising from about 50 weight percent to about 55 weight percent of an active ingredient; from about 20 weight percent to about 40 weight percent hydroxypropyl methylcellulose; from about 5 weight percent to about 15 weight percent lactose, from about 4 weight percent to about 6 weight percent microcrystalline cellulose, and from about 1 weight percent to about 5 weight percent of silicon dioxide. Other aspects of the invention relate to the use of this formulation in the treatment of epilepsy and to methods for manufacturing this dosage form.
U.S. Patent Nos. 6511678, 6528090, 6713086 and 6720004 relates to a new oral polymeric controlled release formulation suitable for the once-a-day administration of valproate compounds, such as divalproex sodium. The disclosed formulation minimizes the variation between peak and trough plasma levels of valproate over a 24 hour dosing period and follows a zero-order release pattern thus producing essentially flat plasma levels of valproate, once steady-state levels have been achieved.

U.S. Patent No. 6528091 relates to a controlled release tablet formulation which permits once daily dosing in the treatment of epilepsy comprises from about 50 weight percent to about 55 weight percent of an active ingredient selected from the group consisting of valproic acid, a pharmaceutically acceptable salt or ester of valproic acid, divalproex sodium, and valpromide; from about 20 weight percent to about 40 weight percent hydroxypropyl methylcellulose; from about 5 weight percent to about 15 weight percent lactose, from about 4 weight percent to about 6 weight percent microcrystalline cellulose, and from about 1 weight percent to about 5 weight percent silicon dioxide having an average particle size ranging between about 1 micron and about 10 microns. Also disclosed are pre-tableting granular formulations, methods of making the granular formulations and tablets, and a method of treating epilepsy employing the controlled release tablet formulations of the invention.
None of the above cited prior arts comprising divalproex sodium intends to provide liquid pharmaceutical composition. Certain patient populations like children and non-compliant psychiatry patients exist that have difficulty in swallowing tablets or capsules. One solution to overcome the difficulty of administering certain medicaments is to provide the medicaments in a liquid formulation, e.g., in solution, emulsion, suspension or extract form. These liquid formulations are advantageous because they are easy to administer, and typically have organoleptic properties that make the formulation more palatable to the patient. Therefore considering a specific group of patients, there is a need in the art to provide liquid pharmaceutical composition comprising divalproex sodium. However, a prime concern with any liquid formulation is the stability of the active ingredient, both short term and over time. In general, drug substances are less stable in aqueous media

than in the solid dosage form. Thus, it is important to properly stabilize and preserve those formulations, especially if the formulation contains water.
To date, however, no palatable liquid oral formulations comprising divalproex sodium have been provided to meet the especial therapeutic needs of the individuals such as those disclosed above who have difficulty in ingesting and swallowing large dosage forms. The present invention remedies these shortcomings.
SUMMARY OF THE INVENTION:
The present invention relates to a palatable oral liquid composition comprising divalproex sodium and one or more pharmaceutically acceptable excipients.
The present invention further relates to a stable oral liquid composition comprising divalproex sodium and one or more pharmaceutically acceptable excipients, wherein the pH of the composition is more than 6.
The present invention further relates to a process of preparing a stable oral liquid composition comprising divalproex sodium and one or more pharmaceutically acceptable excipients.
The present invention further relates to a process of preparing a stable oral liquid composition comprising divalproex sodium and one or more pharmaceutically acceptable excipients, wherein the pH of the composition is more than 6, wherein the composition is stable over the shelf life of not less than 12 months.
DETAILED DESCRIPTION OF THE INVENTION:
Definitions:
The term "stable" as used herein refers to physical and chemical stability of divalproex sodium with no significant change in pH and assay value, when stored at conditions specified by ICH guidelines for stability testing for not less than 3 months.

The term "divalproex sodium" as used in the invention is meant to cover divalproex sodium in the form of hydrate(s), solvate(s), crystalline form, amorphous form.
The term "excipients" as used herein means a component of a pharmaceutical product that is not an active ingredient for example, preservatives, solubilizers, sweeteners, flavours, colours, co-solvents and the like. The excipients that are useful in preparing a pharmaceutical composition are preferably safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for pharmaceutical use.
The inventors of the present invention have surprisingly found that a stable oral liquid composition, particularly solution comprising divalproex sodium can be prepared with keeping pH of more than 6 of the liquid composition wherein the composition is stable over the shelf life of not less than 12 months.
Development of divalproex oral solution is a major breakthrough for pediatric patients above the age of twelve with epilepsy who are non compliant with oral solid dosage forms such as tablets. It is also beneficial for non compliant geriatric patients of epilepsy those are reluctant to take tablets or have difficulty in swallowing tablets.
While developing the oral liquid composition for divalproex sodium the present inventors found that the manufacturing process plays significant role in the stability of the final composition. The divalproex sodium needs to be dissolved in sodium hydroxide solution first in order to ensure fast and complete dissolution of divalproex sodium. If the divalproex sodium is dissolved directly in water instead of sodium hydroxide solution the quantity of sodium hydroxide required is more for ensuring fast and complete dissolution of divalproex sodium. The other important factor is pH of the composition. The pH is important for stability and clarity of the composition. It was observed that the composition becomes turbid below pH 6.

Accordingly, in one embodiment the present invention provides a palatable oral liquid composition comprising divalproex sodium and one or more pharmaceutically acceptable excipients wherein the said composition is stable over the shelf life of not less than 12 months.
In yet another embodiment the present invention provides a stable oral liquid composition comprising divalproex sodium and one or more pharmaceutically acceptable excipients, having pH more than 6, wherein the said composition is stable over the shelf life of not less than 12 months.
In yet another embodiment the present invention provides a stable oral liquid composition comprising divalproex sodium and one or more pharmaceutically acceptable excipients, having pH more than 7, wherein the said composition is stable over the shelf life of not less than 12 months.
In yet another embodiment the present invention provides a stable oral liquid composition comprising divalproex sodium and one or more pharmaceutically acceptable excipients, having pH between 7 to 8, wherein the said composition is stable over the shelf life of not less than 12 months.
In yet another embodiment the present invention provides a stable oral liquid composition comprising:
a) divalproex sodium from about 2% w/v to about 15% w/v of the composition;
b) preservative from about 0.01 % w/v to about 1.5% w/v of the composition;
c) buffering agent from about 0.05% w/v to about 1.5% w/v of the composition;
d) sweetener from about 0.1% w/v to about 85% w/v of the composition;
e) optionally, one or more colouring and/or flavouring agents.

In yet another embodiment the present invention provides a process of preparing a stable oral liquid composition comprising divalproex sodium and one or more pharmaceutically acceptable excipients, wherein the process comprises the steps of:
a) preparing solution of sodium hydroxide in purified water;
b) dissolving divalproex sodium and one or more pharmaceutically acceptable excipient with stirring in solution of step a) until each ingredient is completely dissolved;
c) adjusting pH of the solution of step b) to more than 6.
The oral liquid composition of the present invention may also contain other pharmaceutically acceptable excipients, such as sweeteners, buffering agents, surfactants, preservative, colors or flavours. The excipients that are useful in preparing a pharmaceutical composition are preferably safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for pharmaceutical use.
A stable oral liquid composition in accordance with the present invention contains divalproex sodium in the amount of from about 20 mg/ml to about 150 mg/ml of composition.
A stable oral liquid composition in accordance with the present invention contains divalproex sodium from about 2% w/v to about 15% w/v of the composition.
The buffering agents according to present invention can be selected from group consisting of potassium dihydrogen phosphate, disodium hydrogen phosphate dihydrate, glycine/sodium hydroxide, sodium carbonate/sodium hydrogen carbonate, sodium tetraborate/sodium hydroxide, sodium bicarbonate/sodium hydroxide and the like or combinations thereof, to expedite the solubility of divalproex sodium.

The oral solutions are buffered to control the pH for more than about 6, more preferably between 6 and 8.
The preferred buffering agent is a combination of potassium dihydrogen phosphate and disodium hydrogen phosphate dihydrate in a ratio of about 1:2 to about 1:13, preferably 1:3.5.
The buffering agents are present from 0.05% w/v to 1.5% w/v of the composition.
The sweeteners according to present invention may be selected from the group consisting of maltitol, sucrose, dextrose, fructose, glucose, glycerin, inulin, isomalt, lactitol, maltose, maltol, mannitol, sucralose, trehalose, xylitol, propylene glycol, sorbitol, sodium saccharin, thaumatin, sodium cyclamate, sucralose and mixtures thereof and the like.
To render the composition pleasant-tasting, sweetener may be present in amount from about 0.1% w/v to about 85% w/v of the composition.
The compositions of present invention contain sufficient preservative to prevent microbial growth.
The preservative according to present invention may be selected from the group consisting of sodium benzoate, sorbates, EDTA, domiphen bromide, butylparaben, propylparaben, ethylparaben, methylparaben, paraben salts and mixtures thereof and the like.
The preservatives are present in the amount of about 0.01% w/v to about 1.5% w/v of the composition.
Optional ingredients include a coloring agent to impart a pleasant color and flavoring to impart a pleasant flavor, thus improving the organoleptic properties of the solution. Color

selection can be made consistent with flavor. Water is present as the major component as vehicle of the composition and to adjust desired volume of the composition.
One aspect of the present invention relates to provide a process to preparing oral liquid composition comprising divalproex sodium. The present liquid composition, particularly oral solution can be prepared by cold method, wherein divalproex sodium is dissolved in sodium hydroxide aqueous solution with further addition of sweeteners and/or mixture of sweeteners. The final pH is adjusted as desired by addition of buffering agents.
The composition of the present invention may comprise liquid, particularly oral solution in a single dosage form or multiple dosage forms such as when different components are maintained separately and are admixed prior to administration or are sequentially administered or simultaneously co-administered or when two or more of the same dosage form are administered to achieve the required therapeutic dose of active ingredient.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the present invention. The examples should not be read as limiting the scope of the present invention.

EXAMPLES: Example No.1
Table No. 1

ingredients mg/ 5 ml
divalproex sodium 269.075
sodium methyl paraben 5.000
sodium propyl paraben 0.500
sugar 1500.000
propylene glycol 250.000
sorbitol solution 70% (non crystalline) 1000.000
glycerin 350.000
sodium hydroxide pellets 34750
colour quinoline yellow 1.250
mango flavour asv 0.0125 ml
sucralose 7.500
potassium dihydrogen phosphate 10.000
disodium hydrogen phosphate dihydrate 35.000
purified water q.s. to 5.000 ml
Procedure:
Preparation of base solution:
Purified water was transferred in a suitable manufacturing tank. Sodium propyl paraben, sodium methyl paraben, sugar and sucralose were added to it and dissolved ensuring complete dissolution. The solution was filtered through 200 mesh nylon cloth. Preparation of drug solution:
Purified water was taken in a suitable manufacturing tank. Sodium hydroxide pellets, divalproex sodium, propylene glycol, glycerin and sorbitol were added to it and dissolved ensuring complete dissolution. The earlier base solution was mixed with this drug solution under stirring.

Preparation of Buffer solution:
Disodium hydrogen phosphate dihydrate and potassium dihydrogen phosphate were dissolved in purified water and mixed with previously prepared bulk solution. Suitable colour and flavour solutions were added to it. The pH of the final solution was adjusted using 20% w/v sodium hydroxide solution.
Example No 2 Table No. 2

Ingredients mg/ 5 ml
divalproex sodium 269.075
methyl paraben 5.000
propyl paraben 0.500
sugar 1250.000
sorbitol solution 70% (non crystalline) 2000.000
glycerin 350.000
propylene glycol 250.00
mango flavour 0.0125 ml
quinoline yellow 1.25
sodium hydroxide pellets 21.00
sucralose 7.50
purified water 5.000 ml
Procedure:
Preparation of base solution:
Purified water was transferred in a suitable manufacturing tank. Propyl paraben, methyl paraben and sugar were added to it and dissolved ensuring complete dissolution. The solution was filtered through 200 mesh nylon cloth.

Preparation of drug solution:
Purified water was taken in a suitable manufacturing tank. Sodium hydroxide pellets
were added and dissolved in the purified water. Then divalproex sodium, glycerin,
sucralose, propylene glycol, colour, sorbitol and flavour were added to it and dissolved,
ensuring complete dissolution. The earlier base solution was mixed with this drug
solution under stirring.
Adjusting the pH of the Solution- pH of the solution was adjusted with 10% w/v of
sodium hydroxide solution.
Three different batches of composition as shown in table No. 2 were taken and
subjected to stability studies and obtained data presented below in table No. 3, 4 and 5
respectively.
Table No. 3

Batch No. 1 Conditions / Duration
Tests Specification Initial

Accelerated (40°C± 2°C,75%RH± 5%RH) Real Time (30°C ±2°C, 65% RH ± 5%RH)

1M 2M 3M 6M 3M 6M 12M 18M
Description Yellow clear solution Complies Complies Complies Complies Complies Complies Complies Complies Complies
pH Between 6.0 And 8.0 7.55 7.37 7.10 7.06 7.10 7.10 7.07 7.19 7.20
Assay (%)
Divalproex
sodium
determined
as valproic
acid 90.0 to 110.0 101.9 102.7 102.1 100.9 100.3 101.5 99.6 100.6 100. 5

Table No. 4

Batch No. 2 Conditions / Duration
Tests Specification Initial

Accelerated (40°C± 2°C,75%RH± 5%RH) Real Time (30°C ±2°C, 65% RH ± i%RH)

1M 2M 3M 6M 3M 6M 12M 1BM
Description Yellow clear solution Complies Complies Complies Complies Complies Complies Complies Complies Complies
PH Between 6.0 And 8.0 7.35 7.34 7.16 7.08 7.10 7.18 7.17 7.20 7.27
Assay (%)
Divalproex
sodium
determined
as valproic
acid 90.0 to 110.0 102.9 102.2 102.6 100.7 100.4 101.1 100.0 101.2 100.2
Table No. 5

Batch No. 3 Conditions / Duration
Tests Specificati on Initial

Accelerated Real Time
(40°C± 2°C,75%RH± 5%RH) (30°C ±2°C, 65% RH ±
5%RH)

1M 2M 3M 6M 3M 6M 12M 18M
Description Yellow tf> U) w c/> in (0 in U)
clear (n lie ie lie ie lie ie ie ie
Q. ex Q. Q. a. a. Q. Q.
solution Q. E E E E E E E E
E o o o o o o o o
o a O o O o O O o O
PH Between 6.0
And 8.0 7.15 7.05 6.86 6.82 6.84 6.90 6.84 6.89 6.90
Assay(%)
Divalproex 90.0 to
sodium 110.0
determined 99.9 100.6 100.8 98.3 98.7 98.3 98.7 98.9 98.8
as valproic
acid

Example No 3 Table No. 6
Ingredients mg/ 5 ml
divalproex sodium 269.075
sodium methyl paraben 5.000
sodium propyl paraben 0.500
sugar 1250.000
sorbitol solution 70% (non crystalline) 2000.000
glycerin 350.000
propylene glycol 250.00
quinoline yellow 1.250
sodium hydroxide pellets 31.00
mango flavour 0.0125 ml
sucralose 7.50
potassium dihydrogen phosphate 5.00
disodium hydrogen phosphate 17.50
purified water qs to 5 ml
Procedure:
Preparation of base solution:
Purified water was transferred in a suitable manufacturing tank. Sodium propyl paraben,
sodium methyl paraben and sugar were added to it and dissolved ensuring complete
dissolution. The solution was filtered through 200 mesh nylon cloth.
Preparation of drug solution:
Purified water was taken in a suitable manufacturing tank. Sodium hyroxide pellets were
added and dissolved in the purified water. Then divalproex sodium, glycerin, sucralose,
sorbitol, propylene glycol, colour and flavour were added to it and dissolved ensuring

complete dissolution The earlier base solution was mixed with this drug solution under
stirring.
Adjusting the pH of the Solution- pH of the solution adjusted with 20% w/v of sodium
hydroxide solution.
Addition of buffer- purified water was taken in a suitable manufacturing tank and buffer salt was added to it and obtained buffer solution was mixed with the earlier entire bulk solution.
Example No 4

Table No. 7
Ingredients mg/ 5 ml
divalproex sodium 269.075
sodium methyl paraben 5.000
sodium propyl paraben 0.500
sugar 1250.000
sorbitol solution 70% (non crystalline) 2000.000
glycerin 350.000
propylene glycol 250.00
quinoline yellow 1.25
sodium hydroxide pellets 31.00
mango flavour 0.0125 ml
sucralose 7.50
potassium dihydrogen phosphate 2.50
disodium hydrogen phosphate 32.50
purified water qs to 5 ml
Procedure:
Preparation of base solution:

Purified water was transferred in a suitable manufacturing tank. Sodium propyl paraben,
sodium methyl paraben and sugar were added to it and dissolved ensuring complete
dissolution. The solution was filtered through 200 mesh nylon cloth.
Preparation of drug solution:
Purified water was taken in a suitable manufacturing tank. Sodium hydroxide pellets were
added and dissolved in the purified water. Then divalproex sodium, glycerin, sucralose,
sorbitol, propylene glycol, flavor and colour were added to it and dissolved ensuring
complete dissolution. The earlier base solution was mixed with this drug solution under
stirring.
Adjusting the pH of the Solution- pH of the solution was adjusted with 20% w/v of
sodium hydroxide solution.
Addition of buffer- purified water was taken in a suitable manufacturing tank and buffer
salt was added to it and obtained buffer solution was mixed with the earlier entire bulk
solution.

Example No. 5 Table No. 8
Ingredients mg/ 5 ml
divalproex sodium 269.075
sodium methyl paraben 5.000
sodium propyl paraben 0.500
sugar 1250.000
sorbitol solution 70% (non crystalline) 2000.000
glycerin 350.000
propylene glycol 250.00
quinoline yellow 1.250
sodium hydroxide pellets 31.00

mango flavour 0.0125 ml
sucralose 7.50
Potassium Dihydrogen phosphate 10.00
Disodium hydrogen phosphate 17.50
Purified Water qs to 5 ml
Procedure:
Preparation of base solution:
Purified water was transferred in a suitable manufacturing tank. Sodium propyl paraben,
sodium methyl paraben and sugar were added to it and dissolved ensuring complete
dissolution, the solution was filtered through 200 mesh nylon cloth.
Preparation of drug solution:
Purified water was taken in a suitable manufacturing tank. Sodium hydroxide pellets
were added and dissolved in the purified water. Divalproex sodium, glycerin, sucralose,
sorbitol, propylene glycol, flavor and colour were added to it and dissolved ensuring
complete dissolution. The earlier base solution was mixed with this drug solution under
stirring.
Adjusting the pH of the Solution- pH of the solution was adjusted with 20% w/v of
sodium hydroxide solution.
Addition of buffer- purified water was taken in a suitable manufacturing tank and buffer
salt was added to it and obtained buffer solution was mixed with the earlier entire bulk
solution.

Example No 6 Table No 9
Ingredients mg/ 5 ml
divalproex sodium 269.075
sodium methyl paraben 5.000
sodium propyl paraben 0.500
sugar 1500.00
sorbitol solution 70% (non crystalline) 1000.000
glycerin 350.000
propylene glycol 250.00
mango flavour 0.0125 ml
quinoline yellow 1.250
sodium hydroxide pellets 21.00
sucralose 7.50
potassium dihydrogen phosphate 5.00
disodium hydrogen phosphate 17.500
purified water qs to 5 ml
Procedure:
Preparation of base solution:
Purified water was transferred in a suitable manufacturing tank, heat it to boil. Sodium propyl paraben, sodium methyl paraben and sugar were added to it and dissolved ensuring complete dissolution. The solution was filtered through 200 mesh nylon cloth. Preparation of drug solution:
Purified water was taken in a suitable manufacturing tank. Sodium hydroxide pellets were added and dissolved in the purified water. Divalproex sodium, glycerin, propylene glycol, colour, flavour, sucralose and sorbitol were added to it and dissolved ensuring

complete dissolution. The earlier base solution was mixed with this drug solution under
stirring.
Addition of buffer- purified water was taken in a suitable manufacturing tank and buffer
salt was added to it and obtained buffer solution was mixed with the earlier entire bulk
solution.
Adjusting the pH of the Solution- pH of the solution was adjusted with 20% w/v of
sodium hydroxide solution.
Three different batches of composition as shown in table No. 9 were taken and
subjected to stability studies and obtained data presented below in table No. 10, 11 and
12 respectively.
Table No. 10

Batch No. 1 Conditions / Duration
Tests Specification Initial

Accelerated (40°C± 2°C,25%RH± 5%RH) Real Time
(30°C±2oC.35% RH ± 5%RH)

1M 2M 3M 6M 3M 6M
Description Yellow clear
solution Complies Complies Complies Compfies Complies Complies Complies
pH Between 6.0 And 8.0 7.62 7.55 7.44 7.30 7.32 7.38 7.30
Assay (%)
Divalproex
sodium
determined
as valproic
acid 90.0 to 110.0 102.36 101.68 101.37 102.18 98.7 102.32 100.2

Table No. 11

Batch No. 2 Conditions / Duration
Tests Initial

Accelerated {40°C± 2°C,25%RH± 5%RH) Real Time
(30°C ±2°C,
35% RH ±
5%RH)

1M 2M 3M 6M 3M 6M
Description Yellow clear solution Complies Complies Complies Complies Complies Complies Complies
pH Between 6.0 And 8.0 7.53 7.53 7.39 7.26 7.30 7.34 7.39
Assay (%)
Divalproex
sodium
determined
as valproic
acid 90.0 to 110.0 100.79 101.52 101.26 102.19 102.6 101.58 100.4
Table No. 12

Batch No. 3 Conditions t Duration
Tests Specification Initial Accelerated (40°C± 2°C,25%RH± 5%RH) Real Time
{30°C ±2°C,
35% RH ±
5%RH)

1M 2M 3M 6M 3M 6M
Description Yellow clear solution Complies Complies
_i Complies Complies Complies Complies Complies
PH Between 6.0 And 8.0 7.56 7.54 7.44 7.32 7.32 7.34 7.35
Assay {%)
Divalproex
sodium
determined
as valproic
acid 90.0 to 110.0 101.87 100.64 100.9 101.79 103.0 101.72 103.2

Example No 7 Table No. 13
Ingredients mg/ 5 ml
divalproex sodium 269.075
sodium methyl paraben 5.000
sodium propyl paraben 0.500
sugar 1500.00
sorbitol solution 70% (non crystalline) 1000.000
glycerin 350.000
propylene glycol 250.00
mango flavour 0.0125 ml
quinoline yellow 1.250
sodium hydroxide pellets 31.00
sucralose 7.50
potassium dihydrogen phosphate 10.00
disodium hydrogen phosphate 35.00
purified water qs to 5 ml
Procedure:
Preparation of base solution:
Purified water was transferred in a suitable manufacturing tank. Sodium propyl paraben,
sodium methyl paraben and sugar were added to it and dissolved ensuring complete
dissolution, the solution was filtered through 200 mesh nylon cloth.
Preparation of drug solution:
Purified water was taken in a suitable manufacturing tank. Sodium hydroxide pellets
were added and dissolved in the purified water. Divalproex sodium, glycerin, propylene
glycol, colour, flavour sucralose and sorbitol were added to it and dissolved ensuring

complete dissolution. The earlier base solution was mixed with this drug solution under
stirring.
Addition of buffer- purified water was taken in a suitable manufacturing tank and buffer
salt was added to it and obtained buffer solution was mixed with the earlier entire bulk
solution.
Adjusting the pH of the Solution- pH of the solution was adjusted with 20% w/v of
sodium hydroxide solution.
Three different batches of composition as shown in table No. 13 were taken and subjected to stability studies and obtained data presented below in table No. 14, 15 and 16 respectively.

Table No. 14
Batch No. 1 Conditions / Duration
Tests Specification Initial

Accelerated (40°C± 2°C,25%RH± 5%RH) Real Time
(30°C ±2°C, 35% RH ± 5%RH)

1M 2M 3M 6M 3M 6M
Description Yellow clear
solution Complies Complies Complies Complies Complies Complies Complies
pH Between 6.0 And 8.0 7.70 7.68 7.66 7.69 7.67 7.68 7.70
Assay (%)
Divalproex
sodium
determined
as valproic
acid 90.0 to 110.0 102.3 102.6 102.6 103.7 100.7 102.9 103.0

Table No. 15

Batch No. 2 Conditions / Duration
Tests Specification Initial

Accelerated (40oC± 2oC.25%RH± 5%RH) Real Time
(30°C ±2°C, 35% RH ± 5%RH)

1M 2M 3M 6M 3M 6M
Description Yellow clear solution Complies Complies Complies Complies Complies Complies Complies
pH Between 6.0 And 8.0 7.82 7.80 7.75 7.82 7.83 7.79 7.80
Assay {%)
Divalproex
sodium
determined
as valproic
acid 90.0 to 110.0 102.5 100.1 99.4 98.9 101.7 99.7 103.7
Table No. 16

Batch No. 3
Tests Specification Initial Conditions / Duration

Accelerated (40°C+ 2°C,25%RH± 5%RH) Real Time
(30°C ±2°C, 35% RH ± 5%RH)

1M 2M 3M 6M 3M 6M
Description Yellow clear solution Complies Complies Complies Complies Complies Complies Complies
PH Between 6.0 And 8.0 7.64 7.65 7.63 7.62 7,64 7.63 7.62
Assay(%)
Divalproex
sodium
determined
as valproic
acid 90.0 to 110.0 98.5 101.6 102.6 102.3 103.5 98.2 102.6

Example No 8 Table No. 17

Ingredients mg/ 5 ml
divalproex sodium 538.150
sodium methyl paraben 5.000
sodium propyl paraben 0.500
sugar 1500.00
sorbitol solution 70% (non crystalline) 1000.000
glycerin 350.000
propylene glycol 250.00
mango flavour 0.0125m|
quinoline yellow 1.250
sodium hydroxide pellets 31.00
sucralose 7.50
potassium dihydrogen phosphate 10.00
Disodium Hydrogen phosphate 35.00
Purified Water qs to 5 ml
Procedure:
Preparation of base solution:
Purified water was transferred in a suitable manufacturing tank. Sodium propyl paraben, sodium methyl paraben and sugar were added to it and dissolved ensuring complete dissolution. The solution was filtered through 200 mesh nylon cloth. Preparation of drug solution:

Purified water was taken in a suitable manufacturing tank. Sodium hydroxide pellets
were dissolved in the purified water. Divalproex sodium, glycerin, propylene glycol,
colour, flavour sucralose and sorbitol were added to it and dissolved ensuring complete
dissolution. The earlier base solution was mixed with this drug solution under stirring.
Addition of buffer- purified water was taken in a suitable manufacturing tank and buffer
salt was added to it and obtained buffer solution was mixed with the earlier entire bulk
solution.
Adjusting the pH of the Solution- pH of the solution was adjusted with 20% w/v of
sodium hydroxide solution.
One batch of composition as shown in table No. 17 was taken and subjected to stability
studies and obtained data presented below in table No. 18.

Table No. 18
Tests Specification Initial Conditions / Duration

Accelerated (40QC± 2°C,25%RH± 5%RH) Real Time
(30°C ±2°C, 35%
RH ± 5%RH)

1M 2M 3M 6M 3M 6M
Description Yellow clear solution Complies Complies Complies Complies Complies Complies Complies
pH Between 6.0 And 8.0 7.92 7.95 7.90 7.94 7.90 7.93 7.92
Assay(%)
Divalproex
sodium
determined
as valproic
acid 90.0 to 110.0 101.9 102.1 99.6 101.4 102.8 101.9 100.9

WE CLAIM
1. A stable oral liquid composition comprising divalproex sodium and one or more pharmaceutically acceptable excipients.
2. The composition according to claim 1, wherein the divalproex sodium is present from about 2% w/v to about 15% w/v of the composition.
3. The composition according to claim 1, wherein the composition is in the form of solution, emulsion or suspension.
4. The composition according to claim 1, wherein the pH of the composition is more than 6.
5. The composition according to claim 4, wherein the pH of the composition is more than 7.
6. The composition according to claim 5, wherein the pH of the composition is between 7 to 8.
7. The composition according to claim 1, wherein the composition is stable over the shelf life of not less than 12 months.
8. The composition according to claim 1, wherein the pharmaceutically acceptable excipient is selected from the group consisting of preservatives, flavors, flavorings, sweeteners, buffering agents, coloring agents and mixtures thereof.
9. The composition according to claim 8, wherein the preservative is selected from the group consisting of sodium benzoate, sorbates, EDTA, domiphen bromide, butylparaben, propylparaben, ethylparaben, methylparaben, paraben salts and mixtures thereof.

10. The composition according to claim 8, wherein the preservative is present from about 0.01% w/v to about 1.5% w/v of the composition.
11. The composition according to claim 8, wherein the sweetener is selected from the group consisting of maltitol, sucrose, dextrose, fructose, glucose, glycerin, inulin, isomalt, lactitol, maltose, maltol, mannitol, sucralose, trehalose, xylitol, propylene glycol, sorbitol, sodium saccharin, thaumatin, sodium cyclamate, sucralose and mixtures thereof.
12. The composition according to claim 8, wherein the sweetener is present from about 0.1% w/v to about 85% w/v of the composition.
13. The composition according to claim 8, wherein the buffering agent is selected from group consisting of potassium dihydrogen phosphate, disodium hydrogen phosphate dihydrate, glycine, sodium carbonat, sodium hydrogen carbonate, sodium tetraborate, sodium bicarbonate, sodium hydroxide and mixtures thereof.
14. The composition according to claim 8, wherein buffering agent is present from about 0.05% w/v to about 1.5% w/v of the composition.
15. The composition according to claim 13, wherein the buffering agent is a combination of potassium dihydrogen phosphate and disodium hydrogen phosphate dihydrate in the ratio of 1:2 to about 1:13.
16. A stable oral liquid composition comprising :

a) divalproex sodium from about 2% w/v to about 15% w/v of the composition;
b) preservative from about 0.01% w/v to about 1.5% w/v of the composition;
c) buffering agent from about 0.05% w/v to about 1.5% w/v of the composition;
d) sweetener from about 0.1% w/v to about 85% w/v of the composition;

e) optionally, one or more colouring and/or flavouring agents.
17. The composition according to claim 16, wherein the composition is in the form of solution, emulsion or suspension.
18. The composition according to claim 16, wherein the pH of the composition is more than 6.
19. The composition according to claim 18, wherein the pH of the composition is more than 7.
20. The composition according to claim 19, wherein the pH of the composition is between 7 to 8.
21. The composition according to claim 16, wherein the composition is stable over the shelf life of not less than 12 months.
22. The composition according to claim 16, wherein the preservative is selected from the group consisting of sodium benzoate, sorbates, EDTA, domiphen bromide, butylparaben, propylparaben, ethylparaben, methylparaben, paraben salts and mixtures thereof.
23. The composition according to claim 16, wherein the sweetener is selected from the group consisting of maltitol, sucrose, dextrose, fructose, glucose, glycerin, inulin, isomalt, lactitol, maltose, maltol, mannitol, sucralose, trehalose, xylitol, propylene glycol, sorbitol, sodium saccharin, thaumatin, sodium cyclamate, sucralose and mixtures thereof.
24. The composition according to claim 16, wherein the buffering agent is selected from group consisting of potassium dihydrogen phosphate, disodium hydrogen phosphate dihydrate, glycine, sodium carbonat, sodium hydrogen carbonate, sodium tetraborate, sodium bicarbonate, sodium hydroxide and mixtures thereof.

25. The composition according to claim 24, wherein the buffering agent is a combination of potassium dihydrogen phosphate and disodium hydrogen phosphate dihydrate in a ratio of 1:2 to about 1: 13.
26. A process of preparing a stable oral liquid composition comprising divalproex sodium and one or more pharmaceutically acceptable excipients, wherein the process comprises steps of:

a) preparing solution of sodium hydroxide in purified water;
b) dissolving divalproex sodium and one or more pharmaceutically acceptable excipient with stirring in solution of step a) until each ingredient is completely dissolved;
c) adjusting the pH of the solution of step b) to more than 6.