MX2013012827A

MX2013012827A - Oral liquid composition comprising divalproex sodium and process for preparing thereof.

Info

Publication number: MX2013012827A
Application number: MX2013012827A
Authority: MX
Inventors: Dipak Sahana; Prasad Patil; Ganesh Narayan Phadtare; Manish Grover; Shripad Jathar
Original assignee: Abbott Healthcare Private Ltd
Priority date: 2011-05-02
Filing date: 2012-04-26
Publication date: 2014-02-11
Also published as: WO2012150607A2; CL2013003137A1; WO2012150607A3; BR112013027685A2; ECSP13013043A; CO6801771A2

Abstract

The present invention is directed to palatable 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.

Description

ORAL LIQUID COMPOSITION COMPRISING SODIUM DIVALPROEX AND PROCESS TO PREPARE THE SAME Field of the Invention The present invention relates to a liquid oral composition comprising divalproex sodium and to processes for preparing it. Particularly, the present invention relates to a liquid, stable oral composition, such as a solution comprising sodium of divalproex and to a process for preparing the same.

Background of the Invention Valproate is a broad spectrum antiepileptic with efficacy in a wide range of types of seizures and epilepsy syndromes. Valproate is a drug of choice for recently diagnosed children with epilepsy (generalized or localized), idiopathic generalized epilepsy, epilepsies with prominent myoclonic seizures or with multiple types of seizures, and photosensitive epilepsies. The 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 coordination compound that it comprises sodium valproate and valproic acid in a molar ratio of 1: 1, and which is formed during the partial neutralization of valproic acid with 0.5 equivalents of sodium hydroxide. It is described as a stable crystalline solid, and is designated as sodium bis (2-propylpentanoate). Divalproex sodium is considered to work by increasing the levels of a neurotransmitter in the brain called gamma-aminobutyric acid (GABA). It is considered that the increase of inhibitory reaction of GABA in cerebral neurons, includes the capacity that has the sodium sodium of divalproex to diminish cosions, manic behaviors and decrease in the frequency of migraines. Divalproex is also an approved drug (USFDA) for the prophylaxis of migraine and the treatment of bipolar disorder. Clinically, many doctors prefer divalproex for pediatric migraine. Childhood epilepsies are a heterogeneous group of conditions that differ in the criteria of diagnosis and management, and have dramatically different results. The low potential for paradoxical seizure aggravation and the long-term efficacy of the drug are additional important factors that contribute to its excellent profile. Clinically, it is the drug of choice for paediatricians or pediatric neurologists.

U.S. Patent No. 5009897 describes granules, suitable for tabletting, the granules comprising a sodium center of divalproex and a coating of a mixture of a polymer and microcrystalline cellulose.

US Patent No. 5019398 discloses a sustained-release divalproex sodium tablet in a matrix of hydroxypropyl methylcellulose and hydrated silica.

US Patent No. 6419953, pertains to a hydrophilic matrix tablet suitable for once-a-day administration of valproate compounds, such as divalproex sodium, comprising from about 50% by weight to about 55% by weight of an ingredient active; from about 20% by weight to about 40% by weight of hydroxypropyl methylcellulose; from about 5% by weight to about 15% by weight of lactose, from about 4% by weight to about 6% by weight of microcrystalline cellulose, and from about 1 by weight to about 5% by weight of silicon dioxide. Other aspects of the present 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, refer to a new controlled release oral polymer formulation, suitable for once-a-day administration of valproate compounds, such as divalproex sodium. The formulation described, minimizes the variation between high and low plasma levels of valproate during a 24-hour dosing period, and follows a zero-order release pattern, thus producing essentially flat plasma valproate levels, once levels have been achieved. constant state.

US Patent No. 6528091, refers to a controlled release tablet formulation that allows dosing once a day in the treatment of epilepsy, comprising from about 50% by weight to about 55% by weight of a selected active ingredient from the group consisting of valproic acid, a pharmaceutically acceptable salt thereof or valproic acid ester, divalproex sodium, and valpromide; from about 20% by weight to about 40% by weight of hydroxypropyl methylcellulose; from about 5% by weight to about 15% by weight of lactose, from about 4% by weight to about 6% by weight of microcrystalline cellulose, and from about 1% by weight to about 5% by weight of silicon dioxide which has an average particle size that fluctuates between about 1 miera and about 10 micras. Also described are granular formulations prior to the generation of tablets, methods for making the granular formulations and tablets, and a method for treating epilepsy, which employs the formulations of the release tablet. controlled of the present invention.

None of the above mentioned techniques comprising divalproex sodium, is intended to provide a liquid pharmaceutical composition. Certain populations of child-like patients, and psychiatric patients who do not comply with treatment, have difficulty swallowing tablets or capsules. A solution to overcome the difficulty of administering certain medicaments is to provide the medicaments in a liquid formulation, for example, in solution, emulsion, suspension or extract form. These liquid formulations are convenient because they are easy to administer, and usually have organoleptic properties that make the flavor formulation more palatable to the patient. Accordingly, considering a specific group of patients, there is a need in the art to provide a liquid pharmaceutical composition comprising divalproex sodium. However, a main aspect with any liquid formulation is the stability of the active ingredient, both in the short term and with time. In general, the drug substances are less stable in aqueous media than in the solid dosage form. Therefore, it is important to adequately stabilize and preserve these formulations, especially in formulations containing water. However, to date, oral, liquid, flavor formulations have not been provided It is desirable that they comprise divalproex sodium, to meet the special therapeutic needs of individuals such as those described above, who have difficulty swallowing and swallowing large dosage forms. The present invention remedies these drawbacks.

Brief Description of the Invention The present invention relates to an oral liquid composition of pleasant taste, comprising divalproex sodium and one or more pharmaceutically acceptable excipients.

The present invention further relates to a liquid, stable oral composition comprising sodium of divalproex and one or more pharmaceutically acceptable excipients, characterized in that the pH of the composition is greater than 6.

The present invention further relates to a process for preparing a stable, liquid oral composition comprising divalproex sodium and one or more pharmaceutically acceptable excipients.

The present invention further relates to a process for preparing a liquid, stable oral composition comprising divalproex sodium and one or more pharmaceutically acceptable excipients, characterized in that the pH of the composition is greater than 6, characterized in that the composition is stable in the Shelf life for not less than 12 months.

Detailed description of the invention: Definitions: The term "stable", as used in the present invention, refers to the physical and chemical stability of sodium of divalproex, without significant change in the pH value and of the assay, when stored under conditions specified by the ICH guidelines. for stability tests during or less than 3 months.

The term "divalproex sodium" as used in the present invention, is understood to cover the sodium of divalproex in the form of hydrate (s), solvate (s), crystalline form and amorphous form.

The term "excipients", as used in the present invention, means a component of a pharmaceutical product that is not an active ingredient, for example, preservatives, solubilizers, sweeteners, flavorings, colors, cosolvents and the like. The excipients that are useful for preparing a pharmaceutical composition are preferably non-toxic, and neither biological nor otherwise undesirable, and are acceptable for pharmaceutical use.

The inventors of the present invention have surprisingly found that a liquid, stable oral composition, particularly a solution comprising divalproex sodium, can be prepared by maintaining a pH of no more than 6 of the liquid composition, characterized in that the composition It is stable in shelf life, for not less than 12 months.

The development of an oral solution of divalproex, is an important advance for pediatric patients, with ages above twelve years with epilepsy, who do not comply with oral, solid dosage forms, such as tablets. It is also beneficial for geriatric patients with epilepsy who do not comply with the prescription, who are reluctant to take tablets, and have difficulty swallowing them.

While developing the liquid oral sodium composition of divalproex, while the inventors of the present invention are developing the liquid oral sodium composition of divalproex, they found that the manufacturing process plays an important role in the stability of the final composition. The sodium of divalproex needs to be first dissolved in a solution of sodium hydroxide, in order to ensure a rapid and total dissolution of divalproex sodium. If divalproex sodium dissolves directly in water, instead of the sodium hydroxide solution, the amount of sodium hydroxide required is greater to ensure rapid and total sodium dissolution of divalproex. The other important factor is the pH of the composition. The pH is important for stability and clarity of the composition. It was observed that the composition becomes turbid with a pH less than 6.

Accordingly, in one embodiment, the present invention provides an oral, liquid, palatable composition comprising divalproex sodium and one or more pharmaceutically acceptable excipients, characterized in that the composition is stable in shelf life for less than 12 months.

In yet another embodiment, the present invention provides an oral, liquid, stable composition comprising divalproex sodium and one or more pharmaceutically acceptable excipients, having a pH greater than 6, characterized in that the composition is stable in shelf life, during no less than 12 months.

Yet another embodiment of the present invention provides a stable, oral, liquid composition comprising divalproex sodium and one or more pharmaceutically acceptable excipients, having a pH of no greater than 7, characterized in that the composition is stable in shelf life during no less than 12 months.

In yet another embodiment, the present invention provides an oral, liquid, stable composition comprising sodium of divalproex and one or more pharmaceutically acceptable excipients, having a pH of between 7 to 8, characterized in that the composition is stable in shelf life. , for not less than 12 months.

In yet another embodiment, the present invention provides an oral, liquid, stable composition comprising: a) divalproex sodium of approximately 2% w / to approximately 15% w / v of the composition; b) conservative from about 0.01% w / v to about 1.5% w / v of the composition; c) damping agent of about 0.05% w / v to about 1.5% w / v of the composition; d) sweetener of about 0.1% w / v to about 85% w / v of the composition; e) optionally, one or more coloring and / or flavoring agents.

In yet another embodiment, the present invention provides a process for preparing an oral, liquid, stable composition comprising divalproex sodium and one or more pharmaceutically acceptable excipients, characterized in that the process comprises the steps of: a) prepare the sodium hydroxide solution in purified water; b) dissolving the sodium of divalproex and one or more pharmaceutically acceptable excipients with agitation in the solution of step a), until each ingredient is completely dissolved; c) adjust the pH of the solution from step b) to more than 6.

The liquid, oral composition of the present invention may also contain other pharmaceutically acceptable excipients, such as sweeteners, buffering agents, surfactants, preservatives, colors or flavors. The excipients which are useful for preparing a pharmaceutical composition are preferably safe, non-toxic, and neither biological nor otherwise undesirable, and are acceptable for pharmaceutical use.

A liquid, oral, stable composition according to the present invention contains sodium of divalproex in an amount of about 20 mg / ml to about 150 mg / ml of the composition.

A liquid, oral, stable composition according to the present invention contains divalproex sodium of about 2% w / v to about 15% w / v of the composition.

The buffering agents according to the present invention may be selected from the group consisting of potassium dihydrogen phosphate, disodium hydrogen phosphate dihydrate, glycine / sodium hydroxide, sodium carbonate / sodium hydrogen carbonate, tetraborate sodium / sodium hydroxide, sodium bicarbonate / sodium hydroxide and the like, and combinations thereof, to accelerate 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 buffer 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 up to 1.5% w / v of the composition.

The adulterants according to the 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, sucrose and mixtures thereof, and the like.

To make the composition taste-pleasing, a sweetener may be present in an amount of about 0.1% w / v to about 85% w / v of the composition.

The compositions of the present invention contain sufficient preservative to prevent microbial growth.

The preservative according to the present invention can 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 an amount of about 0.01%) w / v to about 1.5% w / v of the composition.

Optional ingredients include an agent of coloring to impart a pleasant color, and a flavoring to impart pleasant flavor, to thereby improve the organoleptic properties of the solution. The color selection can be consistent with the taste. Water is present as the major component as a vehicle of the composition, and to adjust the desired volume.

One aspect of the present invention relates to providing a process for preparing an oral, liquid composition comprising divalproex sodium. The liquid composition of the present invention, particularly the oral solution, can be prepared through a cold method, characterized in that the sodium of divalproex is dissolved in an aqueous solution of sodium hydroxide, with the addition of additional sweeteners and / or mix of sweeteners. The final pH is adjusted as desired, through the addition of buffering agents.

The composition of the present invention may comprise a liquid solution, particularly oral in a single dosage form or multiple dosage forms, such as when different components are kept separate, and mixed in additions prior to administration, or administered in sequences or are coadministered simultaneously, or when two or more of the same dosage forms are administered, to achieve the required therapeutic dose of the active ingredient.

The following examples are provided to enable one skilled in the art to practice the present invention, and are merely illustrative of the present invention. The excerpts should not be read as limiting the scope of the present invention.; EXAMPLES Example No. 1 Table No. 1 Process: Preparation of the base solution: Purified water was transferred into a suitable manufacturing tank. Sodium propylparaben was added, Methylparaben sodium, sugar and sucrose, and dissolved to ensure total dissolution. The solution was filtered through a 200 mesh nylon cloth.

Preparation of drug solution: Purified water was taken in a suitable manufacturing tank. To this were added sodium hydroxide pellets, divalproex sodium, propylene glycol, glycerin and sorbitol, and dissolved to ensure total dissolution. The above base solution was mixed with this drug solution under agitation.

Preparation of buffer solution: Disodium hydrogen phosphate dihydrate and potassium dihydrogen phosphate were dissolved in purified water and mixed with the previously prepared volume solution. Color and flavor solutions were added to this.

The pH of the final solution was adjusted using a 20% w / v sodium hydroxide solution.

Example No 2 Table No. 2 Process: Preparation of base solution: The purified water was transferred into a suitable manufacturing tank. Propylparaben, methylparaben and sugar were added to this, and dissolved to ensure total dissolution. The solution was filtered through a 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. Subsequently, divalproex sodium, glycerin, sucrose, propylene glycol, were added to this color, sorbitol and flavor, and dissolved to ensure total dissolution. The previous base solution was mixed with this drug solution under agitation.

Adjustment of the pH of the Solution - the pH of the solution was adjusted with 10% w / v of a solution of sodium hydroxide.

Three different batches of the composition were taken as shown in table No. 2, and were subjected to stability studies and the data obtained are presented below in tables No. 3, 4 and 5, respectively.

Table No. 3 or in O in Example No 3 Table No. 6 Process: Preparation of base solution: Purified water was transferred into a suitable manufacturing tank. Sodium propylparaben, sodium methylparaben and sugar were added to this, and dissolved to ensure total dissolution. The solution was filtered through a 200 mesh nylon cloth.

Preparation of drug solution: Purified water was taken in a suitable manufacturing tank. To this were added sodium hydroxide pellets in purified water. Subsequently, sodium of divalproex, glycerin, sucrose, sorbitol, propylene glycol, color and flavor were added thereto and dissolved until complete dissolution was ensured. The above base solution was mixed with this drug solution under stirring.

Adjusting the pH of the Solution - the pH of the solution was adjusted with 20% w / v of a sodium hydroxide solution.

Addition of buffer - purified water was taken in a suitable manufacturing tank and the buffer salt was added thereto, and the obtained buffer solution was mixed with all the previous volume solution.

Example No. 4 Table No. 7 Process: Preparation of the base solution: Purified water was transferred into a suitable manufacturing tank. Sodium propylparaben, sodium methylparaben and sugar were added to this, and dissolved to ensure complete dissolution. The solution was filtered through a 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 purified water. Subsequently, divalproex sodium, glycerin, sucrose, sorbitol, propylene glycol, flavor and color were added thereto and dissolved to ensure total dissolution. The previous base solution was mixed with this solution I 'of drug under agitation.

PH adjustment of the solution - the pH of the solution was adjusted with 20% w / v of the sodium hydroxide solution: Addition of buffer - purified water was taken in a suitable manufacturing tank, and added to lesto! buffer salt, and the obtained buffer solution was mixed with all the previous volume solution.

Example No. 5 Table No. 8 Process: Preparation of the base solution: Purified water was transferred into a suitable manufacturing tank. To this were added sodium propyl paraben, sodium methylparaben and sugar, and dissolved to ensure total dissolution, the solution was filtered through a 200 mesh nylon cloth.

Preparation and solution of drug: Purified water was taken in a suitable manufacturing tank. They were added and dissolved in the purified water sodium hydroxide pellets. Divalproex sodium, glycerin, sucrose, sorbitol, propylene glycol, flavor and color were added thereto and dissolved to ensure total dissolution. The above base solution was mixed with this drug solution under stirring.

Adjusting the pH of the Solution- the pH of the solution was adjusted with 20% w / v of the sodium hydroxide solution; Addition of buffer - Purified water was taken in a suitable manufacturing tank, and buffer salt was added thereto, and the obtained buffer solution was mixed with all the previous volume solution.

Example No 6 Table No 9 Process: Preparation of the base solution: Purified water was transferred into a suitable manufacturing tank, heated to boiling. Sodium propylparaben, sodium methylparaben and sugar were added to this, and dissolved to ensure complete dissolution. The solution was filtered through a 200 mesh nylon cloth.

Preparation of the 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, color, flavor, sucrose and sorbitol were added thereto, and dissolved to ensure total dissolution. The above base solution was mixed with this drug solution under stirring.

Addition of buffer - the purified water was taken in a suitable manufacturing tank, and buffer salt was added to it, and the obtained buffer solution was mixed with all the previous volume solution.

PH adjustment of the solution - the pH of the solution was adjusted with 20% w / v of the sodium hydroxide solution.

Three different batches of the composition were taken as shown in table No. 9, and subjected to stability studies, and the data obtained are presented in tables No. 10, 11 and 12, respectively.

Table No. 10 Table No. 11 Table No. 12 Example No 7 Table No. 13 Process: Preparation of the base solution: Purified water was transferred into a suitable manufacturing tank. To this were added sodium propyl paraben, sodium methylparaben and sugar, and dissolved to ensure complete dissolution. The solution was filtered through a 200 mesh nylon cloth.

Preparation of the drug solution: Purified water was taken in a suitable manufacturing tank. They were added and dissolved in the purified water sodium hydroxide pellets. Sodium of divalproex, glycerin, propylene glycol, color, flavor, sucrose and sorbitol were added thereto, and dissolved to ensure complete dissolution. The above base solution was mixed with this drug solution under stirring.

As shown in Table No. 13, three different batches of the composition were taken and subjected to stability studies, and the data obtained are presented in tables No. 14, 15 and 16, respectively.

Table No. 14 Table No. 15 Table No. 16 Example No 8 Table No. 17 Process: Preparation of the base solution: Purified water was transferred into a suitable manufacturing tank. Sodium propylparaben, sodium methylparaben, and sugar was added to it, and dissolved to ensure complete dissolution. The solution was filtered through a 200 mesh nylon cloth.

Preparation of the drug solution: Purified water was taken in a suitable manufacturing tank. The pellets were dissolved in the purified water. sodium hydroxide. Sodium of divalproex, glycerin, propylene glycol, color, flavor, sucrose and sorbitol were added thereto, and dissolved to ensure complete dissolution. The above base solution was mixed with this drug solution under stirring.

Addition of buffer - purified water was taken in a suitable manufacturing tank, and the buffer salt was added thereto, and the obtained buffer solution was mixed with all the previous volume solution.

As shown in Table No. 17, a batch of the composition was taken and subjected to stability studies * and the data obtained are presented below in Table No. 18.

Table No. 18

Claims

1. An oral, liquid, stable composition comprising divalproex sodium and one or more pharmaceutically acceptable excipients.

2. The composition as described in claim 1, characterized in that the divalproex sodium is present from about 2% w / v to about 15% w / v of the composition.

3. The composition as described in claim 1, characterized in that the composition is in the form of a solution, emulsion or suspension.

4. The composition as described in claim 1, characterized in that the pH of the composition is greater than 6.!

5. The composition as described in claim 4, characterized in that the pH of the composition is greater than 7.

6. The composition as described in claim 5, characterized in that the pH of the composition is between 7 and 8.

7. The composition as described in claim 1, characterized in that the composition is stable in shelf life, for not less than 12 months.

8. The composition as described in claim 1, characterized in that the excipient Pharmaceutically acceptable is selected from the group consisting of preservatives, flavors, flavorings, sweeteners, buffering agents, coloring agents and mixtures thereof.

9. The composition as described in claim 8, characterized in that the preservative is selected from the group consisting of sodium benzoate, sorbates, EDTA, domifen bromide, butylparaben, propylparaben, ethylparaben, methylparaben, paraben salts and mixtures thereof .

10. The composition as described in claim 8, characterized in that the preservative is present in an amount of about 0.01% w / v to about 1.5% w / v of the composition.

11. The composition as described in claim 8, characterized in that the sweetener is selected from the group consisting of maltitol, sucrose, dextrose, fructose, glucose, glycerin, inulin, isomalt, lactitol, maltose, maltol, mannitol, sucrose, trehalose, , xi M to I, propylene glycol, sorbitol, sodium saccharin, thaumatin, sodium cyclamate, sucrose and mixtures thereof.

12. The composition as described in claim 8, characterized in that the sweetener is present in an amount of about 0.1% w / v to about 85% w / v of the composition.

13. The composition as described in claim 8, characterized in that the buffering agent is selected from the group consisting of potassium dihydrogen phosphate, disodium hydrogen phosphate dihydrate, glycine, sodium hydrogen carbonate, sodium tetraborate, sodium bicarbonate, sodium, sodium hydroxide and mixtures thereof.

14. The composition as described in claim 8, characterized in that the buffering agent is present in an amount of about 0.05% w / v to about 1.5% w / v of the composition.

15. The composition as described in claim 13, characterized in that 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.

16. An oral, liquid, stable composition, characterized in that it comprises: a) divalproex sodium of about 2% w / v to about 15% w / v of the composition; b) conservative from about 0.01% w / v to about 1.5% w / v of the composition; | c) buffer agent from about 0.05% w / v to about 1.5% w / v of the composition; d) sweetener of approximately 0.1% w / v up 37 about 85% w / v of the composition; e) optionally, one or more coloring and / or flavoring agents.

17. The composition as described in claim 16, characterized in that the composition is in the form of a solution, emulsion or suspension.

18. The composition as described in claim 16, characterized in that the pH of the composition is greater than 6.

19. The composition as described in claim 18, characterized in that the pH of the composition is greater than 7.

20. The composition as described in claim 19, characterized in that the pH of the composition is between 7 and 8.

21. The composition as described in claim 16, characterized in that the composition is stable in shelf life for not less than 12 months.

22. The composition as described in claim 16, characterized in that the preservative is selected from the group consisting of sodium benzoate, sorbates, EDTA, domifen bromide, butylparaben, propylparaben, ethylparaben, methylparaben, paraben salts and mixtures thereof .

23. The composition as described in claim 16, characterized in that the sweetener is selected from the group consisting of maltitol, sucrose, dextrose, fructose, glucose, glycerin, inulin, isomalt, lactitol, maltose, maltol, mannitol, sucrose, trehalose, xylitol, propylene glycol, sorbitol, saccharin, sodium, thaumatin, sodium cyclamate, sucrose and mixtures thereof.

24. The composition as described in claim 16, characterized in that the buffering agent i is selected from the group consisting of potassium dihydrogen phosphate, disodium hydrogen phosphate dihydrate, glycine, sodium hydrogen carbonate, sodium tetraborate, sodium bicarbonate, sodium hydroxide and mixtures thereof.

25. The composition as described in claim 24, characterized in that 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 for preparing an oral, liquid, stable composition comprising divalproex sodium and one or more pharmaceutically acceptable excipients, wherein the process comprises the steps of: a) prepare the sodium hydroxide solution in purified water; b) Dissolve divalproex sodium and one or more excipients pharmaceutically acceptable with stirring in the solution of step a), until each ingredient is completely dissolved; c) adjust the pH of the solution from step b) to more than 6.